@article {pmid42045851,
year = {2026},
author = {Liu, X and Xu, H and Han, X and Zhang, Q},
title = {Association between triglyceride-glucose index and vascular dementia in ICU patients with cerebrovascular disease: a retrospective study based on the MIMIC-IV database.},
journal = {BMC neurology},
volume = {26},
number = {1},
pages = {},
pmid = {42045851},
issn = {1471-2377},
support = {HPYJ202409//Faculty Scientific Research Fund of Heping Hospital Affiliated to Changzhi Medical College/ ; },
abstract = {BACKGROUND: Vascular dementia (VaD) is the second most common type of dementia after Alzheimer’s disease. Previous studies have confirmed a significant correlation between white matter changes and cognitive dysfunction, especially in patients with metabolic syndrome, suggesting that silent vascular risk factors may promote cerebrovascular pathology with advancing age. The Triglyceride-Glucose (TyG) Index, a novel metabolic indicator calculated based on fasting triglyceride and glucose levels, reflects insulin resistance (IR).

METHODS: Our research aimed to analyze data from the Medical Information Mart for Intensive Care IV (MIMIC-IV) database, using logistic regression analysis and constructing restricted cubic spline (RCS) curves to evaluate the association between the TyG index and VaD in patients with cerebrovascular disease (CVD). Subgroup analyses were performed, but no statistically significant associations were observed within individual strata. Additionally, univariate and multivariate logistic regression analyses were conducted to identify factors associated with VaD. Exploratory analyses were also performed.

RESULTS: After the implementation of the inclusion criteria, a total of 1,754 patients with CVD were enrolled. Among them, 13.91% were diagnosed with VaD. Logistic regression showed that patients in the highest TyG quartile had significantly higher odds of VaD compared with the lowest quartile (Model 3: OR = 2.315, 95% CI: 1.437–3.776, p < 0.001). RCS showed a significant linear association (P = 0.046). No statistically significant subgroup effects were observed. Exploratory association analyses were performed, but formal validation was not conducted.

CONCLUSION: Higher TyG levels were independently associated with increased odds of VaD in patients with CVD after adjusting for potential confounders. Future prospective studies are needed to confirm these associations and explore their clinical implications.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12883-026-04915-4.},
}

@article {pmid42079285,
year = {2026},
author = {Phasuk, S and Tooley, KB and Sun, JL and Pagala, V and Palacios, G and Deats, S and Garland, G and Robinson, LL and Wang, X and Belingon, B and Cook, J and Tan, H and Lkhagva, A and Yuan, ZF and Wu, L and Johnson, A and Bradberry, M and Robinson, CG and High, AA and Korstanje, R and Vevea, JD},
title = {APOE is a presynaptic protein that accumulates with age and modulates neurotransmitter release.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
pmid = {42079285},
issn = {2692-8205},
abstract = {The synaptic vesicle (SV) cycle is the fastest membrane trafficking and protein sorting process in biology. It underlies neuronal communication and cognition, yet synaptic function declines during normal aging, increasing vulnerability to neurologic disease. How the SV cycle is maintained across the lifespan of a complex organism remains unclear. Here, we used wild-type mice (C57BL/6J) to define the age- and sex-stratified molecular landscape of SVs and identified apolipoprotein E (APOE) as an abundant presynaptic protein further enriched in aged female samples. Super-resolution imaging, cell-type selective expression, and protease protection assays demonstrate that APOE originates from astroglia and associates with the cytosolic face of SVs. Using iGluSnFR and pHluorin optophysiology, we find that both decreased and increased APOE levels impair neurotransmission during stimulus trains. Together, these findings place APOE at the synapse and establish it as a cell-nonautonomous regulator of the SV cycle.},
}

@article {pmid42128444,
year = {2026},
author = {Atri, A and Apostolova, LG and Iwata, A and Wessels, AM and Atkins, A and Lu, M and Ye, W and Ryan, S and Doty, EG},
title = {Clinical Meaningfulness of Donanemab in Early Symptomatic Alzheimer Disease: Data From the Randomized Phase 3 TRAILBLAZER-ALZ 2 Trial.},
journal = {Neurology. Clinical practice},
volume = {16},
number = {3},
pages = {e200621},
doi = {10.1212/CPJ.0000000000200621},
pmid = {42128444},
issn = {2163-0933},
mesh = {Humans ; *Alzheimer Disease/drug therapy ; Aged ; *Cognitive Dysfunction/drug therapy ; Male ; Female ; *Antibodies, Monoclonal, Humanized/therapeutic use/pharmacology ; Aged, 80 and over ; Disease Progression ; Activities of Daily Living ; *Outcome Assessment, Health Care ; },
abstract = {BACKGROUND AND OBJECTIVES: Understanding the meaningfulness of clinical trial outcomes is essential for people living with Alzheimer disease (AD) and their clinicians to make evidence-based shared treatment decisions in real-world clinical care. Donanemab, a monoclonal antibody targeting the insoluble form of β-amyloid found in plaques, significantly slows cognitive and functional decline of AD in participants with mild cognitive impairment (MCI) or mild AD-related dementia. This analysis reviews the efficacy of donanemab across various clinical outcome assessments, using both published data and new complementary analyses to provide context on its potential benefits for patients and caregivers.

METHODS: We present findings from prespecified and post hoc analyses from the TRAILBLAZER-ALZ 2 trial. Clinical outcomes assessed were Integrated AD Rating Scale (iADRS), comprising the 13-item AD Assessment Scale-Cognitive Subscale (ADAS-Cog13) and AD Cooperative Study-Instrumental Activities of Daily Living (ADCS-iADL); Clinical Dementia Rating (CDR)-Sum of Boxes (CDR-SB) for clinical severity and individual cognitive and functional domains; CDR-Global for clinical severity stage progression; meaningful within-patient change (MWPC); and ADCS-Activities of Daily Living dependence score.

RESULTS: Donanemab reduced the risk of progression from MCI to mild AD by 33% (hazard ratio [HR] = 0.67; 95% CI 0.52-0.87; p = 0.003) and from mild to moderate AD by 50% (HR = 0.50; 95% CI 0.33-0.78; p = 0.002). In addition, donanemab reduced MWPC risk over 76 weeks by 38% for CDR-SB (HR = 0.62; 95% CI 0.52-0.75; p < 0.001) and 30% for iADRS (HR = 0.70; 95% CI 0.58-0.84; p < 0.001). Donanemab-treated participants exhibited significant slowing of clinical progression across multiple ADAS-Cog13 and ADCS-iADL items and all CDR-SB cognitive and functional domains. Donanemab also slowed progression of dependence least-squares mean change difference, -0.14 [95% CI -0.24 to -0.04; p = 0.007]), representing 23% slowing of progression (95% CI 6.17%-40.32%), and reduced risk of progression to requiring in-home support by 27% (HR = 0.74; 95% CI 0.59-0.91; p = 0.005).

DISCUSSION: These results add to the evidence and further support clinically meaningful donanemab-mediated effects on cognition and function for patients and their caregivers and may aid communication of realistic treatment expectations and informed decision-making.

ClinicalTrials.gov NCT04437511. Submitted: June 17, 2020; First patient enrolled: June 19, 2020. clinicaltrials.gov/study/NCT04437511 EudraCT Number 2020-000077-25. Start date of recruitment: June 19, 2020. clinicaltrialsregister.eu/ctr-search/trial/2020-000077-25/results.},
}

Humans
*Alzheimer Disease/drug therapy
Aged
*Cognitive Dysfunction/drug therapy
Male
Female
*Antibodies, Monoclonal, Humanized/therapeutic use/pharmacology
Aged, 80 and over
Disease Progression
Activities of Daily Living
*Outcome Assessment, Health Care

@article {pmid42128467,
year = {2026},
author = {Tan, S and Gourabi, S and Cribbet, MR and Cundiff, JM and McDonough, IM},
title = {Sleep quality is associated with default mode and salience network connectivity differently across age and sex.},
journal = {Neurobiology of aging},
volume = {165},
number = {},
pages = {76-91},
doi = {10.1016/j.neurobiolaging.2026.05.002},
pmid = {42128467},
issn = {1558-1497},
abstract = {Aging and biological sex are critical moderators of sleep quality, which contributes significantly to age-related cognitive decline and Alzheimer's disease (AD) risk. This study investigated how age and sex moderated the relationship between subjective sleep quality and resting-state functional connectivity (rsFC) within networks associated with hyperarousal and cognitive processing. Using an exploratory-confirmatory approach across two datasets (N = 95 and N = 1244), we examined connectivity of the default mode network (DMN), salience network (SN), and amygdala with the rest of the brain. Results revealed distinct age- and sex-dependent patterns: in the DMN, a three-way interaction (Age×Sex×Sleep Quality) showed that poorer sleep quality was associated with reduced DMN-superior parietal lobule (SPL) connectivity in younger women but hyperconnectivity in older women. This hyperconnectivity correlated with poorer episodic memory performance, consistent with patterns observed in preclinical AD. For the SN, an age-dependent interaction showed that poorer sleep was associated with SN-sensorimotor hyperconnectivity in younger adults-supporting the hyperarousal hypothesis-but lower connectivity in older adults, suggesting a shift toward different mechanisms, such as circadian or homeostatic decline, in late life. No significant effects were found for the amygdala or blood-based biomarkers of AD pathology, inflammation, or sex hormones. These findings highlight a selective vulnerability of the DMN to sleep impairments in older women and suggest that the neural correlates of poor sleep shift from hyperarousal in youth to neurodegenerative-like patterns in older age.},
}

@article {pmid42128684,
year = {2026},
author = {Zhang, QT and Wu, WQ and Deng, YH and Dong, L and Xu, YM and Fu, XJ and Jiang, HQ},
title = {[Establishment of reference intervals for plasma p-tau181, Aβ1-42, Aβ1-40, and Aβ1-42/40 ratio and a preliminary study of their correlation with corresponding cerebrospinal fluid reference intervals].},
journal = {Zhonghua yu fang yi xue za zhi [Chinese journal of preventive medicine]},
volume = {60},
number = {5},
pages = {784-790},
doi = {10.3760/cma.j.cn112150-20251227-01232},
pmid = {42128684},
issn = {0253-9624},
mesh = {Humans ; *Amyloid beta-Peptides/cerebrospinal fluid/blood ; *tau Proteins/blood/cerebrospinal fluid ; Cross-Sectional Studies ; *Peptide Fragments/cerebrospinal fluid/blood ; Reference Values ; Alzheimer Disease/blood/cerebrospinal fluid ; Adult ; Biomarkers/cerebrospinal fluid/blood ; Male ; Female ; Middle Aged ; Phosphorylation ; Aged ; },
abstract = {Objective: To establish reference intervals for Alzheimer's disease (AD)-related biomarkers in plasma and cerebrospinal fluid (CSF) of adults in Shanghai using single molecule immune detection. Methods: In this cross-sectional study, which included residual plasma samples from 454 healthy individuals and CSF samples from 106 non-AD patients were collected from the Department of Laboratory Medicine, Huashan Hospital, Fudan University, between March and July 2024. The concentrations of phosphorylated tau protein-181 (p-tau181), amyloid-beta peptide 1-42 (Aβ1-42), and amyloid-beta peptide 1-40 (Aβ1-40) were detected using the AST-Dx90 fully automated fluorescence immunoassay analyzer. After normality testing and outlier removal, reference intervals were determined by the non-parametric method and validated using plasma samples from 20 healthy individuals. Results: Spearman correlation analysis revealed no significant correlations with age for plasma Aβ1-42 (R=0.047, P=0.344), the Aβ1-42/40 ratio (R=-0.050, P=0.326), or for CSF p-tau181 (R=-0.078, P=0.438), Aβ1-42 (R=0.002, P=0.980), Aβ1-40 (R=-0.084, P=0.400), and the Aβ1-42/40 ratio (R=0.173, P=0.083) (|R|<0.2, P>0.05). Although plasma p-tau181 (R=-0.102, P=0.032) and Aβ1-40 (R=0.150, P=0.002) showed statistically significant associations with age (P<0.05), the strength of these correlations was very weak (|R|<0.2).Z-tests indicated that there were no statistically significant differences (Z }

Humans
*Amyloid beta-Peptides/cerebrospinal fluid/blood
*tau Proteins/blood/cerebrospinal fluid
Cross-Sectional Studies
*Peptide Fragments/cerebrospinal fluid/blood
Reference Values
Alzheimer Disease/blood/cerebrospinal fluid
Adult
Biomarkers/cerebrospinal fluid/blood
Male
Female
Middle Aged
Phosphorylation
Aged

@article {pmid42128892,
year = {2026},
author = {Mlinarič, T and Van Den Kerchove, A and Barinaga, ZI and Van Hulle, MM},
title = {Correction: EEG-based classification of alzheimer's disease and frontotemporal dementia using functional connectivity.},
journal = {Scientific reports},
volume = {16},
number = {1},
pages = {},
doi = {10.1038/s41598-026-49348-8},
pmid = {42128892},
issn = {2045-2322},
}

@article {pmid42129136,
year = {2026},
author = {Huo, Y and Huang, W and Liu, Z and Chen, H and Bai, T and Wang, Y and Wang, K and Zhang, D and Cheng, J and Sun, Y and Ma, G and Zhao, C and Zhang, Z and Shu, N},
title = {Functional system-specific brain aging across the Alzheimer's disease continuum.},
journal = {Translational psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41398-026-04081-8},
pmid = {42129136},
issn = {2158-3188},
support = {82301608, 32271145, 81871425, 210510238//National Natural Science Foundation of China (National Science Foundation of China)/ ; L252087//Natural Science Foundation of Beijing Municipality (Beijing Natural Science Foundation)/ ; },
abstract = {Accelerated brain aging is implicated in Alzheimer's disease (AD). However, the spatial heterogeneity of brain aging patterns across different functional systems along the AD continuum remains largely unexplored. We developed functional system-specific brain age models derived from structural magnetic resonance imaging in a healthy adult cohort (n = 22,672) and applied them to 1478 participants across the AD continuum. Using up to 6 years of retrospective longitudinal data before clinical AD conversion, we quantified predicted age differences (PADs) and their change rates, characterized heterogeneous brain aging trajectories, and examined their associations with AD biomarkers, cognitive performance, and clinical progression. Progressive mild cognitive impairment (MCI) individuals showed early PAD deviations in the default mode network and accelerated changes in attention and control networks. System-wise PAD dynamics mediated the effects of AD-related biomarkers on cognitive decline. Integrating PAD features can improve predictive accuracy of MCI-to-AD conversion (AUC = 0.95). Functional system-specific PADs can be sensitive biomarkers for early detection and monitoring of individualized AD risk.},
}

@article {pmid42129145,
year = {2026},
author = {Pulst, SM and Paul, S and Nguyen, H and Dansithong, W and Figueroa, KP and Gandelman, M and Bonini, NM and Scoles, DR},
title = {A human Staufen1 BAC transgenic mouse exhibits abnormal autophagy and neurodegeneration across the central nervous system.},
journal = {Cell death & disease},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41419-026-08830-x},
pmid = {42129145},
issn = {2041-4889},
support = {R21NS127028//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; R01NS137233//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; R01NS097903//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; R21NS128630//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; R61/R33NS124965//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; R21NS128630//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; R35NS097275//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; R56NS033123//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; R37NS033123//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; R35NS127253//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; R61/R33NS124965//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; },
abstract = {RNA-binding proteins (RBPs) play an essential role in development, normal functioning, and human disease. Staufen1 (STAU1) is an RBP that regulates mRNA degradation and subcellular localization, and is part of the ATXN2 protein complex. Previously, we showed that STAU1 is overabundant in patient fibroblasts and in mouse models of Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and spinocerebellar ataxia type 2 (SCA2), where it is associated with impaired autophagic flux due to STAU1-mediated upregulation of mTOR translation. STAU1 overabundance and impaired autophagy cause accumulation of biomolecular condensates and abnormal unfolded protein response (UPR). We generated a mouse model expressing the entire human STAU1 gene (hSTAU1) in a bacterial artificial chromosome (BAC) construct. hSTAU1 in these mice was expressed in cerebral hemispheres, cerebellum, and spinal cord, as well as cultured cortical neurons and cortical and spinal cord astrocytes, and microglia. Expression of hSTAU1 caused dysregulated gene expression, abnormal autophagy, glial activation, and changes in neuronal marker proteins. All of these were significantly improved by reducing STAU1 abundance by RNAi, but exacerbated in BAC-STAU1 mice crossed with Prp-TDP-43(Q331K) transgenic mice. Similar results were also obtained in eye phenotypes in ALS- and SCA2-relevant fly models upon changing staufen-1 dosage. Despite the molecular changes, we observed no overt behavioral changes in mice up to 55 weeks of age, suggesting that STAU1 may function as an epistatic modifier of neuronal degeneration. The BAC-hSTAU1 mouse will be useful for developing therapies targeting the human STAU1 gene.},
}

@article {pmid42129267,
year = {2026},
author = {Wang, Z and Xia, X},
title = {Cytokine gene polymorphisms and serum cytokine levels identify a neuroinflammatory nexus in Alzheimer's disease.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-52911-y},
pmid = {42129267},
issn = {2045-2322},
abstract = {Neuroinflammation, orchestrated by glial cells and mediated by cytokines, is now recognized as a pivotal pathogenic mechanism in Alzheimer's disease (AD). However, the interplay between host genetic variations driving inflammatory responses and the resultant central or peripheral inflammatory milieu in AD susceptibility remains poorly defined. This study aimed to decode the crosstalk between functional polymorphisms in key cytokine genes and their corresponding serum cytokine levels in relation to AD risk. We performed a case-control investigation involving 160 patients with newly diagnosed, sporadic late-onset AD and 280 age- and gender-matched cognitively healthy controls. Four important cytokines from serum were quantified using high-sensitivity ELISA. Functional single nucleotide polymorphisms in the regulatory regions of their genes were genotyped using PCR-RFLP. AD patients exhibited significantly elevated concentrations of all above cytokines (all p < 0.001). Several SNPs were associated with altered AD risk (IL-1β -511 C/T; TNF-α -308 G/A; IL-10 -1082 G/A). This cross-sectional case-control study demonstrates that specific cytokine gene polymorphisms are associated with AD risk in this Chinese cohort, and these genetic variants correlate with altered serum cytokine levels. These findings suggest an association between host genetic variation in inflammatory genes and AD susceptibility, but do not establish causality. The observed elevations in peripheral cytokines may reflect systemic inflammation rather than AD-specific neuroinflammation.},
}

@article {pmid42129367,
year = {2026},
author = {Rickman, NC and Liu, G and Franz, AR and Bernhard, W and Bearer, CF},
title = {The role of choline in neurodevelopment.},
journal = {Pediatric research},
volume = {},
number = {},
pages = {},
pmid = {42129367},
issn = {1530-0447},
abstract = {Choline was first declared to be an essential nutrient in 1998. Current research on choline intake has been sufficient for the Food and Nutrition Board of the National Academies of Science, Engineering & Medicine to establish a loose guideline, but more investigation into healthy choline intakes is necessary to clarify guidelines. Choline is intimately involved in human metabolism, as an essential precursor for cell membrane components such as phosphatidylcholine and sphingomyelin, lipoprotein and fatty acid trafficking, and the neurotransmitter acetylcholine. It plays an essential role in histone, RNA, and DNA methylation, creatine synthesis, and more. Choline-related pathologies have already been implicated in multiple severe developmental diseases, such as schizophrenia, Down syndrome, and neural tube defects, and age-related diseases such as Alzheimer's. Choline supplementation has been shown to alleviate the symptoms of neurodevelopmental diseases, such as Fetal Alcohol Spectrum Disorder and neonatal hyperbilirubinemia. The choline intake by most adults is estimated to be less than the current recommendations. Choline supplementation, particularly for vulnerable populations such as pregnant women, preterm infants, and cystic fibrosis patients, requires further investigation to establish adequate recommendations and to fully elucidate the consequences of malnutrition. Outcomes of choline deficiency and supplementation, such as neurodevelopment, should be measured. IMPACT: What this article adds to the existing literature An up-to-date summary of the metabolism of choline A review of the role of choline in normal and abnormal neurodevelopment A concise description of sources of choline.},
}

@article {pmid42129462,
year = {2026},
author = {Liu, Z and Che, C and He, G and Wu, H and Cai, L and Cui, L and Liang, L},
title = {Mandarin speech-based early detection of SCD: a feature-fusion residual network method.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {5},
pages = {e71460},
pmid = {42129462},
issn = {1552-5279},
support = {//Basic and Applied Basic Research Foundation of Guangdong Province/ ; //2024B1515230001/ ; GDMULCJC2024006//Special Project for Clinical and Basic Sci&Tech Innovation of Guangdong Medical University/ ; LCYJ2021B001//Affiliated Clinical Research Project of Guangdong Medical University/ ; 4SG22307P//Special Project of Songshan Lake Medical-Engineering Integration Innovation Centre at Guangdong Medical University/ ; },
mesh = {Humans ; Male ; Female ; *Cognitive Dysfunction/diagnosis ; Cross-Sectional Studies ; Early Diagnosis ; Aged ; *Alzheimer Disease/diagnosis ; *Speech/physiology ; Middle Aged ; },
abstract = {INTRODUCTION: Alzheimer's disease (AD) poses a global health challenge. Early intervention during the stage of subjective cognitive decline (SCD) - a potential window for delaying disease progression - is crucial. This study aims to assess an exploratory speech-based model for rapid SCD screening.

METHOD: This study included 459 participants, comprising individuals with AD, mild cognitive impairment (MCI), SCD, and normal controls. We used Pic-Talk clips and Mandarin speech with residual network features for SCD screening.

RESULTS: In this cross-sectional study, our model achieved high performance with accuracy, recall, precision, F1, and area under the curve of 81.77 ± 2.78%, 80.53 ± 2.64%, 82.27 ± 2.38%, 81.39 ± 1.85%, and 82.85 ± 2.01%, respectively, outperforming other speech models.

DISCUSSION: This non-invasive exploratory approach to SCD assessment shows potential, revealing acoustic differences at the group level between SCD and other diagnostic groups. It is expected that the future integration of biomarkers will enhance the model's accuracy and expand its applicability.},
}

Humans
Male
Female
*Cognitive Dysfunction/diagnosis
Cross-Sectional Studies
Early Diagnosis
Aged
*Alzheimer Disease/diagnosis
*Speech/physiology
Middle Aged

@article {pmid42129508,
year = {2026},
author = {Liu, W and Shimogori, T},
title = {Spatiotemporal brain transcriptomics reveal risk gene hot-spots in major neuropsychiatric disorders.},
journal = {Communications biology},
volume = {9},
number = {1},
pages = {},
pmid = {42129508},
issn = {2399-3642},
mesh = {Humans ; *Brain/metabolism/growth & development ; *Transcriptome ; *Mental Disorders/genetics ; *Genetic Predisposition to Disease ; Gene Expression Profiling ; Spatio-Temporal Analysis ; Genome-Wide Association Study ; },
abstract = {Brain development is guided by dynamic gene expression programs that vary across brain regions and developmental stages. Although numerous risk genes for neuropsychiatric disorders have been identified, the spatiotemporal contexts in which they act remain unclear. Here we show the spatiotemporal expression patterns of genome-wide risk gene sets across 15 neuropsychiatric traits, including autism, attention deficit hyperactive disorder, obsessive compulsive disorder, major depression, bipolar disorder, schizophrenia, epilepsy, Alzheimer's disease and Parkinson's disease, using bulk and single-cell transcriptomic data from the human brain. We identify trait-specific spatiotemporal enrichment patterns, allowing a classification of disorders into prenatally and postnatally enriched groups that align with known ages of disease onset. Integration with brain imaging datasets and gene co-expression network analysis further identifies synaptic development and function, as well as RNA processing during early brain development, in neuropsychiatric risk. These findings provide a systems-level framework linking genetic risk to neurodevelopmental and neuroanatomical contexts.},
}

Humans
*Brain/metabolism/growth & development
*Transcriptome
*Mental Disorders/genetics
*Genetic Predisposition to Disease
Gene Expression Profiling
Spatio-Temporal Analysis
Genome-Wide Association Study

@article {pmid42129577,
year = {2026},
author = {Stark, M and Wagner, M and Kuhn, E and Roeske, S and Amthauer, H and Bartels, C and Boecker, H and Brosseron, F and Buchert, R and Buerger, K and Daamen, M and Drzezga, A and Düzel, E and Ersözlü, E and Essler, M and Ewers, M and Fliessbach, K and Glanz, W and Hellmann-Regen, J and Incesoy, EI and Janowitz, D and Kafali, K and Kilimann, I and Krause, BJ and Kronmüller, M and Laske, C and Maier, F and Maurer, A and Michely, J and Perneczky, R and Peters, O and Preis, L and Priller, J and Rauchmann, BS and Reimold, M and Rominger, A and Schmid, M and Schneider, A and Sodenkamp, S and Spottke, A and Spruth, EJ and Teipel, S and Wiltfang, J and , and Jessen, F and Kleineidam, L},
title = {Minor neuropsychological deficits and stage 2 of Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {5},
pages = {e71458},
pmid = {42129577},
issn = {1552-5279},
support = {//Gemeinnützige Hertie-Stiftung/ ; BN012//Deutsches Zentrum für Neurodegenerative Erkrankungen/ ; //Life Molecular Imaging/ ; U01AG024904/NH/NIH HHS/United States ; W81XWH-12-2-0012//U.S. Department of Defense/ ; /AG/NIA NIH HHS/United States ; /EB/NIBIB NIH HHS/United States ; //AbbVie/ ; /ALZ/Alzheimer's Association/United States ; //Alzheimer's Drug Discovery Foundation/ ; //Araclon Biotech/ ; //Biogen/ ; //Bristol-Myers Squibb/ ; //CereSpir, Inc./ ; //Cogstate/ ; //Eisai/ ; //Elan Pharmaceuticals, Inc./ ; //Eli Lilly and Company/ ; //EuroImmun Medizinische Labordiagnostika/ ; //F. Hoffmann-La Roche/ ; //Genentech/ ; //Fujirebio/ ; //GE Healthcare/ ; //IXICO Ltd./ ; //Janssen Alzheimer Immunotherapy Research & Development, LLC./ ; //Lumosity/ ; //Lundbeck/ ; //Merck & Co., Inc./ ; //Meso Scale Diagnostics, LLC./ ; //NeuroRx Research/ ; //Neurotrack Technologies/ ; //Novartis Pharmaceuticals Corporation/ ; //Pfizer Inc./ ; //Piramal Imaging/ ; //Servier/ ; //Transition Therapeutics/ ; /CAPMC/CIHR/Canada ; U24 AG072122/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *Alzheimer Disease/diagnosis/psychology ; Female ; Aged ; Neuropsychological Tests/statistics & numerical data ; Male ; *Cognitive Dysfunction/diagnosis ; Longitudinal Studies ; Biomarkers ; Aged, 80 and over ; },
abstract = {INTRODUCTION: Subtle symptoms, like subjective cognitive decline (SCD) and minor neuropsychological deficits (MNPD), can improve the risk stratification in preclinical Alzheimer´s disease (AD) but their importance is insufficiently elaborated.

METHODS: We pooled data from cognitively normal individuals participating in three longitudinal cohort studies (N = 13,192, 8,359[63.3%] female, mean [SD] age 71.0[8.4]).

RESULTS: Compared to participants without SCD and MNPD (SCD-/MNPD-), SCD-/MNPD+, SCD+/MNPD-, and SCD+/MNPD+ participants had an increased risk for mild cognitive impairment (MCI) and dementia, including in amyloid-positive individuals. Focusing on SCD+/MNPD+ participants triples the positive predictive value of amyloid biomarker testing for the 5-year prediction of MCI and reduces the required samples size for trials in preclinical AD to one fourth, compared to considering all cognitively normal participants regardless of subtle symptoms.

