@article {pmid42862306,
year = {2026},
author = {Sahu, S and Jain, P and Dharme, KK and Yadav, K},
title = {CRISPR/Cas9-based nanodelivery systems for precision gene editing in neuroinflammation.},
journal = {Inflammation research : official journal of the European Histamine Research Society ... [et al.]},
volume = {75},
number = {1},
pages = {},
pmid = {42862306},
issn = {1420-908X},
support = {Probecell/Res/2026/124//Probecell Scientific Pvt. Ltd./ ; },
mesh = {Humans ; Animals ; *Neuroinflammatory Diseases/genetics/therapy ; *Gene Editing/methods ; *CRISPR-Cas Systems ; Nanoparticles/administration & dosage ; },
abstract = {BACKGROUND: Neuroinflammation is a characteristic feature of many neurological diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. Uncontrolled activation of microglia and astrocytes results in the production of proinflammatory mediators that contribute to neuronal dysfunction and degeneration.

PURPOSE: CRISPR/Cas9 genome-editing technology provides highly precise targeting of genes involved in these pathways, enabling the deletion, correction, or modulation of disease-associated genetic alterations. Nonetheless, effective delivery of CRISPR components to the central nervous system (CNS) remains a major challenge because of protective barriers such as the blood-brain barrier (BBB), as well as concerns regarding genomic instability and immunogenicity.

METHODS: Nanotechnology-guided delivery platforms, such as lipid nanoparticles, liposomes, dendrimers and polymeric carriers, have been developed as promising strategies to address these challenges. These nanosystems can improve biodistribution, pharmacokinetic behavior, and cellular uptake, while potentially reducing off-target effects and systemic toxicity.

RESULTS: The preclinical studies demonstrate successful modulation of key neuroinflammatory targets, including the NLRP3 inflammasome, triggering receptor expressed on myeloid cells 2 (TREM2), Janus kinase (JAK) signaling, and the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway, with potential therapeutic relevance to neurodegenerative diseases. In addition, novel techniques, such as mitochondrial base editing, prime editing, and epigenetic modulation, expand the scope of CRISPR-mediated therapeutic strategies. Although outcomes from animal models are promising, translation to the clinical setting requires careful consideration of safety, ethical concerns, and long-term efficacy.

CONCLUSIONS: This review highlights the potential of integrating CRISPR/Cas9 with nanodelivery systems to advance precision medicine for neuroinflammatory disorders, while emphasizing their potential for therapeutic applications in complex CNS conditions. Ongoing studies aimed at optimizing delivery and reducing off-target effects will be essential for advancing these approaches toward clinical practice.},
}

Humans
Animals
*Neuroinflammatory Diseases/genetics/therapy
*Gene Editing/methods
*CRISPR-Cas Systems
Nanoparticles/administration & dosage

@article {pmid42862409,
year = {2026},
author = {Singh, S and Ayaz, A and Ansari, O and Farooqi, H and Narang, J},
title = {Multiplexed impedimetric zinc oxide nanorods-modified aptasensor on carbon ink-inscribed paper electrodes for the specific and sensitive co-detection of Alzheimer's and Parkinson's disease.},
journal = {Biomedical microdevices},
volume = {28},
number = {4},
pages = {},
pmid = {42862409},
issn = {1572-8781},
mesh = {Humans ; *Carbon/chemistry ; *Paper ; *Parkinson Disease/diagnosis ; *Biosensing Techniques/instrumentation ; *Alzheimer Disease/diagnosis ; *Aptamers, Nucleotide/chemistry ; Electrodes ; *Nanotubes/chemistry ; Amyloid beta-Peptides/analysis ; *Zinc Oxide/chemistry ; Limit of Detection ; *Ink ; *Electrochemical Techniques/instrumentation ; alpha-Synuclein ; },
abstract = {Neurodegenerative diseases, including Alzheimer's disease (AD) and Parkinson's disease (PD), represent a growing health burden, while early diagnosis remains challenging because established diagnostic approaches, including cerebrospinal fluid analysis and neuroimaging, are invasive, expensive, and unsuitable for decentralized point-of-care testing. Recent progress in electrochemical and paper-based biosensors has enabled low-cost, portable, and multiplexed biomarker analysis. However, their clinical translation remains limited by low biomarker concentrations, matrix interference, nonspecific adsorption, sensor-to-sensor variability, storage stability, and the need for validation using clinical samples. Herein, a paper-based multiplex electrochemical aptasensor was developed for simultaneous impedimetric detection of amyloid beta-42 (Aβ-42) and alpha synuclein-60 (αS-60), biomarkers associated with AD and PD, respectively. The device comprised screen-printed carbon and silver electrodes on a cellulose substrate, two independently functionalized working electrodes, zinc oxide nanorods (ZnO-NRs) as electroactive signal-amplification layers, and target-specific DNA aptamers as biorecognition elements. Electrochemical impedance spectroscopy was used for label-free measurement of target-induced changes in charge-transfer resistance. The sensor exhibited a linear response from 0.1 ng/mL to 10 µg/mL for both biomarkers, with limits of detection of 4.41 ng/mL for Aβ-42 and 2.62 ng/mL for αS-60. The platform further detected both analytes in artificial cerebrospinal fluid and artificial saliva, demonstrating that the paper-based sensing interface remains responsive in physiologically mimicked matrices. Overall, this study provides a low-cost, disposable, label-free, and multiplexed proof-of-concept platform for simultaneous AD- and PD-associated biomarker detection. Although the system demonstrates promising performance in artificial matrices, further optimization of sensitivity, surface immobilization, antifouling behaviour, long-term storage, and validation using real clinical saliva and CSF samples will be required before practical diagnostic deployment.},
}

Humans
*Carbon/chemistry
*Paper
*Parkinson Disease/diagnosis
*Biosensing Techniques/instrumentation
*Alzheimer Disease/diagnosis
*Aptamers, Nucleotide/chemistry
Electrodes
*Nanotubes/chemistry
Amyloid beta-Peptides/analysis
*Zinc Oxide/chemistry
Limit of Detection
*Ink
*Electrochemical Techniques/instrumentation
alpha-Synuclein

@article {pmid42862481,
year = {2026},
author = {de Oliveira Maciel, VCB and de Moura Arruda, J and Silva, RC and da Rosa, MM},
title = {PPARγ Signaling in the Central Nervous System: A Review of the Implications in Synaptic Plasticity, Neuroinflammatory and Neoplastic Processes.},
journal = {Neurochemical research},
volume = {51},
number = {5},
pages = {},
pmid = {42862481},
issn = {1573-6903},
mesh = {Humans ; *Neuronal Plasticity/physiology ; Animals ; *PPAR gamma/metabolism ; *Signal Transduction/physiology ; *Neuroinflammatory Diseases/metabolism ; *Central Nervous System/metabolism ; PPAR-gamma Agonists ; },
abstract = {Peroxisome proliferator activated receptor gamma (PPARγ) is a ligand activated nuclear receptor traditionally associated with lipid and glucose metabolism. Emerging evidence, however, identifies PPARγ as a central immunometabolic regulator in the central nervous system (CNS), coordinating mitochondrial function, neuroinflammation, synaptic plasticity, and neurovascular integrity. Beyond its classical metabolic actions, PPARγ regulates microglial activation, astrocytic inflammatory responses, oxidative stress, and mitochondrial biogenesis, thereby influencing neuronal resilience and circuit stability. This narrative review synthesizes knowledge of PPARγ structure, activation, CNS distribution, endogenous ligands, and synthetic agonists, including thiazolidinediones and selective modulators. We highlight how PPARγ controls transcriptional programs related to energy homeostasis, inflammatory signaling, including NF κB dependent pathways, and blood brain barrier function. Attention is devoted to synaptic remodeling and plasticity, positioning PPARγ as a molecular bridge between metabolic state and neuronal adaptability. We propose that PPARγ signaling dysregulation represents a convergent mechanism in neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, and adrenoleukodystrophy; psychiatric conditions, such as depression and anxiety; and neurooncological processes. Integrating evidence across these conditions supports PPARγ as a master regulator of neuroimmune metabolic coupling in the brain. Finally, we discuss translational challenges and opportunities, including brain penetrant, functionally selective ligands, clarification of cell type specific signaling, and expansion of rigorous clinical trials. Integrating mechanistic, preclinical, and clinical trial evidence, this review critically examines the therapeutic potential of PPARγ across neurodegenerative, psychiatric, and neurooncological CNS conditions, while identifying priorities for future therapeutic development in diverse brain disorders.},
}

Humans
*Neuronal Plasticity/physiology
Animals
*PPAR gamma/metabolism
*Signal Transduction/physiology
*Neuroinflammatory Diseases/metabolism
*Central Nervous System/metabolism
PPAR-gamma Agonists

@article {pmid42862512,
year = {2026},
author = {Geng, C and Chen, C},
title = {Plasma p-tau217 and neurodegeneration-related biomarkers predict incident cognitive impairment in obstructive sleep apnea: a prospective cohort study.},
journal = {Sleep & breathing = Schlaf & Atmung},
volume = {30},
number = {6},
pages = {},
pmid = {42862512},
issn = {1522-1709},
mesh = {Humans ; *Sleep Apnea, Obstructive/blood/complications/epidemiology ; Biomarkers/blood ; Prospective Studies ; Female ; Male ; *Cognitive Dysfunction/blood/diagnosis/etiology/epidemiology ; *tau Proteins/blood ; Middle Aged ; Neurofilament Proteins/blood ; Amyloid beta-Peptides/blood ; Polysomnography ; Cohort Studies ; Aged ; Adult ; Incidence ; },
abstract = {BACKGROUND: Obstructive sleep apnea (OSA) is associated with cognitive decline, but biomarkers for identifying cognitively unimpaired patients at increased future risk remain limited. We evaluated the prognostic value of plasma biomarkers associated with neuroaxonal injury and Alzheimer's disease-related biology in OSA.

METHODS: In this prospective cohort study, 286 cognitively unimpaired adults with polysomnography-confirmed OSA underwent baseline measurement of plasma NfL, GFAP, p-tau181, p-tau217, Aβ42, and Aβ40 and were followed for incident cognitive impairment. Cox regression, predictive performance analyses, and linear mixed-effects models were used.

RESULTS: During a median follow-up of 4.18 years, 68 participants (23.78%) developed incident cognitive impairment. In fully adjusted Cox models, each 1-SD increase in NfL was associated with a 46% higher risk of incident cognitive impairment (HR = 1.46, 95% CI 1.17-1.83, P = 0.001), and each 1-SD increase in p-tau217 was associated with a 58% higher risk (HR = 1.58, 95% CI 1.25-2.00, P < 0.001). When modeled jointly, both NfL (HR = 1.34, 95% CI 1.06-1.69, P = 0.014) and p-tau217 (HR = 1.47, 95% CI 1.14-1.89, P = 0.003) remained associated with incident cognitive impairment. In longitudinal analyses, higher baseline NfL and p-tau217 were also associated with faster annual declines in MoCA scores when modeled jointly (NfL × time: β = -0.10, 95% CI - 0.18 to - 0.02, P = 0.014; p-tau217 × time: β = -0.16, 95% CI - 0.25 to - 0.07, P = 0.001). Adding both biomarkers to the clinical model increased the C-index from 0.72 to 0.81 and the 4-year time-dependent AUC to 0.81; the optimism-corrected C-index was 0.79.

CONCLUSIONS: Higher plasma NfL and p-tau217 levels were independently associated with incident cognitive impairment and faster longitudinal cognitive decline in cognitively unimpaired patients with OSA.},
}

Humans
*Sleep Apnea, Obstructive/blood/complications/epidemiology
Biomarkers/blood
Prospective Studies
Female
Male
*Cognitive Dysfunction/blood/diagnosis/etiology/epidemiology
*tau Proteins/blood
Middle Aged
Neurofilament Proteins/blood
Amyloid beta-Peptides/blood
Polysomnography
Cohort Studies
Aged
Adult
Incidence

@article {pmid42862590,
year = {2026},
author = {Molina-Henry, DP and Liu, A and Langford, O and Raman, R and Dass, D and Clark, E and Day, GS and Okhravi, HR and Joshi, P and Cazares, P and Turner, RS and Braunstein, JB and Verghese, P and Venkatesh, V and West, T and Dhadda, S and Irizarry, M and Johnson, K and Rissman, RA and Grill, JD and Aisen, P and Sperling, RA},
title = {Plasma Phosphorylated Tau 217 Percentage by Race and Ethnicity in Preclinical Alzheimer Disease.},
journal = {JAMA neurology},
volume = {},
number = {},
pages = {},
doi = {10.1001/jamaneurol.2026.3598},
pmid = {42862590},
issn = {2168-6157},
abstract = {IMPORTANCE: In trials targeting preclinical Alzheimer disease (AD), defined as amyloid pathology without cognitive symptoms, racial and ethnic differences in plasma phosphorylated tau 217 percentage (%p-tau217) may influence screening eligibility.

OBJECTIVE: To characterize racial and ethnic differences in %p-tau217 and determine whether associations between %p-tau217, cognition, and amyloid positron emission tomography (PET) differ across groups.

This was a cross-sectional analysis of AHEAD 3-45 screening participants conducted from July 2020 to October 2024 at 106 sites across 4 world regions. Adults aged 55 to 80 years with %p-tau217 measured before medical and cognitive exclusions (N = 15 612) were included.

EXPOSURES: Self-reported race (Asian, Black, and White) and ethnicity (Hispanic and non-Hispanic) and apolipoprotein E ε4 (APOE ε4) carrier status.

MAIN OUTCOMES AND MEASURES: %p-tau217 levels and associations of %p-tau217 with Preclinical Alzheimer Cognitive Composite 5 (PACC5) score and amyloid PET were evaluated across racial and ethnic groups using multivariable linear regression.

RESULTS: Among 15 612 participants, the mean (SD) age was 68.4 (6.2) years; 9941 (63.7%) were female and 5755 (36.9%) were APOE ε4 carriers. %p-tau217 levels were lower among Asian, Black, and Hispanic participants than among White and non-Hispanic participants. APOE ε4 status was associated with higher %p-tau217 across all groups. The association between APOE ε4 status and %p-tau217 differed by race (APOE ε4 × race: F2,14 973 = 10.06; P < .001) and ethnicity (APOE ε4 × ethnicity: β, 0.042; 95% CI, 0.017 to 0.067; P = .005) (Asian: β, 0.05; 95% CI, 0.02 to 0.08; P = .01; Black: β, 0.05; 95% CI, 0.03 to 0.08; P = .002; Hispanic: β, 0.04; 95% CI, 0.02 to 0.07; P = .005). The %p-tau217-PACC5 association showed no pairwise differences across racial groups but differed by ethnicity (β, -0.53; 95% CI, -0.85 to -0.21; P = .008) and APOE ε4 × ethnicity (β, 0.78; 95% CI, 0.26 to 1.30; P = .02). The %p-tau217-PET association showed no significant pairwise differences across racial groups but differed by ethnicity (β, -6.30; 95% CI, -9.10 to -3.51; P < .001) and APOE ε4 × ethnicity (β, 7.12; 95% CI, 2.52 to 11.73; P = .01).

CONCLUSIONS AND RELEVANCE: In this cross-sectional study, plasma %p-tau217 varied across racial and ethnic groups. Consistent %p-tau217-PACC5 score and %p-tau217-PET associations across racial groups support plasma-based screening before PET confirmation, while ethnicity-related findings warrant further investigation.},
}

@article {pmid42862637,
year = {2026},
author = {Gupta, A},
title = {Using Alzheimer's Disease Cerebrospinal Fluid Biomarkers in CKD: A Caution for Clinicians.},
journal = {Journal of the American Society of Nephrology : JASN},
volume = {},
number = {},
pages = {},
pmid = {42862637},
issn = {1533-3450},
}

@article {pmid42862642,
year = {2026},
author = {Lin, Y and Garcia Ptacek, S and Eriksdotter, M and Xu, H},
title = {Authors' Reply: Using Alzheimer's Disease Cerebrospinal Fluid Biomarkers in CKD: A Caution for Clinicians.},
journal = {Journal of the American Society of Nephrology : JASN},
volume = {},
number = {},
pages = {},
pmid = {42862642},
issn = {1533-3450},
}

@article {pmid42862762,
year = {2026},
author = {Howe, MD and Zide, BS and Hayes, K and Ross, D and Barker, MS and Kunicki, ZJ and Rudolph, J and Huey, E},
title = {Symptom-Guided Blood Biomarker Testing for Alzheimer's Disease.},
journal = {Dementia and geriatric cognitive disorders},
volume = {},
number = {},
pages = {1},
doi = {10.1159/dem/aciag010},
pmid = {42862762},
issn = {1421-9824},
abstract = {Introduction Blood-based biomarkers can accurately detect Alzheimer's disease (AD) pathology, but symptom-guided testing approaches are understudied. This study evaluated the utility of early symptom and biomarker changes in predicting cognitive decline due to AD. Methods We analyzed data from the Alzheimer's Disease Neuroimaging Initiative-2 (development, n=603) and -3 (validation, n=378). The primary outcome was 4-year progression to mild cognitive impairment or dementia associated with amyloid-beta neuropathology. Machine learning estimated baseline symptom burden from subjective ratings. Logistic regression calculated area under the curve (AUC), relative risk, and time-to-event. Results Symptom burden predicted clinical progression (AUC=0.79), which further improved with blood biomarkers (AUC=0.90). Participants with elevated symptoms and biomarkers had a progression incidence of 72.1% and a 19-fold higher progression risk. Findings replicated in validation. Conclusion Findings underscore the potential of pairing symptoms and biomarkers to more efficiently and accurately detect AD cases at risk of clinical progression. Trial Parent study registrations: NCT01231971; NCT02854033.},
}

@article {pmid42862765,
year = {2026},
author = {Cihák, M and Bezdicek, O and Horáková, H and Motýl, J and Vyhnálek, M and Nikolai, T},
title = {Uniform Dataset 3 Neuropsychological Battery: Czech Normative Study of a Battery assessing cognitive functioning in older adults.},
journal = {Dementia and geriatric cognitive disorders},
volume = {},
number = {},
pages = {1},
doi = {10.1159/dem/aciag011},
pmid = {42862765},
issn = {1421-9824},
abstract = {INTRODUCTION: The Uniform Data Set Neuropsychological Battery, version 3 (UDSNB 3), is a comprehensive, non-proprietary tool designed to assess cognitive domains relevant to neurodegenerative disorders, particularly Alzheimer's disease. This study aimed to establish Czech norms for the UDSNB 3, including the Lewy body disease module, using continuous norming methods.

METHODS: A normative sample of 171 cognitively healthy adults aged 50 - 95 years was recruited. Participants completed the Czech adaptation of the UDSNB 3. Continuous norming was performed using a semi-parametric approach. Education and age effects were examined, and selected scores were compared with previous Czech normative studies.

RESULTS: Cognitive performance generally declined with age across measures. Compared to previous Czech normative studies, differences were small and inconsistent across tests.

DISCUSSION: The present study provides the first Czech normative data for UDSNB 3 using continuous norming approach, supporting its clinical applicability. Continuous norming appears to be a viable approach for developing norms in contexts of countries with limited resources or smaller populations, where collecting large stratified samples of older adults can be difficult.},
}

@article {pmid42862793,
year = {2026},
author = {Ffrench-Constant, C},
title = {Does perturbed adaptive myelination contribute to cognitive dysfunction in Alzheimer's disease?.},
journal = {PLoS biology},
volume = {24},
number = {10},
pages = {e3004033},
pmid = {42862793},
issn = {1545-7885},
mesh = {*Alzheimer Disease/physiopathology/pathology/metabolism ; Humans ; Oligodendroglia/metabolism/pathology/physiology ; *Myelin Sheath/pathology/metabolism/physiology ; Animals ; *Cognition Disorders/physiopathology/pathology ; Gray Matter/pathology/metabolism ; },
abstract = {The consequences of oligodendrocyte involvement in Alzheimer's disease are poorly understood. Could a key role of gray-matter oligodendrocytes-activity-dependent adaptive myelination to sustain changes in activity-be perturbed, leading to cognitive loss?},
}

*Alzheimer Disease/physiopathology/pathology/metabolism
Humans
Oligodendroglia/metabolism/pathology/physiology
*Myelin Sheath/pathology/metabolism/physiology
Animals
*Cognition Disorders/physiopathology/pathology
Gray Matter/pathology/metabolism

@article {pmid42863052,
year = {2026},
author = {Zussy, C and Mathias, M and Vitalis, M and Moujellil-Legagneur, T and Malhaire, F and Canet, G and Desrumaux, C and Claeysen, S and Gómez-Santacana, X and Goudet, C and Llebaria, A and Givalois, L},
title = {Shedding light on left hippocampal mGlu5 in Alzheimer's disease.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {123},
number = {42},
pages = {e2535413123},
doi = {10.1073/pnas.2535413123},
pmid = {42863052},
issn = {1091-6490},
support = {MND202003011477-OPA//Fondation pour la Recherche Médicale (FRM)/ ; MUSE-AAP20REC-FRS09-GAiA//Université de Montpellier (UM)/ ; ANR-22-CE14-0042-EpiNeurAge//Agence Nationale de la Recherche (ANR)/ ; ANR-11-LABEX-0021-LipSTIC//Agence Nationale de la Recherche (ANR)/ ; 10.13039/501100011033//Ministerio de Ciencia e Innovación, Agencia Estatal de Investigación/ ; PID2020-120499RB-I00//EC | European Regional Development Fund (ERDF)/ ; 2021 SGR 00508//Catalan government/ ; ANR-22-CE36-0003-DENTALCOG//Agence Nationale de la Recherche (ANR)/ ; },
mesh = {Animals ; *Alzheimer Disease/metabolism/physiopathology/genetics/pathology ; *Receptor, Metabotropic Glutamate 5/metabolism/genetics ; *Hippocampus/metabolism/physiopathology ; Mice ; Mice, Transgenic ; Disease Models, Animal ; Signal Transduction ; Humans ; Glycogen Synthase Kinase 3 beta/metabolism ; Male ; },
abstract = {Metabotropic glutamate receptor 5 (mGlu5) is essential for synaptic plasticity and memory, making it a potential therapeutic target in Alzheimer's disease (AD). While hemispheric asymmetries in hippocampal function have been observed in AD patients, the lateralized contribution of mGlu5 signaling to cognitive decline remains unclear. Here, we show a physiological left-right asymmetry in hippocampal mGlu5 expression in wild-type mice, with higher levels in the left hemisphere, consistent with previous reports. This physiological asymmetry is lost in two distinct mouse models of AD, the J20 and 5xFAD mice, revealing a hemisphere-specific disruption of hippocampal mGlu5 regulation. Using the light-controllable negative allosteric modulator Alloswitch-1, we show that selective inhibition of left, but not right, hippocampal mGlu5 restores working and short-term memory in AD mice. This finding indicates that altered mGlu5 expression does not simply reflect receptor loss, but rather a dysregulated signaling state that remains functionally relevant and pharmacologically targetable. Left-specific modulation also normalizes pathological downstream signaling, including aberrant Pyk2 and GSK-3β activation and tau hyperphosphorylation, across both hemispheres, indicating a widespread impact of hemisphere-selective intervention. These findings establish a functional lateralization of hippocampal mGlu5 signaling and identify the left hippocampus as a critical site for mGlu5-dependent memory dysfunction in AD. They also highlight the therapeutic potential of region-specific photopharmacology for precise intervention in early AD pathology, providing a strategy for spatially targeted modulation of pathological synaptic signaling in neurodegenerative disease.},
}

Animals
*Alzheimer Disease/metabolism/physiopathology/genetics/pathology
*Receptor, Metabotropic Glutamate 5/metabolism/genetics
*Hippocampus/metabolism/physiopathology
Mice
Mice, Transgenic
Disease Models, Animal
Signal Transduction
Humans
Glycogen Synthase Kinase 3 beta/metabolism
Male

