@article {pmid42061951,
year = {2026},
author = {Brayne, C and Richard, E},
title = {Innovation in Alzheimer's disease needs more than pharmaceutical solutions.},
journal = {BMJ (Clinical research ed.)},
volume = {393},
number = {},
pages = {s788},
doi = {10.1136/bmj.s788},
pmid = {42061951},
issn = {1756-1833},
}

@article {pmid42062001,
year = {2026},
author = {Colasuonno, F and D'Eletto, M and Bellanca, V and Piacentini, M and Di Sano, F and Rossin, F},
title = {Cell death detection in iPSC-derived cortical neurons as model of neurodegeneration.},
journal = {Methods in cell biology},
volume = {206},
number = {},
pages = {217-233},
doi = {10.1016/bs.mcb.2026.02.021},
pmid = {42062001},
issn = {0091-679X},
mesh = {*Induced Pluripotent Stem Cells/cytology/pathology/drug effects/metabolism ; *Neurons/pathology/drug effects/metabolism/cytology ; Amyloid beta-Peptides/toxicity ; Humans ; Cell Death/drug effects ; Peptide Fragments/toxicity ; *Cerebral Cortex/pathology/cytology ; Cells, Cultured ; Alzheimer Disease/pathology/metabolism ; In Situ Nick-End Labeling/methods ; *Neurodegenerative Diseases/pathology ; Animals ; Cell Differentiation ; },
abstract = {Induced pluripotent stem cells (iPSCs) represent an innovative tool to model neurodegenerative disorders, providing access to disease-relevant cell types such as neurons that are otherwise inaccessible. In the context of Alzheimer's disease (AD), iPSC-derived neural cultures offer a unique opportunity to investigate pathological mechanisms in a controlled environment, overcoming limitations of animal models. Central to AD pathogenesis is the amyloid cascade hypothesis, which is based on the concept that accumulation and aggregation of the toxic oligomeric species, initiates a cascade of events leading to synaptic dysfunction, neuronal loss, and cognitive decline. It is known that application of the Aβ oligomers to neurons reproduces key features of synaptic impairment, preceding overt neuronal death. In this study, we proposed an optimized protocol employing iPSC-derived neurons exposed to Aβ1-42 peptide. This approach provides a clear and reliable method to evaluate neurotoxic effects of Aβ peptide on neuronal morphology and viability. Indeed, on the one hand neuronal morphology, assessed through immunofluorescence using specific neuronal markers, allows precise monitoring of neurite length and synaptic connectivity, crucial parameters to evaluate neuronal health. On the other hand, cytotoxicity is directly quantified using terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assays, which confirm Aβ-induced neuronal injury. Notably, this combined approach provides novel insights into early Aβ-driven neurodegenerative processes and offers a platform to identify therapeutic strategies targeting the initial phases of AD pathology.},
}

*Induced Pluripotent Stem Cells/cytology/pathology/drug effects/metabolism
*Neurons/pathology/drug effects/metabolism/cytology
Amyloid beta-Peptides/toxicity
Humans
Cell Death/drug effects
Peptide Fragments/toxicity
*Cerebral Cortex/pathology/cytology
Cells, Cultured
Alzheimer Disease/pathology/metabolism
In Situ Nick-End Labeling/methods
*Neurodegenerative Diseases/pathology
Animals
Cell Differentiation

@article {pmid42062191,
year = {2026},
author = {Abraham, B and Carl, S and Ye, L and Wegner, F and Höllerhage, M and Schulze Westhoff, M and Konen, F and Schneidereit, IV and Skripuletz, T and Klietz, M},
title = {The influence of beta-amyloid and tau proteins on cognitive changes in Parkinson's disease.},
journal = {Parkinsonism & related disorders},
volume = {},
number = {},
pages = {108332},
doi = {10.1016/j.parkreldis.2026.108332},
pmid = {42062191},
issn = {1873-5126},
abstract = {BACKGROUND: Parkinson's disease (PD) is the second most common neurodegenerative disorder after Alzheimer's dementia (AD), characterized by both motor and non-motor symptoms. Cognitive impairment is frequent and can progress to dementia. Early detection of cognitive dysfunction and timely intervention are crucial for maintaining quality of life. Identifying prognostic biomarkers for cognitive impairment therefore remains a key subject in PD research.

OBJECTIVE: This literature review examines the prognostic value of AD-associated cerebrospinal fluid (CSF) biomarkers (beta-amyloid 1-42, beta-amyloid 1-40, total tau, and phosphorylated tau) in relation to cognitive impairment in patients with PD.

METHODS: A systematic search was conducted in PubMed. Inclusion criteria required a formal diagnosis of PD, CSF analysis as well as cognitive testing. Studies without longitudinal data were excluded.

RESULTS: 18 studies met the inclusion criteria, 11 of which utilized data from the Parkinson's Progression Markers Initiative (PPMI). Several studies demonstrated that lower CSF beta-amyloid 1-42 (Aβ42) levels and lower Aβ42:40 ratios were associated with faster cognitive decline. Findings for total tau and phosphorylated tau were inconsistent.

CONCLUSION: Aβ and tau proteins show potential as biomarkers for cognitive decline in PD, but current evidence is insufficient to support their clinical use. Inconsistencies across studies, methodological variability and short follow-up periods limit their predictive value. Future research should include larger cohorts, standardized cognitive testing and extended follow-up periods to clarify their role.},
}

@article {pmid42062297,
year = {2026},
author = {Londono-Correa, D and de la Fuente, J and Davies, G and Cox, SR and Deary, IJ and Harden, KP and Tucker-Drob, EM},
title = {Crystallized and fluid cognitive abilities have different genetic associations with neuropsychiatric disorders.},
journal = {Nature communications},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41467-026-72477-7},
pmid = {42062297},
issn = {2041-1723},
support = {R01MH120219//U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH)/ ; R01AG073593//U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH)/ ; },
abstract = {Previous research on the genetic links between cognition and psychopathology has largely treated cognitive function as unitary, in part due to a lack of well-powered genome-wide association studies on specific cognitive domains, particularly crystallized knowledge (also known as crystallized intelligence). Here, we parse the genetics of cognitive test performance into components representing reaction time, fluid reasoning, and crystallized knowledge. This multivariate approach allows us to report results from a genome-wide association study meta-analysis of crystallized knowledge (N ~ 439,000). We report that multiple neuropsychiatric disorders (Schizophrenia, Bipolar Disorder, Autism Spectrum Disorder, Attention Deficit Hyperactivity Disorder, and Alzheimer's Disease) are also genetically correlated with these three cognitive domains, and with a non-cognitive factor associated with educational attainment, with genetic correlations differing in both magnitude and direction depending on the specific domain and disorder. Neuropsychiatric disorders show specific and heterogeneous patterns of genetic associations with different domains of cognitive and noncognitive function.},
}

@article {pmid42062336,
year = {2026},
author = {Parra-Martínez, C and Callejón-Leblic, B and Rodrigo-Lara, H and Fernández-Vega, I and Guerrero-Márquez, MC and Rábano, A and García-Barrera, T},
title = {Correction: Post-mortem human Alzheimer's brain metallome depends on Braak stages and brain regions.},
journal = {Scientific reports},
volume = {16},
number = {1},
pages = {},
doi = {10.1038/s41598-026-46852-9},
pmid = {42062336},
issn = {2045-2322},
}

@article {pmid42062482,
year = {2026},
author = {Yu, J and Li, F and Chen, XJ and Mou, C and Yao, D and Bi, Z and Chen, X and Du, L and Feng, Z and Zhang, X and Yu, X and Zacharias, LG and DeBerardinis, RJ and Zhang, L and Li, Z and Luo, B and Hu, XL and Ge, WP},
title = {Characterizing the metabolomes of microglia, astrocytes and neurons in ageing and Alzheimer's brains.},
journal = {Nature cell biology},
volume = {},
number = {},
pages = {},
pmid = {42062482},
issn = {1476-4679},
support = {32170964//National Natural Science Foundation of China (National Science Foundation of China)/ ; 82171367//National Natural Science Foundation of China (National Science Foundation of China)/ ; 2024M752878//China Postdoctoral Science Foundation/ ; },
abstract = {Neurons and glia are distinct in their morphology, development and function, possessing unique transcriptomes and proteomes, but little is known about their metabolomes. The challenge of brain cell metabolic profiling is to obtain a large number of cells for reliable analysis. Here we purified microglia, astrocytes and neurons from mouse brains, identifying >70 metabolites through targeted metabolomics and 9,854 metabolite features via untargeted metabolomics. We systematically characterized cell type-enriched metabolites and metabolic pathways, revealing an enrichment of glutathione (GSH) and polyamine metabolism in microglia. This enrichment was validated in vivo and showed significant decreases with ageing and in an Alzheimer's disease model. Notably, GSH and polyamine metabolism correlated strongly with chemokine-related gene expression. Disrupting the GSH pathway in microglia resulted in downregulation of chemokine-related genes, aberrant morphogenesis and β-amyloid deposition. Our results provide a valuable resource (https://metabolismocean.org/braincell) for metabolic studies related to ageing, Alzheimer's disease and other neurological diseases.},
}

@article {pmid42062506,
year = {2026},
author = {Houston, S},
title = {Sex differences in Alzheimer's.},
journal = {Nature immunology},
volume = {27},
number = {5},
pages = {885},
doi = {10.1038/s41590-026-02519-1},
pmid = {42062506},
issn = {1529-2916},
}

@article {pmid42062774,
year = {2026},
author = {O'Shea, DM and Wang, L and Lukacsovich, D and Dhanekula, D and Zhang, W and Galvin, C and Joshi, M and Besser, L and Rundek, T and Galvin, JE},
title = {Development and validation of MethylCog, a blood DNA methylation proxy for cognition.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {5},
pages = {e71421},
doi = {10.1002/alz.71421},
pmid = {42062774},
issn = {1552-5279},
support = {NIA U01AG009740/AG/NIA NIH HHS/United States ; U01AG058499/AG/NIA NIH HHS/United States ; RC2 AG036495/AG/NIA NIH HHS/United States ; RC4 AG039029/AG/NIA NIH HHS/United States ; R01AG071514/AG/NIA NIH HHS/United States ; 1K12TR004555/TR/NCATS NIH HHS/United States ; R01NS101483/NS/NINDS NIH HHS/United States ; },
mesh = {Humans ; *DNA Methylation ; Male ; Female ; *Cognitive Dysfunction/blood/diagnosis/genetics ; Biomarkers/blood ; Aged ; *Cognition/physiology ; Alzheimer Disease/blood/diagnosis ; Cohort Studies ; Aged, 80 and over ; Neuropsychological Tests ; Middle Aged ; },
abstract = {INTRODUCTION: Heterogeneity in cognitive ability increases with age and predicts mild cognitive impairment (MCI) and dementia, but scalable blood-based biomarkers are lacking. We developed and validated MethylCog, a parsimonious DNA methylation (DNAm) marker of general cognitive ability (g).

METHODS: MethylCog was developed using elastic net regression on principal components analysis (PCA) -derived g in a population-based cohort (n = 2,069; training/test split) externally validated (n = 112). Criterion validity, MCI discrimination, and specificity relative to GrimAge and Alzheimer's disease (AD) biomarkers were assessed.

RESULTS: MethylCog (29 CpGs) predicted g in the test set (R[2] = 0.17) and external cohort (R[2] = 0.13), explaining ∼11% of variance beyond age and sex. MethylCog improved MCI discrimination beyond demographics (ΔAUC = 0.03-0.07) and outperformed GrimAge but did not add value beyond cognitive screeners. Exploratory analyses showed no significant associations with AD plasma biomarkers or MRI measures.