DISCUSSION: SCD and MNPD offer a powerful approach for risk stratification in preclinical AD, which can improve clinical trial designs, risk counseling, and future case identifications for early treatment.},
}

Humans
*Alzheimer Disease/diagnosis/psychology
Female
Aged
Neuropsychological Tests/statistics & numerical data
Male
*Cognitive Dysfunction/diagnosis
Longitudinal Studies
Biomarkers
Aged, 80 and over

@article {pmid42129676,
year = {2026},
author = {Ning, K and Abdin, E and Asharani, PV and Isvoranu, AM and Epskamp, S and Ng, LL and Chong, SA and Subramaniam, M},
title = {Mapping the network structure of dementia and its associated factors among older adults in Singapore: evidence from two national cross-sectional studies.},
journal = {BMC geriatrics},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12877-026-07535-2},
pmid = {42129676},
issn = {1471-2318},
abstract = {BACKGROUND: Dementia arises from the interplay of multiple sociodemographic, behavioural, physical, and psychosocial factors that often coexist and interact in later life. Traditional epidemiological studies have typically examined these factors in isolation, overlooking their complex interrelations. Network analysis provides an integrative framework to visualise and quantify these interconnections, offering insights into how dementia and its associated factors coexist within a broader system.

METHODS: Data were drawn from two nationally representative cross-sectional surveys of older adults aged ≥60 years in Singapore: the Well-being of the Singapore Elderly (WiSE) 2023 study (n=2010) and the WiSE 2013 study (n=2565). Dementia was assessed using the 10/66 diagnostic criteria. Variables included factors identified by the Lancet Commission on Dementia Prevention, Intervention, and Care, and established indices including the Lifestyle for BRAin health (LIBRA), Cardiovascular Risk Factors, Aging and Incidence of Dementia (CAIDE), Australian National University Alzheimer's Disease Risk Index (ANU-ADRI), and World Health Organization (WHO) guidelines. Network structure was estimated using mixed graphical models. Sensitivity analyses were conducted to assess the robustness of the network.

RESULTS: Across both surveys, dementia showed the strongest conditional associations with age, educational attainment, employment status, being physically active, walking frequency, stroke, daytime sleepiness, and difficulty maintaining friendships. The overall network structures were comparable in the two surveys, indicating stable interconnections among demographic, behavioural, and social domains. Majority of these interconnections were also not found to vary by gender and ethnicity.

CONCLUSIONS: This study highlights the complex web of interrelations linking dementia with social, behavioural, and health-related factors in later life. Rather than implying causal direction, these findings illustrate how multiple factors cluster and coexist within older adults' lives. These interconnections may inform the design of holistic strategies that integrate employment opportunities, physical activity promotion, social participation, sleep health, and cerebrovascular prevention into comprehensive dementia prevention and care frameworks.},
}

@article {pmid42129775,
year = {2026},
author = {Börsch, AL and Riethues, F and Schulte-Mecklenbeck, A and Wang, X and Heming, M and Lu, IN and Müller-Miny, L and Wiendl, H and Gross, CC and Bernard-Valnet, R and Meyer Zu Hörste, G},
title = {A CSF disease-associated macrophage signature defines progressive multiple sclerosis.},
journal = {Journal of neuroinflammation},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12974-026-03861-9},
pmid = {42129775},
issn = {1742-2094},
abstract = {OBJECTIVE: Progression in multiple sclerosis (MS) often corresponds to irreversible disability in MS patients. Cellular changes in the cerebrospinal fluid (CSF) have provided biomarkers and mechanisms in relapsing-remitting MS (RRMS) but remain understudied in primary and secondary progressive MS (summarized herein as PMS).

METHODS: We combined retrospective flow cytometry of CSF cells from RRMS (n = 169), PMS (n = 56), and non-inflammatory controls (n = 74) with prospective CSF single-cell transcriptomics of 35 individuals (11 controls, 12 RRMS, and 12 PMS) and with confirmatory CSF ELISA. Available CSF single-cell data from age-matched and Alzheimer's disease (AD) patients served as additional controls.

RESULTS: Proportions of CD14[+] monocytes in CSF are increased in PMS and correlated with clinical surrogate markers of progression. Transcriptionally, these monocytes resembled border-associated macrophages (BAM)-like cells with a chronically activated antigen-presenting phenotype. Additionally, these monocytes shared some features with disease-associated microglia/macrophages (DAM), previously identified in neurodegeneration. Induction of DAM-associated molecules, including transcribed and soluble TREM2 (sTREM2), characterized secondary progressive MS (SPMS) and supported its differential diagnosis.

INTERPRETATION: We thus identified MS stage-specific CSF signatures and shared cellular features of degeneration detectable in CSF of PMS patients.},
}

@article {pmid42129839,
year = {2026},
author = {Yang, D and Liu, P and Han, M and Ke, Z and Tan, Y and Yu, L and Hu, Z and Mao, C and Cheng, Y and Zhang, H and Zhang, Y and Zhu, X and Xu, Y},
title = {Plasma extracellular vesicle proteins biomarker for cerebral small vessel disease related cognitive impairment.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02078-5},
pmid = {42129839},
issn = {1758-9193},
support = {2023ZD0504902//Noncommunicable Chronic Diseases-National Science and Technology Major Project/ ; 82130036//the National Natural Science Foundation of China/ ; 2022ZD0211800//the STI2030-Major Projects/ ; ZDXK202216//iangsu Province Key Medical Discipline/ ; },
abstract = {BACKGROUND: Cerebral small vessel disease (CSVD) is a major contributor to vascular dementia. Given the absence of effective treatments, the development of blood-based biomarkers for early diagnosis and prediction is paramount to facilitate targeted clinical interventions. We aimed to identified blood-based extracellular vesicle (EV) biomarkers for screening CSVD with normal cognition (CSVD-NC) or cognitive impairment (CSVD-CI), and predicting disease progression.

METHODS: We conducted a multi-center cross-sectional and longitudinal study involving patients with CSVD-NC and CSVD-CI, healthy controls (HCs), and patients with CI due to Alzheimer's disease (AD-CI). Plasma EV proteomics were profiled using LC-MS/MS in a discovery set. Candidate EV biomarkers identified in this phase were subsequently validated in a larger independent set using parallel reaction monitoring. Machine learning was applied to develop and optimize diagnostic combinations for identifying CSVD and predicting disease progression.

RESULTS: Plasma EV proteins exhibiting progressive changes during CSVD progression were predominantly enriched in immune-inflammatory and ribosomal dysfunction. Three plasma EV proteins (ATP6V1F, HNRNPU, and RPL38) demonstrated robust, cross-dataset consistency from HC to CSVD-NC to CSVD-CI continuum, and displayed distinct expression patterns between CSVD-CI and AD-CI (P < 0.001). These EV biomarkers demonstrated high diagnostic accuracy for CSVD with or without CI (AUC = 0.849-0.897), and effectively stratified high-risk versus low-risk populations for CSVD cognitive progression (P = 0.005). Moreover, they were associated with CSVD-related structural injury and specific cognitive functions: EV ATP6V1F with hippocampal atrophy, language, and memory; EV RPL38 with WMH burden and white matter integrity; and EV HNRNPU with visuospatial function and executive function.

CONCLUSION: The identified plasma EV biomarkers reliably reflect CSVD-related vascular injury and cognitive decline, and hold promise as minimally invasive tools for early screening and risk stratification of CSVD-related CI, especially in community settings.},
}

@article {pmid42129847,
year = {2026},
author = {Lu, Y and Abdullah, M and Healy, LR and Yin, T and Yesiltepe, M and D'Adamio, L and Tambini, MD},
title = {Valosin-containing Protein is cargo in Amyloid Precursor Protein extracellular vesicles.},
journal = {Cell communication and signaling : CCS},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12964-026-02936-7},
pmid = {42129847},
issn = {1478-811X},
support = {R01AG063407/AG/NIA NIH HHS/United States ; R00AG065441/AG/NIA NIH HHS/United States ; },
abstract = {The Amyloid Precursor Protein (APP), a genetic cause of Alzheimer's disease (AD), is a type-I transmembrane protein that is metabolized by proteolysis in the endolysomal system. APP and its metabolites are secreted by cells in extracellular vesicles (EVs). To study the function of APP-containing EVs, we isolated App-EVs from rat primary neuronal conditioned media and proteomic analysis identified the Valosin-containing protein (Vcp) as molecular cargo. Pharmacological modulation of Vcp activity was found to alter App processing and global EV secretion in rat primary neurons. AD-associated knock-in App mutations were found to alter the abundance of App-EVs and the trafficking of App metabolites within App-EVs, in a manner related to the epitopes generated by the nonamyloidogenic processing of App.},
}

@article {pmid42130238,
year = {2026},
author = {Lim, HK and Shih, AY and Gust, J},
title = {Leukocyte-endothelial interactions and brain capillary function in neurological diseases.},
journal = {Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism},
volume = {},
number = {},
pages = {271678X261441983},
doi = {10.1177/0271678X261441983},
pmid = {42130238},
issn = {1559-7016},
abstract = {Enhanced leukocyte-endothelial interactions are a hallmark pathological feature in brain disease. Preclinical studies have demonstrated increased leukocyte adhesion at the capillary level as a major contributor to cerebral blood flow (CBF) reductions across diverse neurological disorders, including Alzheimer's disease, ischemic stroke, and epilepsy. Remarkably, even modest levels of capillary obstruction (2%-5%) lead to disproportionate reductions in cerebral perfusion at the network level. Beyond acute perfusion deficits, chronic leukocyte obstruction contributes to long-term consequences such as structural capillary remodeling and altered blood-brain barrier function. This review synthesizes preclinical and clinical evidence across various neurological conditions to establish mechanistic links between leukocyte-driven neuroinflammatory pathology and cerebrovascular dysfunction at the capillary level. We integrate evidence on the structural and molecular basis of leukocyte adhesion, the multiscale impacts of increased leukocyte recruitment on capillary dysfunction, downstream inflammatory cascades, and neurological disease pathology. We address translational implications for therapeutic intervention arising from these mechanistic links.},
}

@article {pmid42130250,
year = {2026},
author = {Akar, S and Alvur, O and Evyapan, G and Ozdem, B and Porsuk Doru, I},
title = {Escin Attenuates Amyloid Beta 1-42-Induced Oxidative Stress, Apoptosis, and Neuroinflammation in Neuron-Like SH-SY5Y Cells.},
journal = {Journal of biochemical and molecular toxicology},
volume = {40},
number = {5},
pages = {e70903},
doi = {10.1002/jbt.70903},
pmid = {42130250},
issn = {1099-0461},
support = {TSA-2023-10713//Van Yuzuncu Yıl University Research Fund/ ; },
mesh = {*Amyloid beta-Peptides/toxicity ; Humans ; *Oxidative Stress/drug effects ; *Apoptosis/drug effects ; *Peptide Fragments/toxicity ; Cell Line, Tumor ; *Neurons/metabolism/pathology/drug effects ; *Escin/pharmacology ; Reactive Oxygen Species/metabolism ; *Neuroprotective Agents/pharmacology ; *Neuroinflammatory Diseases/metabolism/pathology/drug therapy ; Cell Survival/drug effects ; Alzheimer Disease/metabolism/drug therapy/pathology ; NF-kappa B/metabolism ; Inflammation/metabolism ; },
abstract = {The pathogenesis of Alzheimer's disease (AD) involves amyloid beta (Aβ)-induced oxidative stress, apoptotic cell death, and neuroinflammation, contributing to neuronal dysfunction. In our study, a differentiation protocol using retinoic acid was applied to SH-SY5Y cells to generate a neuron-like phenotype, and the neuroprotective efficacy of Escin was investigated by inducing Aβ1-42-mediated cytotoxicity. The experimental protocol involved an initial treatment with 2 µM Escin prior to Aβ1-42 application. Cell viability, intracellular reactive oxygen species (ROS), apoptosis, and inflammatory mediator expression (NF-κB, TNF-α, IL-1β) were assessed by MTT assay, flow cytometry with DCFH-DA, flow cytometry with Annexin V-FITC/7-AAD staining, and RT-qPCR, respectively. In our results, Aβ1-42 exposure was found to significantly reduce cell viability and increase ROS production. Additionally, it was observed to enhance apoptotic cell death and increase pro-inflammatory gene expression. Escin pretreatment was found to significantly mitigate these effects by reducing oxidative stress, apoptosis, and NF-κB-mediated inflammatory signaling. Furthermore, galantamine (10 µM), an approved AD treatment agent, was used as a positive control to compare the effects of Escin and confirmed the experimental model by exhibiting protective effects. In conclusion, these findings demonstrate that Escin is a promising neuroprotective agent and warrant further investigation into its potential to mitigate Aβ-related neuronal damage in AD.},
}

*Amyloid beta-Peptides/toxicity
Humans
*Oxidative Stress/drug effects
*Apoptosis/drug effects
*Peptide Fragments/toxicity
Cell Line, Tumor
*Neurons/metabolism/pathology/drug effects
*Escin/pharmacology
Reactive Oxygen Species/metabolism
*Neuroprotective Agents/pharmacology
*Neuroinflammatory Diseases/metabolism/pathology/drug therapy
Cell Survival/drug effects
Alzheimer Disease/metabolism/drug therapy/pathology
NF-kappa B/metabolism
Inflammation/metabolism

@article {pmid42130394,
year = {2026},
author = {Chen, F and Zhang, H and Huang, Y and Zhu, J and Cui, F and Liang, S and Li, Y and Wang, Y and Xie, X and Liu, R},
title = {Neuronal PRRT3 coordinates amyloidogenic processing and Tau phosphorylation via distinct Ras-ERK-AP-1 and CaMKII/PP2A pathways.},
journal = {Acta biochimica et biophysica Sinica},
volume = {},
number = {},
pages = {},
doi = {10.3724/abbs.2026085},
pmid = {42130394},
issn = {1745-7270},
abstract = {Alzheimer's disease (AD) is characterized by extracellular β-amyloid (Aβ) deposition and intracellular Tau hyperphosphorylation, yet upstream factors that coordinately regulate both pathologies remain poorly understood. Here, we identify proline-rich transmembrane protein 3 (PRRT3) as a previously unrecognized, neuron-enriched upstream regulator of AD dual pathology. PRRT3 expression is elevated in brain tissues from AD patients and exhibits abnormal persistence in APP/ PS1 mice. PRRT3 knockdown markedly reduces APP, PS1, and BACE1 mRNA expressions, thereby decreasing Aβ generation in neuronal cells. Mechanistically, PRRT3 promotes the expressions of these amyloidogenic genes via activation of the activator protein-1 (AP-1) complex, as evidenced by reduced phosphorylation of c-Fos and c-Jun after PRRT3 knockdown. Transcriptomic profiling further reveals broad downregulation of calcium signaling-related receptors and intracellular calcium-handling proteins, accompanied by attenuated calcium signaling and ERK activity. Artificially elevating intracellular calcium with thapsigargin completely reverses the neuroprotective effects of PRRT3 knockdown, restoring both the Ras-ERK-AP-1-dependent amyloidogenic machinery and CaMKII/PP2A-mediated Tau hyperphosphorylation. In parallel, PRRT3 knockdown shifts the balance between the Ca [2+]-dependent Tau kinase CaMKII and the phosphatase PP2A, leading to reduced Tau hyperphosphorylation at multiple AD-relevant sites. Collectively, these findings establish PRRT3 as a neuron-enriched upstream regulator linking calcium dysregulation to both amyloidogenic processing and Tau phosphorylation. Targeting PRRT3 may therefore represent a promising strategy to simultaneously modulate the two core pathological processes in AD.},
}

@article {pmid42130449,
year = {2026},
author = {Suk, K and Lee, WH},
title = {GV1001: repurposing a telomerase-derived peptide for neurological therapeutics.},
journal = {Expert opinion on investigational drugs},
volume = {},
number = {},
pages = {},
doi = {10.1080/13543784.2026.2674652},
pmid = {42130449},
issn = {1744-7658},
abstract = {INTRODUCTION: Neurodegenerative and demyelinating diseases represent major unmet medical needs, with existing therapeutics demonstrating limited efficacy and significant safety concerns. Drug repurposing offers accelerated development timelines and established safety profiles. GV1001, a 16-amino acid telomerase-derived peptide originally developed as a cancer vaccine, has emerged as a promising multi-mechanism neuroprotective agent.

AREAS COVERED: This review examines preclinical evidence demonstrating GV1001 efficacy across Alzheimer's disease, stroke, experimental autoimmune encephalomyelitis, and depression models. Convergent mechanisms include gonadotropin-releasing hormone receptor-mediated neuroprotection, mitochondrial stabilization, modulation of glial functional states away from tissue-damaging inflammation, and promotion of remyelination. Clinical translation through Phase 2 trials in Alzheimer's disease demonstrated statistically significant cognitive improvements consistent with neurotrophic benefit, with excellent safety profiles lacking amyloid-related imaging abnormalities.

EXPERT OPINION: The network pharmacology approach of GV1001-simultaneously addressing multiple pathological processes - positions it as a differentiated alternative to single-target therapeutics. The dual anti-inflammatory and pro-remyelination profile of the peptide addresses critical unmet needs in progressive multiple sclerosis. Phase 3 confirmation, biomarker-driven patient stratification, and combination therapy investigations represent critical development priorities. Successful development may help validate multi-mechanism approaches in neurodegeneration, potentially catalyzing paradigm shifts from reductionist single-target strategies.},
}

@article {pmid42130461,
year = {2026},
author = {Tian, M and Wang, D and Zhang, C and Fan, J and Li, W and Liu, X and Shi, J},
title = {Gut Microbiota Dysbiosis Drives Early Alzheimer's Pathogenesis via Microglial TREM2/SYK/NF-κB Signaling Axis.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.6c00173},
pmid = {42130461},
issn = {1948-7193},
abstract = {Gut microbiota dysbiosis is implicated in Alzheimer's disease (AD), but causal evidence and mechanisms linking it to microglial dysfunction remain unclear. This study aimed to determine whether gut microbiota drives neuroinflammation and cognitive impairment via the microglial TREM2/SYK signaling axis in early AD. Using six-month-old APP/PS1 mice, fecal microbiota transplantation (FMT) was performed between AD and wild-type mice. Cognitive function, gut microbiota composition (16S rRNA sequencing), serum metabolites, hippocampal neuroinflammation, microglial polarization, and TREM2/SYK/NF-κB pathway activity were assessed. BV2 microglial cells were treated with Aβ oligomers, a TREM2 agonist, or a SYK inhibitor for mechanistic validation. AD mice exhibited cognitive decline, reduced microbial diversity (e.g., decreased Bacteroidetes and Lactobacillus), and altered circulating metabolites, including decreased butyrate and elevated LPS. Their hippocampi exhibited heightened glial activation, elevated pro-inflammatory cytokines (TNF-α, IL-1β, IL-6), and a shift toward pro-inflammatory activation markers (M1-associated). At the molecular level, TREM2 expression was downregulated, whereas SYK phosphorylation and NF-κB activation were enhanced, concomitant with synaptic protein loss. Critically, FMT from healthy donors reversed these abnormalities and improved cognition, whereas AD microbiota induced mild pathology in wild-type mice. In vitro, TREM2 activation or SYK inhibition attenuated Aβ-induced M1 polarization and cytokine release in microglia. Gut microbiota dysbiosis promotes early AD pathogenesis by dysregulating the microglial TREM2/SYK/NF-κB pathway, thereby driving neuroinflammation and synaptic dysfunction. Targeting this microbiota-signaling axis may offer novel therapeutic strategies.},
}

@article {pmid42130608,
year = {2026},
author = {Xu, Y and Sachdev, PS and Lennon, MJ},
title = {Vascular cognitive impairment and dementia drug-development pipeline 2025.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {12},
number = {},
pages = {e70263},
pmid = {42130608},
issn = {2352-8737},
abstract = {INTRODUCTION: There are currently no approved medicines for vascular cognitive impairment and dementia (VCID).

METHODS: We reviewed clinical trials across nine registries and included, summarized, and evaluated trials that had not yet published peer-reviewed results by August 22, 2025.

RESULTS: We found 88 clinical trials using 62 drugs. Cardiovascular disease-targeted therapies accounted for 37% (23 drugs). Synthetic and plant-based cognitive function enhancers accounted for 21% (13 drugs) each. Drugs targeting neuropsychiatric symptoms comprised 10% of the pipeline (six agents), biological disease-targeted therapies 5% (three agents), and other drugs 6% (four agents). There were 30 trials assessing 25 drugs in Phase 4, 24 trials assessing 21 drugs in Phase 3, 29 trials assessing 28 drugs in Phase 2, and five trials assessing four drugs in Phase 1.

DISCUSSION: While small relative to Alzheimer's disease (138 drugs, 182 trials in 2025), the drug pipeline for VCID shows some promise and will require further investment.},
}

@article {pmid42130609,
year = {2026},
author = {Gobbi, S and Silvestri, E and Tonietto, M and Klein, G and van den Heuvel, M and Magon, S},
title = {Functional connectome metrics reveal distinct prognostic subtypes in two Phase 3 gantenerumab trials.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {12},
number = {},
pages = {e70259},
pmid = {42130609},
issn = {2352-8737},
abstract = {INTRODUCTION: Alzheimer's disease (AD) heterogeneity poses significant challenges for drug development, identification of individuals at risk, and treatment response prediction. Scientists have leveraged graph theory and resting-state functional magnetic resonance imaging (rs-fMRI) to successfully stratify people with AD. Still, the prognostic value of rs-fMRI graph metrics in AD clinical trials remains unclear.

METHODS: We analyzed rs-fMRI from participants in amyloid-lowering clinical trials. Four graph metrics-global efficiency, clustering coefficient, modularity, and shortest path length-were computed and baseline clusters defined using unsupervised k‑means. We investigated the baseline connectome of each cluster to assess the level of network dysfunction and impairment (i.e., loss of global integration, resulting in disrupted communication between brain regions and reduced global efficiency). These clusters were related to a 116-week change in cognition and brain volume using covariate-adjusted mixed-effects models.

RESULTS: Three clusters emerged with distinct functional connectome efficiency, demographic, and AD-related biomarkers profiles. These baseline differences led to significant variations in disease progression. The most impaired‑connectome cluster declined fastest, whereas the most integrated declined slowest.

DISCUSSION: rs-fMRI graph metrics might effectively stratify participants with AD in clinical trials and serve as potential prognostic biomarkers.},
}

@article {pmid42130716,
year = {2026},
author = {Deau, E and Simon, C and Hogrel, G and Caillette, J and Dairou, J and Herault, Y and Morlet, B and Miyata, Y and Meijer, L and Lindberg, MF},
title = {Mapping the Brain Interaction Network of the Dual-Specificity, Tyrosine Phosphorylation-Regulated Kinase 1A (DYRK1A) Targeted by Leucettinib-21 Using Affinity Chromatography.},
journal = {ACS pharmacology & translational science},
volume = {9},
number = {5},
pages = {1204-1227},
pmid = {42130716},
issn = {2575-9108},
abstract = {Leucettinibs are substituted 2-aminoimidazolin-4-ones inspired by the marine sponge natural product Leucettamine B and developed as pharmacological inhibitors of DYRK1A (dual-specificity, tyrosine phosphorylation-regulated kinase 1A), a therapeutic target for indications such as Down syndrome, Alzheimer's disease, Parkinson's disease, diabetes, myocardial infarction, etc. Leucettinib-21 is currently being tested in a phase 1 clinical trial. In this study, four different affinity chromatography-based approaches were developed to identify the rat brain targets of Leucettinib-21: (1) Leucettinib-21 (and its kinase-inactive isomer as control) immobilized on agarose beads, (2) immobilized metal affinity chromatography, (3) KinAffinity bead competition assays, and (4) immunoprecipitation with DYRK1A-specific antibodies. Altogether, these complementary methods (1) confirm known targets of Leucettinib-21, and identify (2) new protein kinases and nonkinases interacting with Leucettinib-21, (3) potential new partners of DYRK1A, and (4) pathways and cellular mechanisms potentially modulated by Leucettinib-21. These methods can be expanded to various cells and tissues from models of pathologies where Leucettinib-21 demonstrates efficacy.},
}

@article {pmid42130721,
year = {2026},
author = {Kumar, S and Upadhyay, A},
title = {Roles of RNA-Binding Nuclear Proteins in Alzheimer's Disease Pathophysiology.},
journal = {ACS pharmacology & translational science},
volume = {9},
number = {5},
pages = {1055-1067},
pmid = {42130721},
issn = {2575-9108},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder associated with cognitive decline. Pathologically, AD is characterized by the accumulation of amyloid β (Aβ) monomers that may generate oligomers or fibrils in the extracellular space and inside the neurons. With time, the oligomers and fibrils aggregate into insoluble plaques, which may trigger a cascade of molecular events. These include altering gene expression at a broader level, implicating cross-talk with the nuclear machinery, including transcription. There is now emerging evidence implicating the role of RNAs and other nuclear proteins in AD pathogenesis, especially those associated with RNA splicing and ribonucleoproteins, which, along with post-transcriptional modifications, give rise to multiple functional proteoforms. Notably, RBPs themselves exist as multiple proteoforms, adding complexity to the proteome involved in AD. Therefore, in this review, we limit the discussion to the canonical protein forms of RBPs already established to have some role in AD pathophysiology. Recently, our proteomic study identified three such RBPs (SRSF2, hnRNPH1, and hnRNPA2B1) copurifying with amyloid, suggesting a possible interaction with Aβ and contribution to AD pathology. SRSF2 is a splicing factor involved in tau exon splicing, while hnRNPH1 and hnRNPA2B1 are both heterogeneous nuclear RBPs (hnRNPs) involved in mRNA processing. Some of the other hnRNPs have previously been implicated in AD and tau pathology. This review focuses on some of the recent evidence that suggests a possible involvement of RNA-associated nuclear proteins in dysregulation of widespread RNA processing affecting the AD pathogenesis pathways. We discuss how their dysfunction could modulate Aβ and tau-associated changes with an emphasis on understanding the linkage between nuclear RNA machinery and AD pathophysiology. Understanding this crosstalk may offer new insights into our understanding of AD and could provide RNA-centric therapeutic avenues.},
}

@article {pmid42130756,
year = {2026},
author = {von Borcke, N and Purwien, AV and Steiert, A and Hasecke, H and Bouter, Y},
title = {Reduced CB1 Cannabinoid Receptor Expression in Alzheimer's Disease and Transgenic Mouse Models.},
journal = {Aging medicine (Milton (N.S.W))},
volume = {9},
number = {2},
pages = {168-184},
pmid = {42130756},
issn = {2475-0360},
abstract = {OBJECTIVES: Therefore, in the present study, the CB1 receptor (CB1R) expression in the hippocampal and cortical tissue of a clinically and neuropathologically characterized cohort of AD patients was analyzed.

METHODS: Post-mortem brain tissue from patients with sporadic AD and non-demented control subjects was analyzed immunohistochemically, focusing on the hippocampus, medial frontal gyrus, and superior temporal gyrus. CB1R expression levels were measured and correlated with neuropathological hallmarks of AD (amyloid-β and tau pathology), neuroinflammatory markers (GFAP and IBA1), cognitive status (Reisberg scale), ApoE genotype, and age. Complementary analyzes were performed in two AD mouse models (5xFAD and Tg4-42).

RESULTS: CB1R expression was significantly reduced in the hippocampus, medial frontal gyrus, and superior temporal gyrus of AD patients. CB1R levels negatively correlated with both amyloid-β and tau pathology but showed no association with cognitive performance, neuroinflammatory markers, age, or ApoE genotype. Consistent with the human findings, CB1R expression was also reduced in the cortex of 5xFAD mice and in the hippocampus of Tg4-42 mice.