@article {pmid42863225,
year = {2026},
author = {Basavaraju, KC and Priyadarshini, P},
title = {Targeting tau acetylation in Alzheimer's disease: Molecular mechanisms, pathological consequences, and therapeutic opportunities of dietary phytochemicals.},
journal = {Biochemical and biophysical research communications},
volume = {839},
number = {},
pages = {154717},
doi = {10.1016/j.bbrc.2026.154717},
pmid = {42863225},
issn = {1090-2104},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterised by cognitive decline, synaptic dysfunction, and neuronal loss. Emerging evidence identifies tau acetylation as a crucial post-translational modification that contribute significantly to tauopathies associated pathology in AD. Aberrant tau acetylation results in autophagy dysregulation, DNA damage, altered lipid metabolism, endoplasmic reticulum (ER) stress, and neuroinflammation ultimately leading to cognitive decline and neuronal death. Dysregulation of acetyltransferases such as p300/CBP and reduced deacetylase activity, including sirtuins, further promote pathological tau accumulation and propagation. Dietary phytochemicals have emerged as promising multi-targeted neuroprotective agents due to their antioxidant, anti-inflammatory, and epigenetic regulatory properties. Notably, studies investigating dietary phytochemicals that directly regulate tau acetylation remain very limited, making this an important and promising area for future research. Nevertheless, several dietary phytochemicals have been reported to modulate the activities of SIRT1 and EP300 across a range of experimental models and various disease conditions. Future investigations should focus on incorporating these dietary phytochemicals into experimental models of AD to elucidate their potential to modulate tau acetylation and associated pathogenic mechanisms. Such studies will provide critical insights into their therapeutic potential and may facilitate the development of novel phytochemical-based interventions for tau acetylation in AD. This review provides a comprehensive overview of the mechanisms by which tau acetylation contributes to AD pathology and highlights therapeutic opportunities of dietary phytochemicals.},
}

@article {pmid42863333,
year = {2026},
author = {Zhu, W and Tang, R and Wu, F and Yi, L and Ouyang, Y and Zhang, Z},
title = {Structure-activity relationship of uronic acid oligosaccharides as potential anti-Alzheimer's disease agents.},
journal = {Carbohydrate research},
volume = {570},
number = {},
pages = {110126},
doi = {10.1016/j.carres.2026.110126},
pmid = {42863333},
issn = {1873-426X},
abstract = {Alzheimer's disease (AD) is the most common neurodegenerative disorder and the primary cause of dementia. Although natural polysaccharides exhibit significant therapeutic potential against AD due to their multi-target activities, the structure-activity relationship (SAR) of uronic acid oligosaccharides-particularly the influence of specific glycosidic linkages and monosaccharide compositions-remains insufficiently characterized. To address this, we utilized a highly selective TEMPO oxidation system to prepare four structurally distinct uronic acid oligosaccharides (α1,4-G, β1,4-G, β1,3-G, and β1,4-M/G) from diverse natural polysaccharides. NMR spectroscopy showed that the resulting oligosaccharides retained the major glycosidic linkage characteristics of their parent polysaccharides, while oxidation and depolymerization also occurred during the reaction. Comprehensive in vitro and in vivo evaluations demonstrated that the β-1,4-glycosidic linkage is a critical structural determinant for neuroprotective activity against Aβ-induced neuronal damage and cognitive impairment, while β1,4-M/G and β1,4-G showed different effects under the present experimental conditions. Mechanistic studies revealed that both β1,4-G and β1,4-M/G ameliorated Aβ-induced cognitive impairment and were associated with alterations in the gut microbiota and related metabolites. Importantly, fermentation products generated from these oligosaccharides by the AD microbiota were associated with enhanced Treg differentiation, which may potentially contribute to the observed neuroprotective effects. These findings provide systematic insights into the SAR of uronic acid oligosaccharides and support the further investigation of β-1,4-linked uronic acid oligosaccharides as potential neuroprotective candidates.},
}

@article {pmid42863347,
year = {2026},
author = {Zhao, J and Qu, L and Guan, H and Che, H and Shi, F and Yang, Y},
title = {Immunosenescence as a modifiable driver of neurodegenerative diseases: Pathways and multidimensional emerging strategies for Alzheimer's and Parkinson's diseases.},
journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics},
volume = {23},
number = {6},
pages = {e01096},
doi = {10.1016/j.neurot.2026.e01096},
pmid = {42863347},
issn = {1878-7479},
abstract = {Immunosenescence represents a core upstream driver of Alzheimer's disease (AD) and Parkinson's disease (PD), exerting its pathological effects through four mechanistically interconnected cascades: chronic inflammatory imbalance mediated by the senescence-associated secretory phenotype (SASP), oxidative stress arising from immune-metabolic reprogramming, protein homeostasis dysfunction caused by autophagy-lysosomal failure, and disrupted neuro-immune crosstalk secondary to breakdown of central nervous system (CNS) immune privilege. Current clinical practice remains largely constrained to neurotransmitter-based symptomatic management, which can neither arrest upstream pathological progression nor restore lost neuronal populations. Emerging intervention strategies targeting immunosenescence, including senolytic agents, antioxidant and metabolic modulators, autophagy restoration, and precision-targeted nanocarrier delivery, have demonstrated substantial capacity to delay disease progression in preclinical and early clinical investigations. These strategies act through selective clearance of senescent immune cells, remodeling of the neuroinflammatory microenvironment, and restoration of cellular quality-control mechanisms. The multidimensional treatment strategy approaches from the perspectives of artificial intelligence (AI) guided target discovery, nanocarrier engineering, and gut microbiota intervention to simultaneously address multiple nodes in the immunosenescence network, thereby overcoming the inherent limitations of single-target strategies. This review consolidates current mechanistic evidence and translational data to establish immunosenescence as an actionable therapeutic target and to provide a conceptual framework for precision disease-modifying therapy in AD and PD.},
}

@article {pmid42863362,
year = {2026},
author = {Zhou, Z},
title = {Uncovering the mechanism of gastrodin in treating Alzheimer's disease through bioinformatics, machine learning, and virtual gene knockout technology.},
journal = {Computational biology and chemistry},
volume = {126},
number = {Pt 2},
pages = {109464},
doi = {10.1016/j.compbiolchem.2026.109464},
pmid = {42863362},
issn = {1476-928X},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline. Gastrodin is a natural compound with neuroprotective activity; however, the precise molecular mechanisms underlying its therapeutic effects on human AD remain unclear. This study employed bioinformatics approaches to systematically elucidate the therapeutic mechanisms of gastrodin in AD. Pharmacokinetic analysis showed that gastrodin exhibited favorable drug-like properties (bioavailability score: 0.55; LogP: -0.85) and an acceptable overall toxicity profile, although predicted nephrotoxicity (0.71) and ototoxicity (0.908) scores suggest potential safety concerns warranting further investigation. Next, differentially expressed genes (DEGs) associated with AD were screened from GEO datasets, yielding 13 core targets that overlapped with gastrodin-responsive genes. Functional enrichment analysis indicated significant enrichment of these targets in signaling pathways closely related to neuroinflammation and cell survival, including the Ras-proximate 1 (Rap1), Ras, mitogen-activated protein kinase (MAPK), and phosphatidylinositol 3-kinase-protein kinase B (PI3K-Akt) pathways. The Ridge model achieved AUCs of 0.898 in the training set and 0.859 in the GSE37263 cohort, but showed modest generalizability in the GSE138260 cohort (AUC = 0.684), highlighting the heterogeneity of external datasets. Further single-cell transcriptomic analysis revealed specific upregulation of insulin-like growth factor 1 receptor (IGF1R) in brain endothelial cells of AD patients. Virtual gene knockout simulations demonstrated that IGF1R knockout substantially disrupted core networks associated with endothelial functions and neurovascular homeostasis, including focal adhesion and calcium signaling pathways. Finally, molecular docking and molecular dynamics (MD) simulations revealed stable binding conformations of gastrodin to EGFR and MET, while the gastrodin-IGF1R complex exhibited a more dynamic binding behavior with conformational flexibility, suggesting an induced-fit binding mechanism. MM/PBSA calculations revealed favorable enthalpic contributions (ΔH = -17.43, -13.63, and -10.41 kcal/mol for EGFR, IGF1R, and MET, respectively) for gastrodin-target binding. In conclusion, this study suggests that gastrodin exerts multi-target effects via coordinated regulation of multiple signaling pathways. Notably, gastrodin targets IGF1R in brain endothelial cells, modulating focal adhesion/calcium signaling networks, thus providing a novel mechanistic hypothesis for AD treatment by restoring neurovascular unit homeostasis.},
}

@article {pmid42863472,
year = {2026},
author = {Hategan, LA and Luo, JQ and Creighton, SD and Pirri, F and McLean, TAB and Hua, S and Dahi, TA and Jin, Z and Winston, SM and Reeves, IL and Johnston, K and Fahnestock, M and Brimble, MA and Walters, BJ and Murphy, PJ and Zovkic, IB},
title = {The histone variant H2A.Z regulates sex differences in Alzheimer's disease pathophysiology.},
journal = {Neuron},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuron.2026.09.019},
pmid = {42863472},
issn = {1097-4199},
abstract = {Alzheimer's disease (AD) disproportionately affects women, yet mechanisms underlying this sex difference remain unclear. Histone variants are overrepresented components of aging neuronal chromatin, but their contribution to AD is unknown. Here, we identify the histone variant H2A.Z as a sex-specific regulator of AD in the postmortem human hippocampus and in 5xFAD mice. H2A.Z occupancy decreased in female but increased in male AD patients. In females, reduced H2A.Z occupancy at the transcription start site (TSS) occurred despite increased total H2A.Z, indicating that H2A.Z is redistributed to sites of lower H2A.Z occupancy. Similar sex-dependent alterations were observed in 5xFAD mice over disease progression. Whereas H2A.Z.1 depletion improved memory and AD pathology in females at early and late disease stages, it impaired memory in male mice at early stages and improved memory in late stages. Together, these data identify H2A.Z as a regulator of sex- and stage-dependent AD outcomes, with implications for the sex-specific therapeutic targeting of chromatin factors.},
}

@article {pmid42863578,
year = {2026},
author = {Said, G and Ramos da Silva, AS and da Silva Rodrigues, G},
title = {EXERCISE, DNA METHYLATION, AND ALZHEIMER'S DISEASE: MECHANISTIC LINKS AND FUTURE DIRECTIONS IN INTERGENERATIONAL RESEARCH.},
journal = {Ageing research reviews},
volume = {},
number = {},
pages = {103415},
doi = {10.1016/j.arr.2026.103415},
pmid = {42863578},
issn = {1872-9649},
abstract = {Alzheimer's disease (AD) is the most common cause of dementia and remains without a cure; recently introduced disease-modifying therapies provide only modest slowing in selected patients. Physical exercise is associated with better cognitive and functional outcomes, but the molecular mechanisms underlying these benefits remain incompletely understood. DNA methylation is a potential interface linking environmental stimuli to gene regulation and neural function. This narrative review examines evidence connecting exercise, DNA methylation, and AD, with emphasis on AD-related loci and on the possible intergenerational implications of parental exercise. We examine methylation findings involving amyloid precursor protein (APP) and presenilin-1 (PSEN1), which are relevant to amyloid-β production; microtubule-associated protein tau (MAPT), which encodes tau; and apolipoprotein E (APOE), which influences lipid transport and amyloid-β clearance. These findings suggest potential epigenetic contributions to AD-related biology, although their direction and functional significance vary across studies. We also discuss exercise-responsive pathways involved in energy sensing, autophagy, and redox signaling. We also evaluate whether exercise-associated epigenetic remodeling could influence amyloid-β accumulation, Tau homeostasis, and neuronal function. Evidence that exercise modifies DNA methylation is growing, whereas studies that integrate exercise interventions, genome-wide methylation, and AD-related outcomes remain scarce. Evidence for an inherited reduction in AD susceptibility is even more limited and currently supports a hypothesis rather than an established mechanism. Future studies integrating behavioral, neuropathological, cell-type-resolved epigenomic, and other multi-omic outcomes are needed to determine whether exercise-induced DNA methylation changes mediate neuroprotection in AD or primarily reflect broader physiological adaptation.},
}

@article {pmid42863610,
year = {2026},
author = {Xu, Q and Zhao, H and Zhang, H and Zhao, Y and Ju, A and Chen, H and Liu, H},
title = {Microplastics detection in freshly harvested human brain tissues of northeast Chinese postmortem donors and their correlation with Alzheimer's disease- related pathological proteins.},
journal = {Neurotoxicology},
volume = {},
number = {},
pages = {103588},
doi = {10.1016/j.neuro.2026.103588},
pmid = {42863610},
issn = {1872-9711},
abstract = {Microplastics (MPs) and nanoplastics (NPs) (MNPs) have been linked to various health risks, but their presence in the human brain and association with Alzheimer's disease (AD)-related pathological proteins remain poorly understood. In this study, superior temporal gyrus tissues of 16 northeast Chinese postmortem donors were analyzed via pyrolysis-gas chromatography-mass spectrometry (Py-GC/MS) and laser direct infrared spectroscopy (LDIR) to characterize MNPs, while AD-related pathological proteins Aβ and p-tau levels in the hippocampus were detected by immunohistochemical staining and quantified by H-score. Py-GC/MS quantification revealed polymers corresponding to polyethylene (PE), polyvinyl chloride (PVC), polystyrene (PS) and polypropylene (PP) in all samples, with PE as the dominant type (63.3% of total polymers concentrations). The overall mean concentration of these four polymers was 105.70μg/g ranging from 24.69μg/g to 184.77μg/g. LDIR of four selected samples further identified 17 additional types of MPs besides the aforementioned four; additionally, 80.8% of MPs had diameters smaller than 60 μm, and 84.7% were spherical and irregular in shape. Exploratory multiple linear regression suggested positive associations of PE and PS with Aβ levels. This study provided evidence of plastic polymers in fresh human brain tissue and established a preliminary association between polymers burden and AD-related pathological proteins, might provide a valuable basis for future studies investigating the association between MNPs and AD.},
}

@article {pmid42863691,
year = {2026},
author = {Urano, Y and Maeda, W and Noguchi, N},
title = {Inhibition of glycan sialylation reduces amyloid-β secretion via suppression of amyloid-β exocytosis.},
journal = {Biochimie},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.biochi.2026.10.016},
pmid = {42863691},
issn = {1638-6183},
abstract = {Among nutrient-sensitive regulatory mechanisms, protein glycosylation is a key post-translational modification that links metabolism to protein function. Amyloid-β (Aβ) peptides play a crucial role in the pathogenesis of Alzheimer's disease (AD). Because excessive accumulation of Aβ is believed to drive AD progression, approaches that reduce Aβ production and secretion remain of considerable therapeutic interest. Accumulating evidence suggests that protein glycosylation influences the processing and trafficking of amyloid-β precursor protein (APP) and other proteins involved in Aβ metabolism. However, while N-linked protein glycosylation has been shown to affect Aβ production, the specific contribution of protein terminal glycan sialylation remains incompletely understood. In this study, we investigated the effects of inhibiting glycan sialylation on Aβ production using CHO cells stably expressing human APP. Treatment with the sialyltransferase inhibitor P-3Fax-Neu5Ac (P-3Fax) significantly reduced extracellular Aβ levels, while intracellular Aβ levels were increased. Importantly, P-3Fax treatment did not alter β-secretase- or γ-secretase-mediated cleavage of their substrates, indicating that changes in secretase activity do not account for the reduction in extracellular Aβ. In addition, P-3Fax treatment markedly reduced plasma membrane levels of lysosome-associated membrane protein 1 (LAMP1), consistent with impaired lysosomal exocytosis. Taken together, these results indicate that inhibition of sialylation by P-3Fax reduces extracellular Aβ levels independently of secretase activity, potentially through impaired lysosomal exocytotic pathways. Our findings identify glycan sialylation as a key regulatory factor in Aβ trafficking and provide new insight into the cellular mechanisms controlling Aβ homeostasis.},
}

@article {pmid42863694,
year = {2026},
author = {Tanahashi, M and Kozuka, A and Sasakawa, N and Niikura, T},
title = {Humanin attenuates neuronal cellular senescence and preserves neurotransmitter release in differentiated PC12 cells.},
journal = {Neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuroscience.2026.10.017},
pmid = {42863694},
issn = {1873-7544},
abstract = {Cellular senescence, characterized as a permanent arrest of cell proliferation, is triggered by various types of stress. Senescent cells are identified by markers, including senescence-associated β-galactosidase (SA-β-gal) activity and the secretion of senescence-associated secretory phenotype (SASP) factors. These senescent phenotypes have been observed in neurons, suggesting that cellular senescence may contribute to the pathogenesis of neurodegenerative diseases. Humanin (HN), an endogenous short peptide, mitigates Alzheimer's disease-associated pathologies, including amyloid β-induced neuronal cell death. Overexpression of HN extends the lifespan of nematodes, suggesting a potential anti-aging role for this peptide. Here, we first investigated the effect of HN on cellular senescence in mouse primary cortical neurons. Chronic treatment with HNG, a highly potent HN derivative, attenuated prolonged culture-induced senescence. To further determine whether this anti-senescent effect is associated with preserved exocytotic function, we employed a glutamate-induced senescence model in neuronal-differentiated PC12 cells. In this system, HNG mitigated changes in senescence-associated markers, including increases in SA-β-gal activity, Ki67 expression, and SASP factor expression. In addition, acetylcholine-induced dopamine release was reduced in senescent PC12 cells, whereas chronic HN treatment sustained the expression levels of synapsin 1 and synaptophysin and attenuated the senescence-associated decrease in neurotransmitter release. These findings suggest that HN suppresses senescence and sustains exocytosis activity in neuronal cells, supporting an anti-aging function of HN at the cellular level.},
}

@article {pmid42863717,
year = {2026},
author = {Tukiran, N and Kolb, T and Maggioni, L and Rai, S and Rafath, Z and Borsini, A},
title = {Cytokine dysregulation and hippocampal neurogenesis: A shared mechanism underlying cognitive impairments across neuropsychiatric and neurodegenerative disorders.},
journal = {Brain, behavior, and immunity},
volume = {},
number = {},
pages = {107069},
doi = {10.1016/j.bbi.2026.107069},
pmid = {42863717},
issn = {1090-2139},
abstract = {Neuropsychiatric and neurodegenerative disorders, such as major depressive disorder, bipolar disorder, schizophrenia, Alzheimer's disease, and Parkinson's disease, all show a neuroimmune signature with dysregulated inflammatory cytokine profile and cognitive impairment. Although these deficits are clinically relevant, the immunological mechanisms that cause cognitive dysfunction across these conditions remain poorly defined. Recent studies demonstrate that inflammatory cytokines actively modulate adult hippocampal neurogenesis, a process critical for learning, memory, and affective regulation. Here, we synthesise clinical evidence to characterise the disorder-specific inflammatory profile of each of these five disorders, representing each profile with three frequently dysregulated cytokines rather than a single cytokine signature shared across conditions. We also integrate preclinical data where cytokines induce behavioural, cognitive, and hippocampal-related deficits in animal and cellular models. Hence, this review develops a mechanistic framework that links brain-immune communication directly to cognitive impairment through hippocampal neurogenesis, thereby suggesting neuroimmune targets for therapeutic intervention.},
}

@article {pmid42863728,
year = {2026},
author = {Li, Y and Tang, ZL and Liu, FW and Chen, M and Chang, SQ and Ding, FM and Bian, QL and Pan, JP and Qiu, ZC and Kong, MW and Li, Y and Chen, JX},
title = {Si-Shen-San Attenuates Alzheimer's Disease Pathology and Cognitive Deficits Through Multi-Target Regulation of Astrocyte Function and Synaptic Plasticity.},
journal = {Journal of ethnopharmacology},
volume = {},
number = {},
pages = {122475},
doi = {10.1016/j.jep.2026.122475},
pmid = {42863728},
issn = {1872-7573},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder pathologically characterized by cognitive decline, amyloid-β (Aβ) deposition, tau hyperphosphorylation, synaptic dysfunction, and astrocyte dysregulation. The constituent herbs of the traditional Chinese medicine formula Si-Shen-San (SSS) have been used to ameliorate cognitive impairment. However, the comprehensive chemical profile, core bioactive constituents, and underlying mechanisms of action of SSS remain to be fully elucidated.

AIM OF THE STUDY: This study aims to systematically investigate the therapeutic potential of SSS against AD and to clarify its multi-faceted mechanisms of action, with a focus on astrocyte-mediated neuroprotection, synaptic repair, and modulation of core AD pathologies.

MATERIALS AND METHODS: Ultra-high performance liquid chromatography-quadrupole/time-of-flight mass spectrometry (UHPLC-Q/TOF-MS) was used to characterize the chemical constituents of SSS extract and SSS-containing serum. In vivo, 3×Tg-AD mice were orally administered SSS. And cognitive function, AD-related pathology, synaptic integrity, and astrocyte-associated molecular changes were evaluated using behavioral, histological, biochemical, ultrastructural, and electrophysiological approaches. In vitro, an astrocyte-conditioned medium paradigm was used to examine whether SSS-induced changes in astrocytes were associated with protection of HT22 neurons against glutamate-induced injury.

RESULTS: UHPLC-Q/TOF-MS tentatively annotated 525 and 318 compounds in the SSS extract and drug-containing serum. In 3×Tg-AD mice, SSS improved cognitive performance, reduced hippocampal 6E10- and ThS-positive Aβ-like immunoreactivity and tau phosphorylation at Thr231 and Ser404, and preserved synaptic structure and function. The reduction in tau phosphorylation was accompanied by changes in GSK-3β signaling. SSS treatment was also associated with reduced astrocyte reactivity, increased GLT-1 expression, and restoration of astrocyte-associated homeostatic markers. In vitro, conditioned medium derived from SSS-treated C8-D1A astrocytes alleviated glutamate-induced injury in HT22 neurons and was accompanied by activation of neuronal CREB-BDNF signaling.

CONCLUSION: SSS ameliorated cognitive deficits and multiple AD-related pathological alterations in 3×Tg-AD mice. These effects were associated with restoration of astrocyte-related homeostatic features, improved glutamate regulation, preservation of synaptic integrity, and activation of CREB-BDNF signaling. These findings provide an experimental foundation for SSS as a potential therapeutic strategy for AD and highlight astrocyte homeostasis as a promising target for future drug development.},
}

@article {pmid42864178,
year = {2026},
author = {Ko, JS and Jung, W and Suh, PS and Heo, H and Shim, WH and Kim, DH and Lee, SH and Kim, M and Lee, N and Kim, S and Kim, SJ and Suh, CH},
title = {Automated Structured Reporting of Neurodegenerative Imaging Markers Using Quantitative MRI and Large Language Models.},
journal = {Academic radiology},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.acra.2026.09.056},
pmid = {42864178},
issn = {1878-4046},
abstract = {RATIONALE AND OBJECTIVES: To evaluate the feasibility of a quantitative magnetic resonance imaging (MRI)-to-structured reporting pipeline that integrates quantitative MRI software with large language models (LLMs) for structured drafting of neurodegenerative imaging markers and generating clinician-facing report conclusions.

MATERIALS AND METHODS: A total of 192 patients with 3D T1 and 2D or 3D FLAIR MRI images from the Alzheimer's Disease Neuroimaging Initiative database were randomly selected. A deep-learning model generated structured report findings based on nine indices related to brain atrophy, white matter hyperintensities, and cerebrospinal fluid (CSF) space abnormalities, and compared with neuroradiologist-generated reference reports. Four LLMs (GPT-OSS 20B, MedGemma 4B, Phi-3, and Llama 3.1 8B) generated clinician-facing conclusions from the structured findings. Generated conclusions were evaluated using a five-point Likert scale across four metrics (accuracy, relevance, clarity, and satisfaction). Output errors were assessed across four categories: language, omission, addition, and numeric errors.