DISCUSSION: MethylCog provides initial evidence that parsimonious DNAm scores can index individual differences in cognitive ability, with potential utility where direct assessment is unavailable.},
}

Humans
*DNA Methylation
Male
Female
*Cognitive Dysfunction/blood/diagnosis/genetics
Biomarkers/blood
Aged
*Cognition/physiology
Alzheimer Disease/blood/diagnosis
Cohort Studies
Aged, 80 and over
Neuropsychological Tests
Middle Aged

@article {pmid42062795,
year = {2026},
author = {Li, L and Yang, M and Tao, J and Zhao, Y and Zhao, N and Sun, S},
title = {Kaempferol Improves Alzheimer's Disease by Inhibiting Neuronal Ferroptosis via Activating GPX4/AKR1C3 Signaling Pathway.},
journal = {Pharmacology research & perspectives},
volume = {14},
number = {3},
pages = {e70255},
doi = {10.1002/prp2.70255},
pmid = {42062795},
issn = {2052-1707},
support = {2022ZD050//Corps Guiding Science and Technology Projects/ ; 2025DA013//Scientific and technological research projects in key fields of the Corps/ ; },
mesh = {Animals ; *Alzheimer Disease/drug therapy/metabolism ; *Ferroptosis/drug effects ; *Kaempferols/pharmacology/therapeutic use ; PC12 Cells ; Rats ; Signal Transduction/drug effects ; Amyloid beta-Peptides/metabolism ; *Phospholipid Hydroperoxide Glutathione Peroxidase/metabolism ; Mice ; Male ; Neurons/drug effects/metabolism ; Disease Models, Animal ; NF-E2-Related Factor 2/metabolism ; Peptide Fragments ; Mice, Inbred C57BL ; *Neuroprotective Agents/pharmacology ; Humans ; },
abstract = {Kaempferol has been shown to be beneficial in the treatment of Alzheimer's disease (AD) in animal models. However, the action mechanism remains unclear. AKR1B1 has been identified as a target of kaempferol, initially suggested by the Therapeutic Target Database, DrugBank, and PubChem, and subsequently confirmed through experimental validation. Kaempferol treatment facilitated the expression of AKR1B1 in PC12 cells exposed to Aβ1-42. Kaempferol treatment mitigated the Aβ1-42-induced increases in Fe[2+], MDA, and lipid ROS and Aβ1-42-induced decreases in GSH synthesis and SOD activity. The reduction in ferroptosis-related proteins (GPX4, NQO1, SLC7A11, AKR1C1, and AKR1C3) and the inhibition of Nrf2 nuclear translocation and Nrf2/HO-1 signaling caused by Aβ1-42 were also reversed by kaempferol. Overexpressing AKR1B1 led to decreased levels of Fe[2+], MDA, and lipid ROS, along with increased GSH synthesis and SOD activity in Aβ1-42-treated cells, although these effects were negated by Nrf2 inhibition. The upregulation of GPX4 and AKR1C3 by AKR1B1 overexpression was also reversed when Nrf2 expression was inhibited. Notably, silencing AKR1B1 counteracted the protective effects of kaempferol against Aβ1-42-induced neuronal ferroptosis. In vivo studies revealed that kaempferol improved cognitive impairments, reduced deposition of Aβ and p-Tau, and alleviated neuronal ferroptosis in the hippocampal tissues of an AD mouse model in a dose-dependent manner, effects that were diminished by inhibiting AKR1B1 expression. Following kaempferol treatment, the levels of GPX4 and AKR1C3 in the hippocampus of AD mice were found to be reduced. Overall, our findings indicate that kaempferol treatment enhances cognitive function and mitigates pathological alterations in AD mice by inhibiting neuronal ferroptosis through the activation of the Nrf2/HO-1/GPX4/AKR1C3 signaling via upregulation of AKR1B1. This research supports the need for further investigation and clinical exploration of kaempferol.},
}

Animals
*Alzheimer Disease/drug therapy/metabolism
*Ferroptosis/drug effects
*Kaempferols/pharmacology/therapeutic use
PC12 Cells
Rats
Signal Transduction/drug effects
Amyloid beta-Peptides/metabolism
*Phospholipid Hydroperoxide Glutathione Peroxidase/metabolism
Mice
Male
Neurons/drug effects/metabolism
Disease Models, Animal
NF-E2-Related Factor 2/metabolism
Peptide Fragments
Mice, Inbred C57BL
*Neuroprotective Agents/pharmacology
Humans

@article {pmid42063002,
year = {2026},
author = {Jain, SS and Ang, TFA and Sunderaraman, P and Au, R and Chen, J},
title = {Gender differences in informal caregiving costs and burden in Alzheimer disease: a multinational cross-sectional analysis.},
journal = {BMC public health},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12889-026-27524-9},
pmid = {42063002},
issn = {1471-2458},
support = {U19-AG068753/AG/NIA NIH HHS/United States ; 20SFRN35360180//American Heart Association/ ; },
abstract = {BACKGROUND: Informal caregiving is a major driver of the societal impact of Alzheimer's disease (AD) and has important implications for caregiver health, workforce participation, and gender equity. While prior research indicates that female informal caregivers of people living with AD experience greater physical and psychological burden than their male counterparts, most studies are limited to single-country contexts, and little is known about gender differences in nonmedical societal costs. To address these gaps, we examined caregiver-gender differences in informal care costs and caregiver burden associated with AD across seven countries.

METHODS: We conducted a cross-sectional analysis of harmonized baseline data from community-dwelling individuals with clinically diagnosed AD and their informal caregivers in four cohort studies: GERAS-EU (France, Germany, United Kingdom), GERAS-II (Italy, Spain), GERAS-JP (Japan), and GERAS-US (United States), accessed via the AD Data Initiative's AD Workbench. Monthly informal care costs (e.g., costs of caregiver time and missing work) were derived using the Resource Utilization in Dementia Questionnaire and quantified in US dollars. Caregiver burden was assessed using the Zarit Burden Interview (ZBI) questionnaire (total score: 0-88). We estimated caregiver-gender differences in informal care costs using two-part models (logistic regression followed by gamma regression) and differences in ZBI using linear regression. All models were adjusted for care recipient and caregiver characteristics and country. Secondary analyses stratified the models by disease severity, caregiver employment status, and country.

RESULTS: Among 3,318 caregivers (66.2% women; mean age 63.1 ± 13.8 years), female caregivers had higher monthly informal care costs than male caregivers (adjusted mean difference: 191.8 USD; 95% CI: 27.4 to 356.1; P=.02) and greater burden (adjusted mean difference in ZBI: 4.0 points; 95% CI: 2.6 to 5.3; P<.001). Gender-disparity patterns were significant or directionally consistent in most stratified analyses and were also consistently observed in sensitivity analyses using an imputed dataset.

CONCLUSIONS: Across seven countries, women providing informal care for people living with AD experienced higher costs and greater burden than men, highlighting gender-disparity in unpaid care. These findings support public health and policy efforts to strengthen caregiver supports (e.g., workplace accommodations and tailored caregiver support programs) to reduce burden and productivity loss, particularly for women.},
}

@article {pmid42063156,
year = {2026},
author = {Urso, D and Vitulli, A and Giannoni-Luza, S and Gnoni, V and Giugno, A and Rollo, E and Vilella, D and Zecca, C and Ray, N and Logroscino, G},
title = {Incidence of primary progressive aphasia in Salento, Italy: a population-based study.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02046-z},
pmid = {42063156},
issn = {1758-9193},
support = {D.G.R. 1284/2022//Regione Puglia/ ; },
abstract = {INTRODUCTION: Data on the population-based incidence of primary progressive aphasia (PPA), including all variants and Alzheimer's disease (AD) biomarker profiles, are scarce.

METHODS: We conducted a 4-year, prospective, population-based study in the Salento region of Southern Italy, identifying incident PPA cases through a territory-wide surveillance network. Clinical diagnoses followed consensus criteria; AD pathology was defined by positive CSF or amyloid PET biomarkers.

RESULTS: We identified 35 incident PPA cases, yielding an overall incidence of 1.14 (95% CI, 0.79-1.59) per 100,000 person-years. Incidence peaked in the early 60s for men and in the late 70s for women. The logopenic variant was most frequent and invariably associated with AD pathology. Approximately 20% of nonfluent and semantic cases, and the majority unclassified cases, also showed AD biomarkers.

DISCUSSION: These findings provide real-world epidemiological evidence and underscore the need for systematic biomarker assessment in PPA to guide diagnosis, prognosis, and access to emerging therapies.},
}

@article {pmid42063169,
year = {2026},
author = {Lee, SH and Kim, S and Lee, SB},
title = {Discovering non-linear dynamics of miRNAs in Alzheimer's disease-related cognitive impairment: a cross-species approach with explainable machine learning.},
journal = {Biology direct},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13062-026-00819-y},
pmid = {42063169},
issn = {1745-6150},
support = {RS-2024-00439078//Ministry of Science and ICT, South Korea/ ; },
abstract = {BACKGROUND: MicroRNA (miRNA) biomarker studies in Alzheimer's disease (AD) typically assume monotonic relationships between expression levels and disease status, overlooking the non-linear, context-dependent nature of miRNA regulatory networks. This simplification limits mechanistic insight and clinical translation. We aimed to characterise non-linear contribution patterns of miRNAs across the AD continuum using explainable machine learning and to define stage-specific "operating windows" where individual miRNAs drive classification.

METHODS: Candidate miRNAs were prioritised from APPtg/TAUtg mouse hippocampus (accession number GSE110743) using minimum-redundancy-maximum-relevance selection. A three-miRNA panel (miR-155-5p, miR-339-5p, and miR-455-5p) was validated in human serum (GSE120584; AD, MCI, and healthy controls). Linear and non-linear classifiers were compared, and SHAP dependence analysis was used to quantify sample-level contributions across expression ranges.

RESULTS: Non-linear models (SVM-RBF and k-NN) consistently outperformed linear classifiers, with discrimination strongest for MCI vs. healthy controls (AUC: 0.844). SHAP analysis revealed that miR-155-5p functions as a stable primary driver across disease stages, whereas miR-339-5p and miR-455-5p act as context-dependent modulators contributing only within restricted expression ranges. Each miRNA exhibited distinct, stage-specific non-linear operating windows with threshold effects and inflection points rather than uniform dose-response patterns.

CONCLUSIONS: This study reframes circulating miRNAs as dynamic, interaction-governed signals rather than static biomarkers. The operating window framework provides interpretable, threshold-aware guidance for clinical decision-making and supports stage-sensitive early screening strategies.},
}

@article {pmid42063212,
year = {2026},
author = {Goo, S and Lee, S and Chae, JW and Jung, S and Yun, HY},
title = {Interpretable Deep Survival Analysis of Alzheimer's Disease via Metabolic Genetic Variants.},
journal = {Bioinformatics (Oxford, England)},
volume = {},
number = {},
pages = {},
doi = {10.1093/bioinformatics/btag213},
pmid = {42063212},
issn = {1367-4811},
abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disease. Traditional models for estimating AD onset cannot capture nonlinear interactions (epistasis) among the numerous genetic variables that contribute to AD risk.

METHODS: We developed a feedforward neural network (FFN)-Weibull survival model to predict AD onset using large-scale single-nucleotide polymorphism (SNP) data. We integrated an XAI technique, Shapley additive explanations (SHAP), to address the black-box nature of deep learning, interpret model predictions, and quantify the contribution of each genetic factor to AD.