CONCLUSIONS: Our data demonstrate a region-specific downregulation of CB1R in both human AD brains and transgenic mouse models, which correlates with key neuropathological hallmarks of the disease. These findings suggest a potential role for CB1R in AD pathophysiology and support further investigation into its utility as a biomarker or therapeutic target.},
}

@article {pmid42130761,
year = {2026},
author = {Ahn, J and Kim, SY and Lee, MB and Kwon, OI and Rhee, HY and Jung, YJ and Kim, Y and Park, S and Ryu, CW and Lee, J and Jahng, GH},
title = {Evaluation of conductivity tensor image along the perivascular space in the brains of patients with cognitive impairments.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1794175},
pmid = {42130761},
issn = {1663-4365},
abstract = {BACKGROUND: The diffusion tensor imaging analysis along the perivascular space (DTI-ALPS) index has been proposed as an imaging marker of impaired perivascular water transport across the Alzheimer's disease (AD) continuum. Whether a conductivity-based ALPS derived from conductivity tensor imaging (CTI) provides a distinct physiological perspective remains to be explored. This work introduces the CTI-ALPS index. The purpose of this study was (1) to introduce the CTI-ALPS index and (2) to evaluate both the CTI-ALPS and DTI-ALPS indices in cognitively normal (CN) older adults, amnestic mild cognitive impairment (aMCI), and mild-to-moderate AD.

METHODS: In this prospective cross-sectional study, 110 participants (CN, n = 30; aMCI, n = 52; AD, n = 28) underwent diffusion MRI (b = 800 and 2,000 s/mm[2]) and magnetic resonance electrical property tomography (MREPT)to calculate DTI-ALPS and CTI-ALPS, respectively. Diagnostic performance and correlation with cognitive function were evaluated.

RESULTS: CTI-ALPS showed lower in AD but did not differ significantly across groups and demonstrated weaker associations with Mini-Mental State Examination (MMSE) scores. In age-adjusted ROC analyses for differentiating AD from CN, CTI-ALPS achieved modest discrimination, whereas DTI-ALPS provided slightly higher diagnostic performance.

CONCLUSION: CTI-ALPS demonstrated a non-significant trend towards a reduction in AD and modest diagnostic utility, with weaker clinical associations than DTI-ALPS in this cohort. As an initial exploratory study, conductivity-based ALPS may serve as a distinct physical contrast reflecting ionic physiological perivascular marker, alongside diffusion-based measures, and warrants further validation with larger, age-matched datasets and reproducibility-focused designs.},
}

@article {pmid42130762,
year = {2026},
author = {Liu, XY and Yan, YZ and Jiang, AJ and Tan, SJ and Fang, YY and Zeng, P},
title = {Integrating network pharmacology and experimental validation strategies to investigate the mechanisms and key flavonoids in medicinal and edible citrus plants against Alzheimer's disease.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1801263},
pmid = {42130762},
issn = {1663-4365},
abstract = {INTRODUCTION: Due to the complexity of the Alzheimer's disease (AD) pathophysiological processes, there is currently a lack of effective therapeutic drugs. The medicinal and edible substances have multiple advantages in treating AD, but their specific components and mechanisms remain unclear. This study aims to investigate the potential mechanisms of flavonoids in medicinal and edible citrus plants in treating AD and their key phytochemicals.

METHODS: We collected flavonoids identified by UHPLC-Q-TOF-MS/MS in citrus plants from the literatures and evaluate their pharmacological and toxicological parameters. We obtained and systematically analyzed the action targets of the flavonoids of citrus plants and screened the targets related to AD key pathophysiological processes and the corresponding phytochemicals. The results of network pharmacological analysis were further validated through molecular docking, GEO database, and BV2 microglial cells.

RESULTS: A total of 51 flavonoids in medicinal and edible citrus plants were identified, which exhibit favorable pharmacological properties and safety profiles. Multiple flavonoid compounds such as isoquercitrin, astragalin, cynaroside, troxerutin and lonicerin serve as potential acetylcholinesterase inhibitors for the symptomatic treatment of AD. The study identified 45 flavonoids in citrus plants that correspond to 304 AD-related targets, which are involved in multiple pathophysiological processes. Quercetin, nobiletin, hesperidin, apigenin, HTMF, tangeretin and hesperetin have been identified as the key flavonoids of citrus plants that regulate the pathogenesis of AD in a multitargeted manner. The flavonoids of citrus plants primarily regulate the core targets AKT1, TNF, IL6, TP53, IL1B, STAT3, INS, JUN, CASP3 and CTNNB1. Targeting ferroptosis is one of the mechanisms by which citrus plants to ameliorate AD. In vitro experiments also demonstrated that hesperidin and naringin alleviated LPS-induced pro-inflammatory activation of BV2 cells.

CONCLUSION: The various citrus plants flavonoids examined in this study exhibit significant potential for clinical translation, particularly in the early prevention and adjuvant treatment of AD.},
}

@article {pmid42130812,
year = {2026},
author = {Rajalakshmi, R and Ramya, CM and Naaz, R and Madhunapantula, SV and Uthaiah, CA and Salimath, PV},
title = {Glycemic dysregulation and cognitive impairment in aging adults: a cross-sectional study with amyloid biomarker correlation.},
journal = {Frontiers in aging},
volume = {7},
number = {},
pages = {1696711},
pmid = {42130812},
issn = {2673-6217},
abstract = {BACKGROUND: Type 2 Diabetes Mellitus (T2DM) is a rising health concern, particularly affecting the elderly population. Beyond its well-established metabolic consequences, growing evidence suggests a strong association between type 2 diabetes mellitus and cognitive decline. The core features of diabetes, viz., chronic hyperglycemia and insulin resistance (IR), not only contribute to the neurodegenerative changes in the brain but also promote the generation and accumulation of amyloid-β (a hallmark feature in Alzheimer's disease). These molecular changes triggered by T2DM play a pivotal role in the onset of cognitive damage. In this study, we have explored the interplay between glycemic status, cognitive performance, and plasma amyloid-β (Aβ) levels in an ageing population.

METHODOLOGY: A cross-sectional study was conducted among 396 individuals aged 51-80 years. Based on their HbA1c levels, the study participants were categorized into four glycemic groups: individuals without diabetes, individuals with prediabetes, individuals with diabetes, and individuals with uncontrolled diabetes. Cognitive function was evaluated using the Modified Mini-Mental State Examination (3MSE). Fasting glucose, insulin, Homeostatic Model Assessment (HOMA)-IR, lipid profiles, and plasma Aβ 1-40 and Aβ 1-42 were measured. Statistical analyses were carried out using Chi-square tests, logistic regression, Spearman correlation, and Receiver Operating Characteristic (ROC) curve analysis.

RESULTS: A comparative assessment in the study revealed the prevalence of cognitive impairment across all glycemic groups, with 40.15% of participants overall affected. It was observed that the prevalence increased with the glycemic index, with 26.97% of individuals without diabetes affected, 35.92% of individuals with prediabetes, 55.03% of individuals with diabetes under control, and 70.91% of individuals with uncontrolled diabetes (p < 0.001). Logistic regression indicated progressively higher odds of cognitive impairment with worsening glycemic control (OR for individuals with uncontrolled diabetes ≈6.87, p < 0.001). Age and HbA1c were significantly inversely correlated with 3MS scores. Plasma Aβ 1-40 and Aβ 1-42 levels were elevated in individuals with diabetes groups, while the Aβ 1-42/Aβ 1-40 ratio was positively associated with cognitive performance. The ROC curve analysis of the logistic regression indicated an Area Under Curve (AUC) of 0.76, suggesting good predictive capability.

CONCLUSION: Impaired glycemic status was found to be strongly associated with increased cognitive decline, alongside altered amyloid biomarker profiles, in elderly populations. These findings suggest the heightened importance of metabolic homeostasis and also underscore the critical need for early metabolic interventions and cognitive screening in the individuals with diabetes to mitigate the risk of early neurodegeneration.},
}

@article {pmid42130814,
year = {2026},
author = {Huvent-Grelle, D and Beuscart, JB and Hubert, A and Bouteloup, V and Amouyel, P and Puisieux, F and Hamroun, A and Aymes, E},
title = {Living alone and risk of dementia, cognitive decline, and institutionalization in the MEMENTO cohort.},
journal = {Frontiers in aging},
volume = {7},
number = {},
pages = {1782176},
pmid = {42130814},
issn = {2673-6217},
abstract = {INTRODUCTION: Alzheimer's disease and related dementias (ADRD) represent a public health challenge, with prevention strategies focusing on modifiable risk factors such as isolation. Living alone is used as a proxy for social isolation, although its relationship with ADRD outcomes remains unclear, partly due to the distinction between objective isolation and subjective loneliness. This study examined the association between living alone and the risk of dementia, cognitive decline, and institutionalization in the MEMENTO cohort, a French clinic-based study of individuals with cognitive complaints or mild cognitive impairment.

METHODS: Living alone at baseline was the main exposure. Perceived isolation was assessed using self-reported measures. Outcomes included incident dementia, institutionalization; and trajectories of Mini-Mental State Examination (MMSE) scores over a 5-year median follow-up. Cause-specific Cox models accounting for competing risks were used for dementia and institutionalization, and linear mixed models for MMSE trajectories.

RESULTS: Among 2,269 participants (median age 71.5 years, 62% women, median MMSE 28), 30.7% lived alone and 6.5% reported perceived isolation. At 60 months, estimated cumulative incidences were 15% for dementia, 1.0% for institutionalization and 3.6% for death. Living alone was not associated with incident dementia (HR = 0.88 [95%CI: 0.67-1.16], p = 0.38), or cognitive decline. In contrast, it was associated with a higher risk of institutionalization (HR = 3.21 [95%CI: 1.09-9.48], p = 0.03).

DISCUSSION: Living alone was not linked to dementia risk or cognitive decline, but was associated with a higher risk of institutionalization. This finding may indicate that living alone captures vulnerability related to reduced day-to-day support rather than cognitive decline itself.},
}

@article {pmid42131436,
year = {2026},
author = {Gusmão, LA and Metzke, A and Deau, E and Meijer, L and Tedesco, AC and Köster, RW},
title = {Nitrogen-Doped Graphene Quantum Dots Conjugated to Leucettinib-21 Rescue Differentiating Zebrafish Purkinje Cells by Inhibiting Dyrk1A Kinase.},
journal = {ACS applied nano materials},
volume = {9},
number = {18},
pages = {8023-8038},
pmid = {42131436},
issn = {2574-0970},
abstract = {A major challenge in treating neurological diseases is the transport of compounds across the blood-brain barrier. Herein, we report the synthesis and characterization of nitrogen-doped graphene quantum dots (GQDs) that exhibit high tolerance in zebrafish larvae at high concentrations. In contrast to classical semiconductor quantum dots, vascular microinjection of these fluorescent carbon-based nanomaterials results in rapid tissue distribution and efficient neuronal internalization within the brain, highlighting their potential as nanocarriers for central nervous system delivery. Vascular microinjections of these quantum dots conjugated with the high-affinity Dyrk1A kinase inhibitor Leucettinib-21 (LCTB21) at nanomolar concentrations rescued cell-autonomous dendrite deficiencies in cerebellar Purkinje cells overexpressing human Dyrk1a. LCTB21 concentrations were significantly lower than those of the inhibitor alone. Dyrk1A activity is responsible for neurological defects in Down syndrome and acts as a priming kinase for Alzheimer's disease-associated proteins Tau and APP. Thus, efficient nanodelivery of Dyrk1A inhibitors across the blood-brain barrier improves therapeutic options while minimizing the treatment dose and potential side effects.},
}

@article {pmid42131631,
year = {2026},
author = {Egbuchiem, AN and Ezeamii, VC},
title = {County-Level Ecological Association Between Glyphosate Exposure and Chronic Disease Mortality in Midwestern US Agricultural Communities.},
journal = {Cureus},
volume = {18},
number = {4},
pages = {e106908},
pmid = {42131631},
issn = {2168-8184},
abstract = {BACKGROUND: Glyphosate is widely used in the United States (US) agriculture, particularly in regions with intensive crop production. Concerns have been raised regarding potential long-term health effects associated with environmental exposure. Chronic diseases remain a leading cause of mortality in the US, particularly in agricultural and rural communities.

OBJECTIVE:  To examine the ecological association between county-level glyphosate use and chronic disease mortality in Midwestern US agricultural communities.

METHODS: This ecological panel study used county-level mortality data from the Centers for Disease Control and Prevention (CDC) Wide-ranging Online Data for Epidemiologic Research (WONDER) Multiple Cause of Death files and pesticide use estimates from the United States Geological Survey Pesticide National Synthesis Project. The study included counties across 12 Midwestern states from 1999 to 2020. Age-adjusted mortality rates for cancer, heart disease, diabetes, Alzheimer's disease, kidney disease, and chronic respiratory disease were analyzed. The primary exposure was log-transformed glyphosate use scaled per 1,000 kg and lagged by three years. County and year fixed effects regression models were applied.

RESULTS:  Higher three-year lagged glyphosate use was significantly associated with increased heart disease mortality at the county level (β = 5.04; p < 0.001), indicating that increases in glyphosate exposure were associated with modest increases in county-level heart disease mortality rates. No significant associations were observed for the other chronic disease outcomes.

CONCLUSION: This study highlights a population-level association between glyphosate use and heart disease mortality in Midwestern counties. Continued monitoring and research using individual-level data are warranted.},
}

@article {pmid42131707,
year = {2026},
author = {Misra, A and Wang, Y and Taheri, MR and Chiang, GC and Cho, J},
title = {Oxygen extraction fraction is differentially associated with pathological biomarkers in Alzheimer's disease and non-Alzheimer's dementias.},
journal = {Frontiers in neuroscience},
volume = {20},
number = {},
pages = {1754415},
pmid = {42131707},
issn = {1662-4548},
abstract = {INTRODUCTION: We aimed to understand the pathophysiological differences between 16 Alzheimer's disease (AD) and 15 non-AD dementia patients by quantifying oxygen extraction fraction (OEF) in cortical (CGM) and deep gray matter (DGM) regions.

METHODS: To achieve this, we used a novel MRI-based OEF mapping technique, QQ, which estimates OEF from routine multi-echo gradient echo data. Multiple linear regression analyses were performed to compare the associations between OEF and white matter hyperintensities (WMH) or cognitive impairment (measured by Montreal Cognitive Assessment (MoCA) between the two groups.

RESULTS: In the AD and non-AD group, OEF showed negative associations with WMH in DGM and positive associations with MoCA in DGM and CGM.

DISCUSSION: Our study suggests that QQ is a promising tool for differentiating between AD and non-AD dementias, by revealing abnormalities in tissue oxygen usage and their relationships to microvascular changes and cognitive impairment.},
}

@article {pmid42131724,
year = {2026},
author = {Ma, W and Zhou, F and Cai, H and Fang, L},
title = {Decoding Pathogenic Mutational Landscapes in Alzheimer's Disease Through Integrated Transcriptomics.},
journal = {Human mutation},
volume = {2026},
number = {},
pages = {6627566},
pmid = {42131724},
issn = {1098-1004},
mesh = {Humans ; *Alzheimer Disease/genetics/diagnosis ; *Mutation ; *Transcriptome ; *Gene Expression Profiling/methods ; Computational Biology/methods ; Machine Learning ; Tubulin/genetics ; },
abstract = {Alzheimer's disease (AD) is increasingly understood as a disorder driven not only by amyloid and tau pathology but also fundamentally shaped by underlying genetic mutations. By integrating multiple AD gene expression datasets with machine learning approaches-including random forest, XGBoost, LASSO, and SVM-we identified 172 differentially expressed genes, with TUBB2A, RTN4, and YWHAZ emerging as top mutation-associated hub genes. Critically, TUBB2A not only exhibited strong diagnostic potential (AUC = 0.822) but also harbored somatic mutations in our patient cohort, directly linking mutational events to disease manifestation. Unsupervised clustering revealed two distinct AD subtypes: one marked by widespread early gene overexpression and another (Cluster 2) dominated by endoplasmic reticulum stress-likely reflecting divergent mutational landscapes. Pseudotemporal trajectory analysis demonstrated a continuous progression from normal samples to Cluster 2, suggesting that a pivotal mutational event may initiate this transition and accelerate disease progression. These findings underscore the central role of somatic and germline mutations-particularly in TUBB2A-in AD pathogenesis. Our study strongly supports a paradigm shift toward mutation-centric biomarker development and advocates for SNP-based strategies to enable early diagnosis and personalized therapeutic interventions tailored to individual mutational profiles.},
}

Humans
*Alzheimer Disease/genetics/diagnosis
*Mutation
*Transcriptome
*Gene Expression Profiling/methods
Computational Biology/methods
Machine Learning
Tubulin/genetics

@article {pmid42132079,
year = {2026},
author = {Dong, H and Zhao, L and Guo, G and Chang, A and Cheng, M and Qian, Y and Hu, L and Zhou, J and Ye, Y and Zhou, Y and Ma, Y and Li, Z and Xu, M},
title = {Photocontrollable Electrochemical Molecular Probe for the Detection of Cu[2+] in Brain Dialysates of Alzheimer's Disease Mice.},
journal = {ACS sensors},
volume = {},
number = {},
pages = {},
doi = {10.1021/acssensors.6c00637},
pmid = {42132079},
issn = {2379-3694},
abstract = {Alzheimer's disease (AD), a progressive neurodegenerative disorder, is closely associated with the dyshomeostasis of copper ions (Cu[2+]) in the brain. Aberrant cerebral Cu[2+] accumulation induces the aggregation of amyloid-β peptides and the generation of reactive oxygen species, which represent the key pathological hallmarks of AD. Herein, we report a photocontrollable electrochemical molecular probe (TPMP) for the highly selective and sensitive detection of Cu[2+] in the brain dialysates of AD model mice. TPMP is rationally engineered with three core functional moieties: a 2-nitrobenzyl group as the photolabile unit, hydroquinone (HQ) as the electroactive reporter, and picolinate as the Cu[2+] recognition group. In the dark, the specific binding of Cu[2+] to the picolinate moiety of TPMP triggers the hydrolytic cleavage of picolinate, yet this reaction only yields a stable reaction intermediate without the release of electrochemically active HQ, thus rendering the probe in an electrochemically silent state with no detectable electrochemical signal. Only upon subsequent irradiation with 365 nm ultraviolet (UV) light does the 2-nitrobenzyl photolabile group in the intermediate undergo irreversible photolytic cleavage, which enables the quantitative release of free electroactive HQ and thereby produces a distinct turn-on electrochemical response for the specific detection of Cu[2+]. The probe exhibits excellent analytical performance, including high selectivity against coexisting interfering metal ions and biological molecules and favorable sensitivity with a limit of detection of 30 nM. Furthermore, TPMP has been successfully applied for the accurate quantification of Cu[2+] in the brain dialysates of AD model mice, validating its practicability and reliability in complex biological matrices. This photocontrollable sensing strategy achieves sequential Cu[2+] recognition and light-triggered signal activation, which effectively eliminates nonspecific interference from complex biological samples and provides a promising analytical tool for investigating Cu[2+]-mediated pathological processes in AD. It also offers a novel design strategy for the development of photocontrollable electrochemical probes for the early diagnosis of AD and other metal ion-related neurodegenerative diseases.},
}

@article {pmid42132527,
year = {2026},
author = {Caldwell, B and Ye, X and Maerivoet, A and Madine, J and Arnolds, H},
title = {Using light polarisation to unravel the structure of insulin fibril polymorphs.},
journal = {Physical chemistry chemical physics : PCCP},
volume = {},
number = {},
pages = {},
doi = {10.1039/d5cp04579g},
pmid = {42132527},
issn = {1463-9084},
abstract = {Amyloid fibrils lie at the core of major human degenerative diseases, such as Alzheimer's, Parkinson's, and diabetes. The structural polymorphism of amyloid fibrils has been linked to disease severity and many polymorph structures of proteins such as Aβ or α-synuclein are now known in detail. Amyloid fibril polymorphism has also been observed for insulin amyloid fibrils, but very little is known about the underlying structural differences. Here, we investigate the structure of insulin amyloid fibril polymorphs created in different solvents by Raman, infrared and fluorescence spectroscopy. We show that insulin polymorphs have different twists of their β-sheets which impacts alignment of backbone carbonyls relative to the fibril axis, changes β-turn structure and disulfide bond conformation, changes alignment of tyrosines and the hydrogen-bonding state of Gln and Glu side chains. These different structures arise because solvent composition changes hydrophobic and hydrogen-bonding interactions between insulin monomers. This work is a first step towards understanding how different environmental conditions create specific insulin fibril structures.},
}

@article {pmid42132557,
year = {2026},
author = {Liu, D and Hu, M and Zhan, X and Siu, SWI},
title = {MEGCAM: MEta-Graph and Causal Attention Method for Drug Repurposing on Heterogeneous Drug-Target-Disease Knowledge Network.},
journal = {Journal of chemical information and modeling},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.jcim.6c00440},
pmid = {42132557},
issn = {1549-960X},
abstract = {Drug repurposing is a highly effective strategy in drug development that identifies new therapeutic applications for existing drugs, offering accelerated timelines and reduced risks compared to traditional de novo approaches. With the rapid growth of large-scale biomedical data, new computational methods have been developed to predict relationships between drugs and diseases, thereby facilitating drug repurposing efforts. Nevertheless, current methods often fail to capture heterogeneous information in biomedical networks, including diverse node types and multityped edges, which limits their prediction accuracy. To address this challenge, we propose MEGCAM, a model that effectively extracts heterogeneous information from the constructed biomedical information network through the Meta-Graph technique. And a path selection strategy based on a causal attention mechanism has been designed to provide effective guidance for information aggregation. Experimental results demonstrate that MEGCAM performs competitively with state-of-the-art models, showing strong robustness and generalizability across two independent data sets. Furthermore, a case study on Alzheimer's disease demonstrates MEGCAM's practical utility and reliability. Overall, MEGCAM shows great potential to accelerate therapeutic discovery by enhancing prediction accuracy and model interpretability.},
}

@article {pmid42132855,
year = {2026},
author = {Tiburcio, MA and Cali, MP and Pereira, LMB and Graminha, AE and Atienza-Navarro, I and Vendruscolo, M and Garcia-Alloza, M and Carlos, RM},
title = {In vitro and in vivo inhibition of amyloid β aggregation by a Ru(II)-naphthalene diimide complex.},
journal = {Dalton transactions (Cambridge, England : 2003)},
volume = {},
number = {},
pages = {},
doi = {10.1039/d5dt02853a},
pmid = {42132855},
issn = {1477-9234},
abstract = {Amyloid deposits of amyloid-β (Aβ) and hyperphosphorylated tau are pathological hallmarks of Alzheimer's disease (AD), which accounts for most dementia cases worldwide. This study investigates the effect of the complex [Ru(phen)2(pNDIp)][2+] (RuNDI; phen = 1,10-phenanthroline, pNDIp = N,N'-di(1,10-phenanthroline)-1,4,5,8-naphthalenetetracarboxylic diimide) on Aβ aggregation in vitro and in vivo. In vitro, RuNDI markedly attenuated Aβ42 aggregation, as shown by nephelometry, circular dichroism, and transmission electron microscopy, by suppressing β-sheet formation and promoting amorphous assemblies. In vivo, immunofluorescence analysis using Thioflavin-S and the 4G8 antibody in transgenic APP/PS1 mice treated with RuNDI (0.1 mg kg[-1] day[-1], intraperitoneally, for 10 weeks) revealed that, while RuNDI did not affect the size of existing amyloid plaques, it significantly decreased plaque density and burden in the cortex and hippocampus of treated mice. These findings suggest that RuNDI interferes with Aβ aggregation and may be further investigated for modifying plaque pathology.},
}

@article {pmid42132882,
year = {2026},
author = {Albertuni, M and Torrecillas-Lopez, M and Gonzalez-de la Rosa, T and Barrera-Chamorro, L and Marquez-Paradas, E and Del Rio-Vazquez, JL and Navarro-Hortal, MD and Claro-Cala, CM and Montserrat-de la Paz, S},
title = {Oleic and omega-3 fatty acids buffer neuroinflammation in a scopolamine model with Alzheimer's-like features via target-level interactions.},
journal = {Food & function},
volume = {},
number = {},
pages = {},
doi = {10.1039/d6fo00279j},
pmid = {42132882},
issn = {2042-650X},
abstract = {Diet quality, beyond total fat, may shape the immune tone of the brain in Alzheimer's-relevant contexts. We examined whether the fatty acid profile and food matrix of high-fat diets (HFD) modulate hippocampal neuroinflammation in vivo and explored target-level mechanisms with molecular docking. Male B6129SF2/J mice received a standard diet (SD) or HFD enriched with extra-virgin olive oil (EVOO), refined olive oil (ROO), refined palm oil (RPO), or ω3 long-chain polyunsaturated fatty acids (ω3-LCPUFA). During the final week, scopolamine induced acute cholinergic dysfunction. Neuroinflammation was assessed in the dentate gyrus by IHC (Iba-1, COX-2, and TNF-α) and by IF of astrocytes (GFAP intensity and morphology). Docking was employed to evaluate interactions of oleic and palmitic acids, EPA, and DHA with AChE, COX-2, BACE1, and TREM2. All HFD groups attenuated scopolamine-induced increases in Iba-1, COX-2 and TNF-α compared with the SD-scopolamine group, with limited separation among lipid classes under this acute stressor. By contrast, astroglial readouts showed a clear hierarchy: EVOO-HFD produced the lowest GFAP signal and the most ramified morphology, followed closely by ω3-LCPUFA, with ROO being intermediate and SFA being the least favourable. Docking supported a mechanistic framework: EPA/DHA displayed stronger predicted engagement than oleate/palmitate at COX-2 and BACE1, while long-chain fatty acids occupied the AChE peripheral site and a lipid/apoE-responsive surface on TREM2. In conclusion, PUFA-rich feeding, and notably that with the EVOO matrix, preferentially buffers hippocampal neuroinflammation in a scopolamine-induced Alzheimer's-like model. These findings support a composition, binding, and function framework and strengthen the translational rationale for precision nutrition strategies prioritizing ω3-LCPUFA and high-quality olive oils.},
}

@article {pmid42132921,
year = {2026},
author = {},
title = {Correction to: Factors influencing implementation of an Alzheimer's disease blood test among UK old age psychiatrists: mixed-methods study using the theoretical domains framework.},
journal = {Age and ageing},
volume = {55},
number = {5},
pages = {},
doi = {10.1093/ageing/afag146},
pmid = {42132921},
issn = {1468-2834},
}