RESULTS: Structured report findings demonstrated high accuracy for CSF space analysis (77.6%-97.9%). Performance for ordinal visual scales was lower under strict matching (27.1%-57.8%) but improved with a one-grade tolerance (91.7%-97.4%). Among LLMs, GPT achieved the highest scores across most metrics (median score 5) and exhibited the lowest output error rates. Smaller models (Phi-3 and Llama 3.1 8B) showed overall lower performance, with more language, omission, and addition errors. MedGemma demonstrated intermediate performance, but the highest rate of numeric errors.

CONCLUSION: Our quantitative MRI-to-structured reporting pipeline, integrating quantitative MRI software with LLM-based conclusion generation, might be feasible for automated structured drafting of neurodegenerative imaging markers.},
}

@article {pmid42864446,
year = {2026},
author = {Cao, H and Fu, Y and Zhou, X and Duan, Y and Ip, FCF and Chen, Y and Hu, S and Liu, SC and Kwok, TCY and Mok, KY and Cheung, TH and Hardy, J and Fu, AKY and Ip, NY},
title = {Genome-wide analysis of common structural variants in Alzheimer's disease identifies a risk-associated regulatory CCG repeat in FAM193B.},
journal = {Nature neuroscience},
volume = {},
number = {},
pages = {},
pmid = {42864446},
issn = {1546-1726},
support = {C6027-19GF//Research Grants Council, University Grants Committee (RGC, UGC)/ ; T13-605/18W//Research Grants Council, University Grants Committee (RGC, UGC)/ ; AoE/M-604/16//University Grants Committee (UGC)/ ; InnoHK, ITCPD/17-9, ITS/207/18FP, MRP/042/18X//Innovation and Technology Commission (ITF)/ ; },
abstract = {Although Alzheimer's disease (AD) has a polygenic architecture, with numerous associated single-nucleotide polymorphisms (SNPs) identified, the contribution of structural variants (SVs) is unclear. In this study, using long-read (n = 11) and short-read (n = 3,190) sequencing data from the Chinese population, we show that common SVs contribute to AD heritability beyond common SNPs. We identify an expanded CCG repeat in the FAM193B promoter that shows a genome-wide significant association with increased AD risk (odds ratio = 2.20 per 10-repeat increase, P = 5.5 × 10[-13]). The expanded FAM193B-CCG repeat increases FAM193B expression and mediates the pleiotropic association between brain FAM193B expression and AD risk. Analyses of postmortem human brains and cultured neuronal cells show that elevated neuronal FAM193B expression is associated with DNA damage and cell death-related pathways. These findings establish the common FAM193B-CCG repeat as an AD risk genetic factor and highlight the contribution of common SVs to AD heritability.},
}

@article {pmid42864510,
year = {2026},
author = {Zhang, C and Bai, L and Shi, D and Li, W and Ai, L and Ao, F and Bai, Y and Bai, Y and Bao, H and Cai, Q and Cao, J and Chai, L and Chen, F and Chen, F and Chen, K and Chen, Y and Cheng, D and Cole, J and Cui, Z and Dai, H and Deng, D and Du, X and Du, Y and Duan, X and Fu, Y and Gao, Z and Gou, L and Guo, C and Guo, M and Guo, Y and Han, X and He, H and Hou, Y and Hu, B and Hu, J and Hua, T and Huang, C and Huang, P and Lei, J and Li, H and Li, J and Li, J and Li, K and Li, K and Li, S and Li, X and Li, Y and Li, Y and Li, Y and Li, Y and Liang, P and Liao, H and Liao, L and Lin, B and Lin, CP and Liu, J and Liu, J and Liu, W and Liu, Y and Lu, S and Luo, J and Luo, Y and Lui, S and Ma, H and Mao, N and Meng, L and Meng, L and Qiu, J and Shao, J and Shen, Q and Shi, Y and Shu, Z and Tian, D and Tu, Y and Wang, F and Wang, J and Wang, J and Wang, J and Wang, W and Wang, X and Wang, Y and Wang, Y and Wang, Y and Wang, Z and Weng, J and Wu, F and Wu, Y and Wu, Y and Wu, H and Xia, X and Xu, C and Xu, J and Xu, J and Xu, R and Yang, R and Yin, S and Yin, X and Yin, Y and Yu, R and Yuan, Z and Zhang, F and Zhang, H and Zhang, J and Zhang, N and Zhang, R and Zhang, T and Zhang, Y and Zhang, Z and Zhang, Z and Zhao, J and Zhao, L and Zhao, X and Zhao, X and Zhao, X and Zhe, X and Zhou, F and Zhu, J and Zhu, L and Zhuo, Z and Fan, G and Qian, Y and Wang, J and Duan, Y and Liu, Y},
title = {Normative Modeling of Amygdala Subfields and Disease-Specific Vulnerabilities Across Neurological Disorders.},
journal = {Neuroscience bulletin},
volume = {},
number = {},
pages = {},
pmid = {42864510},
issn = {1995-8218},
abstract = {As an integrative center of the limbic system, the amygdala and its subfields participate in diverse neural functions and demonstrate heterogeneous structural changes in various neurological disorders. In this study, three-dimensional T1-weighted MRI data from 22,258 healthy participants were analyzed using normative modeling to establish normative references for the volumes of the amygdala and its subfields. These models elucidated the developmental and aging curves of the amygdala and identified distinct ages at peak volume across subfields, ranging from 24.6 to 43.7 years. Based on these references, individual centile scores were calculated for 4132 patients with mild cognitive impairment, Alzheimer's disease, Parkinson's disease, cerebral small vessel disease, multiple sclerosis, and neuromyelitis optica spectrum disorder. These centile scores not only captured disease-specific deviation patterns of the amygdala subfields but also demonstrated utility in disease classification. Moreover, the centile scores correlated with clinical measures of cognitive function, emotional state, and motor performance across disorders. These findings suggest that normative references of the amygdala subfields provide insights into cross-disease alteration patterns and offer potential neuroimaging biomarkers to aid differential diagnosis and clinical assessment.},
}

@article {pmid42864517,
year = {2026},
author = {Miao, G and Gao, C and Yu, L and Yang, J and Li, Y and Grodstein, F and Schneider, JA and Barnes, LL and De Jager, PL and Yao, B and Bennett, DA and Zhao, J},
title = {Brain DNA methylation, APOE genotype and Alzheimer's disease neuropathology in a large postmortem cohort.},
journal = {Nature aging},
volume = {},
number = {},
pages = {},
pmid = {42864517},
issn = {2662-8465},
support = {RF1AG052476//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; P30AG10161//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; P30AG72975//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01AG15819//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01AG17917//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01DK091369//U.S. Department of Health & Human Services | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (National Institute of Diabetes & Digestive & Kidney Diseases)/ ; R01MH097018//U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH)/ ; },
abstract = {DNA methylation (DNAm) plays a critical role in Alzheimer's disease (AD). Previous epigenome-wide association studies using 450K arrays captured limited CpG coverage and often focused on a single neuropathological measure. Here we profiled DNAm in 1,250 postmortem prefrontal cortex samples from the Rush Alzheimer's Disease cohorts using the Infinium MethylationEPIC v2 array (~930,000 CpGs) and performed epigenome-wide association studies of multiple neuropathologic measures, including AD diagnosis, amyloid-β and tau tangles. We identified 107 differentially methylated probes associated with AD neuropathology, 38 of which were replicated in an independent cohort (n = 139). DNAm also partially mediated the effect of APOE genotype on AD diagnosis (proportion mediated: 8.6%, P = 2 × 10[-6]). Moreover, 39 identified genes (for example, RIN3, LGMN, LHPP) were differentially expressed across major brain cell types, including neurons and astrocytes. These findings expand the epigenetic landscape of AD neuropathology and reveal DNAm as a mediator of APOE-related genetic risk.},
}

@article {pmid42864705,
year = {2026},
author = {Hacker, K and Nickelson, PF and Kansagra, SM and Alongi, J},
title = {The Future of Chronic Disease and the Role of Governmental Public Health.},
journal = {Journal of public health management and practice : JPHMP},
volume = {},
number = {},
pages = {},
pmid = {42864705},
issn = {1550-5022},
abstract = {Chronic diseases have accounted for the leading causes of morbidity and mortality in the United States for decades. Today, the shape and context of chronic disease is changing. Therapeutic advances have transformed fatal conditions like HIV/AIDS and cancer into chronic conditions. Depression and Alzheimer disease are emerging as leading chronic conditions. Biomarkers are helping individuals determine their risk of certain cancers long before they appear, and technological devices like wearables, mobile applications, and self-administered tools are placing prevention in the hands of individuals. It is imperative that governmental public health redefine its role and look at new opportunities in primary prevention and early intervention of chronic disease. To assist the field, the authors offer recommendations and examples of health department-led initiatives that are meeting the moment in data and surveillance, education and communication, relationships with the health care and policy, environment, and systems efforts.},
}

@article {pmid42864795,
year = {2026},
author = {Ramalakshmi, N and Dibenthiran, S and Arunkumar, S and Amuthalakshmi, S and Indrakumar, S and Nalini, CN},
title = {Mechanistic Insights into the Neuroprotective Potential of Luteolin: An Overview.},
journal = {Central nervous system agents in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118715249434117260910074306},
pmid = {42864795},
issn = {1875-6166},
abstract = {Neurodegenerative disorders, such as Alzheimer's and Parkinson's diseases, are characterized by pathologies such as oxidative stress, neuroinflammation, mitochondrial dysfunction, and protein aggregation. Luteolin, a natural flavonoid, is known for its neuroprotective properties, targeting key pathological mechanisms. This review highlights the multi-target effects of luteolin, as demonstrated by in vitro and in vivo studies. Luteolin reduces oxidative damage by scavenging ROS, enhancing antioxidant enzymes, such as SOD, CAT, and GPx, and activating the Nrf2/ARE pathway. It reduces neuroinflammation by inhibiting NF-κB, AP-1, and JNK signalling and by lowering pro-inflammatory cytokines such as TNF-α and IL-1β. Luteolin maintains mitochondrial membrane potential, modulates apoptotic pathways via Bcl-2/Bax and PI3K/Akt signalling, and promotes autophagy by upregulating LC3-II and modulating the p62-Keap1-Nrf2 axis. It disrupts amyloidogenic and tau hyperphosphorylation pathways, inhibits AChE activity, enhances cholinergic transmission, and improves cognitive function by upregulating CREB, BDNF, and synaptic proteins. Although promising, these effects have been observed mainly in preclinical models, with limited clinical evidence. Future research should focus on the clinical validation and improvement of delivery systems to enhance brain bioavailability. This review provides a foundation for the development of luteolin as a therapeutic candidate for neurodegenerative diseases.},
}

@article {pmid42864883,
year = {2026},
author = {Li, J and Ling, C and Peng, Y and Yu, Y and Feng, G and Du, W and Chen, R},
title = {An EEG-based framework for Alzheimer's disease diagnosis via single-channel multi-entropy fusion and ensemble learning.},
journal = {Proceedings of the Institution of Mechanical Engineers. Part H, Journal of engineering in medicine},
volume = {},
number = {},
pages = {9544119261496349},
doi = {10.1177/09544119261496349},
pmid = {42864883},
issn = {2041-3033},
abstract = {Alzheimer's Disease (AD) is a prevalent neurodegenerative disorder characterized by progressive cognitive decline, and its early diagnosis is vital for timely intervention. However, most existing EEG-based diagnostic methods rely on multi-channel devices confined to hospital settings, limiting their accessibility for community screening. To address this gap, this study aims to develop a lightweight processing approach for portable, low-cost devices to support early AD diagnosis using single-channel EEG data, integrating signal purification with complementary entropy-based feature extraction and ensemble learning. Specifically, EEG signals are first decomposed into five brain rhythms (δ, θ, α, β, γ) using Discrete Wavelet Transform (DWT). Empirical Mode Decomposition (EMD) is then applied to extract Intrinsic Mode Functions (IMFs) from the selected rhythm. Four entropy measures, including Differential Entropy (DE), Singular Spectral Entropy (SSE), Fuzzy Entropy (FE), and Sample Entropy (SE), are subsequently extracted from each IMF to construct the Multi-IMF Entropy Matrix (MIMFEM). After that, an ensemble learning framework combining five classifiers is designed to discriminate AD patients from healthy controls (HCs). The proposed method is evaluated on two public datasets using Leave-One-Out Cross-Validation (LOOCV). Using single-channel EEG data, our approach achieves classification accuracies of 97.92% on the Florida-based dataset and 81.54% on the AHEPA dataset, with corresponding F1-scores of 97.87% and 82.86%, respectively. These results, achieved with limited data sources, show that our approach provides an effective, practical solution for single-channel wearable AD screening and addresses the critical need for low-cost, accessible early diagnostic tools, advancing Artificial Intelligence (AI) in healthcare through a lightweight model.},
}

@article {pmid42864910,
year = {2026},
author = {Polzer, O and Salette, L and van Wijhe, M and Siva, TL and Tsonkova, A and Swildens, A and Randoe, RE and Ayyildiz, D and Chameau, P and Lucassen, PJ and Salta, E and Fitzsimons, CP},
title = {miR-124 delivery to the hippocampus reduces excitability, enhances neurogenesis and affects microglia in a model of Alzheimer's disease.},
journal = {Molecular therapy : the journal of the American Society of Gene Therapy},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.ymthe.2026.10.001},
pmid = {42864910},
issn = {1525-0024},
abstract = {MicroRNA-124 (miR-124) has been proposed as therapeutic candidate for Alzheimer's disease (AD), given its regulation of gene networks governing synaptic function, neurogenesis and inflammation. However, its functional role during early disease stages, and the cellular context-dependence of its effects, remain unclear. Here, we investigated the effects of targeted neuronal miR-124 delivery to the hippocampal dentate gyrus (DG) of App[NL-G-F] mice. At an earlier 'presymptomatic' stage, miR-124 reduced intrinsic excitability of mature granule neurons and induced subtle changes in dendritic architecture. Integrative transcriptomic analyses revealed that predicted miR-124 targets were enriched among downregulated genes involved in synapse organization and cell junction assembly. At the same time, miR-124 increased the number of immature neurons and microglia, indicating structural and functional remodeling of the DG. At a later 'symptomatic' disease stage, where AD pathology is established, neuronal miR-124 supplementation reduced DG Aβ40 and Aβ42 levels and decreased local amyloid plaque burden, while also altering the plaque-associated microglial response. Together, these findings identify neuronal miR-124 as a context- and disease-stage-dependent regulator of the DG microenvironment and demonstrate effects extending from neuronal function to other cellular populations and local AD-associated pathology.},
}

@article {pmid42864926,
year = {2026},
author = {Bhardwaj, A and Parveen, N and Singh, R and Bhushan, B},
title = {Unraveling Shared Molecular Mechanisms in Alzheimer's, Parkinson's, and Neuropathic Pain: Targeting p38 MAPK and Wnt/β-Catenin Pathways.},
journal = {CNS & neurological disorders drug targets},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118715273492918261001111401},
pmid = {42864926},
issn = {1996-3181},
abstract = {Neurodegenerative disorders, including Alzheimer's Disease (AD), Parkinson's Disease (PD), and Neuropathic Pain (NP), share overlapping molecular and cellular mechanisms that contribute to progressive neuronal dysfunction, neuroinflammation, and impaired neural repair. Although these conditions present with distinct clinical manifestations, accumulating evidence indicates that dysregulation of the p38 mitogen-activated protein kinase (p38 MAPK) and Wnt/β-catenin signaling pathways represents a common pathogenic axis underlying disease initiation and progression. Activation of p38 MAPK amplifies inflammatory signaling, mitochondrial dysfunction, oxidative stress, neuronal apoptosis, and glial activation, whereas suppression of Wnt/β-catenin signaling disrupts synaptic plasticity, blood-brain barrier integrity, neurogenesis, and neuronal survival. The reciprocal interaction between these pathways further exacerbates amyloid-β accumulation, dopaminergic neuronal degeneration, tau hyperphosphorylation, central sensitization, and persistent neuroimmune activation, thereby linking cognitive decline, motor impairment, and chronic pain. This review comprehensively examines the molecular crosstalk between p38 MAPK and Wnt/β-catenin signaling across AD, PD, and NP, highlighting their roles in regulating neuroinflammation, oxidative stress, mitochondrial homeostasis, and neuronal resilience. In addition, it summarizes emerging pharmacological agents, natural bioactive compounds, and targeted therapeutic strategies designed to inhibit p38 MAPK activation or restore Wnt/β-catenin signaling to promote neuroprotection and functional recovery. Particular emphasis is placed on the translational potential of dual-pathway modulation as a disease-modifying approach that addresses shared pathological mechanisms rather than isolated disease- specific manifestations. By integrating current experimental and clinical evidence, this review provides a unified mechanistic perspective, identifies promising therapeutic opportunities for developing more effective interventions against neurodegenerative disorders and neuropathic pain, and outlines the remaining challenges for future translational research.},
}

@article {pmid42865106,
year = {2026},
author = {Kogularasu, S and Kumar, H and Liang, CK and Kung, HC and Sriram, B and Wang, SF and Huang, BW and Chang-Chien, GP and Lin, YT},
title = {Amino-functionalized MIL-101(Fe)-confined Au nanostructures for advanced electrochemical detection of H2O2 in Alzheimer's disease research.},
journal = {Nanoscale},
volume = {},
number = {},
pages = {},
doi = {10.1039/d6nr01767c},
pmid = {42865106},
issn = {2040-3372},
abstract = {Oxidative stress is a fundamental pathological contributor to Alzheimer's disease and is closely linked to amyloid-beta-mediated toxicity, tau dysregulation, mitochondrial impairment, and progressive neuronal degeneration. Among the associated reactive oxygen species, hydrogen peroxide (H2O2) is a mechanistically relevant redox intermediate and an important oxidative stress biomarker. Herein, an Au@NH2-MIL-101(Fe) hybrid was rationally engineered as an electrocatalytically active sensing interface for H2O2 determination. The hybrid was constructed by integrating conductive Au nanodomains with an amino-functionalized Fe-based metal-organic framework, thereby combining the high surface area, porous architecture, and accessible coordination environment of NH2-MIL-101(Fe) with the superior conductivity and catalytic activity of Au. Electrochemical investigations revealed that Au@NH2-MIL-101(Fe)/SPCE exhibited substantially enhanced interfacial electron-transfer kinetics and electrocatalytic reduction of H2O2 relative to bare SPCE, MIL-101(Fe), and NH2-MIL-101(Fe). Under optimized conditions, the sensor delivered a linear range of 0.01 to 429.7 μM and a limit of detection of 0.063 µM. In addition, the platform showed good selectivity, operational stability, reproducibility, and satisfactory performance in H2O2-spiked serum and urine samples, highlighting its promise for oxidative stress-related electroanalysis relevant to Alzheimer's disease.},
}

@article {pmid42865133,
year = {2026},
author = {Lv, Y and Shi, M and Zhao, Y and Yu, Y and Lv, J and Zhao, H},
title = {Context-dependent TREM2 signalling in myeloid cells: Molecular mechanisms and immunotherapeutic divergence in neurodegeneration and cancer.},
journal = {Clinical and translational medicine},
volume = {16},
number = {10},
pages = {e70863},
doi = {10.1002/ctm2.70863},
pmid = {42865133},
issn = {2001-1326},
support = {ZR2022QH372//Shandong Province Natural Science Foundation/ ; },
mesh = {Humans ; *Receptors, Immunologic/metabolism ; *Membrane Glycoproteins/metabolism ; *Signal Transduction ; *Myeloid Cells/metabolism/immunology ; *Neoplasms/therapy/immunology ; Animals ; *Immunotherapy/methods ; *Neurodegenerative Diseases/therapy/immunology ; },
abstract = {BACKGROUND: Triggering receptor expressed on myeloid cells 2 (TREM2) is a pivotal lipid-sensing receptor that governs the functional plasticity and metabolic fitness of mononuclear phagocytes, including microglia, osteoclasts, dendritic cells and tissue-resident macrophages. While originally identified as a genetic risk factor for Alzheimer's disease (AD), TREM2 functions as a context-dependent immunometabolic checkpoint rather than a uniform phenotypic driver, exerting divergent biological outputs dictated by distinct tissue microenvironments and ligand repertoires.

SUMMARY OF KEY CONTENTS: This review provides a comprehensive synthesis of TREM2 immunobiology, detailing how ligand engagement-including cell-surface phospholipids and apolipoprotein E (ApoE)-activates the DAP12/DAP10-SYK-PI3K-mTOR signalling axis. This coordinated intracellular cascade instructively drives myeloid adaptation towards metabolically competent disease-associated microglia (DAM) and lipid-associated macrophage (LAM) states, sustaining bioenergetics and debris clearance under pathological stress. Across neurodegenerative proteinopathies and acute cerebral ischemia, TREM2 signalling is predominantly neuroprotective by promoting aggregate compaction and mitigating secondary excitotoxicity, although chronic dysregulated activation may drive stage-dependent neuroinflammation. In peripheral inflammatory pathologies such as rheumatoid arthritis and sepsis, TREM2 fine-tunes macrophage efferocytosis and systemic metabolic thresholds. In oncology, TREM2 displays a complex, microenvironment-dependent divergence: in central nervous system malignancies such as glioblastoma (GBM), TREM2 exerts controversial, stage-dependent effects, spanning microglial tumour containment in early stages versus pro-tumoural myelin recycling and immunosuppression by monocyte-derived macrophages in post-treatment recurrence; conversely, in peripheral solid tumours, monocyte-derived TREM2+ tumour-associated macrophages (TAMs) predominantly orchestrate an immunosuppressive, nutrient-deprived niche that impairs cytotoxic T-cell function. Furthermore, we synthesise emerging paradigms along the bidirectional microbiome-gut-brain-tumour axis, elucidating how commensal and intra-tumoural microbial cues dynamically calibrate myeloid signalling tone and therapeutic susceptibility.

CONCLUSION: We address translation bottlenecks-including blood-brain barrier (BBB) shuttles, human trial scarcity and soluble TREM2 (sTREM2) biomarker harmonisation-outlining a biomarker-guided, context-tailored precision therapeutic framework for targeting the TREM2 axis.},
}

Humans
*Receptors, Immunologic/metabolism
*Membrane Glycoproteins/metabolism
*Signal Transduction
*Myeloid Cells/metabolism/immunology
*Neoplasms/therapy/immunology
Animals
*Immunotherapy/methods
*Neurodegenerative Diseases/therapy/immunology

@article {pmid42865136,
year = {2026},
author = {Pinheiro, CN and Song, X and Brock, KE and Harp, JP and Karr, JE},
title = {Measurement of subjective cognitive decline and prediction of longitudinal clinical outcomes in older adults: a systematic review.},
journal = {Journal of clinical and experimental neuropsychology},
volume = {},
number = {},
pages = {1-30},
doi = {10.1080/13803395.2026.2743151},
pmid = {42865136},
issn = {1744-411X},
abstract = {Subjective cognitive decline (SCD) is a preclinical risk factor for Alzheimer's disease and may represent one of the earliest clinical indicators of underlying neurodegeneration. Prevalence estimates vary but suggest that between 20 and 30% of cognitively unimpaired older adults report some form of subjective decline (Rohr et al. 2020). Longitudinal studies indicate that individuals with SCD are at approximately twice the risk of progressing to mild cognitive impairment (MCI) or dementia compared to those without complaints. While not every older adult reporting decline will progress, early detection allows for timely intervention and risk stratification for clinical trials of dementia prevention. The current review examined longitudinal studies of adults aged ≥ 60 to assess and highlight the heterogeneity in operational definitions of SCD and risk of incident MCI or dementia. Among the 26 studies reviewed, 24 distinct definitions of SCD were used, highlighting the need for standardized measurement to improve comparability and generalizability. Of the studies reporting hazard ratios, all nine found that SCD was associated with a significantly higher risk of incident MCI or dementia compared to cognitively healthy older adults not reporting SCD; with the exception that no significant association between SCD and risk of vascular dementia was observed. The consistent association between SCD and risk of progression to MCI and dementia in these studies strengthens the evidence that suggests SCD may not be a benign complaint of aging or psychiatric conditions, but a potentially early clinical indicator of possible underlying neurodegenerative changes. These findings highlight the need for standardization in measurement tools and definitions to refine this pre-MCI construct.},
}

@article {pmid42865229,
year = {2026},
author = {Xiang, X and Li, T and Feng, Z and Yang, J and Gong, Z and Wang, L and Wang, L and Zhang, W},
title = {MAFG as a Redox-Sensitive Node Linking Peripheral Immune Reprogramming to Cognitive Risk in the Sepsis-to-Alzheimer's Disease Continuum: Single-Cell Dissection and Adoptive-Transfer Validation.},
journal = {CNS neuroscience & therapeutics},
volume = {32},
number = {10},
pages = {e71201},
doi = {10.1002/cns.71201},
pmid = {42865229},
issn = {1755-5949},
support = {82173262//National Natural Science Foundation of China/ ; 2024NSFSC1536//Sichuan Province Science and Technology Support Program/ ; },
mesh = {Animals ; Humans ; *Alzheimer Disease/immunology/metabolism/genetics/psychology ; *Sepsis/immunology/metabolism/genetics ; Male ; *Adoptive Transfer/methods ; Mice ; Oxidation-Reduction ; *Repressor Proteins/genetics/metabolism/immunology ; Mice, Transgenic ; Female ; Mice, Inbred C57BL ; },
abstract = {BACKGROUND: Sepsis survivors face an elevated long-term risk of Alzheimer's disease (AD), yet the peripheral pathways linking systemic immune activation to chronic neurodegeneration remain undefined. We mapped peripheral immune reprogramming across sepsis and AD and tested a candidate regulatory node.