RESULTS: The FFN model achieved a mean concordance index of 0.647, demonstrating an approximately 3.6% improvement over the traditional linear baseline (0.625). The FFN-SHAP model validated established findings, identifying APOE E4 as a primary AD risk factor. APOE E2 strongly protected against AD. Metabolic-disorder-related SNPs had conflicting effects, suggesting gene-environment interactions influence AD onset.

CONCLUSIONS: By effectively bypassing the combinatorial explosion of interaction terms, the predictive power of an FFN combined with XAI provides a robust methodological tool for identifying the genetic basis of complex diseases, even in cohorts with limited sample sizes. Our model generated novel testable hypotheses regarding the intricate roles of gene-gene and gene-environment interactions in AD pathogenesis.},
}

@article {pmid42063237,
year = {2026},
author = {Zhang, X and Wen, M and Zhang, S and Rao, C and Gu, T and Zha, Z and He, C and Song, Y and Niu, S and Zhu, L and Yu, C},
title = {Aberrant Brain Entropy in Alzheimer's Disease: Evidence From a Resting-State fMRI Study.},
journal = {Brain and behavior},
volume = {16},
number = {5},
pages = {e71454},
doi = {10.1002/brb3.71454},
pmid = {42063237},
issn = {2162-3279},
support = {Z-2017-24-2509//Yantu Neuroscience Special Research Fund Project/ ; WKZX2023CZ0115//Regional Stroke Risk Factor Early Identification and Prediction System Construction/ ; 202304295107020051//Anhui Province Clinical Medical Research and Transformation Special Project/ ; OMH-2024-031//Hefei Comprehensive National Science Center Institute of Health Research Joint Research Center for Occupational Medicine and Health Project/ ; NCMEH2024Y06//Open Fund of Anhui International Joint Research Center for Nano Carbon-based Materials and Environmental Health/ ; 2024-LC-SX059//Anhui University of Science and Technology First Affiliated Hospital Sanxin Project/ ; Byycxz24045//Graduate Student Research Innovation Program of Bengbu Medical University/ ; },
mesh = {Humans ; *Alzheimer Disease/physiopathology/diagnostic imaging ; Male ; Female ; Magnetic Resonance Imaging/methods ; Aged ; Entropy ; *Brain/physiopathology/diagnostic imaging ; Middle Aged ; Brain Mapping/methods ; Cognitive Dysfunction/physiopathology ; Neuropsychological Tests ; },
abstract = {BACKGROUND: The neurodegenerative disorder, Alzheimer's disease (AD), is typified by insidious onset and increasing prevalence with advancing age. It primarily causes comprehensive functional decline in memory, language, and executive control. The scarcity of reliable imaging biomarkers has led to resting-state functional magnetic resonance imaging (rs-fMRI) becoming a seminal tool for investigating functional alterations in neurological disorders. Brain entropy (BEN) is an indicator derived from rs-fMRI data, quantifying the complexity of functional brain activity and the uncertainty of spontaneous activity. This study aims to utilize BEN technology to elucidate the spatial distribution characteristics of functional complexity within the brains of AD patients.

METHODS: The present study comprised 30 patients diagnosed with AD and 46 healthy controls recruited from the same center. A comprehensive neuropsychological assessment and rs-fMRI data acquisition were carried out for all participants. Intergroup comparisons were conducted using voxel-level BEN value maps. To this end, a partial correlation analysis was conducted with the objective of ascertaining the association between BEN values in regions exhibiting significant intergroup differences and cognitive function scores.

RESULT: This study found significantly decreased BEN in the right superior temporal gyrus, right inferior frontal gyrus, and left posterior parietal gyrus among patients with AD, which was significantly correlated with MMSE and MoCA cognitive scores. Exploratory analyses also revealed abnormal trends in the precuneus, cuneus, and left frontotemporal pole.

CONCLUSION: A widespread reduction in BEN was observed in cerebral regions implicated in language memory, processing, and integrative functions, consistent with cognitive decline in AD. As a sensitive and noninvasive metric, BEN shows promise as an imaging marker for early screening and monitoring of AD.},
}

Humans
*Alzheimer Disease/physiopathology/diagnostic imaging
Male
Female
Magnetic Resonance Imaging/methods
Aged
Entropy
*Brain/physiopathology/diagnostic imaging
Middle Aged
Brain Mapping/methods
Cognitive Dysfunction/physiopathology
Neuropsychological Tests

@article {pmid42063326,
year = {2026},
author = {Yang, Y and Conde, S and Bhullar, R and , },
title = {Adaptive and Maladaptive Behaviours and Their Cognitive Correlates in Aging Adults With Down Syndrome.},
journal = {Journal of applied research in intellectual disabilities : JARID},
volume = {39},
number = {3},
pages = {e70234},
doi = {10.1111/jar.70234},
pmid = {42063326},
issn = {1468-3148},
support = {UO1AG051406/NH/NIH HHS/United States ; UO1AG051412/NH/NIH HHS/United States ; },
mesh = {Humans ; *Down Syndrome/physiopathology ; Adult ; Aged ; Middle Aged ; Male ; Female ; *Adaptation, Psychological/physiology ; *Aging/physiology ; *Problem Behavior ; *Intellectual Disability/physiopathology ; },
abstract = {BACKGROUND: Longer life expectancy in Down syndrome (DS) has shifted concern to age-related declines in everyday functioning. Adaptive and maladaptive behaviours are pivotal to quality of life, yet little is known about their patterns in older adults with DS.

METHOD: Data from 259 cognitively stable adults (25-72 year) in the Alzheimer's Biomarkers Consortium-DS were analysed. Adaptive behaviour (Vineland-3) and maladaptive behaviour (Reiss Screen) were analysed and then regressed on age, intellectual disability level, and cognitive tests.

RESULTS: Higher age and greater disability predicted poorer adaptive functioning, but effects waned after cognition was included. General cognition, cued-recall memory, and inhibitory control independently predicted adaptive skills. Maladaptive behaviours were rare, lacked cognitive or demographic predictors, and correlated negatively with adaptive scores.

CONCLUSIONS: By identifying strengths, vulnerabilities, and predictors of behavioural functioning, this study offers insight into future clinical and caregiving strategies for aging adults with DS.},
}

Humans
*Down Syndrome/physiopathology
Adult
Aged
Middle Aged
Male
Female
*Adaptation, Psychological/physiology
*Aging/physiology
*Problem Behavior
*Intellectual Disability/physiopathology

@article {pmid42063365,
year = {2026},
author = {Sopko, Z and Pačesová, A and Železná, B and Maletinska, L},
title = {Integrative Role of Orexigenic Peptides in Neuroprotection and Neurodegenerative Disease Modulation.},
journal = {Bioscience reports},
volume = {},
number = {},
pages = {},
doi = {10.1042/BSR20250362},
pmid = {42063365},
issn = {1573-4935},
abstract = {The neuroprotective properties of several anorexigenic peptides, including leptin and GLP-1, are well established across models of neurodegenerative diseases. However, less is known about the role of orexigenic neuropeptides-including neuropeptide Y, agouti-related peptide, melanin-concentrating hormone, orexins, galanin, and peripherally released hormone ghrelin- that are best known for their role in energy balance and stimulation of food intake. Growing evidence highlights their broader neuroprotective properties across preclinical models of Alzheimer's disease (AD) and Parkinson's disease (PD). In AD, these peptides reduce hallmark pathologies such as amyloid burden, tau phosphorylation, oxidative stress, and neuroinflammation, while enhancing synaptogenesis, neurogenesis, and cognitive function. In PD models, ghrelin protects nigrostriatal dopaminergic neurons by restoring autophagic flux, suppressing endoplasmic reticulum stress-mediated apoptosis, and reducing microglial activation, whereas orexin A and B preserve tyrosine hydroxylase expression, promote neuronal excitability, and improve motor and cognitive outcomes. Taken together, these findings position orexigenic peptides as promising modulators of neurodegeneration and highlight their potential as potential therapeutic targets in AD and PD.},
}

@article {pmid42063485,
year = {2026},
author = {Huang, Y and Xu, J and Fan, Z and Hu, Y and He, X and Chen, A and Liu, Y and Yin, R and Guo, J and DeKosky, ST and Jaffee, M and Zhou, M and Su, C and Wang, F and Guo, Y and Bian, J},
title = {Identifying Alzheimer's Disease Progression Subphenotypes Via a Graph-based Framework Using Electronic Health Records.},
journal = {Journal of healthcare informatics research},
volume = {},
number = {},
pages = {},
pmid = {42063485},
issn = {2509-4971},
abstract = {Understanding the heterogeneity of neurodegeneration in Alzheimer's disease (AD) and identifying distinct progression pathways is critical for improving diagnosis, treatment, prognosis, and prevention. Motivated by this need, this study aimed to identify disease progression subphenotypes among patients with mild cognitive impairment (MCI) and AD using electronic health records (EHRs). We developed a novel approach that combines a graph neural network (GNN)-based framework with time series clustering to characterize progression subphenotypes from MCI to AD. We applied the proposed framework to a real-world cohort of 2,525 patients (61.66% female; mean age 76 years), of whom 64.83% were Non-Hispanic White, 16.48% Non-Hispanic Black, 2.53% were of other races, and 10.85% were Hispanic. Our model identified four distinct progression subphenotypes, each exhibiting characteristic clinical patterns, with average MCI-to-AD progression times ranging from 805 to 1,236 days. These findings indicate that AD does not follow a uniform progression trajectory but instead manifests heterogeneous pathways, and the proposed framework provides an explainable, data-driven approach for delineating AD progression subphenotypes, offering actionable insights for healthcare informatics research and the clinical management of patients at risk for AD.},
}

@article {pmid42063523,
year = {2025},
author = {Fitri, FI and Rambe, AS and Effendy, E and Kadri, A and Prawiroharjo, P and Lubis, IND and Surbakti, KP and Amin, MM and Rusda, M and Gustianingsih, },
title = {Instrument for Assessment of Neurodegenerative Aphasia in Indonesia or Instrumen Afasia Neurodegeneratif Indonesia (IRFANI): Development and pilot study.},
journal = {Journal of Alzheimer's disease reports},
volume = {9},
number = {},
pages = {25424823251366640},
pmid = {42063523},
issn = {2542-4823},
abstract = {BACKGROUND: Primary progressive aphasia (PPA) is a neurodegenerative disorder causing progressive language impairment. Early diagnosis is crucial for treatment planning, yet no standardized assessment exists for Indonesian speakers.

OBJECTIVE: This study describes the initial development of the Instrumen Afasia Neurodegeneratif Indonesia (IRFANI), focusing on test construction, content validity, and pilot testing.

METHODS: IRFANI was designed to assess syntax, motor speech, semantics, and phonology, following Gorno-Tempini et al. (2011) diagnostic criteria. The blueprint covered key domains, including confrontation naming (nouns/verbs), sentence production/comprehension, single-word comprehension, semantic association, and repetition tasks. Verbal stimuli were selected based on expert input and Indonesian word frequency lists, while custom black-and-white illustrations ensured linguistic and cultural relevance. Five neurobehavioral neurologists assessed content validity using Aiken's Content Validity Index (CVI). A pilot study was conducted with 30 participants diverse in age, sex, education, and ethnicity.