@article {pmid42133009,
year = {2026},
author = {Sodaei, F and Vafaee, MS and Michel, TM and Rad, HS and Noroozian, M},
title = {From MRI to 3D printing: a tangible neuroeducational tool for visualizing hippocampal morphology and Alzheimer's disease progression.},
journal = {Journal of neural transmission (Vienna, Austria : 1996)},
volume = {},
number = {},
pages = {},
pmid = {42133009},
issn = {1435-1463},
support = {99-3-101-45445//Tehran University of Medical Sciences and Health Services/ ; },
abstract = {Alzheimer's disease (AD) affects the hippocampus early and profoundly, yet its complex three-dimensional (3D) anatomy can be difficult to appreciate on conventional imaging. Recognizing hippocampal atrophy in amnestic mild cognitive impairment (MCI) is essential for timely diagnosis and clinical decision-making. This study aimed to create a tangible 3D hippocampal model derived from magnetic resonance imaging (MRI) to support neuroeducation, enhance clinician training, and improve visualization of disease-related change. High-resolution T1-weighted MRI scans were obtained from 9 cognitively healthy controls (HC), 10 individuals with MCI, and 10 with AD. Semi-automated segmentation was used to reconstruct 3D hippocampal models for each group. Volumetric analyses assessed hippocampal atrophy, hemispheric asymmetry, and diagnostic differentiation. The hemisphere showing the most pronounced atrophy was selected for physical modeling, and an experienced neurologist reviewed a 3D-printed hippocampus for anatomical accuracy and educational value. Significant volumetric differences were identified in both hippocampal hemispheres across HC, MCI, and AD (p < .001). The right hippocampus demonstrated the greatest atrophy in AD and early volume loss in MCI. Receiver operating characteristic analysis showed strong diagnostic performance, with areas under the curve of 0.980 for AD versus MCI and 0.833 for MCI versus HC. Based on these findings, the right hippocampus was selected for 3D printing. MRI-derived 3D-printed hippocampal models translate complex neuroimaging data into accessible, tactile representations of AD-related degeneration. This approach has potential value for medical education, clinician training, patient-clinician communication, and public awareness, as it makes hippocampal atrophy more clearly visible and understandable.},
}

@article {pmid42133133,
year = {2026},
author = {Kalra, P and Grewal, AK and Khan, H and Chaturvedi, D and Singh, TG},
title = {From epigenetic scripts to kinase signals: linking DOT1L and RIPK1 in the neurobiology of degeneration.},
journal = {Molecular biology reports},
volume = {53},
number = {1},
pages = {},
pmid = {42133133},
issn = {1573-4978},
mesh = {Humans ; *Receptor-Interacting Protein Serine-Threonine Kinases/metabolism/genetics ; *Epigenesis, Genetic/genetics ; Signal Transduction/genetics ; *Neurodegenerative Diseases/genetics/metabolism ; Animals ; *Histone-Lysine N-Methyltransferase/metabolism/genetics ; Neurons/metabolism ; },
abstract = {With growing insights into brain networks and neurodegenerative diseases (NDDs), it has become evident that alterations in gene expression often arise from epigenetic regulation rather than changes in DNA sequence. Consequently, extensive research has centered on understanding the epigenetic role in the pathophysiology of Alzheimer's, Parkinson's, and Huntington's disease. Epigenetic modifications are essential for maintaining cellular homeostasis by dynamically controlling gene expression, and their characterization may provide greater understanding into disease mechanisms and potential therapeutic targets. A deeper understanding of these regulatory processes may offer valuable insights into disease mechanisms and reveal new therapeutic avenues. Despite significant progress, the influence of epigenetic modifiers on intracellular signaling pathways governing neuronal survival and degeneration remains poorly understood. Notably, the interaction between DOT1L-mediated histone methylation and RIPK1 signalling is still insufficiently explored, representing an important gap in current knowledge. This review emphasizes the emerging interplay between DOT1L and RIPK1 in the regulation of the cell-death pathway, underscoring their potential role in modulating neuronal survival in NDDs.},
}

Humans
*Receptor-Interacting Protein Serine-Threonine Kinases/metabolism/genetics
*Epigenesis, Genetic/genetics
Signal Transduction/genetics
*Neurodegenerative Diseases/genetics/metabolism
Animals
*Histone-Lysine N-Methyltransferase/metabolism/genetics
Neurons/metabolism

@article {pmid42133147,
year = {2026},
author = {Guo, Y and Gao, Y and Liu, Y and Nie, X and Xiong, Q and Ren, Z},
title = {Alterations of homotopic functional connectivity and correlates with core neuropsychological impairments in mild cognitive impairment: a resting-state fMRI study.},
journal = {Brain imaging and behavior},
volume = {20},
number = {3},
pages = {},
pmid = {42133147},
issn = {1931-7565},
support = {(Grant CCNU24JCPT034; CCNU23ZZ001)//the Fundamental Research Funds for the Central Universities/ ; (Grant CCNU24JCPT034; CCNU23ZZ001)//the Fundamental Research Funds for the Central Universities/ ; (Grant CCNU24JCPT034; CCNU23ZZ001)//the Fundamental Research Funds for the Central Universities/ ; (Grant CCNU24JCPT034; CCNU23ZZ001)//the Fundamental Research Funds for the Central Universities/ ; (Grant CCNU24JCPT034; CCNU23ZZ001)//the Fundamental Research Funds for the Central Universities/ ; (Grant CCNU24JCPT034; CCNU23ZZ001)//the Fundamental Research Funds for the Central Universities/ ; },
mesh = {Humans ; *Cognitive Dysfunction/physiopathology/diagnostic imaging ; Male ; Female ; Magnetic Resonance Imaging/methods ; Aged ; Neuropsychological Tests ; Middle Aged ; *Brain/physiopathology/diagnostic imaging ; Neural Pathways/physiopathology/diagnostic imaging ; *Nerve Net/physiopathology/diagnostic imaging ; Brain Mapping/methods ; Rest ; },
abstract = {Identifying individuals with mild cognitive impairment (MCI) who are at risk of progressing to Alzheimer's disease (AD) is crucial for early interventions and understanding disease mechanisms. While previous studies using resting-state fMRI (functional magnetic resonance imaging) have identified various neural markers in MCI, there is limited research on alterations in interhemispheric functional interactions. Fifty-three MCI patients and 68 age-, gender-, and education-matched healthy controls were included in the study. Structural cranial MRI and resting-state fMRI data were collected. We investigated voxel-mirrored homotopic connectivity (VMHC) alterations in patients with mild cognitive impairment (MCI) using resting-state fMRI. Functional connectivity was then calculated using the regions with abnormal VMHC as seed points. Correlation analyses were performed to examine the relationship between altered functional connectivity and Core Neuropsychological Test (CNT) scores. Compared to controls, MCI patients exhibited increased VMHC in the bilateral postcentral gyrus. Functional connectivity was enhanced between the bilateral postcentral gyrus and the left cerebellar Crus I, as well as the right inferior temporal gyrus. In contrast, decreased connectivity was observed with the left Gyrus rectus and right supplementary motor area. Correlation analysis revealed a significant negative relationship between VMHC values and CNT scores, as well as with verbal analogy and Chinese word matching scores. MCI patients not only show disrupted interhemispheric VMHC but also demonstrate significant associations with core neuropsychological impairments. These findings provide insights into cognitive changes in MCI and highlight potential biomarkers for early Alzheimer's disease detection.},
}

Humans
*Cognitive Dysfunction/physiopathology/diagnostic imaging
Male
Female
Magnetic Resonance Imaging/methods
Aged
Neuropsychological Tests
Middle Aged
*Brain/physiopathology/diagnostic imaging
Neural Pathways/physiopathology/diagnostic imaging
*Nerve Net/physiopathology/diagnostic imaging
Brain Mapping/methods
Rest

@article {pmid42133265,
year = {2026},
author = {Sun, T and Zhao, X and Zheng, Q and Su, K and Zhang, C and Wang, Y and Jiao, CN},
title = {superLPNet: a super lightweight parameter deep learning model for brain age estimation from structural MRI.},
journal = {Magma (New York, N.Y.)},
volume = {},
number = {},
pages = {},
pmid = {42133265},
issn = {1352-8661},
support = {61802330//National Natural Science Foundation of China/ ; 61802331//National Natural Science Foundation of China/ ; 2025CXGC020305//Key R&D Program of Shandong Province，China/ ; ZR2024MH072//Natural Science Foundation of Shandong Province/ ; },
abstract = {OBJECTIVES: This study aimed to develop a super lightweight deep learning model for brain age estimation using structural MRI, enabling accurate age estimation with minimal computational cost for deployment in resource-constrained clinical settings.

METHODS: A super lightweight brain age estimation network, termed superLPNet, was proposed. Lightweight convolutional structures inspired by MobileNet were adopted to reduce model parameters and computational burden. Spatial and channel attention mechanisms were further integrated to enhance feature representation without substantially increasing model complexity. The proposed model was evaluated on a combined dataset of 3550 T1-weighted MRI scans and further validated on an independent Alzheimer's disease (AD) cohort.

RESULTS: The superLPNet achieved the lowest mean absolute error compared with state-of-the-art models, demonstrating superior brain age estimation accuracy. The number of parameters was reduced by 56.70%-98.75% relative to competing approaches, highlighting its super lightweight design. From a clinical perspective, patients with AD exhibited a significantly larger brain age gap than healthy controls.

CONCLUSIONS: The proposed model enables accurate and efficient brain age estimation using T1-weighted MRI with substantially reduced complexity, supporting its potential for real-world clinical application.},
}

@article {pmid42133312,
year = {2026},
author = {Rousset, RZ and Honey, MIJ and den Braber, A and van der Flier, WM and Holstege, H and Lorenz, L and Wessels, MHJ and Killestein, J and Huisman, M and Kok, A and Beekman, M and Slagboom, PE and Ligthart, L and de Geus, E and Verberk, IMW and Vermunt, L and Teunissen, CE},
title = {Glial Fibrillary Acidic Protein and Neurofilament Light Reference Intervals in Healthy Individuals.},
journal = {JAMA network open},
volume = {9},
number = {5},
pages = {e2612793},
doi = {10.1001/jamanetworkopen.2026.12793},
pmid = {42133312},
issn = {2574-3805},
mesh = {Humans ; Female ; Male ; *Neurofilament Proteins/blood ; Cross-Sectional Studies ; *Glial Fibrillary Acidic Protein/blood ; Aged ; Reference Values ; Middle Aged ; Biomarkers/blood ; Aged, 80 and over ; Cognitive Dysfunction/blood ; Healthy Volunteers ; Adult ; },
abstract = {IMPORTANCE: Concentrations of plasma neurofilament light (NfL) and glial fibrillary acidic protein (GFAP) should be easily interpretable in the context of a patient's profile.

OBJECTIVES: To develop reference intervals (RI) for NfL and GFAP, accounting for common physiological modifiers of biomarkers and to compare these RIs with concentrations from participants with neurological conditions.

This cross-sectional study included participants with no cognitive impairment (self-reported, assessed by Mini-Mental State Examination score ≥27, or determined by a physician) to generate and validate the RIs as well as individuals, recruited from tertiary clinics, with subjective cognitive decline or mild cognitive impairment due to Alzheimer disease (AD), AD dementia, frontotemporal dementia (FTD), dementia with Lewy bodies, vascular dementia (VaD), or multiple sclerosis, for the comparison group.

EXPOSURES: Age, biological sex (self-reported), body mass index (BMI), and kidney function (measured by estimated glomerular filtration rate [eGFR]).

MAIN OUTCOMES AND MEASURES: Plasma NfL and GFAP RIs, quantified on the Simoa HD-X, defined over age and adjusted for sex, BMI, and/or eGFR.

RESULTS: In 7989 cognitively unimpaired participants (median [range] age, 54 [30-90] years; 4877 [61.3%] female; mean [SD] BMI, 25.9 [4.2]; mean [SD] eGFR, 80.7 [14.7] mL/min/1.73 m2), older age, lower BMI, and reduced kidney function were associated with increased NfL and GFAP concentrations; female sex was associated with increased GFAP concentrations. Median NfL and GFAP concentrations were 6.58 (6.58-6.58) pg/mL and 23.4 (23.4-23.4) pg/mL higher, respectively, in participants with severe compared with no kidney damage (ie, 45 mL/min/1.73 m2 vs 90 mL/min/1.73 m2). Median NfL and GFAP concentrations were 1.72 (1.72-1.72) pg/mL and 12.6 (12.6-12.6) pg/mL lower, respectively, in participants with obesity compared with those with normal weight (ie, BMI of 30 vs 20). Median GFAP concentrations were 6.17 (6.17-6.17) pg/mL higher in female compared with male participants. NfL concentrations were most elevated in participants with FTD (165 of 179 participants [92.2%] had concentrations greater than the median) and VaD (55 of 60 participants [91.7%] had concentrations greater than the median). GFAP concentrations were most elevated in participants with AD dementia (396 of 479 participants [82.7%] had concentrations greater than the median). A user-friendly interface was developed to visualize the biomarker RIs in the context of an individual's age, BMI, eGFR, and sex.

CONCLUSIONS AND RELEVANCE: In this cross-sectional study of 7958 individuals, RIs to identify normal or abnormal biomarker concentrations in the context of a cognitively unimpaired individuals were established to aid the use of plasma NfL and GFAP measures in clinical practice for neurological diseases.},
}

Humans
Female
Male
*Neurofilament Proteins/blood
Cross-Sectional Studies
*Glial Fibrillary Acidic Protein/blood
Aged
Reference Values
Middle Aged
Biomarkers/blood
Aged, 80 and over
Cognitive Dysfunction/blood
Healthy Volunteers
Adult

@article {pmid42133413,
year = {2026},
author = {Berezutsky, MA and Andronova, TA and Belonogova, YV and Durnova, NA},
title = {[Acteoside: neurobiological activity spectrum, potential in the treatment of age-associated neurodegenerative diseases].},
journal = {Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova},
volume = {126},
number = {4},
pages = {41-47},
doi = {10.17116/jnevro202612604141},
pmid = {42133413},
issn = {1997-7298},
mesh = {Humans ; *Glucosides/therapeutic use/pharmacology ; *Parkinson Disease/drug therapy/metabolism ; *Phenols/therapeutic use/pharmacology ; *Alzheimer Disease/drug therapy/metabolism ; *Neuroprotective Agents/therapeutic use/pharmacology ; Endoplasmic Reticulum Stress/drug effects ; Animals ; Amyloid beta-Peptides/metabolism ; Microglia/drug effects ; *Neurodegenerative Diseases/drug therapy ; Polyphenols ; },
abstract = {Acteoside (verbascoside, kusaginin) is a phenylethanoid glycoside, which is found in more than 200 species of plants and is characterized by a wide range of pharmacological activity. The results of studies on the neurobiological effects of acteoside, which can be used in the treatment of Alzheimer's disease (AD) and Parkinson's disease (PD), were summarized and analyzed. The PubMed, Scopus, Google Scholar, and e-Library databases were searched for the following keywords: «acteoside», «Alzheimer's disease», «Parkinson's disease», «pathological activation of microglia», «neurotrophic effect», «endoplasmic reticulum stress», «protection of neurons from beta-amyloid», «inhibition of tau protein hyperphosphorylation», «death of dopaminergic neurons», «aggregation of α-synuclein», «cognitive and motor impairment». Experimental studies have shown the ability of acteoside to inhibit pathological activation of microglia, exert a neurotrophic effect, inhibit endoplasmic reticulum stress, protect neurons from beta-amyloid, inhibit tau-protein hyperphosphorylation, reduce intracellular Ca[2+] mobilization dysfunction, protect neurons from glutamate-induced neurotoxicity, prevent dopaminergic neuron death, reduce α-synuclein aggregation, and attenuate cognitive and motor impairments. This compound has good prospects for chemical modification, as its structure features several reactive sites. In the future, acteoside may be used as a multi-purpose complex therapy for AD and PD.},
}

Humans
*Glucosides/therapeutic use/pharmacology
*Parkinson Disease/drug therapy/metabolism
*Phenols/therapeutic use/pharmacology
*Alzheimer Disease/drug therapy/metabolism
*Neuroprotective Agents/therapeutic use/pharmacology
Endoplasmic Reticulum Stress/drug effects
Animals
Amyloid beta-Peptides/metabolism
Microglia/drug effects
*Neurodegenerative Diseases/drug therapy
Polyphenols

@article {pmid42133414,
year = {2026},
author = {Shavlovskaya, OA},
title = {[Choline alfoscerate in the treatment of cognitive impairment].},
journal = {Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova},
volume = {126},
number = {4},
pages = {48-55},
doi = {10.17116/jnevro202612604148},
pmid = {42133414},
issn = {1997-7298},
mesh = {Humans ; *Cognitive Dysfunction/drug therapy ; *Glycerylphosphorylcholine/therapeutic use/administration & dosage ; Alzheimer Disease/drug therapy ; Administration, Oral ; Injections, Intramuscular ; },
abstract = {Multiple randomized controlled trials (RCTs), systematic reviews, meta-analyses, and multidisciplinary studies in both hospital and outpatient settings have demonstrated the high efficacy and safety of choline alfoscerate (CA) therapy for patients with mild and moderate cognitive impairment (MCI), amnestic cognitive impairment, predementia cognitive impairment in Alzheimer's disease (AD), elderly individuals, and first-degree relatives of patients with AD as preventive therapy. The Russian CA drug Cereton is available in several formulations, including solutions for intravenous and intramuscular injection, capsules, and an oral solution, enabling individualized treatment approaches. In hospital settings, injection therapy with Cereton is administered for 10 days, followed by an oral course lasting up to 60 days. The duration and dosage of Cereton oral solution and capsules are determined by patient age and clinical condition. The oral solution is approved for use in children from 6 years of age, and the capsules are approved for use in children from 11 years of age, with treatment courses lasting up to 60 days. Cereton therapy consists of two stages: initial intravenous or intramuscular administration, followed by oral administration of capsules or the oral solution. The drug is generally well-tolerated, with adverse events being infrequent and minor.},
}

Humans
*Cognitive Dysfunction/drug therapy
*Glycerylphosphorylcholine/therapeutic use/administration & dosage
Alzheimer Disease/drug therapy
Administration, Oral
Injections, Intramuscular

@article {pmid42133594,
year = {2026},
author = {, },
title = {Retraction: Bioassays guided isolation of berberine from Berberis lycium and its neuroprotective role in aluminium chloride induced rat model of Alzheimer's disease combined with insilico molecular docking.},
journal = {PloS one},
volume = {21},
number = {5},
pages = {e0349363},
doi = {10.1371/journal.pone.0349363},
pmid = {42133594},
issn = {1932-6203},
}

@article {pmid42133667,
year = {2026},
author = {Brown, S and Klimitz, FJ and Kipnis, J and Benveniste, H and Ringstad, G and Eide, PK and Azizi, S and Mecca, A and Haykal, S and Pomahac, B},
title = {Exploring Lymphovenous Anastomosis for Alzheimer's Disease: Addressing Brain Lymphatic Dysfunction, Feasibility, and Outcome Metrics.},
journal = {Plastic and reconstructive surgery},
volume = {},
number = {},
pages = {},
doi = {10.1097/PRS.0000000000013179},
pmid = {42133667},
issn = {1529-4242},
}

@article {pmid42133852,
year = {2026},
author = {Juni, JE and Burns, JM and Salat, DH and Hill, D and Tally, S and Martin, JS and Devous, MD and Moriarty, PM},
title = {Treatment of Clinically Diagnosed Alzheimer's Disease by External Counterpulsation A Randomized Clinical Trial.},
journal = {American journal of Alzheimer's disease and other dementias},
volume = {41},
number = {},
pages = {15333175261451918},
doi = {10.1177/15333175261451918},
pmid = {42133852},
issn = {1938-2731},
mesh = {Humans ; *Alzheimer Disease/therapy ; Female ; Male ; Aged ; *Counterpulsation/methods ; Aged, 80 and over ; *Cognitive Dysfunction/therapy ; Treatment Outcome ; Activities of Daily Living ; },
abstract = {ObjectiveTo assess external counterpulsation (ECP) effects on cognitive and functional decline in early AD.MethodsThis 12-month, multicenter, blinded, randomized, sham-controlled trial enrolled 190 patients with early AD (MCI due to AD or mild AD per NIA-AA clinical criteria). Participants received either full-pressure ECP (150-300 mmHg) or sham (25 mmHg): 3-5 weekly one-hour sessions for 35 treatments, then twice-weekly through six months. Assessments occurred at baseline and weeks 6, 12, 18, 24, 36, and 52. Primary endpoints included ADCS-ADL, ADAS-cog-14, and VADAS-cog.ResultsFull-pressure ECP significantly improved ADCS-ADL scores versus sham (mean change 2.57 vs. -0.49; p=0.036) and VADAS-cog scores (9.95 vs. 5.22; p=0.005) at 12-24 weeks. Benefits persisted through 52 weeks despite treatment cessation at 6 months. No serious device-related adverse events occurred.ConclusionsFull-pressure ECP therapy significantly improved cognition and ADL compared to sham treatment in early AD. ECP represents a novel therapeutic approach warranting further investigation.},
}

Humans
*Alzheimer Disease/therapy
Female
Male
Aged
*Counterpulsation/methods
Aged, 80 and over
*Cognitive Dysfunction/therapy
Treatment Outcome
Activities of Daily Living

@article {pmid42133909,
year = {2026},
author = {Rivera Sánchez, M and Mastenbroek, SE and Janelidze, S and Tideman, P and Mattsson-Carlgren, N and Van Westen, D and Stomrud, E and Hansson, O and Palmqvist, S and Ossenkoppele, R},
title = {The Role of Clinical, Plasma, and Imaging Biomarkers in Assessing Future Dementia Risk in Individuals With Subjective Cognitive Decline.},
journal = {Neurology},
volume = {106},
number = {11},
pages = {e214983},
doi = {10.1212/WNL.0000000000214983},
pmid = {42133909},
issn = {1526-632X},
mesh = {Humans ; Female ; Male ; Aged ; *Cognitive Dysfunction/blood/diagnostic imaging ; Biomarkers/blood ; *Dementia/blood/diagnostic imaging/diagnosis ; Longitudinal Studies ; tau Proteins/blood ; Disease Progression ; Middle Aged ; Magnetic Resonance Imaging ; Apolipoprotein E4/genetics ; Risk Assessment ; },
abstract = {BACKGROUND AND OBJECTIVES: Subjective cognitive decline (SCD) is a well-recognized risk state for developing mild cognitive impairment (MCI) and dementia. Optimal risk stratification for early interventions and clinical trial selection remains challenging. This study evaluates progression risk across multimodal biomarker profiles in SCD.

METHODS: We conducted a longitudinal observational study including participants from the BioFINDER-1 and BioFINDER-2 cohorts with a baseline diagnosis of SCD, at least 1 follow-up visit, and available information on dementia progression. Baseline predictors included cognitive performance, APOE4 status, plasma phosphorylated tau (p-tau) 217, "AD-signature" cortical thickness, hippocampal volume, and white matter hyperintensities (WMHs) measured by the Fazekas scale. Missing data were handled using multiple imputation. Predictors were evaluated individually and then combined in progressively complex Cox regression models to predict progression to all-cause dementia, Alzheimer disease (AD) dementia, and MCI (BioFINDER-2 only). Model performance was assessed using the Harrell C-index, and Akaike information criterion was used for comparing model fit.

RESULTS: A total of 469 participants with SCD (mean age 69.1 ± 7.1 years, 51.4% female) were included in the main sample. Eighty-four individuals progressed to dementia over 4.0 ± 2.1 years (66.7% AD dementia). Progressors were older and more frequently APOE4 carriers and showed worse baseline cognition, higher plasma p-tau217, and greater atrophy and WMH burden. Plasma p-tau217 was the strongest individual predictor for AD dementia (C-index = 0.86 ± 0.012), but multivariable models outperformed single-biomarker models. The best model for all-cause dementia included all variables and achieved a C-index of 0.89 ± 0.003. For AD dementia, a more parsimonious model combining plasma p-tau217, cognitive scores, and APOE4 status showed excellent predictive ability (C-index = 0.91 ± 0.009), with only marginal improvement when MRI markers were added. Among 249 individuals from BioFINDER-2, 84 progressed to MCI within 2.3 ± 1.2 years. For MCI prediction, model performance was generally lower and similar between the plasma model and the model including all variables (C-index = 0.83 ± 0.009).

DISCUSSION: A clinically feasible multimodal approach combining cognitive assessment, plasma p-tau217, and APOE4 status accurately predicts AD dementia risk in individuals with SCD. Adding MRI measures of brain atrophy and WMHs further improves prediction for all-cause dementia. These findings underscore the clinical value of plasma p-tau217 in refining risk assessment in SCD and support its potential implementation in memory clinic settings alongside other widely available biomarkers.},
}

Humans
Female
Male
Aged
*Cognitive Dysfunction/blood/diagnostic imaging
Biomarkers/blood
*Dementia/blood/diagnostic imaging/diagnosis
Longitudinal Studies
tau Proteins/blood
Disease Progression
Middle Aged
Magnetic Resonance Imaging
Apolipoprotein E4/genetics
Risk Assessment

@article {pmid42133941,
year = {2026},
author = {Mohammed, A and Ovalle-Eliseo, S and Mohammed, J and Islas Huerta, G and Monserratt, L and Andrade, D and Garcia, J and Kaufman, R and Gutierrez, M and Díaz-Santos, M},
title = {Methodological Framework for the Design and Implementation of a US Latine-Hispanic Digital Brain Health Program: User-Centered Design Approach.},
journal = {JMIR formative research},
volume = {10},
number = {},
pages = {e73445},
pmid = {42133941},
issn = {2561-326X},
mesh = {Humans ; *Social Media ; Pilot Projects ; *Hispanic or Latino ; United States ; COVID-19 ; *Alzheimer Disease/prevention & control/ethnology ; *Health Education/methods ; SARS-CoV-2 ; Female ; Male ; *Dementia/prevention & control ; White ; },
abstract = {BACKGROUND: US Latine and Hispanic communities face a 1.5 times greater risk of developing Alzheimer disease and related dementia (ADRD) with limited access to culturally and linguistically congruent primary prevention education. The COVID-19 pandemic exacerbated the digital divide, highlighting a need to focus on alternative digital methods for delivering brain health and ADRD primary prevention education. Social media emerged as a promising tool.

OBJECTIVE: The objective of this paper is two-fold. We first describe the development and pilot study of our social media-based Latine-Hispanic Digital Brain Health Program guided by evidence-based frameworks in ADRD. We then present the quantitative and qualitative results from the first 14 months of the program (October 2023-December 2024).

METHODS: We used human-centered design to develop the Digital Alzheimer Health Education Model, which was implemented via 3 social media platforms-Facebook, Instagram, and X (formerly known as Twitter). Our bilingual and bicultural team implemented the model by creating and disseminating tailored educational content in English and Spanish for the resulting Latine-Hispanic Digital Brain Health Program, emphasizing consistency and rapport, storytelling, cultural relevance, linguistic inclusivity, and visual representation. A mixed methods analysis (descriptive statistics and sentiment analysis) was conducted using social media data analytics and users' comments to guide program evaluation and refinement.

RESULTS: From October 2023 to December 2024, we retained 857 followers across our social media platforms (Instagram: n=534; Facebook: n=124; and X: n=199). Growth in follows, consistent reach and engagement, and positive sentiment were observed on Facebook and Instagram. X was not included in the analysis due to data access limitations.