METHODS: A single-cell atlas of peripheral immunity was built by integrating scRNA-seq from human sepsis and AD cohorts, using clustering, SCENIC regulatory-network inference and an exploratory pseudotime ordering. The resulting signature was validated in two clinical cohorts (ROC and survival analysis). MAFG-associated subpopulations and redox status were profiled in APP/PS1, cecal ligation and puncture (CLP) and composite models, and causality was tested by lentiviral MAFG knockdown and adoptive transfer into APP/PS1 recipients.

RESULTS: Peripheral immunity was myeloid-skewed in sepsis and lymphoid-dominated in AD, with APP-expressing common myeloid progenitors (CMPs), dendritic cells (DCs), and platelets forming an APP-enriched compartment. A core transcription-factor network differed between disease states, yielding a four-gene signature (MAFG, NFIL3, RGS10, FOXO3) with cross-cohort diagnostic and prognostic value. MAFG was upregulated in septic patients and associated with poorer survival, subpopulation expansion, and systemic oxidative stress. Superimposed CLP aggravated amyloid deposition, microglial activation, and memory deficits in APP/PS1 mice, whereas MAFG silencing restored Aβ uptake and, on adoptive transfer, reduced amyloid burden, attenuated microgliosis, and preserved cognition.

CONCLUSIONS: Peripheral immune states differ across the sepsis-to-AD spectrum and are captured by a MAFG-centered signature. Independent of any trajectory assumption, loss-of-function and adoptive-transfer experiments identify MAFG as a causal, redox-sensitive node constraining peripheral Aβ clearance and a candidate biomarker and therapeutic target in sepsis survivors.},
}

Animals
Humans
*Alzheimer Disease/immunology/metabolism/genetics/psychology
*Sepsis/immunology/metabolism/genetics
Male
*Adoptive Transfer/methods
Mice
Oxidation-Reduction
*Repressor Proteins/genetics/metabolism/immunology
Mice, Transgenic
Female
Mice, Inbred C57BL

@article {pmid42865340,
year = {2026},
author = {Kamonnat, C and Thongdechsri, S and Kraokaew, P and Niamnont, N and Sobhon, P and Meemon, K},
title = {Protective Role of Holothuria leucospilota Extract Against Amyloid-β Toxicity via Autophagy and Antioxidant Mechanisms in Caenorhabditis elegans Model.},
journal = {Oxidative medicine and cellular longevity},
volume = {2026},
number = {1},
pages = {e1471919},
doi = {10.1155/omcl/1471919},
pmid = {42865340},
issn = {1942-0994},
support = {//National Research Council of Thailand/ ; N42A660511//Mahidol University/ ; AN-KME-3-66-02//Central Instrument Facility (CIF)/ ; },
mesh = {Animals ; *Caenorhabditis elegans/drug effects/metabolism ; *Amyloid beta-Peptides/toxicity/metabolism ; *Autophagy/drug effects ; *Antioxidants/pharmacology ; *Holothuria/chemistry ; Oxidative Stress/drug effects ; Disease Models, Animal ; Reactive Oxygen Species/metabolism ; *Plant Extracts/pharmacology ; Caenorhabditis elegans Proteins/metabolism ; Alzheimer Disease/drug therapy ; Animals, Genetically Modified ; },
abstract = {Alzheimer's disease (AD) is a major global health challenge characterized by cognitive decline and neuronal degeneration driven by amyloid-β (Aβ) aggregation and oxidative stress. Given the limited efficacy and adverse effects of current pharmacological therapies, food-derived bioactive compounds have gained increasing attention as potential preventive strategies against neurodegenerative disorders. In this study, we investigated the neuroprotective effects of Holothuria leucospilota extracts using a transgenic Caenorhabditis elegans model of AD. Our results demonstrated that H. leucospilota hexane extract (HLHE) at 500 µg/mL significantly delayed Aβ-induced paralysis and improved chemotaxis behavior. Consistently, HLHE treatment reduced Aβ deposition and decreased both high- and low-molecular weights of Aβ oligomers, as determined by automated Western blot analysis. Additionally, HLHE also reduced reactive oxygen species (ROS) levels. Transcriptomic and RT-qPCR analyses revealed that HLHE enhanced autophagic activity through the upregulation of bec-1 (autophagy initiation) and lysosomal genes (cpr-1, cpr-2, and cpr-5). Furthermore, HLHE activated antioxidant defense pathways via the insulin/IGF-1 signaling (IIS) axis, specifically upregulating genes associated with SKN-1 pathway (pmk-1, skn-1, gst-4, and gst-10) and HSF-1 pathway (hsf-1, hsp-16.1, hsp-12.6, and mtl-1). HLHE also promoted nuclear localization of SKN-1 and increased expression of its downstream target gst-4. Chemical analysis revealed that HLHE contained arachidonic acid (21.12%) and other bioactive lipid compounds as major constituents, suggesting a synergistic role in promoting autophagy and antioxidant responses. Collectively, this study suggests that HLHE confers neuroprotection against Aβ-induced toxicity by activating autophagy and oxidative stress defense mechanisms, supporting its potential development as a food-derived preventive or therapeutic agent for AD.},
}

Animals
*Caenorhabditis elegans/drug effects/metabolism
*Amyloid beta-Peptides/toxicity/metabolism
*Autophagy/drug effects
*Antioxidants/pharmacology
*Holothuria/chemistry
Oxidative Stress/drug effects
Disease Models, Animal
Reactive Oxygen Species/metabolism
*Plant Extracts/pharmacology
Caenorhabditis elegans Proteins/metabolism
Alzheimer Disease/drug therapy
Animals, Genetically Modified

@article {pmid42865478,
year = {2026},
author = {Li, L and Sun, N and Chen, S and Yang, S and Li, H and Li, Q and Zhong, K and Yan, J},
title = {Effect of age-friendly community degree on the cognitive function of older adults.},
journal = {Frontiers in psychiatry},
volume = {17},
number = {},
pages = {1927936},
pmid = {42865478},
issn = {1664-0640},
abstract = {INTRODUCTION: The relationship between individual environmental indicators and the physical and mental health of older adults has been widely studied. However, the holistic impact of age-friendly communities on the wellbeing of older adults has not beenclearly elucidated. This study aimed to explore the correlation between the degree of community friendliness and cognitive function of older adults and provide scientific evidence for healthy aging.

METHODS: This cross-sectional study enrolled 450 residents aged ≥60 years with cognitive impairment in Ningbo, Zhejiang Province, from June to September 2024. Participants provided personal demographic data, and their community's age-friendly status and cognitive function were assessed using the Age-Friendly Community (AFC) Evaluation Scale and the Alzheimer's Disease 8 Questionnaire. A multivariate logistic regression analysis was performed to examine the relationship between demographic characteristics and cognitive function of the older adults.

RESULTS: Among the five dimensions of the AFC evaluation scale, community participation scored the highest at 3.56 ±' 1.21 points. Multivariate linear regression analysis revealed that personal demographic factors (age, sex, education level, economic status, housing conditions, alcohol consumption, and chronic diseases) significantly infiuenced cognitive function (all P < 0.05). Furthermore, residential environment, transportation, and community environment were identified as significant predictors of cognitive impairment (all P < 0.05).

DISCUSSION: Low scores in residential environment, transportation, community environment, and social inclusion in AFC are independent risk factors for cognitive dysfunction. Measures to enhance community age-friendly environments could help improve the cognitive function of older adults.},
}

@article {pmid42865480,
year = {2026},
author = {Li, SY and Zhang, JX and Huang, LZ and Wu, HB and Ye, YB and Liu, A and Chen, J and Lai, S},
title = {Efficacy and safety of lecanemab monoclonal antibody in the treatment of mild to moderate Alzheimer's disease: a systematic review and meta-analysis.},
journal = {Frontiers in pharmacology},
volume = {17},
number = {},
pages = {1947129},
pmid = {42865480},
issn = {1663-9812},
abstract = {BACKGROUND: Lecanemab is a novel therapy for Alzheimer's disease (AD), but comprehensive evidence is lacking. This systematic review and meta-analysis evaluated the efficacy and safety in AD.

METHODS: Registered in PROSPERO (CRD420251146867). PubMed, Embase, Cochrane Library, Web of Science, and Scopus were searched for English-language RCTs. Efficacy and safety were evaluated using the risk difference with a Mantel-Haenszel fixed-effects model. Study quality and sensitivity were assessed using Cochrane risk-of-bias and leave-one-out methods. Primary outcomes: mean changes in Alzheimer's Disease Composite Score (ADCOMS), Clinical Dementia Rating Scale Sum of Boxes (CDR-SB), Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), and amyloid burden on positron emission tomography (PET). Secondary: adverse events including amyloid-related imaging abnormalities with edema (ARIA-E), ARIA with hemorrhage (ARIA-H), death, treatment-emergent adverse events (TEAEs), headache, dizziness, and urinary tract infection.

RESULTS: A total of five articles involving 8 clinical trials were included. Based on the fixed-effect model, lecanemab treatment significantly improved cognitive performance on ADCOMS (SMD -0.1999, 95% CI [-0.2831, -0.1167], I[2] = 0%, P < 0.00001), CDR-SB (SMD -0.1853, 95% CI [-0.2683, -0.1024], I[2] = 0%, P < 0.0001), ADAS-Cog (SMD -0.1821, 95% CI [-0.2670, -0.0973], I[2] = 0%, P < 0.0001) and amyloid burden on PET (SMD -1.1872, 95% CI [-2.2474, -0.1270], I[2] = 96%, P = 0.03). Sensitivity analysis indicated stability. However, lecanemab was associated with an increased risk of TEAEs (MH RR 1.0730, 95% Cl [1.0296, 1.1183], I[2] = 0%, P = 0.0008) and an increased risk of headache (MH RR 1.3617, 95% Cl [1.0243, 1.8103], I[2] = 0%, P = 0.03). Sensitivity analysis indicated that both results were stable. The lecanemab group showed no significant differences in the risks of death, dizziness, or urinary tract infection compared with the control group. In addition, the lecanemab group showed a significantly increased risk of ARIA-E (MH RR 5.9948, 95% CI [3.9047, 9.2037], I[2] = 86%, P < 0.00001) and ARIA-H (MH RR 1.7490, 95% CI [1.3896, 2.2014], I[2] = 41%, P < 0.00001). Sensitivity analyses confirmed the stability of the TEAE finding, while the headache result should be interpreted with caution due to the limited number of studies. After excluding Honig et al. (OLE) 2021 via leave-one-out, results became stable, likely due to its open-label design.

CONCLUSION: Lecanemab slowed cognitive decline versus placebo in mild-to-moderate AD by ADCOMS, CDR-SB, and ADAS-Cog. High heterogeneity in PET amyloid burden warrants future RCTs. Nevertheless, lecanemab was associated with an increased risk of TEAEs and headache.

https://www.crd.york.ac.uk/PROSPERO/view/CRD420251146867.},
}

@article {pmid42865534,
year = {2026},
author = {Li, J and Xiang, X and Long, S and Hu, F and Ding, F},
title = {Association of temporal and masseter muscle thickness with cognitive function and clinical severity in Alzheimer's disease: a retrospective study.},
journal = {Frontiers in neuroscience},
volume = {20},
number = {},
pages = {1905634},
pmid = {42865534},
issn = {1662-4548},
abstract = {BACKGROUND: Temporal muscle thickness (TMT) has emerged as an imaging marker of skeletal muscle status and may be associated with cognitive decline in Alzheimer's disease (AD). However, its relationship with AD severity remains unclear, and the clinical relevance of masseter muscle thickness (MMT) is unknown.

OBJECTIVE: To evaluate the associations of TMT and MMT with cognitive function and disease severity in AD.

METHODS: This retrospective study included 242 patients with AD between December 2023 and April 2025. TMT and MMT were measured on axial T1-weighted MRI, cognitive function was assessed using standardized neuropsychological tests, and disease severity was determined by Clinical Dementia Rating (CDR).

RESULTS: The intraclass correlation coefficients (ICC) for the mean TMT and MMT were 0.868 and 0.896, respectively, indicating good consistency. As the severity of AD progresses, TMT tends to be thinner in severe AD than in mild AD. Spearman's correlation analysis revealed that both TMT and MMT were correlated with the Mini-Mental State Examination (MMSE) and CDR. After adjusting for various confounding factors using ordered logistic regression and multiple linear regression, TMT was found to be independently associated with AD severity (OR: 0.424, 95% CI: 0.290-0.618, p < 0.001) and positively correlated with MMSE scores. MMT showed only a weak independent association with CDR staging (OR: 0.830, 95% CI: 0.724-0.952, p = 0.008), while no significant correlation was observed with the MMSE. Stratified analysis revealed that the TMT maintained a consistent association in both male and female patients, whereas the MMT achieved statistical significance only in females in ordered logistic regression; all other findings were not statistically significant.

CONCLUSION: Temporal muscle thickness is associated with cognitive impairment and clinical severity in patients with AD and may serve as a simple, noninvasive imaging marker; in contrast, the independent associations of MMT with disease severity were weak and sex-specific, suggesting that its clinical utility may be limited and requires further validation.},
}

@article {pmid42865621,
year = {2026},
author = {Tan, W and Han, X and Wang, X and Tang, M and Li, S and Liu, H and Zhang, J and Wang, J and Liu, G},
title = {Multimodal MRI to elucidate cross-organ coupling mechanisms of the heart-brain axis.},
journal = {Frontiers in cardiovascular medicine},
volume = {13},
number = {},
pages = {1914265},
pmid = {42865621},
issn = {2297-055X},
abstract = {Cardiovascular and cerebrovascular diseases (CCVDs) are leading causes of mortality and disability worldwide, and their development is closely linked to bidirectional interactions between the heart and the brain. The heart-brain axis, a systemic framework that integrates neural, humoral, and inflammatory pathways, provides an important theoretical basis for understanding heart-brain comorbidities. With continuous advances in magnetic resonance imaging(MRI), research in this field has progressively shifted from the traditional single-organ diagnostic model to cross-organ and system-oriented strategies for prevention and management. Centered on cardiac magnetic resonance (CMR) and brain MRI, and complemented by quantitative, diffusion, functional, ultra-high-field, and metabolic imaging techniques, multimodal MRI has become a powerful tool for comprehensively characterizing myocardial remodeling, alterations in brain networks, and their coupling relationships. These techniques have been widely applied in studies of representative heart-brain comorbidities, including cardiac dysfunction associated with acute brain injury, cognitive impairment related to heart failure, and cardiovascular abnormalities associated with neurodegenerative diseases, such as Alzheimer's disease (AD). Such studies have not only revealed structural and functional alterations in the heart and brain but have also provided important insights into potential mechanisms, including autonomic imbalance, neuroendocrine activation, and inflammatory responses. However, current heart-brain axis research remains largely based on correlational analyses, whereas causal inference and characterization of dynamic mechanisms remain insufficient. In addition, significant challenges persist in multimodal data integration and clinical translation. Overall, MRI is driving heart-brain axis research from structural characterization toward mechanistic investigation. In the future, integrating imaging, physiological, and genetic information may enable early identification, risk stratification, and precision intervention for heart-brain comorbidities, thereby promoting a transition in medical practice from single-organ management to systemic prevention and treatment.},
}

@article {pmid42865655,
year = {2026},
author = {Contreras, JA and Ortega, NE and Jones, R and Thorpe, RJ and Hayes, CA},
title = {Plasma p-tau181 moderates the association between ten-year atherosclerotic cardiovascular disease risk and mild cognitive impairment - HABS-HD.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1870150},
pmid = {42865655},
issn = {1663-4365},
abstract = {INTRODUCTION: This study examined cross-sectional associations between ten-year American Heart Association (AHA) atherosclerotic cardiovascular disease (ASCVD) risk and plasma Alzheimer's disease (AD) biomarkers in relation to cognitive outcomes and to determine whether ASCVD risk modifies biomarker-cognition relationships.

METHODS: Baseline data were analyzed from cognitively unimpaired and mild cognitive impaired (MCI) participants enrolled in the Health and Aging Brain Study-Health Disparities (HABS-HD), a large, community-based cohort enriched for racial and ethnic diversity. Plasma biomarkers included amyloid-β42/40 (Aβ42/Aβ40), phosphorylated tau (p-tau181 and p-tau217), and neurofilament light (NfL). Ten-year ASCVD risk was calculated using pooled cohort equations. Multivariable logistic regression models examined associations of ten-year ASCVD risk and plasma biomarkers with MCI, while multivariable linear regression models evaluated associations with Mini-Mental State Examination (MMSE) and Clinical Dementia Rating (CDR) Sum of Boxes scores. Separate models were constructed for Aβ42/40, p-tau217, p-tau181, NfL, and apolipoprotein (APOE) ε4 carrier status, and analyses were stratified by race and ethnicity. ASCVD × biomarker interaction terms were tested to evaluate effect modification.

RESULTS: Increased ten-year ASCVD risk was consistently associated with increased odds of MCI, ranging from OR = 2.62 (95% CI: 1.31-5.17) to OR = 4.22 (95% CI: 2.04-8.64), lower MMSE scores, ranging from β = -1.90 (95% CI: -2.62 to -1.18) to β = -2.56 (95% CI: -3.30 to -1.82), and increased CDR Sum of Boxes scores, ranging from β = 0.28 (95% CI: 0.09-0.46) to β = 0.39 (95% CI: 0.20-0.58). The ASCVD × p-tau181 interaction was significant for MCI (OR = 1.91; 95% CI: 1.26-2.95) and CDR Sum of Boxes (β = 0.27; 95% CI: 0.16-0.39). ASCVD associations with CDR Sum of Boxes ranged from β = 0.11 (95% CI: -0.08 to 0.30) to β = 0.24 (95% CI: 0.04-0.43) among non-Hispanic White participants, β = 0.80 (95% CI: 0.10-1.51) to β = 1.17 (95% CI: 0.49-1.86) among non-Hispanic Black participants, and β = 0.36 (95% CI: 0.08-0.65) to β = 0.52 (95% CI: 0.25-0.80) among Hispanic participants.

CONCLUSION: Greater ten-year ASCVD risk was consistently associated with cognitive impairment independent of plasma AD biomarkers, with evidence that p-tau181 modifies these associations and that their magnitude varies across racial and ethnic groups.},
}

@article {pmid42865677,
year = {2026},
author = {Wahbeh, H and Cooley, S and Chamberlin, SR and Brophy, T and Hameroff, S},
title = {Home-administered unfocused transcranial ultrasound in subjective cognitive decline and dementia: an open-label, uncontrolled feasibility pilot study.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1937897},
pmid = {42865677},
issn = {1663-4365},
abstract = {BACKGROUND: Memory and cognitive impairments remain disabling, with few effective treatments. Low-intensity transcranial ultrasound (TUS) is a non-invasive neuromodulation approach with a favorable safety profile and preliminary evidence of cognitive benefit, with one hypothesized but unproven mechanism involving microtubule resonance and reassembly.

OBJECTIVES: This open-label pilot study evaluated the safety and preliminary efficacy of the US Pro2000 unfocused ultrasound device in adults with memory or cognitive difficulties, a sample spanning subjective cognitive decline among self-administering participants to diagnosed dementia among caregiver-rated recipients, and described self-reported symptom trajectories.

METHODS: In a within-participant design, adults with self-reported cognitive impairment, or their caregivers, applied the device at the right temporal window for 5 min three times daily (target 15 min/day), in cycles of 3 weeks on and 1 week off. Outcomes (GAD-7, CESD-5, Inoue battery, and caregiver-rated MDS 3.0) and adverse events were collected online. Mixed-effects models with age and device-use covariates assessed change over time, with False Discovery Rate correction within aim.

RESULTS: Twenty-seven participants enrolled and 26 initiated treatment. Across 2,174 daily assessments, no serious or unanticipated adverse events occurred; only headache (15.4%) and transient jaw clenching (3.8%) were possibly related, and none caused discontinuation. Among self-administered participants, depression (CESD-5) declined significantly (p_FDR = 0.016) and five of eight monthly self-report symptoms improved, including memory, word-finding, and problem-solving (all p_FDR ≤ 0.040); anxiety trended downward, and the objective cognitive battery, near ceiling at baseline, did not change. Caregiver-rated outcomes were stable. Device use showed no dose response, and sensitivity analyses were consistent.

CONCLUSION: Home-based self-administered low-intensity TUS was well tolerated, with only mild transient events, although adverse-event ascertainment relied on unblinded self-report and relatedness judgments were made by unblinded investigators. Efficacy signals were confined to self-report, while objective cognition and caregiver ratings were unchanged. The uncontrolled design, small subgroups, and reliance on self-report preclude causal inference. These findings support the safety and feasibility of TUS and justify an adequately powered, double-blind, sham-controlled trial.},
}

@article {pmid42865723,
year = {2026},
author = {Pascual-Lucas, M and Sarasa, L and Fandos, N and Loscos, J and Romero, J and Sánchez, A and Terencio, J and Ortega-Madueño, I and Cárdenas, MC and Cava-Valenciano, F and Gil-Moreno, MJ and Matias-Guiu, JA and Allué, JA},
title = {Plasma biomarker strategies to reduce diagnostic uncertainty in p-tau217-based assessment of CSF amyloid positivity in secondary-care patients with MCI.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1918304},
pmid = {42865723},
issn = {1663-4365},
abstract = {INTRODUCTION: Plasma p-tau217 accurately reflects amyloid pathology, but dual-cutoff strategies leave a non-negligible grey zone requiring confirmatory testing. We evaluated whether integrating plasma Aβ measurements could reduce diagnostic uncertainty in patients with mild cognitive impairment (MCI).

METHODS: Plasma p-tau217 was measured using the Lumipulse platform, and plasma Aβ40 and Aβ42 were quantified by liquid chromatography-mass spectrometry (ABtest-MS) in 186 secondary-care MCI patients. CSF Aβ42/Aβ40 defined amyloid status. Logistic regression models were compared, and dual-cutoff strategies targeting 95% predictive values were applied.