RESULTS: Expert consultations refined the test blueprint. Qualitative analysis identified ambiguous images, multiple correct answers, and unclear phrasing in naming and sentence tasks. Issues included visually similar images and ambiguous sentence structures. Quantitative validation (CVI = 0.9) confirmed strong expert agreement, with items scoring below 0.8 excluded. The pilot study demonstrated good reliability (0.923) and provided insights for further refinement.

CONCLUSIONS: IRFANI was systematically developed through expert validation, pilot testing, and iterative refinement, ensuring clarity and strong content validity. Further studies are needed to confirm its construct validity, reliability, and diagnostic accuracy.},
}

@article {pmid42063622,
year = {2026},
author = {Yu, Z and Yao, R and Li, Y and Li, H and Shen, F and Wang, Y and Wang, Y},
title = {Exercise-based modulation of the gut-brain axis: a new direction for neurorehabilitation in Alzheimer's disease.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1765016},
pmid = {42063622},
issn = {1663-4365},
abstract = {Gut microbiota dysbiosis contributes to the development of Alzheimer's disease (AD) through gut-brain axis mediated processes, including neuroinflammation, β-amyloid (Aβ) accumulation, tau hyperphosphorylation, disruption of the blood-brain barrier, and progressive cognitive impairment. Exercise, as a non-pharmacological intervention, has been shown to counteract these pathological features by enhancing the production of neuroprotective short-chain fatty acids, reducing systemic and central inflammation, strengthening intestinal barrier integrity, and promoting neuroplasticity. This review integrates preclinical and clinical findings to evaluate the therapeutic potential of exercise in improving cognitive function and attenuating AD pathology, and summarizes key biological mechanisms involving microbiota modulation, short-chain fatty acid (SCFA) metabolism, immune regulation, and gut-brain communication. Current challenges include the limited number of human clinical trials, variability in intervention outcomes, individual differences in responsiveness, and dependence on exercise duration and intensity. Advancing this field will require rigorous longitudinal randomized controlled studies, multimodal therapeutic strategies, and personalized exercise protocols informed by baseline microbiota profiles and genetic risk factors. Although exercise is not curative, it represents an essential component of multitarget interventions and may delay AD progression through modulation of the gut-brain axis.},
}

@article {pmid42063624,
year = {2026},
author = {Rafiee, Z and Santiago, J and Andersson, E and Hansson, O and Wennström, M},
title = {Amyloid beta pathology induces astrocytic pTDP-43 mislocalization and disrupts TDP-43-regulated cryptic exon transcripts.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1766448},
pmid = {42063624},
issn = {1663-4365},
abstract = {BACKGROUND: While amyloid-β (Aβ) and tau are hallmark pathologies of Alzheimer's disease (AD), TDP-43 proteinopathy is increasingly recognized as an important contributor, occurring in up to 57% of AD cases and associated with accelerated cognitive decline. TDP-43 regulates RNA splicing, and its mislocalization leads to cryptic exon inclusion and loss of canonical protein function. While neuronal TDP-43 pathology has been well studied, its role in astrocytes remains less understood. Recent findings suggest increased phosphorylated TDP-43 (pTDP-43) inclusions in astrocytic endfeet in AD and a bidirectional interaction between Aβ and TDP-43, promoting mutual aggregation.

METHODS: We analyzed pTDP-43 immunoreactivity (IR) in astrocytic perivascular end-feet, nuclei, and cytosol in hippocampal sections from 3-month-old and 18-month-old App[NL-F/NL-F] mice and 18-month-old wild-type controls using ImageJ. In vitro, primary fetal human astrocytes were exposed to oligomeric Aβ42, and changes in cytosolic and nuclear pTDP-43 IR were quantified via ImageJ, while TDP-43 and pTDP-43 protein levels were measured using an in-house ELISA. Expression of canonical transcripts ATG4B and KALRN, involved in autophagy and synaptic support, was assessed by qPCR. Corresponding protein-level changes were evaluated using in-house ELISA.

RESULTS: Our findings demonstrate significantly higher pTDP-43 accumulations in astrocytic nuclei, cytosol, and endfeet in 18-month-old App[NL-F/NL-F] mice compared to age-matched wild-type mice. Astrocytes exposed to oligomeric Aβ42 showed elevated cytosolic pTDP-43 IR and total pTDP-43 protein levels. Concurrently, expression of canonical ATG4B and KALRN transcripts was significantly reduced, which was accompanied by corresponding decreases in protein levels.

CONCLUSION: Our findings demonstrate that pTDP-43 accumulates in astrocytic nuclei, cytosol, and endfeet in the presence of AD pathology. The observed Aβ-induced increase in cytosolic pTDP-43 and transcript disruption suggests a mechanistic link contributing to autophagy impairment and cytoskeletal changes in astrocytes, potentially exacerbating AD progression.},
}

@article {pmid42063815,
year = {2026},
author = {Wu, A and Kandel, N and Li, S and Enoki, TA and Hewes, K and Palumbo, J and Buttaci, M and Jones, K and Xia, K and Zhao, J and Dick, RA and Belfort, G and Chen, J and Forth, S and Wang, C},
title = {Lipid Composition Drastically Alters Tau-Membrane Interaction: Implications for Alzheimer's Disease.},
journal = {JACS Au},
volume = {6},
number = {4},
pages = {2264-2273},
pmid = {42063815},
issn = {2691-3704},
abstract = {Dysregulated lipid metabolism is a key driver of Alzheimer's disease (AD), yet how membrane lipid composition influences tau-membrane interaction remains poorly understood. Here, we combine single-molecule total internal reflection fluorescence microscopy with atomistic molecular dynamics (MD) simulations to elucidate the molecular basis of tau association with the supported lipid bilayer. NMR titration suggests that tau associates with negatively charged lipid headgroups via electrostatic interactions involving residues ∼120-400, which encompass the positively charged proline-rich region (PRR) and microtubule-binding repeat domains. Importantly, whereas prior studies have generally suggested that cholesterol uniformly enhances protein binding, our work reveals a much more complex and lipid-dependent mechanism: cholesterol suppresses tau binding to phosphatidylcholine-phosphatidylglycerol (PC/PG) bilayers but enhances tau binding to phosphatidylcholine-phosphatidylserine (PC/PS) bilayers. Large-scale all-atom MD simulations with a polybasic model peptide, KR8, accurately recapitulate this dichotomy at the molecular level and further reveal that the contrasting regulatory effects of cholesterol arise from lipid-dependent shifts in the preferred insertion depth of KR8, together with local conformational rearrangements of its membrane-interacting basic residues at the bilayer interface. Given that tau-membrane association contributes to aggregation and prion-like propagation, these results identify a previously unrecognized lipid-specific regulatory mechanism by which cholesterol modulates tau-membrane interactions and provide mechanistic insight into how cholesterol dysregulation contributes to AD pathogenesis.},
}

@article {pmid42063949,
year = {2026},
author = {Christimann, GM and Sattler, JAG and Fabi, JP},
title = {Mediterranean, MIND, and ketogenic diets in Alzheimer's disease: mechanistic coherence and clinical uncertainty.},
journal = {Frontiers in nutrition},
volume = {13},
number = {},
pages = {1819499},
pmid = {42063949},
issn = {2296-861X},
}

@article {pmid42063954,
year = {2026},
author = {Bonnechère, B and Stephens, EB and Boileau, AC and Ducker, M and Stubbs, BJ},
title = {The effect of exogenous ketone bodies on cognition across health and disease: a systematic review and meta-analysis.},
journal = {Frontiers in nutrition},
volume = {13},
number = {},
pages = {1802531},
pmid = {42063954},
issn = {2296-861X},
abstract = {INTRODUCTION: Cognitive function is closely linked to brain energy metabolism and may be compromised by aging, metabolic stress, and neuropsychiatric disease. Ketone bodies can serve as an alternative cerebral fuel and may also exert signaling effects relevant to cognition. Exogenous ketones (EK) offer a practical means of increasing circulating ketone concentrations without dietary carbohydrate restriction. However, the overall effect of EK supplementation on cognitive performance in humans has not been systematically quantified.

METHODS: A systematic review and meta-analysis were conducted in accordance with PRISMA guidelines. PubMed, Web of Science, and Embase were searched through October 2025 for randomized controlled trials investigating the effects of EK on cognitive outcomes in healthy adults or individuals with neuropsychiatric conditions. Data extraction and quality assessment were performed independently by multiple reviewers using the PEDro scale. Standardized mean differences (SMD) were calculated using random-effects models. Subgroup and meta-regression analyses examined the influence of ketone formulation, intervention duration, dose, population type, and presence of acute cognitive stressors.

RESULTS: 38 studies comprising 41 protocols (1,602 participants) were included in the systematic review, with 29 protocols (1,117 participants) eligible for meta-analysis. EK supplementation was associated with a statistically significant improvement in cognitive performance compared with placebo (SMD = 0.29, 95% CI 0.16-0.41; p < 0.001). Sub-group analyses did not show statistically significant differences between the type of supplementation (p = 0.083), study duration (acute vs. intermediate; p = 0.11), population type (healthy vs. Alzheimer's disease; p = 0.077), or the presence of acute cognitive stressors (p = 0.89). Meta-regression revealed a positive association between daily EK dose and cognitive improvement.

DISCUSSION: EK supplementation is associated with modest improvements in cognitive performance across diverse populations and study designs. These findings support EK as a flexible nutritional strategy for cognitive support and warrant further investigation in well-powered, long-term trials to clarify optimal dosing, formulation, and clinical applicability.

https://www.crd.york.ac.uk/PROSPERO/view/CRD42023471727, CRD42023471727.},
}

@article {pmid42063966,
year = {2026},
author = {Xie, Y and Tian, J and Li, H and Peng, Y and Li, M and Wu, Y},
title = {Oleic acid improves pathological changes in Aβ1-42-induced astrocytes and Alzheimer's disease mouse models through PKA/ACACB/CPT1A.},
journal = {Frontiers in neuroscience},
volume = {20},
number = {},
pages = {1771310},
pmid = {42063966},
issn = {1662-4548},
abstract = {BACKGROUND: Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder. Emerging evidence indicates that fatty acid oxidation is impaired in both patients with AD and AD animal models. In the brain, fatty acid metabolism occurs predominantly in astrocytes. Diets enriched in monounsaturated fatty acids (MUFAs) are often recommended for individuals with AD. Oleic acid (OA), a common dietary MUFA, has been shown to reduce amyloid plaque accumulation in transgenic mouse models of AD. Moreover, OA decreases the expression of acetyl-CoA carboxylase beta (ACACB/ACC2), a key regulator of fatty acid β-oxidation. However, the precise mechanism by which OA may alleviate amyloid plaque deposition through modulation of brain fatty acid metabolism remains unclear.

OBJECTIVE: To determine whether dietary OA supplementation partially restores astrocytic fatty acid metabolism by suppressing ACACB and enhancing fatty acid β-oxidation, thereby attenuating AD-related pathology.

METHODS: Using NHANES 2011-2014 data, we applied survey-weighted multivariable logistic regression to examine the association between energy-adjusted MUFA intake and low cognitive function, with adjustment for multiple testing. We then screened GEO datasets to identify AD-associated genes involved in fatty acid metabolic dysregulation, identifying ACACB as a candidate target. The expression of ACACB and its downstream effector carnitine palmitoyltransferase 1A (CPT1A) were validated in mouse and cell models. APP/PS1 mice received dietary OA supplementation, followed by behavioral testing and brain histopathological analyses. In parallel, an Aβ1-42-induced astrocyte injury model was used to assess lipid droplet accumulation, mitochondrial function, and cellular energy metabolism. ACACB knockdown/overexpression and CPT1A overexpression were used to test pathway-specific effects of OA.