CONCLUSIONS: The development and pilot study of the Latine-Hispanic Digital Brain Health Program have demonstrated potential in leveraging social media to disseminate brain health and ADRD prevention education to the US Latine and Hispanic communities in English and Spanish. Our preliminary findings demonstrate that culturally and linguistically congruent social media-based approaches hold potential to improve engagement with brain health and ADRD primary prevention education among US Latine and Hispanic populations.},
}

Humans
*Social Media
Pilot Projects
*Hispanic or Latino
United States
COVID-19
*Alzheimer Disease/prevention & control/ethnology
*Health Education/methods
SARS-CoV-2
Female
Male
*Dementia/prevention & control
White

@article {pmid42133988,
year = {2026},
author = {Fallot, LB and Anderson, CA and Pinc, JR and Stevenson, A and Schleck, MC and Hawryschuk, E and Li, OZ and Palchak, JC and Toole, JR and Kubiak Ii, RW and Dear, AJ and Michaels, TCT and Limbocker, R},
title = {Glucagon-Like Peptide-1 Receptor Agonists Inhibit the Initiation of Toxic Amyloid-β42 Aggregation.},
journal = {Journal of the American Chemical Society},
volume = {},
number = {},
pages = {},
doi = {10.1021/jacs.6c01289},
pmid = {42133988},
issn = {1520-5126},
abstract = {The aggregation of the 42-residue form of the amyloid-β peptide (Aβ42) is important in Alzheimer's disease (AD). Preclinical and clinical findings support that glucagon-like peptide-1 receptor agonists (GLP-1RAs) can protect against neuroinflammation and neurodegeneration with potential therapeutic relevance for AD, but studies of their direct effects on Aβ42 are limited. Herein, we investigated five FDA-approved GLP-1RAs, and show semaglutide, tirzepatide, and liraglutide inhibit Aβ42 aggregation. Semaglutide and tirzepatide delayed Aβ42 aggregation by targeting the primary nucleation microscopic step, with submicromolar IC50 values for primary nucleation (KIP). Liraglutide was highly effective at suppressing primary nucleation with a very low KIP value, and it demonstrated an additional modest inhibition of secondary nucleation. Consistent with a dominant effect on primary nucleation, Aβ42 formed β-sheet-rich fibrils in the presence of these GLP-1RAs. Aβ42 fibrils formed with semaglutide or tirzepatide had morphological properties and templating efficiencies that were similar to unmodified fibrils, while liraglutide significantly reduced fibril maturity, increased fibril tortuosity and length, and attenuated the ability of fibrils to passively self-replicate whether they were formed in the presence of liraglutide or exposed to this GLP-1RA after their formation. These results provide molecular-level insight into how specific GLP-1RAs can selectively target the fundamental steps governing toxic Aβ42 aggregation. Further studies are warranted to determine if current or next-generation anti-amyloid GLP-1RAs can delay or prevent AD through multifaceted protective mechanisms, including the direct inhibition of Aβ42 aggregation.},
}

@article {pmid42134046,
year = {2026},
author = {Chu, TDX and Hui, LM and Khatri, N and Jean Chen, J},
title = {Resilience to mid-to-late-life depression as a risk factor for Alzheimer's disease: Physiological factors and the role of neuroimaging.},
journal = {Neurobiology of aging},
volume = {166},
number = {},
pages = {1-13},
doi = {10.1016/j.neurobiolaging.2026.05.004},
pmid = {42134046},
issn = {1558-1497},
abstract = {Depression and Alzheimer's Disease (AD) are both diagnosed in women twice as often as in men. Moreover, a history of untreated depression confers a 2-to-5-fold increase in the risk of developing dementia. Finally, biological factors such as sex differences in immune response increase rates of depressive pathology among women. Importantly, the prevalence of mid-to-late-life depression (MLD) worldwide and its misdiagnosis due to clinical overlap with AD hinder accurate assessment and timely treatment of depression among older adults. Correct diagnosis of depression and AD using neuroimaging will enable early adoption of appropriate management, which will improve cognitive resilience. In the context of neural resilience in late-life depression, this review discusses the involvement of sex-related risk factors such as differences in immune response, and the importance of understanding the mid-life neurological signature of depression. We focus on the role of diffusion-weighted magnetic resonance imaging (MRI), which is also specifically linked to the presence of neuroinflammation in depression and the ability to distinguish it from AD despite cognitive overlaps in clinical manifestation. This review highlights the importance of sex differences in promoting resilience against MLD and AD-related declines, and supports neuroimaging as a feasible approach to advance our understanding of the role of neuroinflammation in both depression and Alzheimer's disease as a sex-dependent phenomenon.},
}

@article {pmid42134283,
year = {2026},
author = {Wang, Y and Chen, L and Qiao, C},
title = {Continuous-time causal distribution learning with identifiability for brain dynamic effective connectivity inference.},
journal = {Medical image analysis},
volume = {112},
number = {},
pages = {104124},
doi = {10.1016/j.media.2026.104124},
pmid = {42134283},
issn = {1361-8423},
abstract = {Dynamic effective connectivity (dEC) analysis provides an approach for revealing the causal mechanism of information transmission in human brain. However, existing discrete-time dEC learning models suffer a mismatch between sampling and causal frequencies as well as low efficiency in data utilization. Based on a continuous-time dynamic causality distribution learning framework, we propose a dEC distribution learning model, which uses free energy principle to ensure more proper parameter learning than maximum likelihood estimation. Theoretically, the identifiability of the proposed model is proved, which guarantees the uniqueness of the learned dEC given the same data distribution. Results from the synthetic dataset show that the ability in both causality learning and time series reconstruction of the proposed model outperforms the comparison methods. The dEC results learned from the task functional magnetic resonance imaging (fMRI) data reveal the changing information transmission patterns in brain when dealing with picture-sentence matching tasks. Additionally, during the transition from resting state to task state, information flow in the brain's dEC network becomes increasingly organized around the left supramarginal gyrus, a hub known for the language processing and information integration in parietal lobe. When applied to resting-state fMRI data on Alzheimer's disease, the learned dEC patterns reveal distinct alterations in brain networks associated with Alzheimer's disease. The results suggest that Alzheimer's disease is associated with abnormalities not only in memory and emotion-related networks, but also in networks underlying executive control and visual integration. The source code of the proposed model are available at https://github.com/Yiding00/IDECD-CT.},
}

@article {pmid42134309,
year = {2026},
author = {Lee, J and Zhu, Y and Tseng, HR},
title = {Bioorthogonal Click Chemistry-Enabled Enrichment of Extracellular Vesicles for Integrated Molecular and Functional Liquid Biopsy§.},
journal = {Accounts of chemical research},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.accounts.6c00091},
pmid = {42134309},
issn = {1520-4898},
abstract = {ConspectusExtracellular vesicles (EVs) are lipid bilayer-enclosed nanoparticles released by virtually all cells, carrying protected lipids, nucleic acids, proteins, and active enzymes that faithfully reflect the physiological and pathological states of their cellular origins. Tumor- and neuron-derived EVs are abundantly present in peripheral blood, even at early disease stages, and thus represent highly attractive substrates for liquid biopsy. However, the clinical translation of EV-based diagnostics has been constrained by a central challenge: the inability to selectively enrich disease-relevant EVs from a vast background of normal EVs with sufficient specificity, efficiency, and compatibility for seamless integration with downstream molecular and functional analyses. Conventional physical isolation approaches generate heterogeneous EV mixtures that dilute disease-specific signals, whereas traditional immunoaffinity capture often suffers from nonspecific interactions and low recovery due to sparse and heterogeneous antigen density on EV membranes.To overcome these limitations, our laboratory has developed a chemical biology solution utilizing the bioorthogonal inverse-electron-demand Diels-Alder reaction between trans-cyclooctene (TCO) and tetrazine (Tz). By labeling tumor or neuronal EVs in plasma with TCO-grafted antibodies and covalently immobilizing them onto Tz-functionalized substrates, our three EV enrichment platforms, namely, EV Click Chips, EV Click Beads, and EV Click MagBeads, enable rapid, irreversible, and highly specific capture of defined EV subpopulations. These click chemistry-mediated enrichment strategies reduce nonspecific binding, markedly improve capture efficiency, and preserve EV integrity, providing a robust foundation for downstream genetic, proteomic, and functional analyses. Building on this chemical biology solution, we established three complementary EV assay modalities. Platform #1, the EV Digital Scoring Assay, couples click chemistry-mediated EV enrichment with RT-digital PCR to quantify tumor-specific mRNAs or oncogenic mutations. This "enrich-then-count" strategy has demonstrated strong clinical utility in early detection of hepatocellular carcinoma (HCC), molecular staging of prostate cancer, and detection of actionable gene alterations in pancreatic cancer and Ewing sarcoma. A refined version enables real-time HCC treatment-response monitoring, outperforming serum AFP and radiographic criteria in monitoring treatment responses. Platform #2, the EV Surface Protein Assay, uses antibody-directed click enrichment followed by immuno-PCR or RT-qPCR to quantify tumor-specific EV subpopulations. Analogous to tissue immunohistochemistry but executed in a liquid-biopsy format, this assay has shown accuracy in early detection of HCC, pancreatic ductal adenocarcinoma, and epithelial ovarian cancer and supports longitudinal monitoring in prostate and thyroid cancers. Platform #3, the EV Protease Activity Assay, extends EV analysis into functional biology by measuring enzymatic activities preserved within enriched EVs. In osteosarcoma, matrix metalloproteinase activity profiles stratified localized versus metastatic disease and tracked therapeutic response. In neurology, quantifying β-secretase activity in neuronal EVs enabled highly accurate detection of early Alzheimer's disease and correlated with cognitive performance.Together, these TCO-Tz click chemistry-enabled platforms provide a modular, robust, and clinically adaptable toolkit for noninvasive EV-based diagnostics. By uniting chemical precision with biological and clinical relevance, this framework advances the broader vision of real-time, disease-specific liquid biopsy across oncology and neurodegeneration, laying the foundation for next-generation integrated diagnostic systems.},
}

@article {pmid42134480,
year = {2026},
author = {Wu, Q and Cui, X and Liu, X and Yuan, X and Wang, P and Li, H and Xiu, R},
title = {Tetramethylpyrazine improving cerebral microcirculation in Alzheimer's Disease mice.},
journal = {Brain research bulletin},
volume = {},
number = {},
pages = {111936},
doi = {10.1016/j.brainresbull.2026.111936},
pmid = {42134480},
issn = {1873-2747},
abstract = {Cerebrovascular dysfunction plays a crucial role in the development and progression of Alzheimer's Disease (AD). Tetramethylpyrazine, a bioactive alkaloid monomer derived from Chinese herbal medicine Chuanxiong (Ligusticum chuanxiong), has been demonstrated to improve tissue microcirculation. However, direct in vivo monitoring of cerebral microcirculation is still challenging due to the presence and thickness of the skull. In this study, we constructed a visualized mouse cranial window and utilized photoacoustic microscopy, laser speckle imaging, and Laser Doppler flowmetry to investigate the effect of Tetramethylpyrazine on cortical microvascular function in normal mice, AD mice, and Tetramethylpyrazine-treated AD mice. Our results revealed impaired cerebral microvascular perfusion in AD mice, including significant reductions in blood flow velocity, oxygen saturation, and metabolic rate of oxygen. Tetramethylpyrazine treatment improved cortical microvascular function in AD mice, with endothelium-derived microvascular signals playing a key role in microvascular rhythmic motion. These findings suggest that Tetramethylpyrazine has the ability to enhance cortical microcirculation in AD mice through multiple mechanisms, particularly through endothelial improvement. Tetramethylpyrazine may serve as a potential candidate drug for AD treatment, and photoacoustic microscopy holds promise in the clinical observation of cortical microcirculation in AD.},
}

@article {pmid42134547,
year = {2026},
author = {Decker, KP and Rizzi, NA and Rigas, Z and Awad, C and Habash, EM and Kramer, MK and Cerjanic, AM and Cohen, ML and Johnson, CL and Martens, CR},
title = {The Influence of Blood Lipids on Cerebral Perfusion by Apolipoprotein E Status.},
journal = {Journal of lipid research},
volume = {},
number = {},
pages = {101057},
doi = {10.1016/j.jlr.2026.101057},
pmid = {42134547},
issn = {1539-7262},
abstract = {Elevated blood lipids are strongly associated with increased risk of dementia due to Alzheimer's disease (AD). The Apolipoprotein E (APOE) gene plays an important role in lipid transport and is a known genetic risk factor for the development of AD, with increased risk in ε4 carriers. Reduced cerebral blood flow (CBF) is known to precede the onset of AD pathology; however, the associations between blood lipids and cerebral perfusion by APOE status are not completely understood. This study included 65 midlife and older adults (≥ 50 years old), of which 18 (28%) carried the APOEε4 allele. Using arterial spin labeling, we measured gray matter (GM) and white matter (WM) cerebral blood flow (CBF), and hippocampal blood flow (HBF). Pearson correlations and simple linear regressions were used to assess the associations between blood lipids and cerebral perfusion. Serum triglycerides (TG) and very-low density lipoprotein cholesterol (VLDL-C) were negatively associated with GM CBF, WM CBF, and HBF in all participants. However, when stratified by APOE status, the negative associations of TG and VLDL-C on cerebral perfusion were more pronounced in ε4 carriers than non-ε4 carriers, despite no significant group differences in blood lipids. High-density lipoprotein cholesterol (HDL-C) was positively associated with only WM CBF, without any differences between APOE status. No other blood lipids were associated with resting cerebral perfusion. These findings suggest that blood lipids can influence resting cerebral perfusion, and ε4 carriers are more negatively affected by this association which may partially explain the increased genetic risk for AD pathology.},
}

@article {pmid42134757,
year = {2026},
author = {Manandhar, S and Govindula, A and Atchou, K and Nassar, A and Kabekkodu, SP and Pai, KSR},
title = {In Silico and In Vitro Evaluation of Risedronate as a DKK1 Antagonist: Implications for Neuroprotection through DKK1-LRP6 Modulation.},
journal = {European journal of pharmacology},
volume = {},
number = {},
pages = {178971},
doi = {10.1016/j.ejphar.2026.178971},
pmid = {42134757},
issn = {1879-0712},
abstract = {Dickkopf-1 (DKK1) mediated dysregulation of the Wnt/β-catenin signaling pathway contributes to synaptic loss in Alzheimer's disease (AD). Risedronate, a third-generation bisphosphonate, shows promise in pathologies related to the Wnt pathway, although its direct interaction with the DKK1-LRP6 complex has yet to be investigated. This study aimed to characterize risedronate as a novel small-molecule DKK1 antagonist and evaluate its capacity to restore canonical Wnt signaling and provide neuroprotection. In silico studies were performed using the Schrödinger Maestro (v2018-3) platform, utilizing molecular docking, molecular simualtion, SiteMap and WaterMap analysis to define the thermodynamic hydration energetics of the DKK1-LRP6 interface. In vitro validation was conducted using LRP6-overexpressing HEK-293T cells, with Wnt modulation quantified via immunofluorescence of membrane-associated DKK1 and β-catenin stabilization assays and neuroprotective assay in presence of glutamate in SHSY5Y cells. In silico analysis identified a high-affinity binding site on the DKK1 C-terminal domain (Dscore: 0.998). WaterMap analysis and simulation study revealed that risedronate binding is driven by the displacement of high-energy "unfavorable" water molecules (ΔG > 0) at the Arg203/Lys222 residue cluster. In HEK-293LRP6 cells, risedronate (IC50: 65.94 μM) significantly attenuated DKK1-mediated LRP6 sequestration (p < 0.0001), acting as a molecular "plug" to restore β-catenin signaling. This restoration successfully suggests a potential modulation of downstream of Wnt pathway restoration. Risedronate demonstrates potential inhibitory effects on DKK1 in in vitro and in silico models. By bridging bone pharmacology and neurobiology, this study provides a mechanistically grounded repurposing strategy to counteract Wnt signaling failure in neurodegenerative disorders.},
}

@article {pmid42134886,
year = {2026},
author = {Chinnathambi, S and Rangappa, N},
title = {Biosimilars: Antibody and nanobody-based therapeutic approaches towards protein misfolding diseases.},
journal = {Advances in protein chemistry and structural biology},
volume = {151},
number = {},
pages = {157-195},
doi = {10.1016/bs.apcsb.2025.10.014},
pmid = {42134886},
issn = {1876-1631},
mesh = {Humans ; *Biosimilar Pharmaceuticals/therapeutic use/chemistry/pharmacology ; *Proteostasis Deficiencies/drug therapy/metabolism/pathology ; *Single-Domain Antibodies/therapeutic use ; Amyloid beta-Peptides/metabolism/antagonists & inhibitors ; *Alzheimer Disease/drug therapy/metabolism/pathology ; tau Proteins/metabolism/antagonists & inhibitors/immunology ; *Neurodegenerative Diseases/drug therapy/metabolism ; Animals ; alpha-Synuclein/metabolism/antagonists & inhibitors ; *Parkinson Disease/drug therapy/metabolism/pathology ; },
abstract = {Neurodegenerative diseases, such as Alzheimer's disease, and Parkinson's disease, are characterized by progressive neuronal dysfunction and degeneration. These conditions often share pathological hallmarks such as protein misfolding, oxidative stress, neuroinflammation, and mitochondrial dysfunction. This review focuses on key pathological players like Tau and Amyloid-beta in Alzheimer's disease, highlighting their roles in microtubule destabilization, synaptic dysfunction, and neuronal death. The interplay between oxidative stress and these proteinopathies exacerbates neurodegeneration. Recent advances in therapeutic strategies are also explored, particularly the promise of biosimilars, cost-effective alternatives to biologics, targeting pathological hallmarks in neurodegenerative diseases. Biosimilars targeting Tau and Amyloid-beta in Alzheimer's disease, and alpha-synuclein in Parkinson's disease, hold the potential to improve treatment accessibility and reduce economic burdens. However, their development is still in its early stages. This review underscores the urgent need for innovative, affordable, and globally accessible therapeutic solutions to address the rising burden of neurodegenerative diseases.},
}

Humans
*Biosimilar Pharmaceuticals/therapeutic use/chemistry/pharmacology
*Proteostasis Deficiencies/drug therapy/metabolism/pathology
*Single-Domain Antibodies/therapeutic use
Amyloid beta-Peptides/metabolism/antagonists & inhibitors
*Alzheimer Disease/drug therapy/metabolism/pathology
tau Proteins/metabolism/antagonists & inhibitors/immunology
*Neurodegenerative Diseases/drug therapy/metabolism
Animals
alpha-Synuclein/metabolism/antagonists & inhibitors
*Parkinson Disease/drug therapy/metabolism/pathology

@article {pmid42134887,
year = {2026},
author = {Chinnathambi, S},
title = {Induced-pluripotent stem cell-derived immunotherapy for Tau and Alzheimer's disease.},
journal = {Advances in protein chemistry and structural biology},
volume = {151},
number = {},
pages = {197-224},
doi = {10.1016/bs.apcsb.2025.10.005},
pmid = {42134887},
issn = {1876-1631},
mesh = {*Alzheimer Disease/therapy/immunology/pathology/metabolism ; Humans ; *Induced Pluripotent Stem Cells/cytology/metabolism/immunology ; *tau Proteins/immunology/metabolism ; *Immunotherapy ; Animals ; },
abstract = {Neurodegenerative diseases, such as Alzheimer's disease, are characterized by progressive neuronal death and functional decline. Key pathological hallmarks of Alzheimer's disease include the deposition of aggregated amyloid-β (Aβ) proteins into extracellular plaques and the accumulation of hyperphosphorylated Tau protein into intracellular aggregates. These toxic species triggers neuroinflammation through interactions with glial cells, further exacerbating neurodegeneration. This study explores the potential of induced pluripotent stem cells (iPSCs) in disease modelling, focusing on their application in modelling Alzheimer's disease pathology and therapeutic screening. Additionally, the development of advanced 3D culture systems and organoids offers insights into human-specific Alzheimer's disease mechanisms, overcoming limitations of traditional 2D and animal models. The focus is on the role of microglial polarization in neuroinflammation and its potential therapeutic modulation, offering a promising approach for the treatment of neurodegenerative diseases.},
}

*Alzheimer Disease/therapy/immunology/pathology/metabolism
Humans
*Induced Pluripotent Stem Cells/cytology/metabolism/immunology
*tau Proteins/immunology/metabolism
*Immunotherapy
Animals

@article {pmid42134888,
year = {2026},
author = {Chinnathambi, S and Rangappa, N and Chandrashekar, M},
title = {Antibodies targeting amyloid-β and Tau oligomers in Alzheimer's disease.},
journal = {Advances in protein chemistry and structural biology},
volume = {151},
number = {},
pages = {225-265},
doi = {10.1016/bs.apcsb.2025.10.002},
pmid = {42134888},
issn = {1876-1631},
mesh = {Humans ; *Alzheimer Disease/immunology/metabolism/drug therapy/therapy/pathology ; *Amyloid beta-Peptides/immunology/antagonists & inhibitors/metabolism ; *tau Proteins/immunology/antagonists & inhibitors/metabolism ; Animals ; Immunotherapy ; *Antibodies, Monoclonal/therapeutic use/immunology ; },
abstract = {Alzheimer's disease is a leading neurodegenerative disorder, is characterized by cognitive decline linked to amyloid-beta plaques and Tau tangles. These pathological aggregates disrupt the neuronal communication, induce neuroinflammation, and contribute to synaptic dysfunction. Genetic mutations, aging, environmental and lifestyle factors exacerbate these mechanisms, promoting neurotoxicity. Advances in immunotherapy have targeted Aβ and Tau oligomers using several monoclonal antibodies and Tau-specific antibodies. These therapies aim to neutralize toxic aggregates, facilitate clearance, and slow cognitive decline. Dual-targeting approaches, such as bispecific antibodies, address both Aβ and Tau, enhancing therapeutic efficacy. Despite challenges-like limited blood-brain barrier penetration, off-target effects, and high production costs, innovations in nanobody technology and personalized medicine are the key players. Artificial intelligence-driven antibody design further accelerates development, offering hope for transformative Alzheimer's disease treatments. Future research focuses on optimizing safety and efficacy, paving the way for comprehensive management of this devastating disease.},
}

Humans
*Alzheimer Disease/immunology/metabolism/drug therapy/therapy/pathology
*Amyloid beta-Peptides/immunology/antagonists & inhibitors/metabolism
*tau Proteins/immunology/antagonists & inhibitors/metabolism
Animals
Immunotherapy
*Antibodies, Monoclonal/therapeutic use/immunology

@article {pmid42119549,
year = {2026},
author = {Mishra, J and Singh, C and Bhatti, JS},
title = {Piperine-loaded solid dispersions mitigate amyloid-β-mediated oxidative stress and mitochondrial dysfunction in SH-SY5Y cells: A possible therapeutic strategy for Alzheimer's disease.},
journal = {The Journal of pharmacology and experimental therapeutics},
volume = {393},
number = {5},
pages = {104788},
doi = {10.1016/j.jpet.2026.104788},
pmid = {42119549},
issn = {1521-0103},
abstract = {Alzheimer's disease is a progressive neurodegenerative disorder defined by the presence of extracellular amyloid-β (Aβ) plaques and intracellular neurofibrillary tangles, which together drive cognitive decline and memory impairment. Current therapies provide only symptomatic relief, highlighting the urgent need for disease-modifying strategies targeting the underlying pathology. Piperine, a plant-derived alkaloid with neuroprotective, antioxidant, and antiamyloidogenic properties, has shown preclinical efficacy against Aβ toxicity. However, its clinical translation is limited by poor aqueous solubility and low bioavailability. The present study aimed to develop and characterize spray-dried piperine-loaded solid dispersion (PIP@SDs) to overcome these pharmacokinetic barriers and enhance neuroprotective efficacy. PIP@SDs were prepared using spray drying with leucine as a carrier to improve solubility and stability. Solid-state characterization was performed using differential scanning calorimetry, Fourier-transform infrared spectroscopy, and powdered X-ray diffraction to confirm amorphization and molecular interactions. PIP@SDs demonstrated enhanced solubility, achieving 97.5% drug release in 24 hours, compared with pure drug and improved flow properties suitable for pharmaceutical manufacturing. In SH-SY5Y cells, PIP@SDs markedly increased viability after Aβ insult (from 50.2% to 80.8%, P < .0001), reduced oxidative stress, stabilized mitochondrial membrane potential, restored calcium equilibrium, and lowered apoptosis levels relative to free piperine. Notably, PIP@SDs inhibited cholinesterase activity and prevented Aβ aggregation, with all effects confirmed through quantitative and imaging analyses. In closing, by substantially enhancing solubility and bioavailability and providing superior neuroprotection against Aβ-mediated toxicity, spray-dried PIP@SDs offer a novel, multifunctional platform that supports their continued research as a promising candidate for disease-modifying interventions in Alzheimer's and related neurodegenerative disorders. SIGNIFICANCE STATEMENT: Poor aqueous solubility and limited bioavailability restrict the therapeutic potential of many neuroprotective natural compounds. This study demonstrates that spray-dried piperine-leucine solid dispersions markedly enhance piperine dissolution and significantly attenuate amyloid-β-induced oxidative stress, mitochondrial dysfunction, and apoptosis in neuronal cells. These findings highlight a pharmacologically relevant formulation strategy that improves the bioactivity of piperine and supports its development as a multifunctional therapeutic candidate targeting oxidative and mitochondrial pathways implicated in Alzheimer disease.},
}

@article {pmid42119858,
year = {2026},
author = {Perl, AT and Wu, J and Dong, JD and Brooks, AM and Yoblinski, AR and Vierling, TT and Li, JL and Ruby, DR and Radzicki, D and Dudek, SM and Cushman, JD and Gjoneska, E},
title = {Immune receptor LAG3 regulates microglia function during Alzheimer's disease.},
journal = {Neurobiology of disease},
volume = {},
number = {},
pages = {107447},
doi = {10.1016/j.nbd.2026.107447},
pmid = {42119858},
issn = {1095-953X},
abstract = {Alzheimer's Disease (AD) remains the leading cause of dementia globally, yet the exact etiology is not well defined and effective treatments remain unavailable. Here, we report that deletion of the immune checkpoint receptor lymphocyte activation gene 3 (Lag3) in a familial AD mouse model, 5xFAD[+], can rescue molecular, cellular and behavioral phenotypes of neurodegeneration. Specifically, we demonstrate that amyloidosis and microgliosis in the 5xFAD[+] mice are significantly reduced by Lag3 deletion. Moreover, we show that Lag3 deletion attenuates deficits in neurodegeneration-related behavioral phenotypes in the 5xFAD[+] mice. Transcriptional profiling reveals that Lag3 deletion suppresses aberrant overexpression of disease associated microglia (DAM) genes in 5xFAD[+] microglia, effectively restoring homeostatic transcriptional programs. Finally, we observe reduced CD8[+] T cell infiltration in the brain of 5xFAD[+] animals after Lag3 deletion which likely mediates molecular, cellular and behavioral effects resulting from microglia DAM gene activation. Our results highlight a previously unrecognized role for Lag3 in AD as a critical regulator of microglia function and suggest Lag3 might be a viable target for novel AD therapeutic interventions.},
}

@article {pmid42119901,
year = {2026},
author = {Terao, I and Kodama, W},
title = {Plasma p-Tau217 and Aβ42/40 for Identifying Amyloid PET Positivity in Cognitively Unimpaired Asian Individuals: A Systematic Review and Meta-Analysis.},
journal = {Ageing research reviews},
volume = {},
number = {},
pages = {103173},
doi = {10.1016/j.arr.2026.103173},
pmid = {42119901},
issn = {1872-9649},
abstract = {BACKGROUND: Blood-based biomarkers have emerged as promising tools for detecting Alzheimer disease (AD) pathology, but their performance in cognitively unimpaired Asian populations remains unclear.

METHODS: We conducted a systematic review and random-effects meta-analysis to evaluate the ability of plasma p-tau217, Aβ42/40, and composite biomarkers to discriminate amyloid-β positron emission tomography (Aβ PET) positivity in cognitively unimpaired Asian populations. CENTRAL, PubMed, and CINAHL were systematically searched. The primary analysis pooled the area under the curve (AUC) for p-tau217 and Aβ42/40 separately to evaluate discrimination of Aβ PET positivity. Secondary analyses examined standardized mean differences (SMDs) in biomarker levels between Aβ PET-positive and Aβ PET-negative groups for p-tau217 and Aβ42/40, and additionally pooled AUCs for composite biomarkers, including p-tau217/Aβ42 and combined p-tau217 and Aβ42/40 models.