RESULTS: p-tau217 was the strongest individual biomarker. Models incorporating plasma Aβ measures improved AUC, model fit, and reduced the grey zone from 27.4% with p-tau217 alone to 12.3%. A sequential two-step strategy restricted additional Aβ testing to p-tau217-indeterminate cases and reduced the final grey zone to 13.4%.

DISCUSSION: Plasma Aβ measurements complement p-tau217 by reducing the indeterminate results, with the potential to improve diagnostic efficiency and streamline diagnostic workflows.},
}

@article {pmid42865737,
year = {2026},
author = {Moreno, MDMM and Celis, K and Rajabli, F and Whitehead, PL and Hamilton-Nelson, KL and Dykxhoorn, DM and Nuytemans, K and Mesulam, MM and Bennett, DA and Schuck, T and Weintraub, S and Geula, C and Gearing, M and Alba, C and Dalgard, CL and Davis, DA and Scott, WK and Haines, JL and Pericak-Vance, MA and Griswold, AJ and Vance, JM and Young, JI},
title = {Unraveling changes in mitochondrial processes influenced by ancestry in APOEε4 carriers with Alzheimer disease.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1888862},
pmid = {42865737},
issn = {1663-4365},
abstract = {INTRODUCTION: The APOEε4 allele is the strongest known genetic risk factor for late-onset Alzheimer disease (AD). However, the risk effect of APOEε4 varies substantially by ancestry, with individuals of African ancestry (AF) demonstrating markedly lower risk compared to those of European ancestry (EU). This difference in risk is associated with distinct levels of APOE gene expression. Here, we investigate whether mitochondrial processes in brain cells are also influenced by ancestry in AD APOEε4 carriers, potentially contributing to the observed risk differences.

METHODS: Single nuclei RNA sequencing was performed on frontal cortex from 17 AD patients homozygous for APOEe4 with either African Local Ancestry (AF-LA; N = 7) or European Local Ancestry (EU-LA; N = 10). Differential gene expression was compared between AF and EU samples, with particular focus on mitochondrial pathways. Differential expression and functional enrichment analyses were performed using MAST and PathFindR, respectively. MitoXplorer was used to identify differential mitochondrial processes, while REACTOME facilitated the building of regulatory networks.

RESULTS: Multiple cell types and biological processes contribute to the differences in APOEe4 risk seen between individuals of AF and EU ancestry. AF astrocytes show a less reactive phenotype and L6 and L5/6 excitatory neurons appear to be less vulnerable in AF compared to EU samples. Mitochondrial alterations were more pronounced in EU-LA APOEe4 AD carriers relative to their AF counterparts. Cells highly expressing APOE (astrocytes, microglia, and vascular leptomeningeal cells) showed increased expression of mitochondrial genes, particularly in EU-LA samples. We observed increased expression of pro-apoptotic, oxidative phosphorylation, and mitophagy-related genes in EU samples. Regulatory network analysis identified the transcription factor PPARG as a potential mediator linking APOEε4 expression to mitochondrial gene programs in a cell-type- and ancestry-dependent manner.

CONCLUSION: Our snRNA-seq analysis demonstrates that ancestry-linked regulation of APOEε4 expression influences mitochondrial transcriptome and astrocyte activation in AD. The stronger APOE-PPARG-mitochondrial gene coupling in EU ancestry particularly in astrocytes may underlie increased AD risk, while AF ancestry confers partial decoupling of these pathways. These results underscore the importance of considering ancestry in AD research and suggest that precision therapeutic strategies targeting mitochondrial and glial pathways should account for APOE local ancestry.},
}

@article {pmid42865788,
year = {2026},
author = {Cacciotti, A and Fabbrocino, A and Pappalettera, C and Ginatempo, F and Loi, N and Sottana, D and Deriu, F and Rossini, PM and Vecchio, F},
title = {Electroencephalographic complexity and cognitive decline: Insights from approximate entropy across aging and dementia.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {12},
number = {4},
pages = {e70284},
pmid = {42865788},
issn = {2352-8737},
abstract = {INTRODUCTION: Physiological aging involves gradual modifications of brain activity patterns sometimes leading to pathological outcomes. Understanding changes in brain signal complexity from healthy aging to mild cognitive impairment (MCI) and Alzheimer's disease (AD) may provide insights into cognitive decline and support early diagnosis.

METHODS: Electroencephalography (EEG) data were collected from 269 participants divided into three groups: healthy elderly (HE, n = 109), MCI (n = 75), and AD (n = 85). Approximate entropy (ApEn) was computed for the total EEG spectrum and frequency bands. A random forest classifier with a one-versus-one strategy and recursive feature elimination (RFE) was used for group discrimination. Additionally, group comparisons and correlations with neuropsychological scores were performed to further investigate the functional relevance of these entropy changes by assessing their association with cognitive and functional performance.

RESULTS: Significant group differences in total ApEn were found, particularly in central brain regions, with progressive decreases from HE to MCI and AD. Frequency-specific patterns emerged: (1) delta ApEn was increased in those with AD across the scalp; (2) alpha 1 ApEn showed frontal decreases and occipital increases in the AD group, with an intermediate pattern in MCI; (3) gamma ApEn was markedly reduced in those with AD compared to both HE and MCI groups, with central and frontal localization, and extended occipital differences in those with MCI versus AD. The classifier achieved 66.55% accuracy, with sensitivities of 78.90% (HE), 49.33% (MCI), and 65.88% (AD). Positive correlations were found between ApEn and cognitive scores in both the total EEG spectrum and gamma band; conversely, delta and alpha 1 ApEn showed negative correlations with cognitive and functional scores.

DISCUSSION: The distinct entropy patterns observed across frequency bands and scalp/brain regions may help characterize electrophysiological changes associated with cognitive decline and AD.},
}

@article {pmid42865804,
year = {2026},
author = {Yang, LJ and Deng, NS and Zhu, MJ and Shi, X and Yang, J and Nie, HX},
title = {Immune-related molecular links between asthma and Alzheimer's disease identified by multi-omics, machine learning and single-cell analysis.},
journal = {Frontiers in cell and developmental biology},
volume = {14},
number = {},
pages = {1907664},
pmid = {42865804},
issn = {2296-634X},
abstract = {OBJECTIVE: Epidemiological evidence suggests that asthma increases the risk of Alzheimer's disease (AD), yet their shared immune-related molecular mechanisms remain unclear. This study aimed to identify immune-associated molecular links between the two diseases.

METHODS: Gene expression datasets from GEO were analyzed to identify differentially expressed genes (DEGs) and enriched pathways. WGCNA was used to detect immune-related modules, and machine learning algorithms were applied to refine candidate biomarkers. Mendelian randomization (MR) and experimental validation were conducted to investigate genetic associations and expression correlations. A logistic regression model and nomogram were constructed. Immune characteristics were further explored using GSEA, immune-cell signature analysis, and single-cell RNA sequencing (scRNA-seq).

RESULTS: CD163 and CHST6 were identified as cross-disease candidate genes. MR analyses showed nominal genetic associations of CD163 expression and plasma protein levels with asthma- and AD-related phenotypes, although these associations did not remain significant after FDR correction. CD163 and CHST6 also showed increased expression in independent asthma and AD mouse models. The combined diagnostic model showed good discrimination (AUC >0.87). Immune-cell signature analysis revealed tissue-dependent associations between the candidate genes and immune-related signatures. scRNA-seq revealed cell-type-specific expression patterns, with CD163 predominantly localized to myeloid-lineage populations, including microglia in AD and monocytes in severe asthma, whereas CHST6 showed context-dependent localization across glial and airway epithelial populations.

CONCLUSION: CD163 and CHST6 represent potential cross-disease molecular candidates associated with asthma and AD. CD163 may reflect a systemic immune-associated signal, whereas CHST6 may reflect tissue- and context-dependent cellular changes. These findings provide a preliminary framework for further investigation of asthma-AD comorbidity and require validation in prospective and functional studies.},
}

@article {pmid42865929,
year = {2026},
author = {Ponomareva, EV and Selezneva, ND and Boksha, IS and Savushkina, OK and Prokhorova, TA and Tereshkina, EB and Zozulya, SA and Gavrilova, SI and Kolykhalov, IV},
title = {Pilot clinical study of Taxifolin Aqua effect in patients with amnestic mild cognitive impairment.},
journal = {Frontiers in psychiatry},
volume = {17},
number = {},
pages = {1814042},
pmid = {42865929},
issn = {1664-0640},
abstract = {Taxifolin (dihydroquercetin), a potent antioxidant flavonoid, shows promise for neurodegenerative conditions. Our pilot study aimed at evaluation the efficacy and safety of Taxifolin in patients with amnestic mild cognitive impairment (aMCI) and monitored a set of blood measures. Twenty-three patients (18 female; aged 53-87) received dihydroquercetin oral solution for 8 weeks with a 4-week follow-up period in an open-label study design. Thirteen patients with aMCI were monitored as controls. Outcomes were assessed using cognitive status (MMSE, MoCA, FCSRT-IR), neuropsychiatric symptoms' (NPI-Q, HDRS), and rater's impression (CGI) scales, along with blood measures monitoring (glutathione reductase (GR), glutamate dehydrogenase (GDH), and superoxide dismutase (SOD); plasma neutrophil elastase (NE), alpha-1-proteinase inhibitor (alpha-1PI)). Responder classification using composite Z-score changes was based on all clinical scales. Results: Eleven patients were classified as responders, showing significant MMSE and MoCA improvement (mean +2.73 points, p=0.001) sustained through 4-week follow-up. Non-responders and control group showed slight cognitive decline. Composite Z-score changes at the 4-week follow-up revealed differences between responders/non-responders (ANOVA F(2,20)=17.38, p=0.001); biomarker analysis revealed difference in NE/alpha-1PI ratio (p=0.034), SOD (p=0.023), and GR dynamics (p=0.022), which correlated negatively with clinical response (R=-0.547, p=0.007), and baseline GDH (p=0.049). Conclusion: Taxifolin treatment resulted in significant cognitive benefits in ~half of aMCI patients, with effects sustained for one month post-treatment. Biomarker changes reveal possible mechanisms involving oxidative stress modulation and inflammatory pathways. These findings support further controlled trials of Taxifolin in populations at risk of Alzheimer's disease.},
}

@article {pmid42865955,
year = {2026},
author = {Long, Z and Guo, H and Sun, L},
title = {Mesenchymal stromal cells in age-related neurodegenerative disorders: mechanisms, translational barriers, and precision strategies.},
journal = {Frontiers in immunology},
volume = {17},
number = {},
pages = {1965598},
pmid = {42865955},
issn = {1664-3224},
mesh = {Humans ; *Neurodegenerative Diseases/therapy/metabolism/etiology ; *Mesenchymal Stem Cells/metabolism/immunology ; Animals ; *Aging/immunology ; Extracellular Vesicles/metabolism/transplantation ; *Mesenchymal Stem Cell Transplantation/methods ; Precision Medicine ; Translational Research, Biomedical ; },
abstract = {Ageing remodels the neuroimmune, metabolic, and vascular environment in ways that accelerate neuronal vulnerability and constrain tissue repair. Mesenchymal stromal cells (MSCs) and MSC-derived extracellular vesicles (MSC-EVs) are therefore attractive candidates for neurodegenerative disorders because their effects extend beyond cell replacement to coordinated paracrine, immunomodulatory, trophic, and vascular regulation. This critical review evaluates the biological rationale, disease-specific evidence, translational limitations, and precision-development strategies for MSC-based interventions in Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, multiple system atrophy, and vascular dementia, whilst using selected rare hereditary neurodegenerative disorders as exploratory boundary cases. Current evidence supports three interconnected modes of action: reprogramming maladaptive neuroimmune responses; preserving neuronal homeostasis through trophic support, mitochondrial rescue, and proteostasis regulation; and restoring the neurovascular unit and blood-brain barrier. However, reproducible clinical efficacy remains limited by variation in tissue source, donor age, manufacturing, potency, dose, route, and outcome selection, as well as poor central nervous system exposure and inadequate patient stratification. Ageing-related changes in both the recipient microenvironment and the cellular product further complicate translation. Future development should replace empirical cell administration with mechanism-defined products, validated potency assays, quantitative biodistribution, biomarker-guided enrolment, engineered cells or vesicles, rational combinations, and trials using disease-modifying endpoints. MSC-based therapies are best positioned not as universal regenerative agents, but as mechanism-defined, biomarker-matched products-potentially engineered at the cell or EV level-that regulate biologically active and potentially reversible disease states.},
}

Humans
*Neurodegenerative Diseases/therapy/metabolism/etiology
*Mesenchymal Stem Cells/metabolism/immunology
Animals
*Aging/immunology
Extracellular Vesicles/metabolism/transplantation
*Mesenchymal Stem Cell Transplantation/methods
Precision Medicine
Translational Research, Biomedical

@article {pmid42866056,
year = {2026},
author = {Salem, MA and Hamza, EA and Bedewy, D and Amer, RA and Hamid, AARM and Mahgoub, E and Moustafa, AA},
title = {Childhood trauma and cognitive decline in women: an empirical analysis of cognitive vulnerability in later life.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1848025},
pmid = {42866056},
issn = {1663-4365},
abstract = {Childhood trauma has lasted consequences for women's cognitive health and this may contribute to memory decline and increased vulnerability to cognitive impairment in later life. A cross sectional study was carried out to assess the correlation between childhood trauma and cognitive status among 55 women aged 58-79 years were selected from Departments of Psychiatry and General Medicine, Tanta University Hospital, Egypt. The Montreal Cognitive Assessment (MoCA) was used to evaluate cognitive performance, the Global Deterioration Scale (GDS) for global clinical staging, and the Childhood Trauma Questionnaire (CTQ) for childhood adversity. Overall, emotional abuse was exposed the most with a high mean score on the CTQ subscale. Pearson correlations and multiple linear regression models (controlling for age) showed that emotional neglect and physical neglect were the strongest predictors across both outcomes. For MoCA performance, emotional neglect (β = -0.0877, r = -0.85, p < 0.01) and physical neglect (β = -0.0100, r = -0.80, p < 0.01) showed the largest effects. GDS coefficients had an absolute value that was proportionately smaller (emotional neglect: β = 0.0112; physical neglect: β = 0.0013) and, consistent with the higher-is-worse nature of the GDS, were positive in direction. Additional findings show a greater amount of neglect predicted more advanced clinical staging, and that there was no change to the relative order of effects by predictor compared to the MoCA model. The regression model accounted for 72.5% of the variance (R[2] = 0.725) in MoCA. The results indicate that childhood neglect, especially emotional neglect, might be an important risk factor for cognitive vulnerability in adulthood and highlight the necessity to intervene early in childhood to promote cognitive health in women.},
}

@article {pmid42866370,
year = {2026},
author = {Wang, T and Wang, L and Cao, J and Zhao, Y and He, Z and Lu, F},
title = {Remodeling of the brain immune microenvironment in Alzheimer's disease: interactions among microglia, astrocytes, complement, and the neurovascular unit.},
journal = {Frontiers in immunology},
volume = {17},
number = {},
pages = {1956600},
pmid = {42866370},
issn = {1664-3224},
mesh = {Humans ; *Alzheimer Disease/immunology/pathology/metabolism ; *Microglia/immunology/metabolism/pathology ; *Astrocytes/immunology/metabolism/pathology ; *Complement System Proteins/immunology/metabolism ; *Brain/immunology/pathology/metabolism/blood supply ; Animals ; *Cellular Microenvironment/immunology ; Amyloid beta-Peptides/metabolism ; },
abstract = {Alzheimer's disease is defined by amyloid-β deposition and tau pathology, yet comparable pathological burdens do not necessarily correspond to similar cognitive trajectories, regional patterns of injury, or treatment responses. This discordance suggests that the cellular and tissue microenvironment may materially shape disease progression. Genetic studies, single-cell and spatial omics, and human-derived models further indicate that microglia, astrocytes, the complement system, and the neurovascular unit undergo coordinated remodeling during the preclinical phase of AD and influence pathological spread, synaptic injury, and neurodegeneration through intercellular interactions. Remodeling of the brain immune microenvironment is regionally specific, stage dependent, and heterogeneous across cellular states; conventional pro-inflammatory/anti-inflammatory or activated/resting dichotomies therefore fail to capture its dynamics. This review examines the remodeling of the AD brain immune microenvironment through interactions among microglia, astrocytes, complement, and the neurovascular unit, with emphasis on their roles in Aβ and tau pathology, synaptic injury, lipid homeostasis, and vascular dysfunction, and considers the interpretive limits of single-cell and spatial-omics evidence. Current evidence supports a dynamically reconfigured system rather than a uniformly escalating inflammatory response. Therapeutic strategies should move beyond broad anti-inflammatory approaches to preserve effective pathological clearance within appropriate disease windows, limit maladaptive synaptic injury, and restore glial and neurovascular homeostasis.},
}

Humans
*Alzheimer Disease/immunology/pathology/metabolism
*Microglia/immunology/metabolism/pathology
*Astrocytes/immunology/metabolism/pathology
*Complement System Proteins/immunology/metabolism
*Brain/immunology/pathology/metabolism/blood supply
Animals
*Cellular Microenvironment/immunology
Amyloid beta-Peptides/metabolism

@article {pmid42866406,
year = {2026},
author = {He, X and Zhang, L and Song, C and Liu, Y},
title = {Microbiota-derived metabolite signatures in Alzheimer's disease across the cognitive aging continuum: a human-focused systematic review and evidence-weighted knowledge graph.},
journal = {Frontiers in microbiology},
volume = {17},
number = {},
pages = {1925387},
pmid = {42866406},
issn = {1664-302X},
abstract = {BACKGROUND: Gut microbial metabolism is increasingly implicated in Alzheimer's disease (AD), mild cognitive impairment (MCI), preclinical amyloid accumulation, and cognitive aging. However, existing reviews often focus on microbial taxonomy rather than the metabolite mediators that connect the gut ecosystem with AD pathology, neuroinflammation, and cognition.

OBJECTIVES: To systematically synthesize human and translational evidence on microbiota-derived or microbiota-associated metabolite signatures across the cognitive aging continuum using structured evidence synthesis, evidence mapping, and an evidence-weighted knowledge graph.

METHODS: A systematic search of PubMed, the Web of Science Core Collection, and Academic Search Premier via EBSCOhost was conducted to identify eligible studies. Citation checking and targeted full-text retrieval were used during screening and evidence verification. After de-duplication, records were screened by population, exposure or intervention, comparator, outcome layer, and study design. Human core, human bridge, human intervention, mechanistic/translational, and resource/background-mechanism evidence were coded separately. Module-level quantitative summaries were retained only where data were sufficiently comparable; otherwise, structured direction-of-effect synthesis and evidence mapping were used. Overlapping Alzheimer's Disease Neuroimaging Initiative (ADNI) bile-acid analyses were synthesized as complementary outcome layers rather than treated as independent replications of the same association.

RESULTS: The final evidence pool contains 60 records, including 32 direct, bridge, or intervention human evidence records and 28 mechanistic, translational, animal, cellular, resource, or background-mechanism records. Bile-acid profiles and short-chain fatty acid (SCFA)-related functional capacity were recurrent human evidence modules. Trimethylamine N-oxide (TMAO)/choline-related findings were context dependent, varying by biological matrix, population, renal function, and cardiometabolic context, whereas selected tryptophan/indole/kynurenine pathways remained emerging. Across these metabolite modules, the evidence-weighted knowledge graph showed recurrent convergence on barrier dysfunction, inflammatory and glial signaling, and mitochondrial stress, while retaining context-dependent conflicts and gaps in human validation.

CONCLUSION: The current literature points to a convergent network of microbiota-related metabolic pathways rather than a single metabolite marker or causal route. The synthesis prioritizes external validation of bile-acid signatures, matched multi-compartment assessment of SCFA- and TMAO-related pathways, and direct human testing of indole/kynurenine and lipid-like mechanisms. These priorities require longitudinal and interventional studies with harmonized metabolomics, AD biomarkers, and cognitive outcomes.},
}

@article {pmid42866529,
year = {2026},
author = {Zhang, Q and Wu, J and Fang, Y and Yang, D and Cheng, Y},
title = {Digital empowerment of dance movement therapy: innovative applications and evidence-based evaluation in mental health interventions.},
journal = {Frontiers in psychology},
volume = {17},
number = {},
pages = {1935660},
pmid = {42866529},
issn = {1664-1078},
abstract = {BACKGROUND AND OBJECTIVES: Mental health disorders are a severe global public health crisis. Dance movement therapy (DMT) offers unique benefits, but traditional DMT is limited by subjective evaluation, non-standardized protocols, and restricted access. Digital technologies such as virtual reality, artificial intelligence, and wearable sensors may address these limitations; however, a structural gap remains between technological application and rigorous clinical evidence.

METHODS: This narrative review synthesizes literature from PubMed, Web of Science, Scopus, and CNKI. Sources used for population-specific synthesis were coded by population, intervention modality, outcome measures, study design, and relationship to the review question (direct digital-DMT; digital but non-DMT; conventional DMT/dance; mechanistic/contextual). Claims that extend beyond primary digital-DMT evidence are flagged as interpretive contributions or as findings from adjacent analogue sources.

RESULTS: Digital technologies can make DMT more multi-modal and quantitative, but direct trial evidence for digital DMT remains sparse and heterogeneous. Preliminary support for anxiety-related outcomes comes mainly from one small randomized trial of digital dance-art therapy and from mixed-methods online dance studies. Most population-specific estimates in this review derive from conventional (non-digital) DMT/dance syntheses or from digital but non-DMT analogues (for example, VR exposure therapy or home-based exergaming) and should not be read as direct digital-DMT effects. Conventional long-term dance/DMT programmes show modest cognitive improvements in older adults with mild cognitive impairment, while evidence for Alzheimer's disease remains inadequate. In China, Western theoretical frameworks and cultural constraints also limit localization.

CONCLUSION: Digital DMT requires deep interdisciplinary integration rather than simple technological combination. This review proposes a three-level localization framework for China and calls for large-sample randomized controlled trials, stronger data-privacy protections, and narrowed digital divides.},
}

@article {pmid42866775,
year = {2026},
author = {Bhatia, V and Khatak, A},
title = {A positive Alzheimer's blood biomarker is not a diagnosis: the presence-primacy-permission framework for plasma p-tau217.},
journal = {Annals of medicine and surgery (2012)},
volume = {88},
number = {10},
pages = {6232-6234},
pmid = {42866775},
issn = {2049-0801},
abstract = {Validated plasma phosphorylated tau 217 (p-tau217) assays identify Alzheimer disease pathology with high accuracy. Wider clinical use creates a risk of postanalytic misclassification when pathology is converted directly into a clinical diagnosis or treatment decision. This editorial examines why accuracy relative to amyloid positron emission tomography or cerebrospinal fluid biomarkers does not establish that Alzheimer disease is the principal cause of a patient's cognitive syndrome. It describes three substitutions: pathology for diagnosis, presence for primacy, and diagnosis for treatment eligibility. We propose the presence-primacy-permission framework to distinguish confirmation of pathology from clinical-biological concordance and treatment suitability. Presence requires appropriate patient selection, a validated assay, and context-specific interpretation. Primacy requires integration of cognitive phenotype, trajectory, functional status, neurologic examination, structural imaging, and coexisting pathology. Permission requires assessment of clinical stage, hemorrhagic risk, treatment feasibility, and patient goals. Separate documentation of the biomarker result, syndrome, etiologic attribution, and actionability may reduce premature diagnostic closure while preserving the clinical value of p-tau217.},
}

@article {pmid42867198,
year = {2026},
author = {Yu, M and He, C and Shi, L and Huang, Z and Wang, B and Liu, Q and Cheng, S},
title = {Intelligent assistive technologies in rehabilitation for older adults with Alzheimer's disease: systematic review and thematic analysis.},
journal = {Disability and rehabilitation. Assistive technology},
volume = {},
number = {},
pages = {1-32},
doi = {10.1080/17483107.2026.2735597},
pmid = {42867198},
issn = {1748-3115},
abstract = {PURPOSE: With population ageing, cognitive and functional impairments associated with Alzheimer's disease (AD) place demands on rehabilitation and long term care. Although intelligent assistive technologies (IATs), existing studies remain fragmented in terms of their development, application, and implementation. This study aimed to systematically review evidence on IAT applications in AD rehabilitation and developed, implemented, and evaluated.