RESULTS: Higher MUFA intake was associated with better cognitive function. ACACB as a key fatty acid metabolism-related gene in AD. In APP/PS1 mice, OA improved cognitive performance and reduced Aβ plaque deposition, accompanied by decreased ACACB and increased CPT1A expression in brain tissue. In vitro, OA modulated ACC2 activity through protein kinase A (PKA) signaling, increased fatty acid β-oxidation, reduced lipid droplet accumulation, restored mitochondrial membrane potential and ATP production, and enhanced astrocyte-mediated support of neuronal synaptic growth.

CONCLUSION: OA ameliorates AD-related pathology and cognitive impairment by restoring astrocytic fatty acid β-oxidation through the PKA/ACACB/CPT1A pathway.},
}

@article {pmid42063971,
year = {2026},
author = {Pereira, G and Corbett, M and Vernon, SD and Colburn, S and Chanda, S},
title = {A unifying theory of brain signaling and its possible role in acquired chronic disease.},
journal = {Frontiers in neuroscience},
volume = {20},
number = {},
pages = {1683413},
pmid = {42063971},
issn = {1662-4548},
abstract = {Acquired chronic disease is a significant, growing problem. Research has sought patient abnormalities that drugs can target, but to date, these have only provided equivocal symptom relief and no cures. However, as individual neuronal signals cannot be measured, the role of the brain in such diseases, has not been properly investigated. Here the authors propose that corticotropin-releasing factor (CRF) and serotonin act together in dedicated circuits, to architect precise, bidirectional signals that regulate normal function (e.g., thermoregulation, movement, memory, glomerular filtration rate). The authors propose further that the natural, circuit-specific upregulation of the CRF receptor type 2 (CRFR2), unidirectionally dysregulates these signals to cause chronic symptoms (e.g., low temperature, impaired movement, memory loss, reduced glomerular filtration rate). If confirmed, this view of chronic symptoms as a dysregulation of normal process via neuronal adaptation, has profound implications. It could explain Parkinson's, Alzheimer's and chronic kidney disease, among others, and, as it may be possible to downregulate CRFR2, could reverse the signs and symptoms of such diseases.},
}

@article {pmid42064068,
year = {2026},
author = {Liu, G and Deng, B and Han, X and Zhao, Y and Zeng, S and Yu, S and Wang, L and Wang, S and Wu, Y and Cai, L and Wu, Y and Yang, H and Chen, J},
title = {The complement system in Alzheimer's disease: mechanisms, biomarkers, and therapeutic implications.},
journal = {Frontiers in immunology},
volume = {17},
number = {},
pages = {1798288},
pmid = {42064068},
issn = {1664-3224},
mesh = {Humans ; *Alzheimer Disease/immunology/metabolism/therapy/etiology ; *Complement System Proteins/immunology/metabolism ; Biomarkers/metabolism ; Animals ; Complement Activation ; },
abstract = {Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder in which synaptic loss is closely associated with cognitive decline. Although the amyloid hypothesis has long dominated AD research, the limited efficacy of amyloid-targeted therapies highlights the need to explore additional pathogenic mechanisms. Increasing evidence indicates that dysregulation of the complement system plays a critical role in AD, linking genetic risk, protein aggregation, neuroinflammation, and neurodegeneration. Under physiological conditions, complement signaling is essential for neural development and synaptic refinement; however, in AD, aberrant activation contributes to excessive synaptic pruning and sustained inflammatory responses. As a result, complement components have attracted attention as potential biomarkers and therapeutic targets, despite limitations in disease specificity. This review summarizes current advances in understanding complement system alterations in AD, discusses their roles in disease pathogenesis, and highlights emerging complement-targeted therapeutic strategies, as well as remaining challenges related to intervention timing, patient stratification, and blood-brain barrier delivery.},
}

Humans
*Alzheimer Disease/immunology/metabolism/therapy/etiology
*Complement System Proteins/immunology/metabolism
Biomarkers/metabolism
Animals
Complement Activation

@article {pmid42064165,
year = {2026},
author = {Chisholm, L and Hickman, S and Chou, WY and Unroe, KT},
title = {Navigating Barriers and Enablers to Advance Care Planning for Residents Living With Alzheimer's Disease and Related Dementias Nursing Homes: Strategies for Effective Implementation of the Goals of Care Video a Content Analysis.},
journal = {Sage open aging},
volume = {12},
number = {},
pages = {30495334261436936},
pmid = {42064165},
issn = {3049-5334},
abstract = {BACKGROUND: Providing high-quality advance care planning conversations for nursing home residents living with Alzheimer's Disease and Related Dementias is a persistent challenge, but implementation of advance care planning interventions remains limited.

OBJECTIVE: This study explored barriers and enablers to implementing the Goals of Care video with nursing home staff and identified strategies to implement the video intervention.

METHODS: Nursing home administrators identified staff members involved in ACP discussions with residents and families. A research team member contacted these individuals by email or telephone. Fourteen staff members across six Florida nursing homes participated in in-person or virtual semi-structured interviews. A summative content analysis quantified the frequency of each CFIR construct coded as an enabler or barrier, with frequencies calculated at the nursing home level.

RESULTS: The primary enabler was the alignment of the Goals of Care video with nursing homes' organizational mission. The most identified barrier was the video's perceived length. Strategies to improve implementation included adapting materials, assessing readiness, and addressing site-specific challenges.

CONCLUSIONS: Tailoring the Goals of Care video to the organizational context is essential. Addressing barriers, such as video concerns, while leveraging existing enablers can strengthen adoption and support more consistent advance care planning practices.},
}

@article {pmid42064206,
year = {2026},
author = {Williamson, LE and Horne, D and Mikelyte, R and Grey, EB and Collins, P and Poyner, C and Farnood, A and Oh, TM},
title = {Palliative care conversations with people with dementia who live alone: untapped dimensions from a lived experience.},
journal = {Frontiers in dementia},
volume = {5},
number = {},
pages = {1791608},
pmid = {42064206},
issn = {2813-3919},
abstract = {Dementia is a life-limiting condition, and a palliative care approach can improve both quality of life and quality of care for people living-and dying-with dementia. Research has consistently shown that, compared with other terminal conditions such as cancer, dementia is under-recognised and under-treated within palliative care systems. Considerable attention has been paid to this overall under-representation; however, further inequities exist within palliative dementia care research and practice itself. This position paper draws on an in-depth conversation with a person living alone with Alzheimer's disease and vascular dementia, alongside a critical engagement with existing literature. Using lived experience as a starting point, we identify two untapped dimensions of palliative dementia care: (1) barriers in palliative care conversations when a person with dementia attends clinical appointments unaccompanied; and (2) intersectional disadvantage arising from dementia, living alone, and health and social care systems that overly rely on informal carers or supporters. These contribute to exclusionary research practices that marginalise people living with dementia without close care partners. While the involvement of carers and supporters in shared decision-making should be encouraged when they are present, high-quality palliative care and research must not depend on their presence and should be equally accessible to people living with dementia who attend services alone. We argue that addressing this neglected area requires the meaningful involvement of people with lived experience in shaping both research agendas and clinical practice.},
}

@article {pmid42064679,
year = {2026},
author = {Bollack, A and Schwarz, AJ and Bourgeat, P and Doré, V and Mejan-Fripp, J and Page, C and Bonke, E and Thurfjell, L and Hass, M and Balhorn, W and Nelson, A and Fahmi, R and Mattsson-Carlgren, N and Palmqvist, S and Stomrud, E and Smith, R and Hansson, O and La Joie, R and Farrar, G},
title = {Comparability of Centiloid values from [[18]F]flutemetamol scans using seven commercial and research software.},
journal = {Neuroimage. Reports},
volume = {6},
number = {2},
pages = {100343},
pmid = {42064679},
issn = {2666-9560},
abstract = {UNLABELLED: Quantification using the Centiloid (CL) scale has become a valuable information to consider when interpreting amyloid-PET images and is now implemented in several software packages. This work aims to assess the comparability of CL from [[18]F]flutemetamol scans derived using several research and commercial quantification pipelines.

METHODS: This analysis relies on three datasets: a test-retest cohort, a group of clinically relevant patients with amnestic mild cognitive impairment (aMCI) and a subgroup from the BioFINDER-1 cohort enriched with scans with amyloid loads around potential clinical decision thresholds (0-50CL). Images from the Test-Retest and aMCI cohorts were processed across seven quantification pipelines: three commercial software platforms and four research tools, including the standard SPM8 workflow. The statistical analysis was based on three steps: 1) a repeatability analysis using the test-retest data; 2) a reproducibility analysis across all pipelines using the aMCI cohort; 3) an inter-software reliability analysis around three clinically relevant thresholds: 11, 25 and 37 CL using the aMCI and the BioFINDER-1 data.

RESULTS: In the Test-Retest dataset composed of 10 Alzheimer's Disease (AD) patients, high test-retest repeatability and reliability were observed with an absolute bias of less than 5 CL. Within-individual coefficients of variation ranged from 2.6 to 4.4% and repeatability coefficients from ∼8 to ∼16 CL. CL quantification was generally reproducible across pipelines in a dataset of 80 aMCI individuals (R[2] in [0.94-0.99], slope in [0.98-1.03], intercept in [-4, 4], but the 95% limits of agreement (LoAs) ranged between ∼±12 and ∼±21 CL. Agreement between software around the three clinically relevant thresholds was 92-100% (kappa 0.83-1) in the aMCI data (N = 80) and 75-99% (kappa 0.48-0.96) in the BioFINDER-1 subgroup (N = 110).

CONCLUSION: In this study, CL quantification was shown to be robust across a range of currently available software platforms. Uncertainty estimates should always be considered when interpreting results. In clinical practice, the choice of quantification software should not impact patient management decisions.},
}

@article {pmid42064764,
year = {2026},
author = {Yu, Y and Peng, X and Su, C and Bai, Y and Hou, D},
title = {The impact of antidiabetic drugs on dementia risk: a Bayesian network meta-analysis.},
journal = {Frontiers in endocrinology},
volume = {17},
number = {},
pages = {1780676},
pmid = {42064764},
issn = {1664-2392},
mesh = {Humans ; *Hypoglycemic Agents/therapeutic use ; Bayes Theorem ; *Dementia/epidemiology/prevention & control ; Network Meta-Analysis as Topic ; *Diabetes Mellitus, Type 2/drug therapy ; Risk Factors ; },
abstract = {BACKGROUND: Diabetes is significantly associated with cognitive impairment, particularly the risk of developing dementia. However, the impact of antidiabetic drugs on dementia risk remains unclear. This study aims to comprehensively evaluate the effects of different antidiabetic drugs on dementia risk using Bayesian network analysis.

METHODS: The study systematically searched databases including PubMed, Embase, and the Cochrane Library to identify relevant publications up to September 5, 2025. Eligible randomized controlled trials, cohort studies, and case-control studies were selected. We employed a Bayesian network meta-analysis model to quantitatively assess the relationship between antidiabetic drugs and dementia risk. Data analysis was performed using R version 4.4.1.

RESULTS: A total of 28 articles (involving 4,382,897 patients), network meta-analysis results indicates that compared with placebo, Insulin [OR = 0.11, 95% CrI (0.1, 0.12)], Metformin [OR = 0.79, 95% CrI (0.77, 0.81)], and Pioglitazone [OR = 0.69, 95% CrI (0.56, 0.86)] all reduced the incidence of dementia compared to placebo, a higher incidence of Alzheimer's dementia[OR = 1.78, 95% CrI (1.66, 1.91)] and Vascular dementia[OR = 2.59, 95% CrI (2.33, 2.88)] with DPP4i compared to SGLT_2i.