RESULTS: Nine studies comprising 11 analyzable datasets and 2,566 cognitively unimpaired participants were included. The pooled AUC was 0.88 for plasma p-tau217 and 0.86 for plasma Aβ42/40. In secondary analyses, the pooled SMD between Aβ PET-positive and Aβ PET-negative individuals was 2.28 for p-tau217 and -1.17 for Aβ42/40. Composite biomarkers showed higher discriminative performance, with pooled AUCs of 0.920 for p-tau217/Aβ42 and 0.924 for combined p-tau217 and Aβ42/40 models.

CONCLUSIONS: In cognitively unimpaired Asian populations, plasma p-tau217 and Aβ42/40 showed good discriminative performance for Aβ PET positivity. Further standardization, external validation, and prospective evaluation are needed.},
}

@article {pmid42119956,
year = {2026},
author = {Semnani, PM and Afiyat, S and Tabibian, SS and Ariaee, A and Keshtehgar, H and Ahmadi, S and Eslami, M},
title = {Neuroinvasion Pathways of Treponema denticola and Its Role in Amyloidogenesis and Neuroinflammation: A Systematic Review.},
journal = {Microbial pathogenesis},
volume = {},
number = {},
pages = {108554},
doi = {10.1016/j.micpath.2026.108554},
pmid = {42119956},
issn = {1096-1208},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative condition marked by the accumulation of amyloid-β (Aβ) plaques, tau hyperphosphorylation, and persistent neuroinflammation. Emerging research indicates that Treponema denticola (T. denticola), a prominent periodontal pathogen, plays a role in AD development through various neuroinvasive mechanisms. This systematic review synthesizes current evidence regarding T. denticola ability to penetrate the central nervous system via trigeminal and hematogenous routes, disrupt the blood-brain barrier, and create enduring biofilms within neural tissues. The pathogen's virulence factors, including dentilisin, lipooligosaccharides (LOS), and major surface proteins, trigger β-secretase (BACE1) and mitogen-activated protein kinase (MAPK/JNK) pathways. These processes contribute to increased Aβ production, tau phosphorylation, and neuronal apoptosis. Furthermore, T. denticola-driven activation of microglia and astrocytes intensifies neuroinflammatory responses involving IL-1β, TNF-α, and IL-6, leading to synaptic dysfunction and cognitive impairment. Studies on murine models reveal that prolonged oral infection with T. denticola induces Alzheimer's-like neuropathological changes, such as hippocampal Aβ accumulation and neuron loss. Taken together, these insights emphasize the impact of periodontal pathogens as modifiable risk factors in AD progression and underscore the necessity of further longitudinal and interventional research to clarify causal pathways and therapeutic possibilities. Incorporating targeted antimicrobial approaches and effective periodontal care may provide innovative strategies for reducing AD progression risks.},
}

@article {pmid42119996,
year = {2026},
author = {Tang, H and Zhang, B and Lu, Y and Lu, Y and Amaro, A and Lu, Y and Wolk, DA and Chen, Y},
title = {Patterns and Trends of Glucose-Lowering Therapy in Alzheimer's Disease and Related Dementias.},
journal = {Diabetes, obesity & metabolism},
volume = {},
number = {},
pages = {},
doi = {10.1111/dom.70817},
pmid = {42119996},
issn = {1463-1326},
support = {R01AG073435/NH/NIH HHS/United States ; R56AG074604/NH/NIH HHS/United States ; RF1AG077820/NH/NIH HHS/United States ; },
}

@article {pmid42120060,
year = {2026},
author = {Francis, D and Paonessa, F and Hewitt, VL and Southall, M and Peset, I and Whitworth, AJ and Livesey, FJ and Fabre, CCG and Palacios, IM},
title = {Investigating how changes in the levels of kinesins impact neuronal health in Drosophila and human iPSC-derived neurons AD model.},
journal = {Open biology},
volume = {16},
number = {5},
pages = {},
doi = {10.1098/rsob.250319},
pmid = {42120060},
issn = {2046-2441},
support = {//Isaac Newton Trust/ ; /BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; /WT_/Wellcome Trust/United Kingdom ; //MRC/ ; //VLH/ ; //European Union/ ; //Paris Region fellowship/ ; //European Commission FP7/ ; //Queen Mary University of London/ ; //Paris Region/ ; //Alzheimer's Research Trust/ ; },
mesh = {Animals ; *Kinesins/metabolism/genetics ; *Induced Pluripotent Stem Cells/metabolism/cytology ; Humans ; *Neurons/metabolism/cytology ; *Alzheimer Disease/metabolism/pathology/genetics ; Disease Models, Animal ; Amyloid beta-Peptides/genetics/metabolism ; *Drosophila Proteins/metabolism/genetics ; Axonal Transport ; Drosophila melanogaster ; Mutation ; Drosophila ; },
abstract = {Alzheimer's disease (AD) is the leading cause of dementia and the most common neurodegenerative disorder. Understanding the molecular pathology of AD may help identify new ways to reduce neuronal damage. In the past decades, Drosophila has become a powerful tool in modelling mechanisms underlying human diseases. Here, we investigate how the expression of the human 42-residue β-amyloid (Aβ) carrying the E22G pathogenic 'Arctic' mutation (Aβ42Arc) affects axonal health and behaviour in Drosophila. We find that Aβ42Arc flies present aberrant neurons, with altered axonal transport of mitochondria and aberrant terminal boutons at neuromuscular junctions. We demonstrate that the motor proteins kinesin-1 and kinesin-3 are essential for the correct development of neurons in Drosophila larvae and in human induced pluripotent stem cell-derived cortical neurons. We then show that the overexpression of kinesin-1 or kinesin-3 restores the correct number and morphology of boutons in Aβ42Arc-expressing neurons and rescues neuronal function measured by negative geotaxis locomotor behavioural assay. We therefore provide new evidence towards understanding the mechanisms of axonal transport defects in AD, and our results support the idea that kinesins should be considered as potential drug targets to help reduce dementia-associated disorders.},
}

Animals
*Kinesins/metabolism/genetics
*Induced Pluripotent Stem Cells/metabolism/cytology
Humans
*Neurons/metabolism/cytology
*Alzheimer Disease/metabolism/pathology/genetics
Disease Models, Animal
Amyloid beta-Peptides/genetics/metabolism
*Drosophila Proteins/metabolism/genetics
Axonal Transport
Drosophila melanogaster
Mutation
Drosophila

@article {pmid42120556,
year = {2026},
author = {André, C and Bédard, MA and Daneault, V and Wickens, R and Fliaguine, O and Soucy, JP and Gauthier, S and Lorrain, D and Bastien, C and Hudon, C and Marchi, NA and Montplaisir, J and Gosselin, N and Carrier, J},
title = {Associations between REM sleep EEG slowing and brain cholinergic denervation in aging and Mild Cognitive Impairment.},
journal = {Molecular psychiatry},
volume = {},
number = {},
pages = {},
pmid = {42120556},
issn = {1476-5578},
support = {PJT153259//Gouvernement du Canada | Canadian Institutes of Health Research (Instituts de Recherche en Santé du Canada)/ ; FDN154291//Gouvernement du Canada | Canadian Institutes of Health Research (Instituts de Recherche en Santé du Canada)/ ; MOP123294//Gouvernement du Canada | Canadian Institutes of Health Research (Instituts de Recherche en Santé du Canada)/ ; MOP102631//Gouvernement du Canada | Canadian Institutes of Health Research (Instituts de Recherche en Santé du Canada)/ ; Postdoctoral fellowship//Fonds de Recherche du Québec - Santé (Fonds de la recherche en sante du Quebec)/ ; Postdoc Mobility Fellowship//Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (Swiss National Science Foundation)/ ; },
abstract = {Cholinergic activity supports cortical activation during REM sleep, while other neurotransmitter systems are almost silent. Here, we tested the long-standing hypothesis that early cholinergic denervation may be associated with REM sleep EEG slowing in older adults. Twenty-four older participants without dementia (mean age: 71.29 ± 4.85 years; 58.33% women; 25% participants with amnestic Mild Cognitive Impairment) underwent a night of in-laboratory polysomnography, comprehensive neuropsychological evaluation, structural MRI and molecular PET imaging with [[18]F]-Fluoroethoxybenzovesamicol (FEOBV) to quantify brain cholinergic innervation. Voxel-wise multiple regressions assessed the associations between REM sleep characteristics (i.e., REM sleep percentage, relative theta power and EEG slowing ratios, defined as [delta + theta]/[alpha + beta] power) and FEOBV-PET standard uptake value ratio maps, controlling for sex. Given that FEOBV uptake was higher in women compared to men, we also performed exploratory sex-stratified analyses adjusted for age. Higher REM sleep EEG slowing over frontal (F3-F4), central (C3-C4), parietal (P3-P4), occipital (O1-O2) and temporal (T5-T6) derivations was significantly associated with cortical cholinergic denervation, notably in fronto-parietal areas and the medial temporal lobe. Sex-stratified analyses showed that higher REM sleep EEG slowing ratios were associated with cholinergic denervation mainly in medial temporal regions in women, and neocortical regions in men. These findings suggest that global REM sleep EEG slowing may represent a sensitive marker of cortical cholinergic denervation in older adults without dementia, and may constitute a promising marker for early diagnosis and disease-modifying interventions in Alzheimer's disease.},
}

@article {pmid42120733,
year = {2026},
author = {You, T and Wang, Y and Xu, J and Zhao, Y and Peng, S and Han, Q and Wang, X and Zhang, M and Shen, W and Guo, M and Zhang, J and Yu, H and Yu, J and Dong, Q and Cui, M},
title = {Brain endothelial cell-derived extracellular vesicles (c-BEEVs) as a promising biomarker for brain vascular pathology and cognitive decline.},
journal = {Nature aging},
volume = {},
number = {},
pages = {},
pmid = {42120733},
issn = {2662-8465},
support = {2021YFC2500100//Ministry of Science and Technology of the People's Republic of China (Chinese Ministry of Science and Technology)/ ; STI2030-Major Projects 2030 2021ZD0201806//Ministry of Science and Technology of the People's Republic of China (Chinese Ministry of Science and Technology)/ ; 82271221//National Natural Science Foundation of China (National Science Foundation of China)/ ; 20234Z0013//Shanghai Municipal Health Bureau (Shanghai Municipal Public Health Bureau)/ ; },
abstract = {Accurate measurement of brain vascular pathology is essential for understanding its role in cognitive aging. Here we classified participants using the amyloid-tau-neurodegeneration framework in a multicenter cohort and identified cerebrospinal fluid brain endothelial-derived small extracellular vesicles (c-BEEVs) as a sensitive biomarker, which correlated with vascular risk factors and the severity of small-vessel disease. c-BEEVs showed high diagnostic performance for vascular cognitive impairment and, when combined with p-tau181, effectively distinguished vascular cognitive impairment from Alzheimer's disease. In individuals with mixed Alzheimer's disease and vascular pathology, c-BEEVs were the earliest indicators of abnormalities. It predicted cognitive decline in participants without p-tau181 pathology. To investigate the mechanistic role of c-BEEVs, we established a hypertension mouse model with elevated c-BEEVs and cognitive deficits. Brain endothelial-specific knockdown of extracellular vesicle secretion alleviated cognitive and synaptic impairment. These findings position c-BEEVs as a promising biomarker for brain vascular pathology and highlight their role in neurovascular dysfunction.},
}

@article {pmid42120736,
year = {2026},
author = {Walters, H},
title = {Somatic variants in microglia-like cells linked to Alzheimer's disease pathology.},
journal = {Nature aging},
volume = {},
number = {},
pages = {},
doi = {10.1038/s43587-026-01135-w},
pmid = {42120736},
issn = {2662-8465},
}

@article {pmid42120765,
year = {2026},
author = {Nie, L and Zhao, Y and Liu, W and Zhou, X and Xia, Q},
title = {The Liver-brain Axis: A Three-stage Model Linking MASLD to Cognitive Impairment and Dementia.},
journal = {Journal of molecular neuroscience : MN},
volume = {76},
number = {2},
pages = {},
pmid = {42120765},
issn = {1559-1166},
support = {Hwk2025zd017//Hefei Municipal Health Science and Technology Project/ ; 2025AHGXZK40281//Natural Science Research Projects in Anhui Universities/ ; },
mesh = {Humans ; *Cognitive Dysfunction/etiology/metabolism ; *Brain/metabolism ; *Dementia/etiology/metabolism ; Animals ; *Liver/metabolism ; *Fatty Liver/metabolism/complications ; },
abstract = {Metabolic dysfunction-associated steatotic liver disease (MASLD) is a leading chronic liver condition affecting nearly 40% of the global population, and is increasingly recognized for its systemic impacts beyond hepatic complications. Emerging evidence has highlighted its role as an independent risk factor for cognitive impairment and dementia, particularly Alzheimer's disease, with significant bidirectional interactions mediated through the liver-brain axis. This review delineates a three-stage model, including systemic injury, cerebrovascular damage, and neurodegeneration, via which MASLD promotes cognitive impairment in conjunction with inflammation, oxidative stress, insulin resistance, lipotoxicity, gut-liver-brain axis dysregulation, and impaired ketogenesis. Additionally, we evaluate the emerging therapeutic strategies targeting metabolic dysfunction and neuroinflammation to mitigate the risk of dementia in patients with MASLD. By bridging critical gaps in the understanding of the liver-brain crosstalk, this study underscores the urgency of interdisciplinary research to address the growing burden of MASLD-related cognitive disorders and proposes translational avenues for early intervention and personalized care.},
}

Humans
*Cognitive Dysfunction/etiology/metabolism
*Brain/metabolism
*Dementia/etiology/metabolism
Animals
*Liver/metabolism
*Fatty Liver/metabolism/complications

@article {pmid42120990,
year = {2026},
author = {Lu, X and Jiang, Y and Lin, X and Zhang, Y and Liu, Q and Chen, S},
title = {Porcine plasma-derived extracellular vesicles orchestrate multi-target neuroimmune reconfiguration to alleviate Alzheimer's disease pathology in a 5×FAD mouse model.},
journal = {Journal of neuroinflammation},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12974-026-03866-4},
pmid = {42120990},
issn = {1742-2094},
support = {2021 Sci & Tech 03-28//Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism/ ; 20220701//ECUST-OPM Open Fund/ ; 222201251732//Fundamental Research Funds for the Central Universities/ ; },
abstract = {BACKGROUND: Systemic factors found in young blood possess the capacity to revitalize the aging brain, yet the clinical translation of human-derived therapeutics is severely limited by donor scarcity. We hypothesized that porcine plasma-derived small extracellular vesicles (PpSEVs) could serve as a scalable, cross-species alternative by leveraging evolutionarily conserved bioactive cargoes.

RESULTS: In this study, we demonstrate that PpSEVs efficiently penetrate the blood-brain barrier and show relative enrichment in the hippocampus CA3 region of 5×FAD mice. Transcriptomic profiling and functional assays reveal that PpSEVs reverse AD pathology by reconfiguring the dysregulated neuroimmune network rather than through broad immune suppression. Specifically, PpSEVs exert a dual-action effect on microglia by blocking caspase-1/GSDMD axis-mediated pyroptosis, while simultaneously enhancing CD68-dependent amyloid-β clearance. This microglial modulation occurs in tandem with the reprogramming of reactive astrocytes, characterized by the downregulation of neurotoxic C3 and the upregulation of neuroprotective S100A10. Furthermore, we identify a direct, glia-independent neurotrophic pathway in which PpSEVs activate neuronal BDNF signaling to rescue synaptic integrity and cognitive function.

CONCLUSIONS: By demonstrating robust cross-species efficacy without provoking immunotoxicity, our study positions PpSEVs as a potent, multi-target intervention that decouples therapeutic benefits from human donor reliance, paving the way for sustainable, xenogeneic exosome-based AD therapies.},
}

@article {pmid42121177,
year = {2026},
author = {Pedersen, EK and Øksnebjerg, L and Nielsen, TR},
title = {Validation of the ICECAP-O for assessing wellbeing in people with mild dementia in Denmark.},
journal = {Health and quality of life outcomes},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12955-026-02544-6},
pmid = {42121177},
issn = {1477-7525},
abstract = {BACKGROUND: Assessment of wellbeing is essential in the context of chronic diseases. The Investigating Choice Experiments for the Preferences of Older People-Capability Index (ICECAP-O) is a generic wellbeing measure beyond health. We aimed to assess whether ICECAP-O is a valid measure of capability-wellbeing in people with mild dementia by assessing its discriminative and convergent validity. Further, we assessed its feasibility, internal consistency, and test-retest reliability.

METHODS: Four quality-of-life (QoL) and wellbeing measures were completed by 123 community-dwelling people with mild dementia. Discriminative validity was assessed by the ability of ICECAP-O to distinguish between levels of QoL, wellbeing, and related variables. Convergent validity was assessed by correlations between ICECAP-O index and domain scores, and the 5-level EQ-5D version (EQ-5D-5L), European Quality of Life visual analog scale (EQ VAS), Engagement and Independence in Dementia Questionnaire (EID-Q), and the World Health Organization Wellbeing Index (WHO-5). The feasibility of ICECAP-O in people with mild dementia was evaluated by missing data analysis. Internal consistency was assessed with Cronbach's α, and test-retest reliability was assessed using intraclass correlation coefficient (ICC).

RESULTS: ICECAP-O significantly distinguished between different levels of QoL and wellbeing. Further, ICECAP-O was not affected by sociodemographic characteristics. ICECAP-O index scores were strongly correlated with EQ-5D-5L (ρ = 0.61) and EID-Q (ρ = 0.62), and moderately with WHO-5 (ρ = 0.58) and EQ-VAS (ρ = 0.58). Missing data on ICECAP-O dimensions, ranging from 2% to 3%, indicate good feasibility in people with mild dementia. ICECAP-O demonstrated acceptable internal consistency (α = 0.74) and good test-retest reliability (ICC = 0.86).

CONCLUSION: The Danish version of ICECAP-O is a valid and reliable measure of wellbeing in people with mild dementia, and demonstrated acceptable psychometric properties, providing further evidence for its use in this population.},
}

@article {pmid42121182,
year = {2026},
author = {Shen, C and Su, J and Liu, L and Li, J and Zhao, X and Wang, Z and Jiang, Y and Zhao, D},
title = {Residential green spaces and neurodegenerative diseases in middle-aged and older adults: a systematic review and dose-response meta-analysis.},
journal = {Archives of public health = Archives belges de sante publique},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13690-026-01957-5},
pmid = {42121182},
issn = {0778-7367},
abstract = {BACKGROUND: The potential protective role of residential green space against neurodegenerative diseases (NDs) is a topic of growing interest, yet evidence remains inconsistent. This systematic review and meta-analysis aimed to synthesize the current evidence on this association in middle-aged and older adults.

METHODS: We searched PubMed, Embase, Web of Science, and the Cochrane Library through March 15, 2025, for observational studies that evaluated the association between objectively measured residential green space and the incidence of NDs in middle-aged and older adults. Risk of bias was assessed using the Newcastle-Ottawa Scale (NOS) and the ROBINS-E tool. Random-effects models were used to pool multivariate-adjusted risk estimates comparing the highest versus lowest exposure categories. Subgroup analyses were conducted by disease type (Alzheimer's disease, Parkinson's disease, and cognitive impairment) and other study characteristics. In addition, a dose-response meta-analysis was performed to explore the potential nonlinear relationship between residential green space exposure and NDs risk. The certainty of evidence was assessed using the GRADE framework.

RESULTS: A total of twelve studies involving over 1.7 million participants were included. Higher residential green space exposure was associated with a lower risk of NDs (pooled HR = 0.85, 95% CI: 0.79-0.91). Subgroup analyses suggested that the inverse association was generally consistent across different disease types, although the magnitude of association varied. The dose-response analysis indicated a nonlinear association, with risk reductions observed at increasing levels of green space exposure, followed by a plateau at higher exposure levels. However, this association was accompanied by extremely high and unexplained statistical heterogeneity across studies (I² > 90%).

CONCLUSIONS: Our findings suggest a potential protective association between residential green space and NDs. This conclusion must be interpreted with extreme caution, as the overall certainty of the evidence was rated "Very Low" due to profound inconsistency and a serious risk of bias in the primary studies. Methodologically rigorous longitudinal research with improved exposure assessment is urgently needed to provide more definitive evidence.

TRIAL REGISTRATION: The study protocol received prospective registration in the International Prospective Register of Systematic Reviews (PROSPERO; registration number: CRD420251020592).},
}

@article {pmid42121190,
year = {2026},
author = {Gao, Y and Tao, X and Wang, Y and Wang, Y and Li, H and Yu, Y and Tu, M and Liu, Y and Zhou, J and Li, Y and Wei, W and Wang, X and Zheng, J and Zhang, Y and Xu, H and Wang, JZ},
title = {Calbindin-D28k deficiency mediates tau-driven hippocampal hyperexcitement and cognitive impairment.},
journal = {Translational neurodegeneration},
volume = {15},
number = {1},
pages = {},
pmid = {42121190},
issn = {2047-9158},
support = {91949205//Natural Science Foundation of China/ ; 31730035//Natural Science Foundation of China/ ; 81721005//Natural Science Foundation of China/ ; 2024M762504//China Postdoctoral Science Foundation General Program/ ; WZ21Q21//Wuhan Health Commission Project/ ; 2025T084HB//China Postdoctoral Science Foundation-Hubei Joint Support Program/ ; },
mesh = {Animals ; *Cognitive Dysfunction/metabolism/genetics/pathology ; *Hippocampus/metabolism/pathology ; Mice ; *tau Proteins/metabolism/genetics ; Mice, Transgenic ; *Calbindin 1/deficiency/genetics ; Humans ; Epilepsy, Temporal Lobe/metabolism ; Male ; Neurons/metabolism ; Alzheimer Disease/metabolism ; },
abstract = {BACKGROUND: Medial temporal lobe hyperexcitation or seizures originating from the hippocampus are frequently observed in Alzheimer's disease (AD) patients, contributing to accelerated cognitive decline. As the hippocampus is an early vulnerable area of tau pathology, the mechanisms by which abnormal tau aggregation promotes temporal lobe epilepsy (TLE) remain poorly understood.

METHODS: We investigated the role of AD-like hippocampal tau aggregation in neuronal hyperexcitation using transgenic (Tg) tau-driven mice. Effects of tau aggregation on intracellular calcium dynamics were assessed by calcium imaging. Neuronal/network hyperexcitability and seizure susceptibility were evaluated through patch-clamp electrophysiology, [18]F-FDG PET/CT, and optogenetic induction. A tetracycline-controlled (Tet-on) system in Tg hTau368 mice enabled spatiotemporal induction of tau pathology to investigate its interactions with calbindin-D28k (CB) and synaptic proteins. Adeno-associated virus (AAV)-mediated CB supplementation in hippocampal CA1 and dentate gyrus (DG) excitatory neurons was performed to correct hyperexcitability and cognitive deficits. Finally, the relationship between CB and disease progress was analyzed using an AD public database.

RESULTS: Tau accumulation in the hippocampal CA1/DG CaMKII-positive excitatory neurons reduced CB expression with disruption of calcium homeostasis. This dysregulation increased neuronal excitability, diminished synaptic protein levels, and increased seizure susceptibility and cognitive impairment. AAV-driven CB restoration in CA1/DG neurons attenuated both hyperexcitability and cognitive deficits. In the brains of AD patients, reduced CB expression was associated with cognitive deterioration and advanced disease stages.

CONCLUSIONS: Tau aggregation drives calcium dysregulation and hippocampal neuronal hyperexcitation through reducing CB expression. These results establish a potential mechanistic link between tauopathy and TLE pathogenesis in AD, providing evidence for CB as a promising therapeutic target for mitigating seizure risk and related cognitive decline in AD.},
}

Animals
*Cognitive Dysfunction/metabolism/genetics/pathology
*Hippocampus/metabolism/pathology
Mice
*tau Proteins/metabolism/genetics
Mice, Transgenic
*Calbindin 1/deficiency/genetics
Humans
Epilepsy, Temporal Lobe/metabolism
Male
Neurons/metabolism
Alzheimer Disease/metabolism

@article {pmid42121212,
year = {2026},
author = {Fowler, DK and Savage, TM and Mackie, DI},
title = {Cannabidiol and other non-psychotropic cannabinoids from Cannabis sativa as therapeutics for microglial-mediated neuroinflammation and neurodegeneration.},
journal = {Journal of cannabis research},
volume = {},
number = {},
pages = {},
doi = {10.1186/s42238-026-00445-5},
pmid = {42121212},
issn = {2522-5782},
abstract = {Non-psychotropic phytocannabinoids produced by Cannabis sativa, including cannabidiol, cannabigerol, cannabichromene and their varin and acidic analogs, are emerging as promising modulators of neuroinflammation, particularly through actions on microglia, the brain's resident immune cells. These compounds engage numerous receptors, ion channels, and intracellular signaling systems in microglia associated with neuroinflammation, and therefore are promising therapeutic candidates to treat chronic microglial inflammation-mediated neurodegenerative disorders. Despite substantial public and scientific interest, comprehensive evaluation of their mechanistic diversity, disease-relevant potential, and translational gaps across neurodegenerative disorders remains limited. Commonly, gaps also exist between cannabis breeders' and cultivators' knowledge of phytocannabinoid diversity and translational scientists' understanding of therapeutic potential. In this review, we first provide an in-depth overview of the main non-psychotropic phytocannabinoids, their biosynthesis, and the genetics that control their production in cannabis. We then summarize the known mechanisms of action for each cannabinoid in microglial-expressed molecular targets and signaling pathways relevant to neuroinflammation. Lastly, we review the effects of non-psychotropic phytocannabinoids in pre-clinical models and clinical trials of four neuroinflammation-associated neurodegenerative diseases: Alzheimer's disease, Parkinson's disease, multiple sclerosis, and Huntington's disease. Current evidence supports meaningful biological activity and complex cannabinoid-specific polypharmacology, yet substantial gaps persist, especially for cannabinoids other than cannabidiol; addressing these gaps in disease-relevant models will be essential for translating these compounds into future therapeutic strategies. Further, we anticipate the summarized information will foster collaboration between cannabis breeders/cultivators and applications scientists for therapeutic evaluation and development of emerging non-psychotropic phytocannabinoids.},
}

@article {pmid42121218,
year = {2026},
author = {Strang, P and Salaj, D and Schultz, T},
title = {End-of-life dementia: demographic, clinical as well as direct health care cost differences in nursing homes vs. ordinary housing.},
journal = {BMC health services research},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12913-026-14703-y},
pmid = {42121218},
issn = {1472-6963},
abstract = {BACKGROUND: In late stages, dementia is a palliative diagnosis and the majority of those affected are cared for in nursing homes, but some manage in ordinary housing. The aim was to study how these two groups differ as regards clinical characteristics, healthcare utilization and costs.

METHODS: A registry study (Region Stockholm) was performed on deceased patients (≥ 18 years) with a dementia diagnosis during their last year of life, for the years 2015-2023. Pairwise comparisons between nursing homes and ordinary housing were made and multivariable binary logistic regression models were created.

RESULTS: Persons in ordinary housing were significantly younger (84 vs. 86 years old), more often male (51% vs. 39%), they had higher frailty risk scores (Hospital Frailty Risk Scores) and had more often a concomitant metastatic cancer (9% vs. 2%), p < 0.0001 in all comparisons. To meet the care needs, these persons received more often specialized palliative care, they had a higher use of geriatric services, they had more emergency room visits and died more often in emergency hospitals, p < 0.0001 in all comparisons. In contrast, those who were referred to nursing homes were more often women, older, they had more often Alzheimer´s disease (compared to other dementias), p < 0.0001 in all comparisons. As regards medical utilization, the associated costs were equally distributed between women and men in ordinary housing, whereas the costs were significantly higher for men compared with women in nursing homes.