METHODS: A systematic review was conducted using a predefined search strategy four electronic databases (PubMed, Taylor & Francis Online, Scopus, and Web of Science). Two reviewers independently screened titles/abstracts and full texts according to predefined criteria, yielding 26 eligible studies. Methodological quality was assessed using the Mixed Methods Appraisal Tool (MMAT), and thematic analysis was used to synthesise the findings and extract key themes.

RESULTS: The 26 included studies were generally rated as having moderate to high methodological quality. Most studies were small scale feasibility trials, with reported benefits mainly in user engagement and short term improvements. Evidence for sustained cognitive and functional improvement remains limited. Thematic analysis identified 4 core themes and 15 sub themes, covering technology modalities, intervention design and implementation, rehabilitation outcomes, and influencing factors.

CONCLUSIONS: The proposed Intelligent Intervention Development (IID) framework integrates technology development, intervention design and implementation, rehabilitation outcomes, and influencing factors. Moving beyond feasibility studies, future research should address long term effectiveness, implementation strategies, and scalability in real world care settings.},
}

@article {pmid42867452,
year = {2026},
author = {Keith, CM and Phelps, HE and Smith, SR and Teixeira, CVL and Mehta, RI and Worhunsky, P and Ward, M and Malone, J and Bojarski, L and Marano, G and Sharif, K and Pockl, S and Rajabalee, N and D'Haese, PF and Rezai, A and Haut, MW},
title = {Motor intrusion errors as a novel marker of neurodegeneration and executive dysfunction in Alzheimer's disease.},
journal = {Neuropsychology},
volume = {},
number = {},
pages = {},
doi = {10.1037/neu0001132},
pmid = {42867452},
issn = {1931-1559},
abstract = {Objective: With the development of disease-modifying therapies for Alzheimer's disease, continued clarification of clinical indicators of disease progression is needed. Based on prior observations of motor intrusion errors in amyloid-positive individuals, we sought to characterize differences in clinical, cognitive, and neuroimaging variables between amyloid-positive participants with and without motor intrusions. Method: We examined 284 amyloid-positive participants with mild cognitive impairment or mild dementia evaluated within a multidisciplinary memory clinic setting. Participants with and without motor intrusion errors were compared across neuropsychological performance variables while controlling for demographic, clinical, and neuroimaging factors. Results: Participants with motor intrusion errors demonstrated indicators of more progressed disease on clinical and neuroimaging markers. After controlling for these variables, greater executive dysfunction was observed in participants with motor intrusions with effect sizes ranging from small (ηp[2] = .02) to medium (ηp[2] = .12). Differences in performances on memory, naming, and basic processing speed tasks were not observed between the groups. Conclusions: Overall, the results of the present study suggest that the presence of a motor intrusion error may be associated with greater clinical impairment and, more specifically, executive dysfunction in Alzheimer's disease. (PsycInfo Database Record (c) 2026 APA, all rights reserved).},
}

@article {pmid42867481,
year = {2026},
author = {Babygirija, R and Illiano, JA and Sonsalla, MM and Zhu, G and Jabbarpour, CR and Mathew, T and Molkentin, T and Peterson, M and Winder, C and Nair, ARK and Xiao, F and Wolter, JM and Lamming, DW and Harris, DA},
title = {Sleeve Gastrectomy Improves Metabolic Health, Cognition, and Alzheimer's Disease Pathology in 3xTG Mice.},
journal = {Aging cell},
volume = {25},
number = {10},
pages = {e70767},
doi = {10.1111/acel.70767},
pmid = {42867481},
issn = {1474-9726},
support = {R03AG088813/AG/NIA NIH HHS/United States ; AG056771/AG/NIA NIH HHS/United States ; AG081482/AG/NIA NIH HHS/United States ; AG084156/AG/NIA NIH HHS/United States ; AG085898/AG/NIA NIH HHS/United States ; AG094153/AG/NIA NIH HHS/United States ; P30 AG092586/AG/NIA NIH HHS/United States ; P30-AG062715/AG/NIA NIH HHS/United States ; DK125859/DK/NIDDK NIH HHS/United States ; 6770-2024//Wisconsin Partnership Program/ ; //Wisconsin Alumni Research Foundation/ ; I01-BX004031//US Department of Veterans Affairs/ ; IS1-BX005524//US Department of Veterans Affairs/ ; },
mesh = {Animals ; *Alzheimer Disease/pathology/metabolism/surgery ; *Gastrectomy/methods ; Female ; Mice ; Mice, Transgenic ; *Cognition/physiology ; Disease Models, Animal ; },
abstract = {Obesity and diabetes are well-established risk factors for Alzheimer's disease (AD), implicating metabolic dysfunction in AD pathogenesis. Sleeve gastrectomy (SG) is among the most effective metabolic interventions available, yet its impact on AD progression remains poorly understood. We hypothesized that SG performed early in life would improve metabolic health, attenuate AD pathology, and preserve cognition in a transgenic AD mouse model. Five-week-old female 3xTg-AD mice were preconditioned on a Western diet (WD) to induce obesity and glucose intolerance, then randomized to SG or sham surgery and maintained on either Control or continued WD for 12 months. Metabolic phenotyping, body composition, and cognitive assessments (Novel Object Recognition, Barnes Maze, Fear Conditioning) were performed longitudinally, with histological and molecular brain analysis at endpoint. Under Control-fed conditions, SG reduced fat mass and improved peripheral insulin sensitivity independent of food intake. These changes were accompanied by reduced cortical Aβ plaque burden and attenuated astrocytic (GFAP) and microglial (IBA1) activation, specifically in the cortex. Mechanistically, SG altered the insulin signaling-autophagy axis in a region-specific manner, with increased pAKT and suppressed ATG5/ATG7/ATG16L1 in the cortex. Under persistent WD, SG improved glucose homeostasis, reduced fat mass, lowered frailty, and rescued short- and long-term spatial memory deficits in the Barnes maze, accompanied by reduced cortical Aβ burden. Collectively, these findings provide the first preclinical evidence that SG attenuates AD progression through a brain insulin signaling-autophagy axis, supporting metabolic surgery as a promising disease-modifying intervention for AD prevention in individuals with obesity.},
}

Animals
*Alzheimer Disease/pathology/metabolism/surgery
*Gastrectomy/methods
Female
Mice
Mice, Transgenic
*Cognition/physiology
Disease Models, Animal

@article {pmid42867534,
year = {2026},
author = {Cushing, BJ and Shahidehpour, RK and Abner, EL and Jicha, GA and Neltner, JM and Breig, MK and Teodorescu, KL and Neltner, AM and Coskun, EP and Kovacs, GG and Nelson, PT},
title = {Incident versus prevalent progressive supranuclear palsy: analyses of U.S. Alzheimer's Disease Research Centers data indicate clinical and neuropathological features of a relatively common and underrecognized tauopathy in the aging brain.},
journal = {Acta neuropathologica},
volume = {152},
number = {1},
pages = {},
pmid = {42867534},
issn = {1432-0533},
support = {P30 AG072946, R01 NS118584, RF1 AG082339, P01 AG078116, and R01 AG076932//NIH/ ; },
mesh = {Humans ; *Supranuclear Palsy, Progressive/pathology/epidemiology ; Female ; Male ; Aged ; *Brain/pathology ; Prevalence ; *Tauopathies/pathology/epidemiology ; United States/epidemiology ; Aged, 80 and over ; *Aging/pathology ; *Alzheimer Disease/pathology/epidemiology ; Incidence ; Longitudinal Studies ; tau Proteins/metabolism ; },
abstract = {Progressive supranuclear palsy (PSP) is an adult-onset neurodegenerative disease with a heterogeneous spectrum of clinical and pathological features. The epidemiology of PSP-as defined by the gold standard of autopsy diagnosis-remains unresolved, but prevalence estimates are typically ~1:10,000. Here, we analyzed the National Alzheimer's Coordinating Center (NACC) Neuropathology Data Set, aggregated from 38 U.S. Alzheimer's Disease Research Centers (ADRCs). We compared clinical and neuropathologic features of autopsied participants, stratifying on cognitive status at recruitment into the cohort. The sample comprised 6845 individuals who were followed longitudinally for 4.0 (± 2.9 stdev) approximately yearly visits, n = 297 with eventual autopsy-verified PSP. Participants were not necessarily diagnosed or followed in movement disorder clinics. Among those with dementia or PSP at recruitment (n = 4310), 3.3% had corticobasal degeneration (CBD), 3.0% Pick's disease, and 4.5% PSP pathology. Among those recruited while cognitively normal (n = 1451), 0.7% had CBD, and 0.1% Pick's disease, while 3.2% had PSP pathology. This frequency of incident PSP pathology was higher than expected based on prior epidemiology studies. In comparing between incident (recruited normal) and prevalent (recruited with dementia or clinical PSP) cases with PSP pathology, those with incident PSP died older: 89.5 years vs 76.3 years on average. Furthermore, incident PSP pathology cases were less likely to manifest stereotypical PSP clinical features, but more likely to have parkinsonism. In a convenience sample of individuals with PSP pathology from the University of Kentucky ADRC (n = 23), digital pathology analyses using HALO software and AI-based analytic modules revealed that PSP tau pathology was more severe overall in prevalent PSP. Within the putamen, incident cases had a higher proportion of tufted astrocytes and lower proportion of NFTs. In conclusion, in this large multicenter sample, PSP pathology was more common than other FTLD-Tau subtypes, and incident PSP often differed clinically from "classic" PSP.},
}

Humans
*Supranuclear Palsy, Progressive/pathology/epidemiology
Female
Male
Aged
*Brain/pathology
Prevalence
*Tauopathies/pathology/epidemiology
United States/epidemiology
Aged, 80 and over
*Aging/pathology
*Alzheimer Disease/pathology/epidemiology
Incidence
Longitudinal Studies
tau Proteins/metabolism

@article {pmid42867611,
year = {2026},
author = {Elsharydah, MN and Al-Khoury, Y and Ragunatha Rao, S and Schaffert, J and Saha, A and Kaufman, J and Rezaei, A and Leary, J and Jin, A and Almandoz, JP and Gauthier, CJ and Thomas, BP},
title = {Regional oxygen extraction fraction is higher in older adults with type 2 diabetes and obesity: associations with cognition and metabolic markers.},
journal = {GeroScience},
volume = {},
number = {},
pages = {},
pmid = {42867611},
issn = {2509-2723},
support = {P30 DK127984/DK/NIDDK NIH HHS/United States ; RR180056//Cancer Prevention and Research Institute of Texas/ ; },
abstract = {Type 2 diabetes (T2D) and obesity are highly prevalent among older adults and associated with increased Alzheimer's disease and related dementia (ADRD) risk, but underlying mechanisms linking T2D and obesity to cognitive impairment remain partially understood. Quantitative susceptibility mapping (QSM)-derived oxygen extraction fraction (OEF) provides a noninvasive MRI-based marker of cerebral metabolism and may capture early alterations in brain physiology. In this single-center, cross-sectional pilot study, we examined QSM-derived OEF in older adults with T2D + obesity (N = 14) and age- and sex-matched controls (N = 18) and evaluated associations with blood markers and cognitive performance. Whole-brain OEF was higher in participants with T2D + obesity (29.5% vs 27.3%; p = 0.019), with higher OEF observed across all examined lobar regions (p < 0.05). The T2D + obesity group demonstrated lower Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) Attention (p = 0.035) and Global Cognition (p = 0.022) indices and lower Delis-Kaplan Executive Function System (D-KEFS) Color-Word Switching (p = 0.001) scores. Whole-brain OEF was positively associated with leptin (p = 0.018) and negatively associated with HDL (p = 0.030). Higher regional OEF significantly correlated with lower cognitive performance, particularly D-KEFS (r = -0.40 to -0.62) and RBANS Attention (r = -0.36 to -0.41). This is the first study to support a potential link between altered cerebral oxygen extraction, metabolic dysfunction, and cognitive performance in older adults with T2D and obesity. Larger, longitudinal studies are needed to confirm these associations and determine their relevance to cognitive decline and ADRD risk.},
}

@article {pmid42867612,
year = {2026},
author = {Fang, X and Border, JJ and Zhang, H and Morgan, GC and Gregory, A and Hanscom-Trofy, Y and Dong, R and Yang, J and Hwang, SH and Morisseau, C and Hammock, BD and Fan, F and Roman, RJ},
title = {Inhibition of soluble epoxide hydrolase rescues cognitive deficits by preserving neurovascular integrity and attenuating glial and neuropathology in diabetic-related dementia.},
journal = {GeroScience},
volume = {},
number = {},
pages = {},
pmid = {42867612},
issn = {2509-2723},
support = {AG079336//NIH/ ; AG057842/AG/NIA NIH HHS/United States ; AG094068/AG/NIA NIH HHS/United States ; R35ES030443/ES/NIEHS NIH HHS/United States ; U54NS127758/NS/NINDS NIH HHS/United States ; A25-1690//Harrington Discovery Institute, University Hospitals/ ; 25PRE1365157//American Heart Association/ ; 25POST1363814//American Heart Association/ ; TRIBA/ Physiology Faculty Startup Fund//Augusta University/ ; },
abstract = {Diabetes mellitus (DM) is a major risk factor contributing to the development of Alzheimer's disease-related dementias (ADRD). While one of the early symptoms of both Alzheimer's disease (AD) and DM-related ADRD is a reduction in cerebral blood flow, the underlying biological mechanisms driving this decline remain to be fully elucidated. Genome-wide association studies have linked AD/ADRD to single-nucleotide polymorphisms in the gene encoding soluble epoxide hydrolase (sEH), an enzyme we previously reported to be upregulated in the brains of an AD rat model. Our previous studies also demonstrated that chronic sEH inhibition with 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU) preserves hippocampal-dependent spatial learning and memory and improves cerebral hemodynamics in both AD and DM-ADRD models. In the present study, we found that chronic TPPU treatment (1 mg/kg/day) reduced sEH expression in the brain, improved cortical-based non-spatial recognition memory involving both cortical and hippocampal networks, and reduced anxiety in DM-ADRD rats. TPPU improved brain perfusion and normalized impaired whisker-evoked functional hyperemia, an effect associated with increased Kir2.1 expression and neurovascular coupling in cerebral capillaries. Furthermore, TPPU increased tight junction protein expression (ZO-1 and OCLN), mitigated capillary rarefaction, and suppressed astrocyte and microglial activation in DM-ADRD rats. At the cellular level, TPPU attenuated hippocampal neurodegeneration, restored the expression of synaptic proteins (PSD95 and SY38), and reduced levels of proinflammatory chemokines, including MCP-1, RANTES, and MIP-1α, in the hippocampus of DM-ADRD rats. In conclusion, TPPU preserves cognitive function in DM-ADRD by mitigating cerebrovascular dysfunction, neuroinflammation and gliosis, thereby preserving synaptic integrity and neuronal survival, and represents a promising therapeutic strategy for DM-ADRD.},
}

@article {pmid42867690,
year = {2026},
author = {Wang, C and Ma, CT and Crotty, C and Zeng, FY and Bobkov, A and Covel, JA and Rivera, EK and Sergienko, E and Kosik, KS and Olson, SH and Jackson, MR and Rauch, JN},
title = {High-Throughput Screening Identifies Small-Molecule Inhibitors of the Tau-LRP1 Interaction.},
journal = {ACS chemical biology},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschembio.6c00599},
pmid = {42867690},
issn = {1554-8937},
support = {R01 AG075084/AG/NIA NIH HHS/United States ; R01 AG077672/AG/NIA NIH HHS/United States ; GC-202102-2021435//Alzheimer's Drug Discovery Foundation/ ; },
abstract = {The cellular uptake and propagation of tau are central features of tauopathies, including Alzheimer's disease, and are mediated by the endocytic receptor low-density lipoprotein receptor-related protein 1 (LRP1). While prior studies have implicated LRP1 in tau binding and internalization, the biochemical features of this interaction and its suitability for therapeutic targeting remain incompletely defined. Here, we establish a quantitative and scalable framework to interrogate the tau-LRP1 interaction and identify small-molecule modulators. We engineered and purified the LRP1 ligand-binding domain 4 (BD4), a key region mediating tau interaction, and developed multiple orthogonal assays, including fluorescence polarization, split luciferase complementation, and time-resolved FRET, to measure LRP1-BD4 interactions with tau and a known peptide ligand. Across assay formats, we observe consistent binding affinities in the nanomolar range and demonstrate competitive displacement by tau, receptor-associated protein (RAP), and a peptide ligand, supporting overlapping binding interfaces. Leveraging these platforms, we performed small-molecule high-throughput screening and identified a set of candidate inhibitors of the LRP1-BD4-tau interaction. Selected compounds reduced tau uptake in a cellular assay, phenocopying competitive inhibition by tau and a peptide ligand. Together, these studies define the LRP1-BD4-tau interaction as a biochemically tractable and druggable interface and establish an integrated discovery pipeline linking mechanistic characterization to functional cellular outcomes. This work provides a foundation for the development of therapeutic strategies targeting LRP1-mediated tau uptake.},
}

@article {pmid42867762,
year = {2026},
author = {Pehlivan, ZN and Zıkşahna, K and Adıyıl, R and Ihlamur, M},
title = {Blood-based multiplex nanobiosensing of Alzheimer's disease biomarkers: from nanoengineered ınterfaces to clinical translation.},
journal = {Metabolic brain disease},
volume = {41},
number = {1},
pages = {},
pmid = {42867762},
issn = {1573-7365},
mesh = {*Alzheimer Disease/blood/diagnosis ; Humans ; *Biomarkers/blood ; *Biosensing Techniques/methods ; *Nanotechnology/methods ; Amyloid beta-Peptides/blood ; Animals ; *Translational Research, Biomedical/methods ; },
abstract = {Alzheimer's disease is a progressive neurodegenerative disorder in which molecular and cellular alterations begin years before clinical symptoms, creating a strong need for minimally invasive blood-based tools that can detect disease-related biomarkers with high analytical reliability. This structured narrative review examines recent advances in nanoengineered multiplex biosensors for ultrasensitive profiling of Alzheimer's disease biomarkers in blood-derived matrices. Particular emphasis is placed on amyloid-β 42/40 ratio, phosphorylated tau isoforms, neurofilament light chain, and glial fibrillary acidic protein, which collectively reflect amyloid pathology, tau-associated neurodegeneration, axonal injury, and glial activation. We discuss electrochemical, plasmonic, surface-enhanced Raman scattering, field-effect transistor, nanozyme-assisted, and lab-on-a-chip platforms, focusing on how nanoengineered interfaces improve bioreceptor immobilization, signal amplification, antifouling performance, and low-volume multiplex readout. Although many reported platforms achieve femtomolar to attomolar sensitivity and show potential for point-of-care or near-patient testing, their clinical translation remains constrained by plasma and serum matrix effects, nonspecific adsorption, multiplex channel cross-talk, inconsistent reporting of analytical limits, and batch-to-batch variability in nanomaterial fabrication. We further highlight the importance of matrix-matched calibration, standardized preanalytical workflows, interference testing, reproducibility across independent fabrication batches, and comparison with established clinical reference methods. Overall, nanoengineered multiplex biosensors represent a promising route toward accessible blood-based Alzheimer's disease biomarker profiling, but their implementation in clinical practice will require rigorous analytical validation, scalable manufacturing, and clinically meaningful assay design.},
}

*Alzheimer Disease/blood/diagnosis
Humans
*Biomarkers/blood
*Biosensing Techniques/methods
*Nanotechnology/methods
Amyloid beta-Peptides/blood
Animals
*Translational Research, Biomedical/methods

@article {pmid42857600,
year = {2026},
author = {Moughamian, AJ and La Vallee, L and Kile, S and Urban, T and Momii, A and Manifield, M and Minton, J},
title = {The Advanced Therapeutics for Alzheimer's Disease Review Board: A multidisciplinary model to facilitate safe access to amyloid-targeting therapies in general neurology across the Sutter Health system.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {4},
pages = {e70479},
pmid = {42857600},
issn = {2352-8729},
abstract = {Amyloid-targeting therapies (ATTs) require workup and monitoring that some general neurologists are uncomfortable with. Sutter Health treats over 3.5 million patients with more than 100 neurologists, but only 5 cognitive specialists. We developed the Advanced Therapeutics for Alzheimer's Disease (ATAD) Review Board, a system-wide model to address the shortage of specialists while enhancing safe access to ATTs across the health system. The ATAD Review Board comprises cognitive specialists, a neuroradiologist, a pharmacist, and a registered nurse program manager. Neurologists submit cases to the board for appropriate patient selection and re-review of cases with side effects. We reviewed 447 cases from 51 neurologists and 77% were eligible for treatment. The annual volume increased 148% in 2025. Total amyloid-related imaging abnormality rate was 17.4% for lecanemab and 28.8% for donanemab. We describe a system-wide review board model that supported ATT prescribing by general neurologists and expanded safe access to ATTs across a large integrated health system.},
}

@article {pmid42857741,
year = {2026},
author = {Shimazu, T and Hoshino, E and Nakaseko, M and Homma, K and Suzuki, S and Horikoshi, K and Maruki, Y},
title = {Caregiver-Reported Behavioral Changes After Donepezil Transdermal Patch Therapy in Alzheimer's Disease: An Exploratory Real-World Network Analysis.},
journal = {Neuropsychiatric disease and treatment},
volume = {22},
number = {},
pages = {637015},
pmid = {42857741},
issn = {1176-6328},
abstract = {PURPOSE: To characterize caregiver-reported behavioral changes after donepezil transdermal patch therapy and to examine the descriptive connectivity of co-occurring improvements in patients with Alzheimer's disease (AD).

PATIENTS AND METHODS: This retrospective, single-center observational study included 26 patients meeting the 2011 National Institute on Aging-Alzheimer's Association criteria for probable AD dementia. Approximately 2-4 months after patch initiation, caregivers rated nine behavioral domains using routine, non-validated single-item change assessments as improved, unchanged, or worsened relative to the pre-treatment state. A descriptive co-improvement network was used solely to summarize pairwise co-occurrence of binary improvement indicators using phi-coefficients and observed strength centrality. Because of the small sample and sparse binary events, all network measures were treated as sample-specific descriptive quantities rather than inferential estimates.

RESULTS: The most frequently improved domains were smiling/positive affect (12/26, 46.2%), calmness (9/26, 34.6%), and night-time sleep (8/26, 30.8%). Calmness had the highest observed strength centrality (2.467), followed by grooming behavior (2.059), hobbies/interests (2.009), and housework/instrumental activities of daily living (1.938). Calmness remained the highest-strength node in all 26 leave-one-participant-out sensitivity analyses. No treatment discontinuations or serious adverse events were documented.