CONCLUSION: This study indicate that insulin demonstrates the most pronounced efficacy in reducing the incidence risk of dementia and vascular dementia. Furthermore, SGLT_2i and GLP1 exhibit certain therapeutic benefits in the management of Alzheimer's disease.

https://www.crd.york.ac.uk/prospero/, identifier CRD420251172386.},
}

Humans
*Hypoglycemic Agents/therapeutic use
Bayes Theorem
*Dementia/epidemiology/prevention & control
Network Meta-Analysis as Topic
*Diabetes Mellitus, Type 2/drug therapy
Risk Factors

@article {pmid42064906,
year = {2026},
author = {Nguyen, T and Woods, C and Liu, J and Wang, C and Lin, AL and Cheng, J},
title = {A multimodal AI model for modeling the genetic risk factor of Alzheimer's disease.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.04.13.26350803},
pmid = {42064906},
abstract = {The apolipoprotein E ε 4 (APOE4) allele is the strongest genetic risk factor for late-onset Alzheimer's disease (AD), the most common form of dementia. APOE4 carriers exhibit cerebrovascular and metabolic dysfunction, structural brain alterations, and gut microbiome changes decades before the onset of clinical symptoms. Better understanding of the early manifestion of these physiological changes is critical for development of timely AD interventions and risk reduction protocols. Multi-modal datasets encompassing a wide range of APOE ε 4 and AD associated biomarkers provide a valuable opportunity to gain insight into the APOE4 phenotype; however, these datasets often present analytical challenges due to small sample sizes and high heterogeneity. Here, we propose a two-stage multimodal AI model (APOEFormer) that integrates blood metabolites, brain vascular and structural MRI, microbiome profiles, and other clinical and demographic data to predict APOE4 allele status. In the first stage, modality-specific encoders are used to generate initial representa-tions of input data modalities, which are aligned in a shared latent space via self-supervised contrastive learning during pretraining. The contrastive learning objective encourages learning of informative and consistent representations across modalities through leveraging cross-modality relationships. In the second stage, the pretrained representations are used as inputs to a multimodal transformer that integrates information across modalities to predict a key AD-risk genetic variant (APOE4). Across 10 independent experimental runs with different train-validation-test splits, APOEFormer predicts whether an individual carries an APOE4 allele with an average prediction accuracy of 75%, demonstrating robust performance under limited sample sizes. Post hoc perturbation analysis of the predictive model revealed valuable insights into the driving components of the APOE4 phenotype- including key blood biomarkers and brain regions strongly associated with APOE4.},
}

@article {pmid42064930,
year = {2026},
author = {Chandra, S},
title = {Virtual Spectral Decomposition of Plasma Biomarkers for Non-Invasive Detection of Cerebral Amyloid Pathology: A Multi-Channel Framework with Disease-Exclusion Logic.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.04.14.26350885},
pmid = {42064930},
abstract = {BACKGROUND: Detection of cerebral amyloid pathology currently requires amyloid PET imaging ($5,000-$8,000) or cerebrospinal fluid analysis via lumbar puncture, procedures that are inaccessible for population-level screening. The FDA-cleared Lumipulse G pTau217/Aβ1-42 plasma ratio test (May 2025) represents the first approved blood-based alternative; however, single-ratio approaches cannot distinguish Alzheimer's disease (AD) from non-AD neurodegeneration or provide multi-dimensional disease characterization.

METHODS: We developed Virtual Spectral Decomposition (VSD), a framework that decomposes plasma biomarker profiles into biologically interpretable diagnostic channels. Four plasma biomarkers-phosphorylated tau-217 (pTau217), amyloid-β42/40 ratio, neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP)-were measured in 1,139 Alzheimer's Disease Neuroimaging Initiative (ADNI) participants. Each biomarker was mapped to a VSD channel representing a distinct pathophysiological axis: tau/amyloid phosphorylation, amyloid clearance, neurodegeneration, and astrocytic activation. Channel weights were calibrated via logistic regression, and performance was evaluated against amyloid PET (UC Berkeley) using 10×5-fold repeated cross-validation.

RESULTS: VSD 4-channel fusion achieved AUC = 0.900 (±0.018), exceeding pTau217 alone (0.888±0.022). Optimal sensitivity was 89.7% with 78.1% specificity (NPV = 90.8%). The NfL channel received a negative weight (β = -1.1), functioning as a disease-exclusion signal: elevated neurodegeneration without amyloid-tau coupling actively reduces the AD probability, distinguishing AD from non-AD neurodegeneration. Complementary CSF proteomics analysis (7,008 proteins, 533 participants) identified 17 amyloid-specific proteins (0.24% of the proteome), revealing a 49:1 tau-to-amyloid asymmetry that explains why blood-based tau markers outperform amyloid markers.

CONCLUSIONS: Blood-based VSD provides an interpretable, multi-channel framework for amyloid detection that incorporates explicit disease-exclusion logic unavailable to single-biomarker approaches. The architecture extends to multi-disease screening, where the same blood specimen could be routed through disease-specific modules for AD, Parkinson's disease, and cancer.},
}

@article {pmid42064934,
year = {2026},
author = {Packer, A and Khatun, T and Groves, JW and Wyss-Coray, T and Schott, JM and Proitsi, P and Anderson, EL and Williams, DM},
title = {Plasma proteomics of APOE genotype: age-specific analyses in UK population-based cohorts.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.04.16.26351010},
pmid = {42064934},
abstract = {BACKGROUND: The apolipoprotein E (APOE) locus is the strongest genetic risk factor for late-onset Alzheimer's disease (AD). Variation in APOE isoforms is known to have diverse pleiotropic effects on circulating lipids and other metabolites, but effects on the circulating proteome across the life course are not well characterised. We investigated the specific effects of APOE ε4 and APOE ε2 carriage on the circulating proteome in middle-age and later life.

METHODS: In primary modelling, we analysed associations of APOE ε4 and ε2 carriage (reference ε3/ε3) with circulating proteins in UK Biobank participants (N = 42,642; age = 39.1 to 70.9 years). Using multivariable linear regression, we conducted ancestry-specific analyses of 2,922 assayed plasma proteins across individuals of European (EUR), African (AFR), and South Asian (SAS) ancestry. To identify age-dependent effects, stratified analyses were performed with the sample split into age groups. We then performed replication analyses of APOE -associated proteins in age-matched groups, using data from two independent UK-based cohorts.

RESULTS: We identified 351 proteins associated with ε2 carriage and 480 with ε4 carriage among individuals of European ancestry (n = 40,092); 130 of these were associated with both ε2 and ε4 carriage (with either consistent or inverse association directions). These included established biomarkers of neurodegeneration (GFAP and NEFL) and other proteins implicated by AD genetic risk loci (e.g., TREM2, CTSB, IDUA, SORT1, GRN). Many of these proteins are linked to other neurodegenerative diseases besides AD. In multiple age groups, ε4 carriage was strongly associated with consistent differences in circulating APOE, MENT, and PLA2G7 levels across ancestries and cohorts.

CONCLUSION: APOE ε4 and ε2 exert broad, often age-dependent effects on the plasma proteome, detectable decades before typical ages of AD diagnoses, highlighting a potential early window for monitoring and intervention.},
}

@article {pmid42064938,
year = {2026},
author = {Yang, S and Grilli, MD and Wootton, RE and van de Weijer, MP and Treur, JL and Klimentidis, YC and Sbarra, DA},
title = {Loneliness as a Pathway Linking Hearing Decline to Cognitive Aging: Longitudinal and Genetic Evidence.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.04.16.26351059},
pmid = {42064938},
abstract = {Age-related hearing loss is linked to loneliness and poorer cognitive health, but it remains unclear whether loneliness helps explain associations between hearing difficulties and cognitive performance or dementia, and whether these patterns reflect causal pathways or shared underlying liability. In this preregistered study, we triangulated analyses across multiple data sources spanning approximately 18 years of observational data with 8 sources of molecular genetic information to examine whether loneliness helps explain the association between hearing difficulty and cognitive performance, Alzheimer's disease dementia, and all-cause dementia, and whether hearing-aid use may buffer this association. In longitudinal parallel-process latent growth curve models (N = 10,375) using nine waves of longitudinal data from the Survey of Health, Ageing and Retirement in Europe (SHARE), poorer hearing was associated with greater loneliness, and greater loneliness was associated with poorer cognitive performance, consistent with partial mediation. In contrast, worsening hearing over time was not clearly associated with increasing loneliness over time. Cumulative hearing-aid use did not appear to alter long-term loneliness trajectories, although current hearing-aid use weakened the concurrent association between poorer hearing and greater loneliness. In genetic analyses, we found little evidence that hearing phenotypes or loneliness had clear total or indirect effects on Alzheimer's disease dementia or all-cause dementia. Analyses accounting for shared genetic liability with neuroticism provided some evidence linking loneliness with poorer cognitive performance, and colocalization analyses further suggested shared genetic architecture across hearing, loneliness, cognition, and neuroticism-related traits. Overall, the findings support a robust cross-domain association between poorer hearing, greater loneliness, and poorer cognitive performance, while suggesting that long-term change and genetic evidence are more consistent with shared liability than with a single causal pathway.},
}

@article {pmid42064944,
year = {2026},
author = {Sattari, N and Dave, A and Chen, IY and Lui, KK and Chappel-Farley, MG and Berisha, DE and Sprecher, KE and Riedner, BA and Jones, S and Bendlin, BB and Mander, BA and Benca, RM},
title = {Sex moderates apolipoprotein E ε4 effects on sleep expression and memory retention.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.04.16.26351049},
pmid = {42064944},
abstract = {INTRODUCTION: Sleep-dependent memory consolidation differs by sex and maybe disrupted by Alzheimer's disease (AD) risk. Whether sex moderates associations between apolipoprotein E ε4 (APOE ε4) status, non-rapid eye movement (NREM) sleep, and memory remains unclear.

METHODS: Eighty cognitively unimpaired older adults completed a word-pair memory task with encoding and immediate testing occurring prior to overnight polysomnography with high-density electroencephalography (hdEEG) and delayed recall occurring after sleep. Sleep-memory associations were examined as a function of sex and APOE ε4 status.

RESULTS: In this sample, a sex× APOE ε4 interaction was associated with overnight memory retention, with female carriers exhibiting less overnight forgetting than female non-carriers and male ε4 carriers. NREM sleep differed by sex and APOE ε4 status and was associated with memory retention in ε4 carriers.

DISCUSSION: These findings indicate sex-specific, sleep-dependent memory mechanisms associated with genetic AD risk, highlighting sleep as a potential early target for intervention, pending replication in larger samples.},
}

@article {pmid42064952,
year = {2026},
author = {Dintica, CS and Jiang, X and Shaw, LM and Bryan, RN and Yaffe, K},
title = {Cardiovascular Health at Midlife and Alzheimer Disease Biomarkers.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.04.15.26350968},
pmid = {42064952},
abstract = {BACKGROUND: Cardiovascular health factors are associated with cognitive decline and risk of dementia, including Alzheimer disease (AD); however, this has been mostly studied in late life. We investigated whether vascular and lifestyle factors are associated with AD plasma and imaging biomarkers in midlife.