CONCLUSIONS: Persons with late-stage dementia in ordinary housing are more often younger, men and they have more often comorbidities, including cancer. They have significantly higher health care utilization, and the costs are equally distributed between women and men.},
}

@article {pmid42121219,
year = {2026},
author = {Pinardi, E and Grande, G and Ornago, AM and Valletta, M and Rizzuto, D and Fredolini, C and Dale, M and Laukka, EJ and Mecocci, P and Winblad, B and Fratiglioni, L and Bellelli, G and Vetrano, DL},
title = {Blood biomarkers of Alzheimer's disease and 15-year decline in cognitive and motor functions in older adults.},
journal = {Journal of internal medicine},
volume = {},
number = {},
pages = {},
doi = {10.1111/joim.70110},
pmid = {42121219},
issn = {1365-2796},
support = {//Swedish Ministry of Health and Social Affairs and the participating County Councils and Municipalities/ ; 2021-00178//Swedish Research Council/ ; 2021-03324//Swedish Research Council/ ; //Karolinska Institutet Strategic Research Area in Epidemiology and Biostatistics (SFOepi)/ ; },
abstract = {BACKGROUND: Individuals showing concurrent and rapid declines in cognitive and motor performance (i.e., dual decliners) are at increased risk of faster progression to dementia. Still, the role of Alzheimer's disease (AD) pathology in motor/cognitive joint trajectories remains poorly understood.

OBJECTIVES: To test the association between blood AD biomarkers and different patterns of decline of cognitive and motor functions in an aging, community-dwelling population.

METHODS: We included 1660 dementia-free participants from the Swedish National Study on Aging and Care in Kungsholmen. Cognitive and motor functions were assessed over 15 years using the Mini-Mental State Examination and gait speed. Based on individual decline rates derived from linear mixed models, participants were classified as slow/non-decliners, fast motor decliners, fast cognitive decliners, or dual decliners. Baseline plasma concentrations of AD biomarkers (amyloid-β [Aβ] 42/40 ratio, phosphorylated tau 217 [p-tau217], phosphorylated tau 181 [p-tau181], total tau, neurofilament light chain [NfL], and glial fibrillary acidic protein [GFAP]) were quantified using single-molecule array assays. Associations between standardized biomarker levels and decline patterns were tested using multinomial logistic regression.

RESULTS: Higher plasma levels of p-tau217 (odds ratio [OR] 2.69, 95% confidence interval [CI] 2.34-3.09), p-tau181 (OR 1.78, 95% CI 1.60-1.98), and NfL (OR 1.47, 95% CI 1.34-1.61) were most strongly associated with dual decline, compared with slow/no decline. Although a lower Aβ42/40 ratio and higher GFAP levels were mainly linked to isolated cognitive, p-tau217 alone was associated with future isolated motor decline.

CONCLUSIONS: In this population-based study, distinct AD blood biomarkers were associated with different patterns of cognitive and motor decline. Whether these represent separate pathways or a clinical continuum, further research is needed to clarify underlying mechanisms and inform clinical applications.},
}

@article {pmid42121220,
year = {2026},
author = {Zhou, Z and Gao, J and Wang, Q and Wang, Q and Liu, L and Zhang, X and Li, C and Liu, J and Wei, Y and Zhang, S and Wang, R and Jia, J and Fu, L},
title = {Comparative performance of semi-quantitative methods for amyloid deposition in preclinical autosomal dominant Alzheimer's disease.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02069-6},
pmid = {42121220},
issn = {1758-9193},
support = {82001360//National Natural Science Foundation of China/ ; 82371999//National Natural Science Foundation of China/ ; 82071963//National Natural Science Foundation of China/ ; 24BJZ14//Capital Health Research and Development of Special Fund/ ; 2021ZD0201802//the Science and Technology Innovation 2030/ ; 7242128//Natural Science Foundation of Beijing Municipality/ ; 2025-NHLHCRF-YXHZ-ZD-01//National High Level Hospital Clinical Research Funding/ ; },
abstract = {BACKGROUND: Autosomal dominant Alzheimer's disease (ADAD) provides a unique window into the earliest stages of β-amyloid (Aβ) pathogenesis. However, it remains unclear whether standard Aβ positron emission tomography (PET) semi-quantitative methods, including the standardized uptake value ratio (SUVR), Z-scores, and the Centiloid (CL) scale, which were developed primarily for sporadic Alzheimer's disease (AD), can accurately capture ADAD-specific topographic patterns and Aβ burden in vivo. In this study, we aimed to compare the performance of these Aβ PET semi-quantitative metrics in asymptomatic carriers of ADAD mutations and evaluate their suitability for early detection and staging.

METHODS: Nineteen asymptomatic carriers of ADAD mutations and 21 cognitively normal (CN) controls underwent [18]F-MK6240 hybrid PET/MR and [11]C-PIB PET/CT imaging. Aβ PET images were analyzed using visual assessment (VA), SUVR, Z-score, and CL methods. Amyloid positivity was defined as abnormal increased [11]C-PIB uptake in the striatum and/or cortical regions, with Z-score > 3 and CL > 21 and 30, respectively. ADAD carriers with marked [18]F-MK6240 uptake in intracranial regions were categorized into tau positive (Tau +) group, while others were assigned to tau negative (Tau-) group.

RESULTS: Based on visual assessment of tau-PET, 19 carriers were categorized into two groups: 10 into the Tau- group and 9 into the Tau+ group. The Tau+ group showed significantly higher Aβ burden across all cortical and subcortical regions. VA classified 3 participants in Tau- group and all 9 participants in the Tau+ group as Aβ positive. Their corresponding regions with Z-scores > 3 were found in the basal ganglia and early Aβ deposition regions. CLs of participants in Tau- group were all less than 21. VA and regional z-scores (> 3) were highly concordant, with both methods classifying all participants in the Tau+ group as Aβ-positive. Both the > 21 and > 30 CL thresholds classified only 5 of 9 (56%) participants in the Tau+ group as Aβ-positive; the remaining cases, whose focal Aβ deposition primarily localized to the striatum, were classified as Aβ-negative. Quantitative analysis also revealed that in the Tau+ group, Aβ burden in the caudate, putamen, and thalamus reached 100% positivity, whereas early cortical regions such as the angular gyrus and middle temporal cortex showed 75%-80% positivity. The CL scale is weighted toward the cortical regions, underestimating Aβ burden in ADAD, particularly in cases with a striatal-dominant pattern.

CONCLUSIONS: The standard CL scale underestimates Aβ burden in ADAD due to limited sensitivity to striatal deposition. Regional Z-scores or striatum-weighted metrics should complement standard CL to improve diagnostic accuracy and trial eligibility assessment.},
}

@article {pmid42121268,
year = {2026},
author = {Cho, IH and Putra, HM and Jung, CW and Hyun, GH and Jang, HH and Hwang, IG and Kwon, SW},
title = {Neuroprotective effects of quercetin in animal models of neurodegenerative diseases: A systematic review and meta-analysis.},
journal = {Journal of the science of food and agriculture},
volume = {},
number = {},
pages = {},
doi = {10.1002/jsfa.70699},
pmid = {42121268},
issn = {1097-0010},
support = {RS-2022-RD010385//Rural Development Administration/ ; },
abstract = {Neurodegenerative conditions such as Alzheimer's disease and Parkinson's disease are characterized by progressive neuronal loss driven by oxidative stress and inflammation. Quercetin, a dietary flavonoid with established antioxidant and anti-inflammatory properties, has emerged as a potential neuroprotective agent. This study aimed to quantitatively synthesize and evaluate preclinical evidence regarding the impact of quercetin on neurodegenerative biomarkers and cognitive performance. A comprehensive literature search was conducted using PubMed, Embase, Web of Science, and the Cochrane Central Register of Controlled Trials (CENTRAL). After strict screening and selection, 19 studies were included. These evaluated the effects of quercetin on: Morris water maze (MWM) performance; inflammatory cytokines - including interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and interleukin-10 (IL-10); the oxidative stress marker malondialdehyde (MDA); antioxidant enzymes such as catalase (CAT), superoxide dismutase (SOD), and glutathione (GSH); brain-derived neurotrophic factor (BDNF); and acetylcholinesterase (AChE) activity. Subgroup analyses based on quercetin dose (<100 mg kg[-1] versus ≥100 mg kg[-1]) and treatment duration (<28 versus ≥28 days) were performed. Quercetin improved cognitive performance significantly by reducing escape latency and improving performance on memory retention indicators. It decreased pro-inflammatory cytokines (IL-6 and TNF-α), increased IL-10, enhanced antioxidant enzyme activity (CAT, SOD, and GSH), reduced MDA levels, up-regulated BDNF, and inhibited AChE. Subgroup analyses suggested that quercetin exerted stronger effects at lower doses and with longer treatment durations, although not all subgroup differences were statistically significant. Quercetin demonstrated multi-targeted neuroprotective effects in animal models, improving cognition and modulating inflammatory, oxidative, and neurotrophic pathways. These findings support the potential of quercetin as a therapeutic agent for neurodegenerative diseases, warranting further clinical investigation. © 2026 The Author(s). Journal of the Science of Food and Agriculture published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.},
}

@article {pmid42121297,
year = {2026},
author = {Oliveira, D and Catalán, L and Bozanic, A and Pedrero, V and Miranda-Castillo, C and Brun, P},
title = {Practices and experiences of nursing staff delivering acute care for people with dementia in surgical-medical wards in Chile: qualitative study.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {5},
pages = {e71389},
doi = {10.1002/alz.71389},
pmid = {42121297},
issn = {1552-5279},
support = {DI-01-24/NUC//Dirección General de Investigación (DGI), Universidad Andres Bello (UNAB), Chile - Núcleo de Investigación Multidisciplinaria en Cuidados en la Demencia/ ; },
mesh = {Humans ; Chile ; *Dementia/nursing ; Qualitative Research ; Female ; Male ; *Attitude of Health Personnel ; *Nursing Staff, Hospital/psychology ; Adult ; Middle Aged ; Interviews as Topic ; Hospitals, Public ; },
abstract = {INTRODUCTION: The aim of this study was to explore practices and experiences of nursing staff involved with care delivery to people with dementia in surgical-medical wards at public hospitals in Chile.

METHODS: A qualitative study was conducted through one-on-one semi-structured interviews with 30 registered nurses and nursing technicians in two hospitals. Reflexive thematic analysis was undertaken.

RESULTS: Nursing care took place in a context of multidimensional precarity, where multiple factors interacted to shape the type of care delivered to people with dementia. The intersection between negative views toward aging and dementia, with a risk-aversion culture, resulted in a widespread application of agency-limiting practices. Nursing staff were largely untrained and overly reliant on families and other professionals, resulting in an approach to dementia care based on individual levels of stress, tolerance, and moral standards.

DISCUSSION: Multiple factors hinder the delivery of quality nursing care for people with dementia in Chile and require urgent attention.},
}

Humans
Chile
*Dementia/nursing
Qualitative Research
Female
Male
*Attitude of Health Personnel
*Nursing Staff, Hospital/psychology
Adult
Middle Aged
Interviews as Topic
Hospitals, Public

@article {pmid42121397,
year = {2026},
author = {Zhang, C},
title = {AI for Relational Reconnection and Social Support in Alzheimer's Disease: A Conceptual Framework for Socially Embedded Systems.},
journal = {The Gerontologist},
volume = {},
number = {},
pages = {},
doi = {10.1093/geront/gnag108},
pmid = {42121397},
issn = {1758-5341},
abstract = {Alzheimer's Disease (AD) has traditionally been approached through a biomedical lens, focusing on neurodegenerative markers such as amyloid-β plaques and tau protein accumulation. However, clinical evidence increasingly demonstrates that social dysfunction, which including identity confusion, emotional withdrawal, and breakdowns in social roles. This article reconceptualizes Alzheimer's disease as a disorder in which the primary dimension of decline lies in social relationship management capacity (SRMC), while recognizing that neurobiological and cognitive deterioration remain integral to its manifestation and progression. SRMC refers to a person's ability to identify, interpret, maintain, and regulate social ties embedded in complex networks. This article introduces a conceptual and technical framework for a socially embedded artificial intelligence (AI) framework designed to recognize and compensate for the deterioration of SRMC in AD. Drawing on social capital theory, affective computing, and neural social cognition research, this framework proposes a four-dimensional intervention model: relationship recognition, relationship learning, relationship establishment, and relationship management. By aligning cutting-edge AI techniques with the lived social reality of individuals with AD, this approach not only provides a new path for supportive care but also reorients ethical and technological discourse toward sustaining social personhood in the face of neurodegeneration.},
}

@article {pmid42121902,
year = {2026},
author = {Zhou, Y and Qi, G and Zhou, H and Gong, P and Wang, Z and Song, X and Tian, C and Wu, H and Qin, S},
title = {Early Müller Glial Activation and Retinal Ganglion Cell Synaptic Dysfunction in APP/PS1 Mice.},
journal = {Cells},
volume = {15},
number = {9},
pages = {},
doi = {10.3390/cells15090801},
pmid = {42121902},
issn = {2073-4409},
support = {31871477, 32170971//National Natural Science Foundation of China/ ; },
mesh = {Animals ; *Retinal Ganglion Cells/pathology/metabolism ; Mice ; Mice, Transgenic ; *Synapses/pathology/metabolism ; Disease Models, Animal ; *Alzheimer Disease/pathology/metabolism/genetics ; *Ependymoglial Cells/metabolism/pathology ; *Amyloid beta-Protein Precursor/metabolism/genetics ; *Presenilin-1/metabolism ; Plaque, Amyloid/pathology/metabolism ; Amyloid beta-Peptides/metabolism ; Mice, Inbred C57BL ; Retina/pathology ; },
abstract = {Alzheimer's disease (AD) is increasingly recognized as a multisystem neurodegenerative disorder in which sensory dysfunction accompanies cognitive decline. As an accessible extension of the central nervous system, the retina provides a valuable window for investigating early neurodegenerative processes; however, the cellular mechanisms underlying AD-associated retinal pathology remain incompletely understood. Here, using the APP/PS1 mouse model, we systematically examined structural, functional, and glial alterations in the retina across disease stages. Despite robust age-dependent amyloid plaque accumulation in visual-related brain regions, no plaque-like β-amyloid (Aβ) deposits were detected in the retina even at advanced ages. Nevertheless, young APP/PS1 mice exhibited early thinning of inner retinal layers, impaired retinal electrophysiological responses, and reduced excitatory synaptic inputs to retinal ganglion cells (RGCs), preceding overt neuronal loss. These neuronal changes were accompanied by pronounced Müller glial activation, characterized by upregulation of gliosis markers and extensive morphological remodeling. Functional analyses further revealed dynamic alterations in glial homeostasis, including early elevation followed by age-dependent decline of glutamine synthetase activity, together with increased expression and disrupted perivascular polarity of aquaporin-4. Consistently, transcriptomic profiling of young AD retinas identified coordinated dysregulation of genes involved in amino acid metabolism, transport, and oxidative stress responses. Together, our findings identify Müller glial remodeling as an early feature of AD-associated retinal pathology that coincides with synaptic vulnerability of RGCs and occurs independently of local Aβ plaque deposition, highlighting retinal glia as potential early indicators and modulators of neurodegeneration.},
}

Animals
*Retinal Ganglion Cells/pathology/metabolism
Mice
Mice, Transgenic
*Synapses/pathology/metabolism
Disease Models, Animal
*Alzheimer Disease/pathology/metabolism/genetics
*Ependymoglial Cells/metabolism/pathology
*Amyloid beta-Protein Precursor/metabolism/genetics
*Presenilin-1/metabolism
Plaque, Amyloid/pathology/metabolism
Amyloid beta-Peptides/metabolism
Mice, Inbred C57BL
Retina/pathology

@article {pmid42122805,
year = {2026},
author = {Aslan, K and Karageçili, H and Tahiroglu, V and Yerlikaya, E and Yılmaz, MA and Fidan, M and Gülçin, İ},
title = {Antioxidant Properties and Enzyme Inhibitory Activities of Eminium rauwolffii: LC-MS/MS-Based Polyphenolic Profiling.},
journal = {Plants (Basel, Switzerland)},
volume = {15},
number = {9},
pages = {},
doi = {10.3390/plants15091311},
pmid = {42122805},
issn = {2223-7747},
abstract = {Eminium rauwolffii (Blume) Schott var. rauwolffii is a member of the Araceae a large and mainly tropical family distributed worldwide. The Eminium species are utilized for various purposes including therapeutic uses in traditional medicine and as food. To analyze the antioxidant properties of water extract of E. rauwolffii (WEER) and ethanol extract of E. rauwolffii (EEER), 2,2'-azino-bis-3-ethylbenzthiazoline-6-sulphonic acid (ABTS[•+]) radical and 1,1-diphenyl-2-picrylhydrazyl (DPPH[.]) free radical scavenging, Fe[3+]-2,4,6-tris(2-pyridyl)-S-triazine (TPTZ) and Cu[2+] reducing assays were studied. Antioxidant activities and reducing properties of both extracts were compared to standard antioxidants: BHT, BHA, α-Tocopherol, and Trolox. The IC50 values of EEER for radical scavenging were higher than those of standard antioxidants (25.35 ± 1.42 μg/mL for ABTS[•+] and 106.80 ± 1.88 μg/mL for DPPH[•]). The total phenolic and flavonoid quantities in WEER and EEER were measured in the range of 189.78 ± 0.01 to 298.54 ± 0.01 mg GAE/g and 89.37 ± 0.01 to 178.95 ± 0.01 mg QE/g, respectively. The IC50 values for EEER and WEER against α-glycosidase, acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and carbonic anhydrase I and II (hCA I and II) enzymes were 10.79 ± 5.61 to 13.18 ± 5.77, 36.14 ± 4.61 to 62.63 ± 1.67, 69.37 ± 7.36 to 37.48 ± 0.27, 81.30 ± 5.95 to 62.35 ± 8.03, and 29.34 ± 1.38 to 115.90 ± 3.3 µg/mL respectively. The antioxidant activity and enzymes inhibitory capacity of WEER were close, and comparable to the capacity demonstrated by the standards. The amount of sixteen compounds was identified from EEER. Numerous phytochemicals, including cynaroside, p-coumaric acid, cosmosiin, caffeic acid, and quinic acid, were quantitatively determined using the LC-MS/MS method. This clearly indicates that phenolic- and flavonoid-rich E. rauwolffii may have potential in the management of glaucoma, Alzheimer's disease, diabetes, cardiovascular, and cancer disorders.},
}

@article {pmid42122986,
year = {2026},
author = {Shakaki, N and Yu, M},
title = {Targeting Neuroinflammation and Oxidative Stress to Slow Neurodegeneration in the Visual System.},
journal = {Journal of clinical medicine},
volume = {15},
number = {9},
pages = {},
doi = {10.3390/jcm15093254},
pmid = {42122986},
issn = {2077-0383},
support = {P30-EY025585/EY/NEI NIH HHS/United States ; },
abstract = {PURPOSE: Neuroinflammation and oxidative stress are increasingly recognized as central, interconnected drivers of neurodegeneration in the visual system. This review examines the pathogenic mechanisms shared across glaucoma, age-related macular degeneration (AMD), diabetic retinopathy (DR), and Alzheimer's disease (AD), and evaluates the therapeutic rationale for targeting both pathways simultaneously.

METHODS: A narrative review of peer-reviewed literature was conducted using PubMed. Searches combined the following MeSH terms: neuroinflammation, oxidative stress, retinal neurodegeneration, microglia, Müller glia, mitochondrial dysfunction, glaucoma, age-related macular degeneration, diabetic retinopathy, and Alzheimer's disease. Priority was given to original research, systematic reviews, and high-impact publications from 2000 through 2025. However, seminal foundational works were included regardless of publication date. Studies were selected based on relevance to glial activation, mitochondrial dysfunction, reactive oxygen and nitrogen species, and disease-specific neuronal outcomes.

RESULTS: Across all four diseases, persistent microglial and Müller glial activation, mitochondrial electron transport chain dysfunction, and excess reactive oxygen species (ROS) and reactive nitrogen species (RNS) production form a self-amplifying feed-forward loop that accelerates neuronal injury. In glaucoma, these mechanisms drive intraocular pressure-independent retinal ganglion cell loss. In AMD and DR, lipid dysregulation, complement activation, and chronic hyperglycemia sustain oxidative-inflammatory injury to the retinal pigment epithelium, photoreceptors, and neurovasculature. In AD, retinal amyloid deposition and oxidative stress mirror cortical pathology, positioning the retina as a noninvasive biomarker site.

CONCLUSIONS: Neuroinflammation and oxidative stress constitute unifying upstream mechanisms across major vision-threatening neurodegenerative diseases. Combination therapeutic strategies that simultaneously modulate glial activation and restore redox homeostasis may offer superior neuroprotective efficacy compared to approaches targeting isolated downstream mediators.},
}

@article {pmid42123112,
year = {2026},
author = {Cambi, X and Liu, Z and Guo, K and Xia, W},
title = {Re-Purposing a Rho-Associated Coiled-Coil Kinase (ROCK) Inhibitor for Alzheimer's Disease.},
journal = {Journal of clinical medicine},
volume = {15},
number = {9},
pages = {},
doi = {10.3390/jcm15093379},
pmid = {42123112},
issn = {2077-0383},
support = {BX004730/VA/VA/United States ; AG063913/NH/NIH HHS/United States ; },
abstract = {Background/Objectives: Currently available treatments approved by the Food and Drug Administration for Alzheimer's disease (AD) either only target the symptoms of AD or, if disease-modifying, have severe side effects. This study aims to explore the potential of the FDA-approved Rho-associated kinase (ROCK) inhibitor netarsudil to reduce tau, a pathological protein in AD. Methods: We explored the pharmacokinetic and pharmacodynamic properties of netarsudil following a single intraperitoneal (i.p.) injection in wild-type mice. The efficacy of netarsudil was assessed using ELISA targeting tau/phosphorylated tau (ptau), as well as mass spectrometry-based proteomics. Results: We found that netarsudil is brain permeable, reaches peak concentrations rapidly and has moderate but sustained exposure in the central nervous system (CNS). Additionally, there was a statistically significant negative association between brain netarsudil exposure and tau and phosphorylated tau at residue 181 (ptau181). The exploratory proteomic analysis of mouse brains exposed to netarsudil revealed changes in mitochondrial function, enrichment of metallothioneins Mt1 and Mt2, and suppression of the AD-related genes Pzp and Serpina3m. Conclusions: The apparent reduction in AD pathological protein tau/ptau and a neuroprotective proteomic profile in vivo suggest the potential for netarsudil to be developed as a new AD therapeutic agent.},
}

@article {pmid42123392,
year = {2026},
author = {Swaminathan, P and Theologidis, V and Gram, H and Chatterjee, D and Hammarström, P and Van Den Berge, N and Lindgren, M},
title = {Human and Mouse Alpha-Synuclein Fibrillation: Impact on h-FTAA Binding and Advancing Strain-Specific Biomarkers in PD Animal Models.},
journal = {International journal of molecular sciences},
volume = {27},
number = {9},
pages = {},
doi = {10.3390/ijms27093807},
pmid = {42123392},
issn = {1422-0067},
support = {R223-2015-4222//The Lundbeck Foundation/ ; R284-2016-2518//The Lundbeck Foundation/ ; R361-2020-2654//Danish Research Institute of Translational Neuroscience/ ; },
mesh = {*alpha-Synuclein/metabolism/chemistry ; Animals ; Humans ; Mice ; Biomarkers/metabolism ; Disease Models, Animal ; *Parkinson Disease/metabolism/pathology ; *Amyloid/metabolism ; Species Specificity ; Protein Binding ; Thiophenes/chemistry/metabolism ; },
abstract = {Disease-specific alpha-synuclein (αsyn) strains have been linked to different synucleinopathies. Current αsyn biomarkers are limited to binary detection of pathogenic αsyn in peripheral tissue biopsies or fluids, limiting differential diagnosis. Hence, there is an urgent need for methods that allow strain-specific detection and characterization of αsyn strain architecture. Notably, luminescent conjugated oligothiophenes (LCOs) have been successfully used to detect distinct protein strain conformers in prion diseases and Alzheimer's disease, highlighting their utility in differentiating disease-specific amyloid structures. Species-dependent differences in αsyn structure are increasingly recognized as one of the critical aspects that shape how fibrils form, propagate and interact with molecular LCO probes. Here, we evaluate the potential of the LCO h-FTAA to differentiate species-specific αsyn strains and conduct a translational investigation using peripheral cardiac tissue of a gut-first synucleinopathy rodent model. Our in vitro data demonstrate strain-specific probe-fibril interactions, reflecting a differential strain architecture and cellular micro-environment. While h-FTAA binds with comparable efficiency to mouse (mo-) and human (hu-) pre-formed fibrils (PFFs), h-FTAA exhibits markedly lower quantum yield when bound to moPFFs versus huPFFs. Spectral imaging revealed h-FTAA-moPFF binding produces blue-shifted maxima (505-550 nm), contrasting with the red-shifted maxima (545-580 nm) of huPFFs. Fluorescence lifetime imaging microscopy confirmed h-FTAA's intrinsic sensitivity to species-dependent variations through distinct temporal fluorescence signatures (moPFFs: ~0.60-1.5 ns vs. huPFFs: ~0.65-1.0 ns). Our translational investigation showed h-FTAA binding to peripheral cardiac pathology exhibits comparable red-shifted emission, but distinct fluorescence lifetimes of h-FTAA-bound aggregates in moPFF-injected (~1.0-1.4 ns) versus huPFF-injected (~0.69-0.8 ns) rats. Interestingly, we observed distinct blue-shifted emission profiles in a few selected regions of the heart of moPFF-injected rodents, further characterized by extra-long fluorescence decay shifts (~1.5-1.9 ns), reflecting differences in both aggregate conformation and maturity in moPFF-induced compared with huPFF-induced rats. Taken together, our findings underscore the potential of LCO ligands, like h-FTAA, to enable more precise disease staging and diagnosis through peripheral biopsies, complementing existing αsyn biomarker methods.},
}

*alpha-Synuclein/metabolism/chemistry
Animals
Humans
Mice
Biomarkers/metabolism
Disease Models, Animal
*Parkinson Disease/metabolism/pathology
*Amyloid/metabolism
Species Specificity
Protein Binding
Thiophenes/chemistry/metabolism

@article {pmid42123397,
year = {2026},
author = {Aceves-Hernández, JM and Uribe Diaz, S and Omolewu, A and Al-Ogaili, AS and Castellanos, I and Vazquez, MIN and Miramontes Salinas, AA and Tellez-Isaia, G and Kwon, YM},
title = {In Silico Study of Anti-CD40 DNA Aptamers as Vaccine Adjuvants for Chickens.},
journal = {International journal of molecular sciences},
volume = {27},
number = {9},
pages = {},
doi = {10.3390/ijms27093808},
pmid = {42123397},
issn = {1422-0067},
mesh = {Animals ; Chickens/immunology ; *Aptamers, Nucleotide/chemistry/pharmacology ; Molecular Docking Simulation ; Influenza in Birds/prevention & control/immunology ; *Adjuvants, Vaccine/chemistry/pharmacology ; *Adjuvants, Immunologic/chemistry/pharmacology ; Computer Simulation ; },
abstract = {We performed a protein-docking study for eight DNA aptamers (SEQ1-SEQ8) against chicken Cluster of Differentiation 40 (chCD40), which were experimentally identified via SELEX in our previous study. In silico and molecular docking analyses were performed to predict and obtain the secondary and tertiary structures of the aptamers. Aptamers SEQ3 and SEQ4, which showed the best inhibitory effects, were selected and utilized to produce a DNA-based vaccine adjuvant using rolling circle amplification (RCA). These aptamers had been previously characterized via mass spectroscopy to determine their molecular weight and regions that could potentially interact with chCD40. In the present study, these results were corroborated and expanded. A series of free software methods, including Mfold v.1.0, 3dADN v.2.0, ClusPro v.2.0, Hdock v.1.0, and PLIP v.1.0, were used to determine the aptamers' secondary and tertiary structures and docking interactions, as well as the specific residues involved in the interactions and their distances. The structures were used to explain and thus understand their effect on the binding, selectivity, and stability of the aptamers. The main objective of the study was to determine whether these aptamers could be used as vaccine adjuvants against viral and bacterial pathogens, specifically chicken avian influenza. The docking results were in good agreement with the experimental and biological results. The procedure employed in this study could be an easy and effective tool for exploring the potential of the new technology of systematic evolution of ligands by exponential enrichment (SELEX) in the preparation of aptamers to control viral and bacterial infections as well as diseases, such as cancer and Alzheimer's.},
}