CONCLUSION: Caregiver-perceived calmness, assessed as a single non-validated change item, was the most highly connected domain in this small descriptive co-improvement network. The findings are exploratory and do not establish treatment efficacy, a validated agitation-related outcome, temporal direction, or mechanism. Prospective studies using standardized behavioral measures are needed.},
}

@article {pmid42857751,
year = {2026},
author = {Zhang, S and Ding, X and Caffo, B and Chen, J and Zhang, X and Kharrazi, H and Wang, Z},
title = {CROSS-ATTENTION FUSION OF STRUCTURAL AND DEFORMATION-BASED MRI FEATURES FOR ALZHEIMER'S DISEASE CLASSIFICATION.},
journal = {Proceedings. IEEE International Symposium on Biomedical Imaging},
volume = {2026},
number = {},
pages = {},
pmid = {42857751},
issn = {1945-7928},
support = {R01 AG068002/AG/NIA NIH HHS/United States ; },
abstract = {Accurate assessment of Alzheimer's disease (AD) using neuroimaging is important for understanding disease progression and supporting clinical research. Structural MRI (sMRI) is widely used for this purpose, but most deep learning approaches primarily rely on intensity-based features, which may not fully capture subtle morphological variations. Jacobian determinant maps (JSM) provide complementary information by describing localized brain deformations; however, conventional multimodal fusion strategies such as early or late fusion may not fully capture the interactions between these modalities. To address this, we explore a cross-attention fusion approach that explicitly models the relationship between sMRI intensity and JSM-derived deformation features for AD classification. Using data from the Alzheimer's Disease Neuroimaging Initiative (ADNI), we compare cross-attention with pairwise self-attention and four baseline fusion methods. The proposed approach achieved mean ROC-AUC scores of 0.903 (0.033) for AD vs. cognitively normal (CN) and 0.692 (0.061) for mild cognitive impairment (MCI) vs. CN under five-fold cross-validation. The proposed approach achieved the best performance among fusion strategies and achieved higher or comparable performance with only 1.56 million parameters. These findings suggest that cross-attention fusion may serve as a potentially useful approach for integrating structural and deformation-based MRI features in AD classification tasks.},
}

@article {pmid42857961,
year = {2026},
author = {Chandrakar, K and Panday, A and Patel, D and Poleboina, S},
title = {Neuroprotective effects of lithium and caffeic acid co-loaded liposomes in diabetes-induced Alzheimer's disease: association with GSK-3β and β-catenin.},
journal = {Nanomedicine (London, England)},
volume = {},
number = {},
pages = {1-17},
doi = {10.1080/17435889.2026.2743276},
pmid = {42857961},
issn = {1748-6963},
abstract = {AIM: To investigate the therapeutic effects of co-loaded lithium (Li) and caffeic acid (CA) liposomes in diabetes-induced Alzheimer's disease rats by improving cognitive dysfunction and attenuating neurodegeneration through the modulation of β-catenin/GSK-3β signaling.

METHODS: Li- and CA-co-loaded liposomes were prepared by the ethanol injection method and characterized. A diabetes-induced Alzheimer's disease model was established in male Wistar rats using a high-fat diet followed by low-dose streptozotocin (35 mg/kg) administered intraperitoneally. Li- and CA-co-loaded liposomes were given via the same route every day for 4 weeks. At the end of the experiment, the animals were sacrificed, and various biochemical and oxidative stress parameters, histopathological assessments, and ELISA analyses were performed.

RESULTS: Dual-drug-loaded Li and CA liposomal treatment significantly improved cognitive function, ameliorated metabolic dysfunction, and reduced oxidative stress by restoring antioxidant enzyme levels. Additionally, liposomes attenuated nitrite, acetylcholinesterase, and amyloid-β levels in diabetes-induced Alzheimer's rats. Histopathological assessment confirmed marked neuroprotective and pancreatic protective effects. Further, at a molecular level, Li and CA liposomal treatment reduced the expression of GSK-3β and increased the expression of β-catenin levels in rats.

CONCLUSION: This study provides the first evidence demonstrating the therapeutic potential of Li- and CA-co-loaded liposomes in attenuating diabetes‑associated cognitive dysfunction.},
}

@article {pmid42857983,
year = {2026},
author = {Smitasiri, T and Pongpitakmetha, T and Thanprasertsuk, S and Likitjaroen, Y},
title = {Prevalence and impact of cerebral small vessel lesions in mild cognitive impairment and mild dementia due to Alzheimer's disease patients in memory clinic: Preparation for anti-amyloid therapy in Thailand.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261493065},
doi = {10.1177/13872877261493065},
pmid = {42857983},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease (AD) raises global concern with its impact on daily living. Anti-amyloid therapy (AAT) are specific treatments used in mild cognitive impairment (MCI) and mild dementia stage of AD (mild AD). Severe cerebral small vessel disease (SVD) lesions such as microbleeds, superficial siderosis, lacunes, white matter hyperintensities are listed as exclusions criteria for AAT. In Thailand, there is no prevalence study of SVD lesions specifically in these patient groups.ObjectiveThe purpose of this study is to report the prevalence of SVD burdens which are excluded in AAT, in MCI and mild AD patients in Thailand.MethodsThe study was carried out at Memory Clinic in King Chulalongkorn Memorial Hospital. Patients with amnestic MCI and mild AD were diagnosed using clinical criteria, cognitive tests and brain MRI. Visual rating scales were used to evaluate SVD burden based on STRIVE-2 criteria. Baseline characteristics and cognitive tests were retrieved from electronic medical records.ResultsThe study involving 102 patients, 73.5% had MCI, and 26.5% had mild AD. Twenty-one individuals (20.6%) had either more than 4 microbleeds, more than 2 lacunes, or Fazekas score of 3. There was no evidence of superficial siderosis. Individuals without microbleeds had a higher TMSE score (25.4 versus 23.5; p = 0.009).ConclusionsAmong patients with MCI and mild AD, 20.6% met the exclusion criteria for AAT, in part of SVD lesions. These findings provide important information for evaluating the cost-effectiveness of AAT, which become a treatment option for Thai AD patients.},
}

@article {pmid42858052,
year = {2026},
author = {Qiao, Y and Chen, H and Fan, K and Yang, X and Yu, Y and Wang, R and Xing, Y and Tang, Y},
title = {High-intensity transcranial alternating current stimulation improves sleep quality in patients with mild Alzheimer's disease: Findings from the TRANSFORM-AD study.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261492561},
doi = {10.1177/13872877261492561},
pmid = {42858052},
issn = {1875-8908},
abstract = {BackgroundHigh-intensity transcranial alternating current stimulation (Hi-tACS) has shown beneficial effects on cognitive function in Alzheimer's disease (AD). However, data on the effects of hi-tACS on sleep quality and emotional state in patients with AD are still limited.ObjectiveThis study aimed to investigate the influences of hi-tACS on sleep quality and emotional state in AD.MethodsThe TRANSFORM-AD study was a double-blind, randomized-controlled trial that enrolled individuals with mild AD. Participants were randomized to receive hi-tACS group or sham stimulation group, and underwent 30 one-hour sessions of either 40 Hz tACS or sham stimulation over consecutive 15 consecutive days. Pittsburgh sleep quality index (PSQI), Hamilton anxiety Rating Scale (HAMA), Hamilton depression Rating Scale (HAMD) and Quality of life in Alzheimer's Disease scale (QOL-AD) were evaluated at baseline, and the end of the intervention.ResultsAmong 43 participants with complete baseline and post-intervention assessments, Hi-tACS reduced post-intervention PSQI scores compared with sham after adjustment for baseline PSQI (adjusted mean difference, -2.34 points; 95% CI, -3.63 to -1.05; p < 0.001). Baseline-adjusted effects for HAMA (-1.43; 95% CI, -2.89 to 0.02), HAMD (0.44; 95% CI, -1.28 to 2.15), and QOL-AD (2.07; 95% CI, -1.57 to 5.70) were imprecise and included the null.ConclusionHi-tACS improved subjective sleep quality in patients with mild AD. The present secondary analysis did not provide conclusive evidence of effects on anxiety, depression, or quality of life; these exploratory outcomes require confirmation in larger, adequately powered trials.Trial registration:ClinicalTrials.gov, NCT03920826.},
}

@article {pmid42858057,
year = {2026},
author = {Gu, Y and Liu-Ambrose, T and Falck, RS and Nagamatsu, LS and Tam, RC and Hsiung, GR and Ten Brinke, L and Bullock, A and Grant, S and Hsu, CL},
title = {Interaction of physical fitness and resting state functional connectivity on global cognitive function in older adults with mild cognitive impairment.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261491995},
doi = {10.1177/13872877261491995},
pmid = {42858057},
issn = {1875-8908},
abstract = {BackgroundMild cognitive impairment (MCI) represents a prodromal stage of Alzheimer's disease. Physical fitness, including cardiorespiratory fitness and muscular strength, is associated with cognitive function in older adults. Resting-state functional connectivity (rsFC) is also linked to cognitive function; however, whether physical fitness modifies the association between rsFC and cognitive function remains unclear.ObjectiveTo examine associations of cardiorespiratory fitness and muscular strength with rsFC and their interaction on global cognitive function in older adults with MCI.MethodsA cross-sectional study of 95 older adults with MCI. Cardiorespiratory fitness was estimated by the 400-m walk; muscular strength was indexed using grip strength measured by hand dynamometer. Global cognitive function was indexed by the 13-item Alzheimer's Disease Assessment Scale-Cognitive (ADAS-Cog-13). Using the Yeo 7-network atlas, we computed rsFC within and between seven canonical networks. Significant rsFC-fitness associations were entered into moderation analyses (X = rsFC, Y = ADAS-Cog-13) with cardiorespiratory fitness or grip strength as moderator, adjusted for covariates. Simple slopes were examined at ±1 SD from the mean of moderator.ResultsParticipants had a mean age of 73.49 years, and 53.7% were female. Cardiorespiratory fitness interacted with rsFC in relation to ADAS-Cog-13, whereas grip strength did not. Specifically, greater limbic-visual (standardized b = -0.22, p = 0.009), limbic-somatomotor (b = -0.20, p = 0.049), and limbic-ventral attention (b = -0.19, p = 0.020) rsFC were associated with better global cognitive function among individuals with higher cardiorespiratory fitness.ConclusionsHigher between-network rsFC is generally associated with worse cognitive function. Thus, higher cardiorespiratory fitness may attenuate the negative association between higher between-network rsFC and global cognitive function in MCI.},
}

@article {pmid42858060,
year = {2026},
author = {Ben Brik, S},
title = {Noise or clearance? Reframing plasma amyloid-β variability in Alzheimer's disease as a measurable clearance signal.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261496533},
doi = {10.1177/13872877261496533},
pmid = {42858060},
issn = {1875-8908},
abstract = {Plasma biomarkers, and the amyloid-β 42/40 ratio in particular, are increasingly used to stage Alzheimer's disease and to stratify and monitor clinical trials, on the tacit assumption that a single measurement reflects a stable, steady-state level of pathology. A recent micro-longitudinal study that sampled plasma weekly for five weeks in people with Alzheimer's disease challenged that assumption, reporting that most participants varied by more than half in the amyloid-β 42/40 ratio over that short window. The reflexive response is to treat such movement as measurement noise to be averaged away. Here I argue that a meaningful part of it is unlikely to be noise. In healthy adults the same ratio is among the most stable plasma analytes, so instability concentrated in disease is difficult to attribute to the assay alone. Brain-to-blood clearance of amyloid-β is itself dynamic over days, rising with sleep and falling with fragmentation, apnoea, poor cerebral perfusion, autonomic dysregulation, and sedating or anticholinergic drugs. An instantaneous plasma value therefore partly reports the clearance state of the preceding night. This clearance account is kept distinct from analytical and pre-analytical variance, and from oligomeric amyloid-β dynamics, which are considered separately. The practical problem is not the variance itself but that we measure the molecule without measuring the physiological state that moves it. I propose that an inexpensive, repeatable, bedside index of that state, illustrated here with the Systemic BenBrik Geriatric Score, could be recorded alongside each plasma draw and modelled as a covariate, converting nuisance variance into interpretable signal. The prediction is falsifiable, and a validation design is outlined. This is a hypothesis, not a validated result; the illustrative index used here, the Systemic BenBrik Geriatric Score, is not a validated measure.},
}

@article {pmid42858061,
year = {2026},
author = {Zhou, Y and Zhu, L and Liu, Z and Zhang, Q and Wang, J},
title = {Multi-Dimensional Feature Adaptive Gating Network for Multi-View and Whole-Brain Magnetic Resonance Imaging-Based Alzheimer's Disease Classification.},
journal = {Journal of visualized experiments : JoVE},
volume = {},
number = {236},
pages = {},
doi = {10.3791/73427},
pmid = {42858061},
issn = {1940-087X},
mesh = {*Alzheimer Disease/diagnostic imaging/classification/pathology ; Humans ; *Magnetic Resonance Imaging/methods ; *Brain/diagnostic imaging/pathology ; Cognitive Dysfunction/diagnostic imaging/classification ; *Neuroimaging/methods ; Convolutional Neural Networks ; Deep Learning ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder associated with structural brain alterations detectable by structural magnetic resonance imaging (sMRI). Accurate classification of normal control (NC), mild cognitive impairment (MCI), and AD remains challenging because disease-related changes are subtle, spatially distributed across multiple brain regions, and difficult to interpret in a biologically meaningful manner. Existing deep learning methods often rely on either whole-brain volumetric features or two-dimensional slice-level representations, which may limit the integration of complementary structural information and reduce model interpretability. This study presents a reproducible and explainable deep learning framework, termed the multidimensional feature adaptive gating network (MDFAG-Net), for sMRI-based AD classification and neuroimaging analysis. The framework integrates multidimensional structural MRI representations by combining 2D slice-level features extracted from sagittal, coronal, and axial views using a Vision Transformer backbone with global whole-brain features extracted using a three-dimensional convolutional neural network. An Enhanced Sparse Multiple Instance Learning module is employed to identify informative slices and suppress redundant information in long slice sequences, while an adaptive gating module dynamically fuses multiview and whole-brain features according to sample-specific feature contributions. The framework was evaluated on 842 subjects from the Alzheimer's Disease Neuroimaging Initiative dataset for NC/MCI/AD classification. MDFAG-Net demonstrated competitive classification performance and outperformed representative two-dimensional, three-dimensional, and multibranch comparison models under the same experimental setting. The model achieved an area under the receiver operating characteristic curve of 0.798. Furthermore, Grad-CAM and DeepSHAP analyses revealed anatomically relevant regions associated with AD progression, including the hippocampus, amygdala, posterior cingulate gyrus, parahippocampal gyrus, and ventricular system.},
}

*Alzheimer Disease/diagnostic imaging/classification/pathology
Humans
*Magnetic Resonance Imaging/methods
*Brain/diagnostic imaging/pathology
Cognitive Dysfunction/diagnostic imaging/classification
*Neuroimaging/methods
Convolutional Neural Networks
Deep Learning

@article {pmid42858065,
year = {2026},
author = {Özkurt, Ç},
title = {Single-cell gene networks nominate IKZF1 as an Alzheimer's disease microglial regulator.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261496918},
doi = {10.1177/13872877261496918},
pmid = {42858065},
issn = {1875-8908},
abstract = {BackgroundMicroglia drive neuroinflammation in Alzheimer's disease (AD), yet no approved therapy targets this compartment. Human genome-wide association studies consistently implicate innate immune loci in AD risk, establishing microglial transcriptional programs as therapeutically relevant but pharmacologically underexploited targets.ObjectiveWe sought to identify transcription factors (TFs) governing microglial state transitions computationally and to nominate structurally tractable drug repurposing candidates.MethodsWe applied trajectory inference (PAGA), pseudobulk DESeq2, pySCENIC gene regulatory network (GRN) inference, CellChat, and virtual screening of 1962 approved compounds to 236,002 microglial nuclei from 84 donors (SEA-AD atlas).ResultsIKZF1 was the sole target TF retained under cisTarget v10 motif constraints, with peak regulon activity in LateAD-DAM (pseudotime ρ = + 0.309) and replication in an independent bulk cohort (GSE95587; adjusted p = 0.004). CellChat identified SLIT2→ROBO2 from multiple neuron subtypes (predominantly inhibitory interneurons) as the top predicted pathway to microglia. Tafamidis (→IRF8) and diflunisal (→PPARG) were top virtual screening hits; all evaluated compounds failed the pre-specified selectivity threshold.ConclusionsIKZF1 is prioritized as a candidate late-disease microglial TF, supported by six convergent evidence dimensions including independent bulk replication. Tafamidis and diflunisal are low-confidence repurposing hypotheses requiring experimental validation.},
}

@article {pmid42858068,
year = {2026},
author = {Wang, P and Ge, L and Gao, B and Jiang, S and Wang, S},
title = {Baseline and longitudinal trajectories of peak expiratory flow in relation to incident cognitive impairment among older adults: Evidence from CHARLS.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261494159},
doi = {10.1177/13872877261494159},
pmid = {42858068},
issn = {1875-8908},
abstract = {BackgroundPrevious studies, including CHARLS analyses, have linked lower peak expiratory flow (PEF) with cognitive decline. Evidence regarding incident score-based cognitive impairment, longitudinal PEF patterns, and incremental prediction remains limited.ObjectiveTo examine associations of baseline PEF and exploratory PEF trajectories with incident score-based cognitive impairment and evaluate the incremental predictive value of PEF.MethodsThe primary analysis included 2604 CHARLS participants aged ≥60 years without score-based cognitive impairment at baseline. Cognitive impairment was defined as a global cognitive score ≥1 SD below the wave- and age-specific mean and was not a clinical diagnosis of mild cognitive impairment or dementia. Cox models, sensitivity analyses, prediction analyses, and exploratory trajectory modeling were performed.ResultsOver a median follow-up of 9.0 years, 636 participants developed score-based cognitive impairment. Each 1-SD increase in PEF was associated with lower risk in fully adjusted models (HR = 0.801, 95% CI 0.728-0.880) and after adjustment for baseline cognition (HR = 0.846, 95% CI 0.768-0.930). Nine-year cumulative incidence decreased from 35.6% to 16.6% across PEF quartiles. Adding PEF modestly improved 9-year AUC (ΔAUC = 0.011, p = 0.042). In the exploratory trajectory analysis, the moderate PEF group was not significantly associated with risk versus the high group (HR = 1.294, 95% CI 0.860-1.948), whereas the low PEF group had higher risk (HR = 1.817, 95% CI 1.172-2.817), with no clear graded pattern.ConclusionsLower baseline PEF was associated with wave-specific score-based cognitive impairment, but not under stricter definitions requiring subsequent confirmation with wave-specific or fixed thresholds. PEF trajectories were exploratory, and incremental predictive value was limited.},
}

@article {pmid42858079,
year = {2026},
author = {Yang, X and Ye, T and He, Y and Zhao, J and Wang, J and Cheng, X},
title = {Qi-Fu-Yin Attenuates Frailty by Regulating Gut Microbiota and Neuroendocrine Hormones in 5xFamilial Alzheimer's Disease Transgenic Mice.},
journal = {Journal of visualized experiments : JoVE},
volume = {},
number = {236},
pages = {},
doi = {10.3791/73003},
pmid = {42858079},
issn = {1940-087X},
mesh = {Animals ; *Alzheimer Disease/drug therapy/microbiology/blood/metabolism ; Mice, Transgenic ; Mice ; *Gastrointestinal Microbiome/drug effects ; *Drugs, Chinese Herbal/pharmacology/administration & dosage ; *Frailty/drug therapy/microbiology ; Female ; Male ; Disease Models, Animal ; },
abstract = {Frailty is a common and debilitating feature of Alzheimer's disease (AD), yet effective therapeutic strategies targeting both cognitive decline and physical frailty remain limited. Qi-Fu-Yin (QFY), a traditional Chinese herbal formulation, has been used to treat aging-related disorders, but its effects on frailty in AD and the underlying mechanisms are unclear. This study aimed to evaluate whether QFY alleviates frailty in 5xFamilial Alzheimer's Disease (FAD) transgenic mice and to explore the potential involvement of gut microbiota and neuroendocrine hormones. Mice were treated with QFY at low (2.8 g/kg), medium (5.6 g/kg), or high (11.2 g/kg) doses, or with donepezil as a positive control, for 194 days. Frailty-related behaviors were assessed using CatWalk gait analysis, grip strength, rotarod, nest-building, and aging scoring. Plasma hormone levels were measured, and fecal gut microbiota composition and function were analyzed by 16S rRNA sequencing and metagenomic analysis. QFY treatment significantly improved gait parameters, grip strength, motor coordination, nesting ability, and reduced aging scores in 5xFAD mice, with effects comparable to or superior to those of donepezil. QFY also restored aberrant levels of estradiol, testosterone, and corticosterone, and reshaped gut microbiota composition, particularly by increasing the abundance of Adlercreutzia, which negatively correlated with senescence and testosterone levels. Functional metagenomics revealed that QFY partially restored disease-associated microbial pathways, including those involved in carbohydrate metabolism and virulence. These findings suggest that QFY alleviates frailty in 5xFAD mice, with effects associated with concurrent modulation of gut microbiota and neuroendocrine function, though causal relationships require further validation. These findings support further investigation of QFY as a potential intervention for AD-associated frailty.},
}

Animals
*Alzheimer Disease/drug therapy/microbiology/blood/metabolism
Mice, Transgenic
Mice
*Gastrointestinal Microbiome/drug effects
*Drugs, Chinese Herbal/pharmacology/administration & dosage
*Frailty/drug therapy/microbiology
Female
Male
Disease Models, Animal

@article {pmid42858322,
year = {2026},
author = {Yang, Y and Zhang, X and Zan, X and Niu, C and Wei, X and Feng, P and Li, G and Gao, M},
title = {A Clearance-Repair-Activation Framework for Alzheimer's Disease: A Perspective and Validation Roadmap.},
journal = {Aging and disease},
volume = {},
number = {},
pages = {},
doi = {10.14336/AD.2026.1040},
pmid = {42858322},
issn = {2152-5250},
abstract = {Alzheimer's disease (AD) is a heterogeneous clinicobiological syndrome involving impaired protein clearance, neuroinflammation, synaptic and cellular injury, network dysfunction, and progressive functional decline. Amyloid-directed antibodies provide an evidence-based treatment backbone for selected patients with early symptomatic AD, but adjunctive strategies may be needed to address other disease mechanisms. This Perspective proposes a clearance-repair-activation framework for hypothesis-driven research. Clearance includes established pharmacological treatment and risk management as well as investigational drainage approaches; lymphaticovenous anastomosis (LVA) and deep cervical lymphaticovenous anastomosis (dcLVA) are considered only as research options within this broader domain. Repair includes neural stem-cell (NSC), induced pluripotent stem-cell-derived, engineered-cell, and secretome-based strategies, for which AD evidence remains predominantly preclinical. Activation encompasses invasive and non-invasive stimulation, sensory entrainment, neurofeedback, brain-computer interface (BCI) monitoring, and cognitive rehabilitation; BCI is positioned mainly as an experimental monitoring and adaptive rehabilitation platform. We define falsifiable links between clearance and repair readiness and between repair markers and activation responsiveness, consider adaptive and parallel alternatives to fixed sequencing, and integrate disease stage, heterogeneity, regulation, and combination-trial design. Informatics is limited to trial infrastructure and safety governance. The validation roadmap specifies success criteria, stop rules, interaction testing, clinically meaningful outcomes, and long-term surveillance.},
}

@article {pmid42858330,
year = {2026},
author = {Zhang, K and Zhang, Y and Jiang, X and Chen, X},
title = {Neuroimmune State Configurations at the Amyloid-Tau Interface in Alzheimer's Disease: A Testable Framework.},
journal = {Aging and disease},
volume = {},
number = {},
pages = {},
doi = {10.14336/AD.2026.0888},
pmid = {42858330},
issn = {2152-5250},
abstract = {Neuroimmune mechanisms are central to Alzheimer's disease (AD), but a single continuum of "more inflammation" does not explain why similar amyloid-β (Aβ) and tau burdens are associated with different clinical trajectories, tissue responses, and treatment risks. We present a testable neuroimmune-state framework that integrates, rather than replaces, the AT(N) system, cellular-phase models, and transcriptional descriptions of disease-associated microglia and reactive astrocytes. The framework treats neuroimmune states as multidimensional, regionally heterogeneous configurations defined by pathological substrate, cellular program, biological target, vascular and aging context, and measurable patient-level readouts. We distinguish four meanings of the amyloid-tau interface: a biomarker interface, a spatial tissue interface, a cellular-state interface, and a clinical-progression interface. We then examine the hypothesis of phagocytic target switching, in which clearance pathways that support plaque compaction or debris removal may, under selected tau- and complement-rich conditions, contribute to removal of stressed but potentially functional synapses. We explicitly separate evidence from longitudinal human studies, cross-sectional biomarkers, human genetics, postmortem tissue, animal models, and in vitro systems. Current biomarkers cannot yet assign patients to validated discrete neuroimmune states; proposed state readers should therefore be probabilistic, allow regional coexistence and parallel vascular-immune trajectories, and be tested for incremental value beyond established AD biomarkers and co-pathologies. Finally, we organize immune-directed interventions by clinical evidence level and frame stage matching as a research strategy rather than a treatment algorithm. The model is useful only if its predictions can be prospectively supported or falsified.},
}