METHODS: We investigated 1,406 participants from the Coronary Artery Risk Development in Young Adults (CARDIA) study with information on vascular and lifestyle factors framed from the American Heart Association (AHA) "life's essential 8" (LE8) guidelines for cardiovascular health at early midlife (mean age 45.0 ± SD 3.6) and AD biomarkers in late midlife (mean age 60 ± SD 3.5). LE8 was calculated and categorized into poor (0-49), intermediate (50-79), and ideal (80-100) cardiovascular health, based on 8 components including smoking, diet, body mass index (BMI), sleep, fasting glucose, blood pressure, cholesterol, and physical activity. We assessed the AD plasma biomarkers phosphorylated tau 217 (ptau-217) and amyloid beta 42/40 ratio (Aβ42/40) and the Spatial Pattern of Abnormality for Recognition of Early AD (SPARE-AD), an algorithm that characterizes AD-like brain atrophy on brain MRI. We used linear regression to examine the association between LE8 and log transformed and standardized AD biomarker measures adjusting for age, sex, race, education, and kidney function.

RESULTS: Compared to ideal LE8, intermediate (67.9% of participants) and poor (12.6%) LE8 was associated with lower Aβ42/40 (adjusted mean difference: -2.37, 95% CI: -2.38 to -2.36 and -2.38, 95% CI: -2.40 to -2.36, respectively). There was no association between the LE8 group and ptau-217 level. Moreover, compared to ideal LE8 participants, those with poor LE8 had higher SPARE-AD atrophy pattern (adjusted mean difference: -0.71, 95% CI: -0.81 to -0.62).

CONCLUSION: These findings indicate that poor cardiovascular health in midlife, as defined by the AHA LE8, is linked to less favorable early AD biomarker profiles, particularly reflecting greater amyloid burden and structural brain changes.},
}

@article {pmid42064953,
year = {2026},
author = {Dintica, CS and Porwal, G and Caunca, M and Fleming, N and Bryan, RN and Yaffe, K},
title = {The Association Between Social Determinants of Health and Alzheimer Disease Blood Biomarkers in Midlife.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.04.13.26350798},
pmid = {42064953},
abstract = {BACKGROUND: Social determinants of health (SDOH) are increasingly recognized as contributors to Alzheimer disease (AD) risk, yet the impact of multidimensional social disadvantage early AD-related pathophysiology remains poorly understood.

METHODS: We studied 1,466 participants from the Coronary Artery Risk Development in Young Adults (CARDIA) cohort with SDOH assessed in early midlife (mean age 40 ± 3.6 years) and plasma AD biomarkers measured 20 years later. A comprehensive SDOH index was constructed from 12 indicators spanning five domains (economic stability, education, neighborhood and physical environment, community and social context, and health care access). We examined associations between SDOH quartile and log-transformed, standardized plasma phosphorylated tau 217 (p-tau217), neurofilament light chain (NfL), and amyloid-β42/40 (Aβ42/40) using linear regression adjusted for age, sex, race, and estimated glomerular filtration rate. Linear trends across SDOH quartile were also evaluated.

RESULTS: Participants in the most disadvantaged SDOH quartile had higher p-tau217, higher NfL and lower Aβ42/40 level compared with those in the least disadvantaged quartile (p-tau 217: β = 0.12, 95% CI 0.03-0.21, p = 0.008; NfL: β = 0.20, 95% CI 0.05-0.35, p = 0.009; Aβ42/40: β = -0.15, 95% CI -0.30-0.00, p=0.05). There was also a significant trend across quartile (p-tau 217: p for trend = 0.012; NfL: p for trend =0.001). Analyses of individual SDOH domains indicated that lower economic stability, poorer health care access, and lower education were associated with higher NfL, and poorer health care access was associated with higher p-tau217.

CONCLUSIONS: Greater SDOH disadvantage in early midlife was associated with higher levels of plasma AD biomarkers reflecting AD pathology and neurodegeneration decades later. These findings suggest that social disadvantage during midlife may contribute to early AD-related biological changes and highlight potentially modifiable social factors relevant for dementia prevention.},
}

@article {pmid42065103,
year = {2025},
author = {Cunningham, R},
title = {AMAZING PAPERS in NEUROSCIENCE: Teaching Neurodevelopment Through the Discovery of Adult Neurogenesis.},
journal = {Journal of undergraduate neuroscience education : JUNE : a publication of FUN, Faculty for Undergraduate Neuroscience},
volume = {24},
number = {1},
pages = {102-105},
pmid = {42065103},
issn = {1544-2896},
abstract = {Neurogenesis is a critical process in neurodevelopment, contributing to the formation and function of the central nervous system (CNS). Historically, neurogenesis was thought to occur only during embryonic development. However, Eriksson et al. (1998) conducted the first study to confirm neurogenic regions within the adult human brain, using postmortem brain tissue to establish the presence of adult neurogenesis. This study identified adult neurogenesis to be present specifically within the dentate gyrus of the hippocampus, marking a groundbreaking advancement in neurodevelopmental research. The findings from this study highlight the significance of adult neurogenesis, which is now implicated in learning, memory, and in the understanding of neurological disorders such as Alzheimer's Disease. Integrating this study into undergraduate education introduces students to a pivotal moment in the history of neurodevelopmental research, highlighting its lasting impact on adult neurogenesis research. The study's manageable length, use of immunofluorescent techniques, and relevance to both basic and clinical neuroscience make it an ideal resource for undergraduate education. Students can develop their skills in critical thinking, scientific literacy, and appreciation of methodological innovation in neuroscience - all while learning and deepening their understanding of the importance of neurodevelopment.},
}

@article {pmid42065338,
year = {2026},
author = {Li, FB and Ma, XT and Yao, LL and Liu, SW and Weng, XF and Liu, CF and Hu, H},
title = {Homocysteine Is Associated With Cognitive Impairment and Sarcopenia in Alzheimer's Disease.},
journal = {Psychogeriatrics : the official journal of the Japanese Psychogeriatric Society},
volume = {26},
number = {3},
pages = {e70172},
doi = {10.1111/psyg.70172},
pmid = {42065338},
issn = {1479-8301},
support = {62475179//National Natural Science Foundation of China/ ; ZDXK202217//Jiangsu Provincial Medical Key Discipline/ ; SYW2024081//Suzhou Applied Basic Research (Medical health) Science and Technology Innovation Project - Youth project/ ; ND2023A01//Research Project of Neurological Diseases in the Second Affiliated Hospital of Soochow University Research Center/ ; ND2024A01//Research Project of Neurological Diseases in the Second Affiliated Hospital of Soochow University Research Center/ ; SDFEYLC2343//Pre-research Fund Project for Clinical Application at the Second Affiliated Hospital of Soochow University/ ; //Brain Health Youth Fund - Precision Diagnosis and Treatment of Alzheimer's Disease Research in 2024/ ; 24QL200210//Suzhou Medical College-QiLu Medical Research Program of Soochow University/ ; },
mesh = {Humans ; *Alzheimer Disease/blood/complications/psychology ; *Sarcopenia/blood/epidemiology ; Male ; *Homocysteine/blood ; Female ; Aged ; *Cognitive Dysfunction/blood/diagnosis ; Neuropsychological Tests ; Aged, 80 and over ; Middle Aged ; Case-Control Studies ; },
abstract = {OBJECTIVE: To investigate differences in neuropsychological characteristics between patients with Alzheimer's disease (AD) with and without sarcopenia, and to examine their associations with serum homocysteine (HCY) levels.

METHODS: A total of 41 patients with AD diagnosed at a memory clinic with Aβ-PET confirmation were enrolled, including 21 patients with sarcopenia (ADSa) and 20 without sarcopenia (ADNSa). In addition, 35 cognitively normal individuals were recruited as normal controls (NCs) from a health examination center. Demographic characteristics, sarcopenia-related parameters, neuropsychological assessments, and serum HCY levels were collected. Group differences in neuropsychological performance and HCY levels were compared, and partial correlation analyses were performed after adjustment for potential confounders.

RESULTS: HCY levels were significantly higher in the AD group than in the NC group. The AD group had a higher prevalence of sarcopenia, and its muscle strength, mass, and physical function were significantly worse than those of the NC group (all p < 0.05). The AD-NSa group performed worse on neuropsychological tests such as MoCA, DST, BNT, and AFT. After adjusting for confounding factors, HCY was positively correlated with CDR and five-times sit-to-stand test scores and negatively correlated with MMSE, DSST, and ASMI scores (all p < 0.01). Using a logistic regression model to calculate the odds ratio (OR), the significant correlation between HCY levels and AD status remained after adjusting for potential confounding factors (all p < 0.01).

CONCLUSION: Elevated serum HCY levels are significantly associated with sarcopenia and multidimensional cognitive impairment in patients with AD. In an AD cohort with amyloid pathology confirmed by Aβ-PET, this study provides the first integrative analysis of the associations among HCY, sarcopenia, and cognitive function. These findings suggest that HCY may represent a potential biomarker linking the comorbidity of AD and sarcopenia and may offer a theoretical basis for dual-target interventions addressing both HCY metabolism and muscle function in this vulnerable population.},
}

Humans
*Alzheimer Disease/blood/complications/psychology
*Sarcopenia/blood/epidemiology
Male
*Homocysteine/blood
Female
Aged
*Cognitive Dysfunction/blood/diagnosis
Neuropsychological Tests
Aged, 80 and over
Middle Aged
Case-Control Studies

@article {pmid42065434,
year = {2026},
author = {Majerníková, N and Corci, B and Zhang, Y and Chen, T and van Koeveringe, M and Mensinga, D and Mulder, PPMFA and Verpoorte, E and Mattarei, A and Pendin, D and Mammucari, C and Åberg, C and den Dunnen, W and Dolga, AM},
title = {Microfluidic compartmentalization reveals that ferrostatin-1 restores directional mitochondrial transport in Aβ-challenged neurons.},
journal = {Lab on a chip},
volume = {},
number = {},
pages = {},
doi = {10.1039/d5lc00834d},
pmid = {42065434},
issn = {1473-0189},
abstract = {Mitochondrial dysfunction is a hallmark of neurodegenerative diseases, including Alzheimer's disease (AD). While ferroptosis has been implicated in AD through iron accumulation and amyloid β (Aβ)-mediated toxicity, its role in mitochondrial regulation remains unclear. Here, we examined whether mitochondrial dysfunction in AD increases neuronal vulnerability to ferroptosis and whether ferroptosis inhibition can preserve mitochondrial network integrity. Primary cortical neurons were cultured in a multi-compartment microfluidic platform that facilitated high-resolution tracking of mitochondrial dynamics using time-lapse microscopy. Prolonged exposure to the ferroptosis inducer erastin disrupted neuronal networks, whereas acute exposure to erastin or Aβ significantly enhanced retrograde mitochondrial transport. These effects were blocked by the ferroptosis inhibitor ferrostatin-1 (Fer-1). Using a novel mitochondrial calcium probe (mt-Fura 2.3 AM), we further demonstrated that Aβ acutely increased mitochondrial calcium, which was ameliorated by Fer-1 and by inhibition of the mitochondrial calcium uniporter with MCUi4. In contrast, Aβ-induced hyperactivity recorded on a microelectrode array was prevented by MCUi4, but not Fer-1. Together, these results show that ferroptotic stress profoundly impacts mitochondrial movement and calcium regulation in neurons. Our multimodal microfluidic approach establishes a direct mechanistic link between ferroptosis, mitochondrial dysfunction, and neuronal vulnerability in AD, offering new insights into therapeutic targeting of ferroptosis in neurodegeneration.},
}