Animals
Chickens/immunology
*Aptamers, Nucleotide/chemistry/pharmacology
Molecular Docking Simulation
Influenza in Birds/prevention & control/immunology
*Adjuvants, Vaccine/chemistry/pharmacology
*Adjuvants, Immunologic/chemistry/pharmacology
Computer Simulation

@article {pmid42123478,
year = {2026},
author = {Xiao, Y and Huang, W and Chen, L and Huang, R and Guo, Y and Liu, W and Wang, X and Wang, J and Bao, J and Shu, X},
title = {Amyloid Precursor Protein Abnormalities Destabilize Membrane Ferroportin: A Novel Mechanism Underlying Early Brain Pathologies and Memory Impairment in Alzheimer's Disease.},
journal = {International journal of molecular sciences},
volume = {27},
number = {9},
pages = {},
doi = {10.3390/ijms27093892},
pmid = {42123478},
issn = {1422-0067},
support = {82371195//National Natural Science Foundation of China/ ; 82001281//National Natural Science Foundation of China/ ; No. 2024HBQZYCSB046//Intelligent Cancer Prevention and Control Platform Development and Industrialization/ ; },
mesh = {*Alzheimer Disease/metabolism/pathology/genetics ; Animals ; Ferroportin ; *Amyloid beta-Protein Precursor/metabolism/genetics ; *Cation Transport Proteins/metabolism/genetics ; Mice ; Humans ; *Memory Disorders/metabolism/pathology ; *Brain/pathology/metabolism ; Mice, Transgenic ; Ferroptosis ; Disease Models, Animal ; Amyloid beta-Peptides/metabolism ; Mutation ; Oxidative Stress ; },
abstract = {Alzheimer's disease (AD) research has primarily focused on amyloid beta (Aβ) and tau protein; however, drug development targeting these two proteins has been disappointing. Therefore, there is an urgent need to explore the novel pathogenic mechanisms underlying AD. Recently, we found that expression of the K670N/M671L-mutated amyloid precursor protein (APP) in 293T cells significantly reduced membrane ferroportin (FPN) levels. Furthermore, 2-month-old APP/PS1 mice exhibited a marked decrease in membrane FPN levels, while total FPN expression and Aβ levels remained unchanged. Further studies revealed that features of ferroptosis were present in the brains of 2-month-old APP/PS1 mice, and that treatment with ferroptosis inhibitors or iron chelation significantly alleviated early pathological changes and cognitive impairment in these animals. In addition, supplementation with an APP-FPN binding peptide during the early phase ameliorated AD-related pathologies, including Aβ deposition, neuroinflammation, oxidative stress, and synapse-associated protein deficits, in APP/PS1 mice. Collectively, our findings suggest that APP mutations may contribute to early brain pathological changes and subsequent memory impairment in AD by downregulating membrane trafficking of FPN and inducing ferroptosis, thereby providing new molecular targets for drug development.},
}

*Alzheimer Disease/metabolism/pathology/genetics
Animals
Ferroportin
*Amyloid beta-Protein Precursor/metabolism/genetics
*Cation Transport Proteins/metabolism/genetics
Mice
Humans
*Memory Disorders/metabolism/pathology
*Brain/pathology/metabolism
Mice, Transgenic
Ferroptosis
Disease Models, Animal
Amyloid beta-Peptides/metabolism
Mutation
Oxidative Stress

@article {pmid42123509,
year = {2026},
author = {Li, Y and Yao, Y and Xu, Z and Xiong, Y and Zhang, C and Yu, L and Gao, H and Fei, T},
title = {Genome-Wide CRISPR Screening Identifies Genetic Modulators of Amyloid Precursor Protein Processing.},
journal = {International journal of molecular sciences},
volume = {27},
number = {9},
pages = {},
doi = {10.3390/ijms27093926},
pmid = {42123509},
issn = {1422-0067},
mesh = {Humans ; *Amyloid beta-Protein Precursor/metabolism/genetics ; *CRISPR-Cas Systems ; *Alzheimer Disease/genetics/metabolism ; Amyloid beta-Peptides/metabolism/genetics ; HEK293 Cells ; },
abstract = {The proteolytic processing of the amyloid precursor protein (APP) is a core pathological event in Alzheimer's disease (AD) pathogenesis, yet the global genetic regulatory networks modulating this process have not been fully characterized. To systematically identify novel regulators of APP cleavage, we performed a genome-wide CRISPR/Cas9 knockout screen utilizing an optimized UAS-GAL4-based cellular reporter, and identified genetic modulators governing amyloidogenic and non-amyloidogenic processing. The screen uncovered distinct functional gene clusters regulating the APP, prominently involving cellular metabolism, protein modification, and vesicular trafficking. Specifically, LDHB, PIAS2, CCDC53, and TRIM61 emerged as novel functional modulators. Biochemical validation confirmed that ablating these genes significantly alters the metabolic balance between sAPPα and amyloid-β (Aβ) production. Finally, integration with human AD transcriptomic datasets demonstrated that these identified modulators undergo significant dysregulation in clinics. Together, these findings establish a reporter-based functional screening framework for APP processing and identify candidate regulatory nodes linked to metabolism, protein modification, and vesicular trafficking. These candidates provide a resource for future mechanistic investigation and validation in more disease-relevant AD models.},
}

Humans
*Amyloid beta-Protein Precursor/metabolism/genetics
*CRISPR-Cas Systems
*Alzheimer Disease/genetics/metabolism
Amyloid beta-Peptides/metabolism/genetics
HEK293 Cells

@article {pmid42123553,
year = {2026},
author = {Mahoon, DA and Hamad, O and Butler, AE},
title = {The Role of Antidiabetic Therapies in Mild Cognitive Impairment and Alzheimer's Disease: A Systematic Review of Metformin, Pioglitazone, and GLP-1 Receptor Agonists.},
journal = {International journal of molecular sciences},
volume = {27},
number = {9},
pages = {},
doi = {10.3390/ijms27093967},
pmid = {42123553},
issn = {1422-0067},
mesh = {Humans ; *Alzheimer Disease/drug therapy/metabolism ; *Cognitive Dysfunction/drug therapy/metabolism ; *Pioglitazone/therapeutic use ; *Hypoglycemic Agents/therapeutic use ; *Metformin/therapeutic use ; *Glucagon-Like Peptide-1 Receptor Agonists ; Diabetes Mellitus, Type 2/drug therapy/complications ; },
abstract = {Alzheimer's disease (AD) and mild cognitive impairment (MCI) are major causes of cognitive decline. Antidiabetic medications such as metformin, pioglitazone, and GLP-1 receptor agonists have been proposed as potential neuroprotective therapies. We assessed whether these agents slow cognitive decline or disease progression in people with AD or MCI. PubMed, Embase, and Cochrane Central were searched for randomized controlled trials and observational studies of metformin, pioglitazone, or GLP-1 receptor agonists in AD/MCI. Results were synthesized narratively by drug class. Eleven studies met the inclusion criteria. Metformin, particularly in early-stage disease and metabolically vulnerable groups, demonstrated improvements in episodic memory and selective executive outcomes. Observational data in diabetic MCI suggested improved cognition and preservation of hippocampal and cortical structure, with limited amyloid-β and tau changes. Pioglitazone findings varied. Benefits were mainly reported in mild AD with type-2 diabetes, but not in non-diabetic AD/MCI. GLP-1 receptor agonists demonstrated preserved cerebral glucose metabolism and improved blood-to-brain glucose transport but did not improve cognitive function. Current evidence does not support antidiabetic therapies as effective treatments in AD/MCI. Any benefits appear to depend on disease stage and metabolic status, with metformin being the most promising candidate. Larger, longer-duration biomarker-defined trials are needed to determine whether any sustained clinical benefit is observed.},
}

Humans
*Alzheimer Disease/drug therapy/metabolism
*Cognitive Dysfunction/drug therapy/metabolism
*Pioglitazone/therapeutic use
*Hypoglycemic Agents/therapeutic use
*Metformin/therapeutic use
*Glucagon-Like Peptide-1 Receptor Agonists
Diabetes Mellitus, Type 2/drug therapy/complications

@article {pmid42123555,
year = {2026},
author = {Wang, L and Mao, L and Zong, X},
title = {Extracellular Vesicles in Alzheimer's Disease: Mechanisms, Biomarkers, and Therapeutic Engineering.},
journal = {International journal of molecular sciences},
volume = {27},
number = {9},
pages = {},
doi = {10.3390/ijms27093974},
pmid = {42123555},
issn = {1422-0067},
support = {24CDA1269588//American Heart Association/ ; },
mesh = {*Alzheimer Disease/metabolism/therapy/diagnosis/pathology ; Humans ; *Extracellular Vesicles/metabolism ; *Biomarkers/metabolism ; Animals ; Amyloid beta-Peptides/metabolism ; tau Proteins/metabolism ; },
abstract = {Extracellular vesicles (EVs) are nanoscale membrane-bound particles that mediate intercellular communication by transferring proteins, nucleic acids, lipids, and metabolites. Increasing evidence implicates EVs in Alzheimer's disease (AD) pathogenesis through the propagation of amyloid-β, tau, and neuroinflammatory signals across neural and glial networks. In parallel, EVs isolated from biofluids have emerged as promising sources of disease-associated biomarkers and potential therapeutic carriers. This review aims to synthesize current evidence on EV-mediated mechanisms in AD, evaluate the diagnostic value of EV-associated biomarkers, and discuss emerging EV-based and bioengineered therapeutic strategies. We summarize how EVs derived from neurons, astrocytes, microglia, and peripheral cells contribute to amyloid-β and tau spread, neuroinflammation, synaptic dysfunction, and metabolic stress in AD. Disease-associated alterations in EV cargo from blood, cerebrospinal fluid, and urine are critically assessed for biomarker applications. We further highlight advances in EV bioengineering, including cargo loading, surface modification, targeting strategies, and modulation of EV biogenesis. Finally, key translational challenges-such as EV heterogeneity, biodistribution, immune clearance, and standardization-are discussed to define future directions for leveraging EVs as diagnostic and therapeutic platforms in AD.},
}

*Alzheimer Disease/metabolism/therapy/diagnosis/pathology
Humans
*Extracellular Vesicles/metabolism
*Biomarkers/metabolism
Animals
Amyloid beta-Peptides/metabolism
tau Proteins/metabolism

@article {pmid42123557,
year = {2026},
author = {Khan, MA and Shaibah, HS},
title = {Small-Molecule Targeting of the Iron-Responsive Element in the APP mRNA 5'-UTR to Control Amyloid Translation in Alzheimer's Disease.},
journal = {International journal of molecular sciences},
volume = {27},
number = {9},
pages = {},
doi = {10.3390/ijms27093978},
pmid = {42123557},
issn = {1422-0067},
support = {IRG25444//Alfaisal University/ ; },
mesh = {*Alzheimer Disease/genetics/metabolism/drug therapy ; *5' Untranslated Regions/genetics ; Humans ; *Amyloid beta-Protein Precursor/genetics/metabolism ; RNA, Messenger/genetics/metabolism ; Animals ; *Iron/metabolism ; *Protein Biosynthesis/drug effects ; Amyloid beta-Peptides/genetics/metabolism ; *Response Elements ; *Small Molecule Libraries/pharmacology ; },
abstract = {Amyloid-β (Aβ) protein, a cleavage product of the amyloid precursor protein (APP), is the main component of neuritic plaques in Alzheimer's disease (AD), and its accumulation has been considered as the molecular driver of Alzheimer's pathogenesis. Aβ has been a primary target for therapy since the amyloid cascade theory was put forth, with methods designed to prevent the generation of Aβ. The APP 5'-untranslated region (UTR) mRNA encodes a functional structured iron-responsive element (IRE) that represents a potential target for small molecule inhibitors as an anti-amyloid therapy for AD. Here, we offer a comprehensive strategy that uses RNA-targeted binding to inhibit APP translation. The IRE family is among the few 3-D mRNA regulatory elements with a known 3-D structure. Accordingly, we exploit these structural and functional characteristics as our strategy to target APP IRE structured mRNA to identify anti-amyloid drugs. The mRNA encoding proteins involved in iron metabolism are regulated by this family of similar nucleotide sequences. Post-transcriptional control of cytoplasmic mRNA is a rapidly developing area of biomedicine. Across animals, evolutionarily conserved IRE mRNAs serve as a model system for 3-D mRNAs. IRE mRNAs have shown great promise for chemical manipulation of mRNA and protein expression in biological systems by yielding "proof of principle" data for small molecules targeting mRNA structures. A novel approach to identifying RNA-directed therapeutics to regulate APP expression and Aβ-peptide generation for AD treatments is exemplified by APP 5'-UTR-directed small molecule inhibitors.},
}

*Alzheimer Disease/genetics/metabolism/drug therapy
*5' Untranslated Regions/genetics
Humans
*Amyloid beta-Protein Precursor/genetics/metabolism
RNA, Messenger/genetics/metabolism
Animals
*Iron/metabolism
*Protein Biosynthesis/drug effects
Amyloid beta-Peptides/genetics/metabolism
*Response Elements
*Small Molecule Libraries/pharmacology

@article {pmid42123583,
year = {2026},
author = {Corsi, A and Valentino, A and Bruno, MG and Menichetti, G and Belpinati, F and Pereira, MP and Valenti, MT and Ruggiero, A and Trabetti, E and Bombieri, C and Romanelli, MG},
title = {Regulation of Tau Alternative Splicing: A Novel Role for the Ribonucleoprotein RBM20.},
journal = {International journal of molecular sciences},
volume = {27},
number = {9},
pages = {},
doi = {10.3390/ijms27094001},
pmid = {42123583},
issn = {1422-0067},
support = {Excellence Project 2023-2027 of the Department of Neuroscience, Biomedicine and Movement Sciences of the University of Verona//Ministry of Universities and Research/ ; HORIZON-EIC-2021-PATHFINDEROPEN-01 project 101047177 OpenMIND//European Commission/ ; Young Research Mobility Program 2023//Associazione Giovanna Tosi per la lotta contro i tumori/ ; },
mesh = {*tau Proteins/genetics/metabolism ; *Alternative Splicing ; Humans ; *RNA-Binding Proteins/metabolism/genetics ; Exons ; Neurons/metabolism ; Organoids/metabolism ; Animals ; Brain/metabolism ; Alzheimer Disease/genetics/metabolism ; Tauopathies/genetics/metabolism ; },
abstract = {Tau is a protein associated with microtubules principally expressed in neuronal cells, where it plays a fundamental role in cytoskeleton stabilization and axonal transport. Several diseases collectively named tauopathies, such as Alzheimer's disease, have been associated with an imbalance in the expression of alternative spliced Tau transcripts and the accumulation of hyperphosphorylated Tau, causing dysfunction and death of neuronal cells. Therefore, understanding the Tau exon splicing mechanisms may contribute to elucidating molecular factors that could underlie the development of neurodegenerative disorders. The aim of this study was to define the role of selected splicing factors in regulating Tau exon expression in cell lines and neuronal organoids. We demonstrated the role of the RNA-binding motif protein 20 (RBM20) splicing factor in regulating Tau exon 6 and exon 10, applying RNA-binding assay and qPCR analyses. Furthermore, we demonstrated that Tau expression was regulated during cerebral organoid differentiation, recapitulating in vivo Tau expression. These results suggest the feasibility of using brain organoid technology to study Tau alternative splicing during neural development, confirming that 3D cellular models could be used to study and characterize pathological processes taking place in Tau-related pathologies.},
}

*tau Proteins/genetics/metabolism
*Alternative Splicing
Humans
*RNA-Binding Proteins/metabolism/genetics
Exons
Neurons/metabolism
Organoids/metabolism
Animals
Brain/metabolism
Alzheimer Disease/genetics/metabolism
Tauopathies/genetics/metabolism

@article {pmid42123587,
year = {2026},
author = {Zhang, F and Hao, Z and Song, M and Zhao, Z and Li, W and Chen, J},
title = {Exploring the Research Progress of Vascular Dementia and Key Regulatory Molecules: E2F1.},
journal = {International journal of molecular sciences},
volume = {27},
number = {9},
pages = {},
doi = {10.3390/ijms27094008},
pmid = {42123587},
issn = {1422-0067},
support = {82274395//National Nature Science Foundation of China/ ; },
mesh = {Humans ; *Dementia, Vascular/metabolism/pathology/etiology/genetics ; *E2F1 Transcription Factor/metabolism/genetics ; Animals ; Apoptosis ; },
abstract = {Vascular dementia (VaD) is a type of dementia caused by cerebrovascular factors, which can arise from both ischemic cerebrovascular disease and hemorrhagic cerebrovascular disease. The incidence rate of VaD is second only to Alzheimer's disease and dementia with Lewy bodies. Currently, there are no effective drugs specifically targeting VaD, making the discovery of new therapeutic targets of great significance. This article provides an overview of the research progress on VaD, with a focus on elucidating its pathogenesis, aiming to identify targets that play a regulatory role in the mechanism. Finally, our attention is drawn to the transcription factor E2F1. Through research, it has been found that E2F1 is involved in biological processes such as cell cycle regulation and apoptosis and plays a certain role in neurodegenerative diseases and ischemic encephalopathy. It also participates in the pathogenesis of vascular dementia, suggesting that E2F1 is a key regulatory molecule for VaD and may become a potential pharmacological therapeutic target, which warrants further in-depth research.},
}

Humans
*Dementia, Vascular/metabolism/pathology/etiology/genetics
*E2F1 Transcription Factor/metabolism/genetics
Animals
Apoptosis

@article {pmid42123614,
year = {2026},
author = {Wang, C and Luo, T and Zhou, N and Mou, X},
title = {miRNA-Mediated Regulation of Ferroptosis in Neurological Disorders: Mechanisms and Therapeutic Implications.},
journal = {International journal of molecular sciences},
volume = {27},
number = {9},
pages = {},
doi = {10.3390/ijms27094037},
pmid = {42123614},
issn = {1422-0067},
support = {2022J130//Natural Science Foundation of Ningbo/ ; Y202146345//General Scientific Research Project of the Zhejiang Education Department/ ; },
mesh = {*Ferroptosis/genetics ; Humans ; *MicroRNAs/genetics/metabolism ; *Nervous System Diseases/genetics/metabolism/therapy/pathology ; Animals ; Gene Expression Regulation ; Lipid Peroxidation ; Iron/metabolism ; },
abstract = {Ferroptosis is a form of regulated cell death driven by iron-dependent phospholipid peroxidation and has emerged as a key mechanism of neuronal injury across a broad spectrum of neurological disorders. MicroRNAs (miRNAs), which function primarily as post-transcriptional regulators of gene expression, are increasingly recognized as important modulators of the regulatory networks governing ferroptosis and as potential therapeutic targets in these conditions. In this review, we synthesize current advances in miRNA-mediated regulation of ferroptosis in neurological disorders. We first outline the core molecular pathways governing ferroptosis, with particular emphasis on antioxidant defense, lipid peroxidation, and iron metabolism. We then integrate evidence from ischemic stroke, intracerebral hemorrhage, epilepsy, toxic encephalopathy, spinal cord injury, Parkinson's disease, and Alzheimer's disease, to illustrate how disease-specific miRNA regulatory axes shape ferroptotic vulnerability and its pathological consequences in distinct neurological settings. Importantly, we highlight exosome-based strategies targeting ferroptosis-related miRNA networks as a promising therapeutic approach for neurological disorders, with demonstrated neuroprotective and functional benefits in preclinical studies. Collectively, current evidence supports miRNA-mediated regulation of ferroptosis as an important mechanistic framework and a promising therapeutic target in neurological disorders.},
}

*Ferroptosis/genetics
Humans
*MicroRNAs/genetics/metabolism
*Nervous System Diseases/genetics/metabolism/therapy/pathology
Animals
Gene Expression Regulation
Lipid Peroxidation
Iron/metabolism

@article {pmid42123659,
year = {2026},
author = {Geviti, A and Pagano, L and Grassi, M and Saraceno, C and Facconi, A and Fostinelli, S and Laganà, V and Giacomucci, G and Cotelli, MS and Cantoni, V and Ingannato, A and Bagnoli, S and Bessi, V and Longobardi, A and Russotto, A and Bellini, S and Lagrotteria, D and Paparazzo, E and Binetti, G and Montesanto, A and Nacmias, B and Maletta, R and Borroni, B and Ghidoni, R},
title = {Cumulative Incidence in Monogenic Alzheimer's Disease and Frontotemporal Dementia: Gene-Gene Interaction Effect.},
journal = {International journal of molecular sciences},
volume = {27},
number = {9},
pages = {},
doi = {10.3390/ijms27094081},
pmid = {42123659},
issn = {1422-0067},
support = {European Union-Next Generation EU-NRRP M6C2-Investment 2.1 Enhancement and strengthening of biomedical research in the NHS-PNRR-MR1-2022-12375654-Cup Code: C83C22001300001. Title: Genetic and epigenetic modulAtors in Rare neurodegenerative diseases with D//European Union,/ ; },
mesh = {Humans ; *Frontotemporal Dementia/genetics/epidemiology ; *Alzheimer Disease/genetics/epidemiology ; Female ; Male ; Incidence ; Middle Aged ; Aged ; *Epistasis, Genetic ; Progranulins/genetics ; Genetic Predisposition to Disease ; Presenilin-1/genetics ; Presenilin-2/genetics ; tau Proteins/genetics ; Mutation ; Pedigree ; C9orf72 Protein/genetics ; Age of Onset ; Amyloid beta-Protein Precursor/genetics ; },
abstract = {Monogenic forms of Alzheimer's Disease (AD) and Frontotemporal Dementia (FTD) represent the two principal neurodegenerative disorders leading to early-onset dementia, primarily linked to mutations in key AD- and FTD-associated genes. The marked heterogeneity in age at onset and penetrance among carriers of pathogenic mutations suggests that monogenic variants act within a broader polygenic background. The combined impact of AD- and FTD-related genetic variation on disease incidence in monogenic forms remains largely unexplored. Herein, we investigate gene-gene interaction patterns in monogenic AD and FTD, with a focus on genetic variability in key AD (APP, PSEN1, PSEN2) and FTD (MAPT, GRN, C9orf72)-associated genes and their association with cumulative disease incidence. Within the GARDENIA Consortium, we studied 426 individuals from Italian pedigrees, including patients (n = 319) and presymptomatic (n = 107) carriers of causative variants in APP (n = 39), PSEN1 (n = 71), PSEN2 (n = 13), MAPT (n = 29), GRN (n = 188), and C9orf72 (n = 86). Age at symptoms onset, age at last follow-up and sex were recorded. Whole exome sequencing was performed, focusing on non-causative variants (n = 64) in the key AD (APP, PSEN1, PSEN2) and FTD genes (MAPT, GRN, C9orf72). Weighted genetic burden scores were derived using Fine-Gray competing risk models to estimate variant-specific effects on cumulative AD and FTD incidence, accounting for mutually exclusive outcomes and family clustering. Model fit was evaluated using Akaike Information Criterion. Higher AD-risk-weighted burden scores in AD-related genes were associated with a significantly increased cumulative incidence of AD, while higher FTD-risk-weighted scores in FTD-related genes showed a trend toward association with increased cumulative incidence of FTD. A significant interaction between burden scores was observed. AD and FTD burden scores showed a negative interaction for AD (~79% attenuation) but a modest synergistic effect for FTD (~6% increase). These findings could imply context-dependent pleiotropy rather than simple additive genetic effects. Our study suggests that even in carriers oh highly penetrant AD or FTD causative variants, genetic background could substantially modulate cumulative disease incidence. Integrating polygenic information with monogenic status may improve prognostic stratification and inform precision approaches in dementia research and clinical trials.},
}

Humans
*Frontotemporal Dementia/genetics/epidemiology
*Alzheimer Disease/genetics/epidemiology
Female
Male
Incidence
Middle Aged
Aged
*Epistasis, Genetic
Progranulins/genetics
Genetic Predisposition to Disease
Presenilin-1/genetics
Presenilin-2/genetics
tau Proteins/genetics
Mutation
Pedigree
C9orf72 Protein/genetics
Age of Onset
Amyloid beta-Protein Precursor/genetics

@article {pmid42123692,
year = {2026},
author = {Ormazabal, P and Órdenes-Constenla, P and Gherardelli, C and Bastías-Pérez, M and Brito-Valenzuela, J and Flores-Opazo, M and Inestrosa, NC and Cisternas, P},
title = {Fructose Intake Is Associated with Brain Metabolic Reprogramming and Exacerbation of Alzheimer-like Alterations in APP/PS1 Mice.},
journal = {International journal of molecular sciences},
volume = {27},
number = {9},
pages = {},
doi = {10.3390/ijms27094113},
pmid = {42123692},
issn = {1422-0067},
mesh = {Animals ; *Fructose/adverse effects/administration & dosage ; *Alzheimer Disease/metabolism/pathology/etiology ; Mice, Transgenic ; *Brain/metabolism/drug effects/pathology ; Mice ; Male ; *Amyloid beta-Protein Precursor/genetics/metabolism ; Glucose/metabolism ; Disease Models, Animal ; *Presenilin-1/genetics/metabolism ; Amyloid beta-Peptides/metabolism ; Metabolic Reprogramming ; },
abstract = {Emerging evidence implicates metabolic dysfunction as a key contributor to Alzheimer's disease (AD) pathogenesis. Fructose, a major component of modern diets, promotes systemic metabolic alterations; however, its direct impact on AD-related brain dysfunction remains poorly defined. Here, we investigated the effects of short-term fructose consumption on systemic metabolism, brain glucose handling, and cognitive performance in APP/PS1 transgenic mice. Six-month-old asymptomatic male mice received 15% fructose in drinking water for eight weeks, while controls received plain water. Fructose-fed APP/PS1 mice developed metabolic alterations consistent with early metabolic syndrome, including increased fasting glucose and dyslipidemia. These changes were accompanied by reduced cerebral glucose utilization, increased Aβ42 accumulation, and impaired cognitive performance. In parallel, fructose intake enhanced neuroinflammatory markers, suggesting a coordinated disruption of metabolic and inflammatory pathways in the brain. Collectively, these findings support the idea that fructose consumption may exacerbate Alzheimer-like alterations linking systemic metabolic dysfunction to impaired brain glucose metabolism and neuroinflammation. This study provides mechanistic evidence supporting a role for dietary fructose as a modifiable risk factor in AD vulnerability.},
}

Animals
*Fructose/adverse effects/administration & dosage
*Alzheimer Disease/metabolism/pathology/etiology
Mice, Transgenic
*Brain/metabolism/drug effects/pathology
Mice
Male
*Amyloid beta-Protein Precursor/genetics/metabolism
Glucose/metabolism
Disease Models, Animal
*Presenilin-1/genetics/metabolism
Amyloid beta-Peptides/metabolism
Metabolic Reprogramming