@article {pmid42065441,
year = {2026},
author = {Getachew, J and Carlsson, A and Axell, E and Thacker, D and Olsson, U and Linse, S},
title = {The chaperone DNAJB6b halts amyloid formation through association with transient Aβ oligomers.},
journal = {Physical chemistry chemical physics : PCCP},
volume = {},
number = {},
pages = {},
doi = {10.1039/d6cp00678g},
pmid = {42065441},
issn = {1463-9084},
abstract = {Oligomers are transient toxic species in amyloidoses such as Alzheimer's disease. The binding of oligomers by human chaperone proteins has been inferred from the lack of detectable interactions with monomeric amyloid proteins and delay of fibril formation at sub-stoichiometric chaperone to monomer molar ratios. In this study, we provide direct experimental evidence for the binding of the human chaperone DNAJB6b (JB6) to amyloid peptide oligomers formed during an ongoing fibril formation process leading to the stabilization of these transient species. JB6 is a potent inhibitor of the aggregation of multiple amyloid peptides and here we observe the inhibition of the model amyloid-β (Aβ) 20-34 peptide at an astounding sub-stoichiometric 1 : 100 000 ratio of chaperone to amyloid peptide. Through microfluidic diffusional sizing, we detect an increase in the average hydrodynamic radius of JB6 when added to the supernatant of samples withdrawn from an ongoing fibril formation process, implying an interaction with transient non-monomeric Aβ20-34 and Aβ42 species, which we interpret as oligomers. Furthermore, the oligomer stability towards dissociation was studied using the same method. The results imply that JB6 stabilizes the oligomers against dissociation.},
}

@article {pmid42065636,
year = {2026},
author = {Behler, C and Fay, M and Ramadan, S and Breakspear, M and Behler, A},
title = {Neurophysiology of brain temperature dysregulation in humans.},
journal = {Journal of neurophysiology},
volume = {},
number = {},
pages = {},
doi = {10.1152/jn.00418.2025},
pmid = {42065636},
issn = {1522-1598},
support = {//Tour de Cure (TDC)/ ; //Mark Hughes Foundation Centre for Brain Cancer Research/ ; },
abstract = {Brain temperature, a fundamental modulator of neural function, remains dramatically understudied despite its critical role in health and disease. This review synthesizes current understanding of brain thermoregulation and its disruption in neurological conditions, addressing a significant knowledge gap in neuroscience. We examined the physiological mechanisms maintaining brain temperature homeostasis, including the interplay between cerebral blood flow, metabolism, and cerebrospinal fluid dynamics. Analysis of publication trends reveals brain temperature research is underrepresented by 7- to 37-fold compared to other brain physiological parameters, despite comparable clinical relevance. We evaluated current non-invasive measurement techniques, particularly magnetic resonance-based thermometry, highlighting advances and limitations for clinical application. The review presents evidence for distinct temperature dysregulation patterns in neurological diseases. In Alzheimer's disease, we propose a theoretical framework of early-stage hyperthermia driven by neuroinflammation and hypermetabolism, transitioning to late-stage hypothermia with metabolic decline. Brain tumors exhibit contrasting thermal profiles: glioblastomas frequently present as hypothermic due to necrotic cores acting as metabolic voids, while melanoma metastases show hyperthermia from sustained metabolic activity. These temperature alterations may influence disease progression through effects on protein aggregation, cellular metabolism, and neuron-glial interactions. Looking forward, brain temperature monitoring could provide biomarkers for disease staging and treatment response. Additionally, understanding thermal limits becomes urgent as climate change exposes vulnerable populations with compromised thermoregulation to extreme heat. This review establishes brain temperature as an overlooked but essential axis in neurophysiology, calling for increased research attention to address fundamental questions about thermal regulation in health and disease.},
}

@article {pmid42065913,
year = {2026},
author = {Ouyang, X and Xiang, Y and Tan, L and Zou, J and Long, Y and Ning, K and Zhang, S and Wang, F and Liu, T and Huang, D and Liu, H and Zhang, G},
title = {Targeting PPAR Signaling for Neurovascular Protection: Advances in Natural Product-Based Therapeutics.},
journal = {Aging and disease},
volume = {},
number = {},
pages = {},
doi = {10.14336/AD.2026.0094},
pmid = {42065913},
issn = {2152-5250},
abstract = {Central nervous system diseases such as ischemic stroke, cerebral hemorrhage and Alzheimer's disease have high fatality and disability rate. Their common pathological mechanisms involve neuroinflammation, oxidative stress, mitochondrial dysfunction and blood-brain barrier damage. As a ligand-dependent nuclear transcription factor, peroxisome proliferator activated receptor (PPARs) plays a key role in lipid metabolism, energy homeostasis and inflammation regulation. In particular, PPAR-γ shows significant neurovascular protective effect through multiple signaling axes such as NF-κB, Nrf2 and AMP-activated protein kinase (AMPK). In recent years, a large number of studies have confirmed that a variety of natural products (e.g., flavonoids, phenolic acids, glycosides and triterpenes) can activate or regulate the PPAR pathway, mediate anti-inflammatory, antioxidant, prevent blood-brain barrier damage and promote neurotrophic factor expression, thereby improving the pathological phenotype of ischemic or degenerative encephalopathy. In addition, some components (such as Stevioside, Catalpol, Morin, etc.) have shown potential PPAR regulatory ability, but lack direct validation in encephalopathy models, and are worth further exploration. In conclusion, natural products targeting PPAR signal have the comprehensive advantages of multiple pathways and multiple targets, which represent an important direction for the intervention of cerebrovascular diseases. In the future, we should strengthen the verification of "component pathway phenotype" association, combine multi-omics and structural optimization strategies, so as to promote the development of natural product PPAR modulators to precision and transformation applications.},
}

@article {pmid42065921,
year = {2026},
author = {Eslick, S and Kee-Mun, IC and Chatterjee, P and Jerome, S and Halliwell, B and Martins, R},
title = {The Relationship between Ergothioneine, Allantoin and Neocortical Amyloid Load.},
journal = {Aging and disease},
volume = {},
number = {},
pages = {},
doi = {10.14336/AD.2026.0091},
pmid = {42065921},
issn = {2152-5250},
abstract = {Alzheimer's disease (AD) is characterised by hallmark pathology of amyloid beta (Aβ) plaques and hyperphosphorylated tau neurofibrillary tangles in the brain. Ergothioneine (ET) is a potent antioxidant, and anti-inflammatory compound that has shown potential as a therapeutic for neurodegenerative disease*. Cross-sectional analyses of cognitively normal individuals aged 65-90yrs from the Kerr Anglican Retirement Village Initiative in Ageing Health (KARVIAH) cohort were stratified by amyloid status (Aβ+, SUVR >1.35). Plasma ET, its metabolites and urinary allantoin, were quantified by liquid chromatography-mass spectrometry. Plasma Aβ1-40, Aβ1-42, GFAP, and NFL were measured by SIMOA and pTau181 and pTau231 were measured via ELISA. No differences in plasma ET or metabolites were observed between AB- (n=65) and AB+ (n=35) groups. Partial correlation analysis highlighted positive correlations between allantoin, and NFL (r = 0.40, pFDR < 0.01), pTau181 (r = 0.47, pFDR < 0.01) and GFAP (r = 0.31, pFDR = 0.01). Partial correlation by subgroup, revealed positive correlations between plasma ET (r = 0.48, pFDR = 0.05) with Aβ42/40 in the AB+ group only. Evidence indicates that ET may protect the brain from oxidative damage and neuroinflammation. Higher urinary allantoin levels were associated with higher plasma AD biomarkers. Further, plasma ET levels were higher in individuals with a higher AB42/40 ratio, within the AB+ group, suggestive that high ET may potentially have neuroprotective effects. More research will be imperative to validate the significance of ET as a therapeutic for prevention of cognitive decline.},
}

@article {pmid42066672,
year = {2026},
author = {Mast, N and Bederman, I and El-Darzi, N and Pikuleva, IA},
title = {CYP46A1 activation by low-dose efavirenz uncovers the link between brain cholesterol metabolism, energetics, and vasculature.},
journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie},
volume = {199},
number = {},
pages = {119470},
doi = {10.1016/j.biopha.2026.119470},
pmid = {42066672},
issn = {1950-6007},
abstract = {CYP46A1 converts cholesterol to 24-hydroxycholesterol, the principal mechanism for brain cholesterol removal and turnover. CYP46A1 can be allosterically activated with low-dose anti-HIV drug efavirenz and mitigate the manifestations of various neurologic diseases in mouse models and Niemann-Pick type C disease in humans. Yet the underlying reasons for such a broad range of efavirenz therapeutic effects are currently unknown. Here 5XFAD mice, a model of Alzheimer's disease, were treated with low-dose efavirenz, and assessed for changes in their brain proteome, acetylproteome, and metabolome. Sex-independent increases in brain levels of phosphatidylcholines, sphingomyelins, and certain amino acids were documented, and various functional enrichments were identified. The most notable related to brain energy production, vascularization, and prevention of glutamatergic overactivation. Unexpectedly, these and many other enrichments were mediated by different proteins in female and male 5XFAD mice. Efavirenz treatment of 5XFAD mice was repeated, and energy-related compounds were quantified in the brain after in vivo isotopic labeling. Cerebral vasculature was assessed as well. We found increased glycolysis branching, carbon flux through the tricarboxylic acid cycle, and use of alternative energy sources (fatty acids, ketone bodies, and amino acids). Sex-independent improvements in brain vascularization and integrity of the blood-brain barrier were also documented. Collectively, our data suggested that CYP46A1 activation by efavirenz increases brain metabolic flexibility and thereby brain energetics. This enables the increase in production of the building blocks for cellular and tissue repair and rescue of brain pathology, thus explaining the therapeutic benefits for the broad spectrum of neurologic disorders.},
}

@article {pmid42066770,
year = {2026},
author = {Xie, J and Dai, XJ and Li, Q and Zhang, W and Nie, X and Ji, H and Chen, X and Wang, Y and Feng, J and Li, Z and Liu, Q and Ye, J and Zhang, G and Nie, S},
title = {Escherichia coli Nissle 1917 alleviates Alzheimer's disease in mice through OmpA-containing outer membrane vesicles.},
journal = {Cell reports. Medicine},
volume = {},
number = {},
pages = {102781},
doi = {10.1016/j.xcrm.2026.102781},
pmid = {42066770},
issn = {2666-3791},
abstract = {Gut microbiota dysbiosis is a driving factor in Alzheimer's disease (AD), yet the mechanisms behind remain elusive. Emerging evidence highlights that outer membrane vesicles (OMVs) are critical mediators of microbiota-host communication. Here, we observed a reduction in a gut probiotic Escherichia coli Nissle 1917 (EcN)-like strain in AD patients, and its levels are positively associated with cognitive ability. The EcN OMVs containing outer membrane protein A (OmpA) translocate to the brain, reshaping the dysregulated immune network. Specifically, EcN OMVs are internalized by glia and neurons, suppressing glial hyperactivation and restoring synaptic function, thereby reducing Aβ deposition and cognitive deficits. The results further show that OmpA plays an important role in vesicle trafficking and inflammatory pathways and may be the key regulator of inflammatory mediators in EcN OMVs, modulating astrocyte-microglia-neuron interactions and functionality. This work discloses the substantial therapeutic potential of the probiotic and its secreted OMVs in intervention and treatment of neurological disorders.},
}

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

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

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

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

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

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

GRAPHICAL ABSTRACT: [Image: see text]

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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