@article {pmid42858800,
year = {2026},
author = {Changjian, W and Furui, W and Yanyu, F and Yu, Y and Jianshe, W},
title = {Beyond the brain-centric view: A systems physiology framework for exercise-induced neuroprotection in Alzheimer's disease.},
journal = {Experimental neurology},
volume = {},
number = {},
pages = {116058},
doi = {10.1016/j.expneurol.2026.116058},
pmid = {42858800},
issn = {1090-2430},
abstract = {Alzheimer's disease (AD) is regarded as a multifactorial disease that combines central pathological changes and peripheral organ dysfunction. Its core features include Aβ protein deposition, tau protein pathology, synaptic dysfunction, and neuroinflammation. Exercise has been proven to be one of the most effective non-pharmacological intervention measures. However, its mechanism of action in AD has not been fully elucidated from the traditional brain-centered research perspective. Moreover, most existing studies focus on isolated organ systems or a single signaling pathway, failing to fully reflect the overall peripheral-cerebral physiological interaction mechanism required for neuroprotective effects of exercise. This article provides a structured narrative synthesis of current evidence regarding how exercise may influence AD-related pathological processes through multiple peripheral organ systems. It clarifies the communication mechanisms between these systems and the central nervous system through endocrine, immune, metabolic, neural, and vascular pathways. The study shows that exercise functions by coordinating the regulation of peripheral physiological functions, rather than relying on a single target mechanism. Exercise can regulate multiple signaling pathways such as muscle-brain, gut-brain, liver-brain, adipose-brain, bone-brain, and immune-brain, improving overall metabolic flexibility, inflammation regulation, vascular function, and neuroimmune homeostasis; these peripheral adaptive changes further act on the central nervous system, regulating blood-brain barrier(BBB) integrity, microglial cell activity, neuronal energy metabolism, neurovascular coupling, and synaptic plasticity. In summary, the neuroprotective effect induced by exercise stems from the integration of multiple systems' physiology, rather than isolated molecular signal transduction. This review synthesizes current evidence on exercise-induced peripheral-central interactions in AD from a systems physiology perspective, highlighting the significance of integrating peripheral biomarkers, multi-organ interactions, and central outcomes. It provides a theoretical framework for future personalized and mechanism-oriented exercise intervention studies.},
}

@article {pmid42858944,
year = {2026},
author = {Patel, DR and Rangasamy, SB and Gorai, S and Paidi, RK and Pahan, K},
title = {Glyceryl tribenzoate, a flavoring agent, stimulates hippocampal plasticity and protects memory via PPARα.},
journal = {Neurochemistry international},
volume = {201},
number = {},
pages = {106270},
doi = {10.1016/j.neuint.2026.106270},
pmid = {42858944},
issn = {1872-9754},
abstract = {Glyceryl tribenzoate (GTB) or tribenzoin is a flavoring agent with characteristic anti-microbial property. We have already delineated GTB's immunomodulatory role via the enrichment of regulatory T cells in mouse models of multiple sclerosis and anti-neuroinflammatory role via the reduction of glial activation in a monkey model of Parkinson's disease and a mouse model of Huntington's disease. However, its role has never been explored in Alzheimer's disease (AD), the most common neurodegenerative disorder in human. This study underlines the importance of GTB in promoting the growth and function of hippocampal neurons via upregulation of plasticity-associated genes, enrichment of dendritic spines and stimulation of inotropic calcium influx. Accordingly, oral GTB improved hippocampal plasticity and protected memory and learning in 5xFAD mice. Similarly, GTB treatment also reduced cerebral plaque load and increased the life span of aged 5xFAD mice. Interestingly, we observed that peroxisome proliferator-activated receptor alpha (PPARα), a nuclear hormone receptor, served as a receptor of GTB. Consequently, GTB was shown to improve hippocampal plasticity and increase cognitive functions in 5xFAD, but not 5xFAD/Ppara-null, mice, indicating an important role of PPARα in GTB-mediated neuroprotection. These results suggest that oral GTB may have therapeutic importance for improving hippocampal functions in AD patients.},
}

@article {pmid42859261,
year = {2026},
author = {Maglio, GM and de Melo, NC and de Carvalho, LM},
title = {Integrative Transcriptomic and Interactome Analyses Prioritize Candidate Genes for Alzheimer's Disease.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42859261},
issn = {1559-1182},
support = {2024/21955-3//Fundação de Amparo à Pesquisa do Estado de São Paulo/ ; },
mesh = {*Alzheimer Disease/genetics ; Humans ; *Transcriptome/genetics ; Aging/genetics/pathology ; *Protein Interaction Maps/genetics ; *Gene Expression Profiling ; Signal Transduction/genetics ; Gene Regulatory Networks ; *Genetic Association Studies/methods ; *Genetic Predisposition to Disease ; },
abstract = {Alzheimer's disease (AD) is a heterogeneous neurodegenerative disorder characterized by complex molecular alterations and diverse cognitive, behavioral, and neuropsychiatric manifestations. Although transcriptomic studies have identified several pathways associated with AD, the integration of molecular signatures with disease-related phenotype annotations and pathological aging remains incompletely understood. Therefore, this study aimed to integrate transcriptomic profiling, protein-protein interaction (PPI) network analysis, pathological aging assessment, and curated clinical phenotype annotations to prioritize candidate molecular signatures associated with AD. Differential expression analyses and network-based approaches were applied to publicly available transcriptomic datasets derived from distinct brain regions. Candidate genes and pathways were prioritized through interactome reconstruction, functional enrichment analyses, cluster-based analyses, and independent validation in an external dataset. In addition, transcriptomic signatures were integrated with curated clinical phenotype annotations using a knowledge-based gene overlap strategy. The analysis identified molecular signatures associated with neuroinflammatory signaling, synaptic dysfunction, endocytosis, and pathological aging. Pathways related to MAPK, PI3K/Akt, NF-κB, and TGF-β1 signaling emerged as candidate dysregulated pathways in AD. Comparative analyses of physiological aging and the AD aging comparison enabled the prioritization of candidate genes potentially more closely associated with the AD condition than with aging alone, including FOS and TAB2. Independent validation reinforced the reproducibility of several prioritized genes, including GFAP, CXCR4, CCL2, HSPA1A, FCGR2A, TLR2, CD44, TLR4, FOS, TAB2, CDC42, and SH3GL2. Integration with curated clinical phenotype annotations suggested partially overlapping molecular signatures across neuropsychiatric and cognitive phenotype annotations in AD. Together, these findings demonstrate the utility of integrative bioinformatics approaches for prioritizing candidate genes, pathways, and molecular signatures associated with AD. This systems-level framework may contribute to future mechanistic studies aimed at understanding the molecular heterogeneity of AD and its associated phenotypic complexity.},
}

*Alzheimer Disease/genetics
Humans
*Transcriptome/genetics
Aging/genetics/pathology
*Protein Interaction Maps/genetics
*Gene Expression Profiling
Signal Transduction/genetics
Gene Regulatory Networks
*Genetic Association Studies/methods
*Genetic Predisposition to Disease

@article {pmid42859279,
year = {2026},
author = {Solar, KG and Kashyap, S and Deom, N and Uludağ, K and Zotovic, L and Lanctôt, K and Black, SE and McAndrews, MP},
title = {Characterizing hippocampal activation during pattern separation with multi-echo fMRI in cognitively normal older adults.},
journal = {Brain imaging and behavior},
volume = {20},
number = {5},
pages = {},
pmid = {42859279},
issn = {1931-7565},
support = {CT200401//Weston Family Foundation/ ; },
mesh = {Humans ; *Magnetic Resonance Imaging/methods ; Aged ; Male ; Female ; *Hippocampus/physiology/diagnostic imaging ; Brain Mapping/methods ; Memory, Episodic ; *Cognition/physiology ; Neuropsychological Tests ; Aged, 80 and over ; Alzheimer Disease ; Aging/physiology ; Dentate Gyrus/physiology/diagnostic imaging ; Image Processing, Computer-Assisted ; },
abstract = {Hippocampal hyperactivity, detected with mnemonic similarity task (MST) fMRI, is both a promising marker of risk and a probable driver of degeneration in Alzheimer's disease (AD). However, implementation of such fMRI in interventional research is limited by long scan times and the absence of a framework for identifying prospective participants with hyperactivity who could be targeted with therapeutic approaches aimed at reducing this activity. We used multi-echo fMRI during the MST, an episodic memory task previously shown to engage hippocampal subfields CA3 and dentate gyrus (DG), to characterize activity profiles in 33 cognitively normal older adults. We compared MST-related CA3 and DG activation and behavioural performance across subsets of eight task runs. Behavioural and activation effects were equivalent for the first set of four runs (Runs-A) and the second set (Runs-B), suggesting that robust data can be obtained with four runs. Left and right CA3 + DG activation did not differ. We provide an exemplar framework for the derivation of a threshold for single-participant classification of elevated hippocampal activation as an indicator of AD risk in cognitively normal older individuals. Scalable (~22 min) multi-echo MST fMRI robustly captures hippocampal activation and provides a framework for individual-level characterization of hippocampal function in cognitively normal older adults. This enables individualized detection of elevated hippocampal activation as a modifiable risk factor and may guide enrolment into prevention trials targeting preclinical AD.},
}

Humans
*Magnetic Resonance Imaging/methods
Aged
Male
Female
*Hippocampus/physiology/diagnostic imaging
Brain Mapping/methods
Memory, Episodic
*Cognition/physiology
Neuropsychological Tests
Aged, 80 and over
Alzheimer Disease
Aging/physiology
Dentate Gyrus/physiology/diagnostic imaging
Image Processing, Computer-Assisted

@article {pmid42859348,
year = {2026},
author = {Lin, W and Shu, Z and Liu, G and Fang, J and Ding, S},
title = {The Gut-Brain Axis and Neurodegenerative Diseases: From Mechanistic Pathways to Therapeutic Interventions.},
journal = {Probiotics and antimicrobial proteins},
volume = {},
number = {},
pages = {},
pmid = {42859348},
issn = {1867-1314},
support = {2024RC2053//Yuelushan Laboratory joint talent introduction project/ ; Grant No. kq2502176//Natural Science Foundation of Changsha, China/ ; 24B0219//Scientific Research Project of Hunan Provincial Department of Education/ ; 2025JGZD053//Hunan Province Postgraduate Education Teaching Reform Research Project/ ; 2023YFD1301200//National Key Research and Development Program of China/ ; HARS-06//Hunan Poultry Industry Technology System/ ; },
abstract = {As the global population ages, the incidence of neurodegenerative diseases (NDDs) has increased. Neurodegenerative diseases have complex pathogenesis and currently lack fundamental treatment methods. The gut-brain axis (GBA) participates in the pathogenesis of NDDs through bidirectional communication between the gut microbiota and the central nervous system (CNS). This review systematically introduces the pathogenic characteristics of representative NDDs such as Alzheimer's disease (AD), Parkinson's disease (PD), and multiple sclerosis (MS), as well as the association mechanisms between these diseases and GBA. The pathogenic characteristics of NDDs are closely related to changes in the composition of the gut microbiota and differences in gut microbiota metabolites (such as short-chain fatty acids (SCFAs), neurotransmitters, tryptophan metabolites, etc.). These changes influence the CNS through multiple pathways, including neuroendocrine, vagus nerve, and immune regulation, ultimately contributing to the onset and progression of the diseases. Furthermore, we have collected and summarized preclinical and clinical evidence from recent years regarding therapeutic interventions based on the GBA mechanism, including probiotics, prebiotics, and fecal microbiota transplantation (FMT). Nevertheless, major knowledge gaps remain, particularly regarding causality between gut microbiota changes and NDDs, the underlying molecular mechanisms, and the clinical efficacy of GBA-targeted therapies. This article aims to review the mechanisms of the interaction between the gut microbiota and the brain in neurodegenerative diseases, and based on the existing experimental evidence, provide theoretical basis and future development directions for future prevention and treatment strategies targeting GBA.},
}

@article {pmid42859693,
year = {2026},
author = {Noh, S and Shin, HE and Shim, Y},
title = {Cerebral Hemodynamic Changes in Older Adults With Cognitive Complaints According to the Presence of Peripheral Artery Disease.},
journal = {Aging medicine (Milton (N.S.W))},
volume = {},
number = {},
pages = {},
pmid = {42859693},
issn = {2475-0360},
abstract = {OBJECTIVE: As a systemic expression of atherosclerosis, peripheral artery disease (PAD) has the potential to alter cerebral hemodynamics in elderly individuals presenting with cognitive concerns. However, how PAD status shapes the longitudinal trajectory of cerebral hemodynamics has not been well characterized.

METHODS: We conducted a single-center longitudinal observational study enrolling 132 participants (21 controls, 39 mild cognitive impairment, 72 mild Alzheimer's disease). All participants underwent transcranial Doppler (TCD) ultrasonography, ankle-brachial index (ABI) measurement, brain MRI, and cognitive assessments at baseline and follow-up (~13.45 months). PAD was defined as ABI < 0.90. Bilateral mean flow velocity (MFV), pulsatility index (PI), and resistance index (RI) of the middle cerebral artery (MCA) were tracked longitudinally across both time points.

RESULTS: PAD was identified in 13 participants (9.8%). Baseline TCD parameters, vascular risk factors, white matter lesions on brain MRI, and cognitive measures were comparable between groups. At follow-up, the PAD group showed significantly higher MCA MFV after age adjustment (left p < 0.001; right p = 0.005). MFV increased in the PAD group (left +16.45 cm/s) but decreased in the non-PAD group (left -3.37 cm/s), with a significant between-group difference. PI and RI did not change in either group. Cognitive and functional outcomes were similar across groups throughout the study.

CONCLUSION: These findings identify PAD as a condition associated with progressive MCA MFV elevation in the context of preserved cognition, implying that subclinical cerebrovascular changes are detectable by TCD before overt clinical worsening. Future research involving larger cohorts and extended follow-up is required to determine whether such hemodynamic changes forecast eventual cognitive deterioration.},
}

@article {pmid42859768,
year = {2026},
author = {Jimenez-Maggiora, GA and Bruschi, S and Abdel-Latif, S and Aisen, PS and Rissman, RA},
title = {ATRI LIMS: a cloud-native open-source laboratory information management system for biomarker-driven Alzheimer's disease clinical trials.},
journal = {JAMIA open},
volume = {9},
number = {5},
pages = {ooag198},
pmid = {42859768},
issn = {2574-2531},
abstract = {OBJECTIVES: This article summarizes the architecture, design principles, and implementation strategy of the ATRI Laboratory Information Management System (LIMS), a cloud‑native, open‑source platform supporting biomarker‑driven Alzheimer's disease (AD) clinical research. The system addresses challenges associated with managing large‑scale, multimodal biomarker, and biobanking data across multisite studies.

METHODS: The ATRI LIMS employs a Model-View-Controller architecture implemented in Django, with Single‑Page Application interfaces built in ReactJS. A hybrid database model integrates a normalized core schema with study‑specific extensions. Deployment on Amazon Web Services incorporates multifactor authentication, encryption, and a web application firewall. Regulatory support is provided through audit trails and electronic signatures. Development relied on collaboration between informatics engineers and laboratory personnel, with user acceptance testing guiding workflow and interface refinement.

RESULTS: As of February 2026, the ATRI LIMS supports seven clinical trials and observational studies and manages more than 1.2 million biospecimens. The platform synchronizes biospecimen metadata and assay outputs with clinical datasets, improves operational efficiency through automated workflows and quality control, and facilitates compliant sample sharing for secondary research. AI‑assisted development accelerated feature delivery while maintaining code quality.

DISCUSSION: The ATRI LIMS offers a scalable, adaptable informatics framework for biomarker‑intensive AD research. Its modular design, cloud‑native architecture, and comprehensive data management capabilities support accurate specimen tracking and coordinated data integration. An open-source release is planned to enable adoption and adaptation by other research programs.

CONCLUSIONS: The ATRI LIMS enhances informatics infrastructure for modern AD research by enabling scalable, efficient, and compliant biomarker and biospecimen workflow management.},
}

@article {pmid42860159,
year = {2026},
author = {Wang, M and Zhao, H and Lin, X and Ye, Z and Tu, B and Yang, Y and Wang, C and Fang, X and Fang, Q},
title = {Field-assisted interfacial passivation: Microwave-enhanced EGCG remodeling of amyloid-β42 aggregates.},
journal = {International journal of biological macromolecules},
volume = {},
number = {},
pages = {154811},
doi = {10.1016/j.ijbiomac.2026.154811},
pmid = {42860159},
issn = {1879-0003},
abstract = {Amyloid misfolding and self-assembly are central pathological events of Alzheimer's disease and related proteinopathies. Although soluble oligomers are widely considered as the primary toxic species, how therapeutic modulators alter toxicity-relevant aggregate surfaces remains poorly understood. Here, we combine cell viability assays, thioflavin T (ThT) aggregation kinetics, circular dichroism (CD), transmission electron microscopy (TEM), and atomistic molecular dynamics (MD) simulations to investigate how microwave-assisted Epigallocatechin gallate (EGCG) remodels Aβ42 aggregates. We show that microwave exposure markedly enhanced EGCG-mediated cytoprotection in BV2 microglial cells while concurrently suppressing the formation of canonical ThT-responsive amyloid species. MD simulations revealed that oscillating electric fields promote a constrained, interface-selective remodeling of protofibrillar-like aggregates rather than catastrophic depolymerization. In the initial trajectory pair, field assistance redistributed EGCG contacts across more surface residues, accompanied by reduced overall and hydrophobic protein-only solvent-accessible surface area. At a key hydrophobic interface identified by contact-occupancy analysis, the combined treatment decreased local water density and solvent accessibility, indicating reduced local hydration. We define this collective surface state- characterized by expanded EGCG coverage, reduced hydrophobic exposure, and diminished solvent accessibility - as interfacial passivation. Moreover, simulation analysis revealed that the field-assisted EGCG adsorption state remains stable for at least 500 ns after field removal, suggesting that the electric field facilitates formation of a kinetically stable surface-bound configuration. Together, these findings support field-assisted interfacial passivation as a possible mechanism for amyloid modulation and suggest that passivating toxicity-relevant aggregate surfaces, rather than achieving complete depolymerization, may represent a promising therapeutic strategy.},
}

@article {pmid42860235,
year = {2026},
author = {Ma, C and Lu, W and Guo, R},
title = {Exploratory bone-brain transcriptomic associations and an ODE-based digital-twin framework for fracture healing.},
journal = {Brain research},
volume = {},
number = {},
pages = {150597},
doi = {10.1016/j.brainres.2026.150597},
pmid = {42860235},
issn = {1872-6240},
abstract = {Fracture healing is generally viewed as a local tissue-regeneration process, although skeletal injury can also elicit systemic immune, vascular, and neural responses. We used a stratified analytical strategy combining reanalysis of public transcriptomic datasets, descriptive single-nucleus profiling, and an ordinary differential equation (ODE)-based simulation of fracture healing to examine possible associations between adverse bone phenotypes and Alzheimer disease. In the primary random-effects meta-analysis of three retained human bone-related binary cohorts, 72 prespecified panel genes were measured in all three cohorts; BMP10 and ANGPT1 had the smallest adjusted P values. In the separate GSE48350 whole-brain dataset, 6 of 84 mapped target genes had nominal P < 0.05. Descriptive single-nucleus RNA-sequencing analysis of GSE138852 showed within-dataset, cell-type-specific expression patterns across annotated neural cell populations. The eight-state ODE prototype, built on prespecified assumptions, generated fracture-healing trajectories and scenario-dependent model outputs. Tissue-expression and genetic analyses provided additional exploratory context for the selected genes. These analyses define a hypothesis-generating framework for studying skeletal-neural associations after fracture.},
}

@article {pmid42860380,
year = {2026},
author = {Barthold, D and Zissimopoulos, J and Basu, A and Tysinger, B},
title = {The effects of improved access to diabetes medications on risk of Alzheimer's disease and related dementias.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {10},
pages = {e71794},
doi = {10.1002/alz.71794},
pmid = {42860380},
issn = {1552-5279},
mesh = {Humans ; *Alzheimer Disease/epidemiology/prevention & control ; *Hypoglycemic Agents/therapeutic use ; *Dementia/epidemiology/prevention & control ; *Sodium-Glucose Transporter 2 Inhibitors/therapeutic use ; Glucagon-Like Peptide-1 Receptor Agonists ; Female ; Aged ; Male ; Middle Aged ; Incidence ; *Health Services Accessibility ; *Diabetes Mellitus/drug therapy ; *Diabetes Mellitus, Type 2/drug therapy ; },
abstract = {INTRODUCTION: Diabetes is associated with elevated risk of Alzheimer's disease and related dementias (ADRD). Disease management with pharmaceutical therapies may mitigate this increased risk, but access and use of diabetes therapies are limited, especially for persons at highest risk of ADRD.

METHODS: Using 10 years of data on Americans aged 51 and older with diabetes, we employed dynamic microsimulation to analyze the impact of increased utilization of glucagon-like peptide 1 receptor agonists (GLP1s) and sodium-glucose cotransporter-2 inhibitors (SGLT2s) on ADRD incidence.

RESULTS: Over 10 years, utilization of GLP1s and SGLT2s by people with diabetes and HbA1c > 7 could avert 76,000-201,000 ADRD cases. The risk reduction is largest for Black and Hispanic individuals and individuals with HbA1c > 8.

DISCUSSION: This study shows that improving diabetes management can lead to large reductions in ADRD risk. Improved adherence and access for those with higher HbA1c and higher risk of ADRD will have the largest benefit.},
}

Humans
*Alzheimer Disease/epidemiology/prevention & control
*Hypoglycemic Agents/therapeutic use
*Dementia/epidemiology/prevention & control
*Sodium-Glucose Transporter 2 Inhibitors/therapeutic use
Glucagon-Like Peptide-1 Receptor Agonists
Female
Aged
Male
Middle Aged
Incidence
*Health Services Accessibility
*Diabetes Mellitus/drug therapy
*Diabetes Mellitus, Type 2/drug therapy

@article {pmid42860384,
year = {2026},
author = {Tallapragada, B and Galna, B and Shishegar, R and Markovic, SJ and Brown, BM and Dore, V and Laws, SM and Porter, T and Burnham, S and Lim, YY and Hassenstab, J and Rowe, CC and Jin, L and Fripp, J and Doecke, JD and Tosun, D and Weiner, M and Martins, RN and Morris, JC and Masters, CL and Maruff, P and Sohrabi, HR and , },
title = {Data‑driven cognitive composites predict Aβ‑related decline and progression to MCI: the ADOPIC study.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {10},
pages = {e71917},
doi = {10.1002/alz.71917},
pmid = {42860384},
issn = {1552-5279},
support = {R01-AG058676-01A1/AG/NIA NIH HHS/United States ; 1132604//National Health and Medical Research Council/ ; 1140853//National Health and Medical Research Council/ ; 1152623//National Health and Medical Research Council/ ; 2 U19 AG024904.16//National Health and Medical Research Council/ ; 5U2CAG060426-04//National Health and Medical Research Council/ ; 5R01AG058676-02//National Health and Medical Research Council/ ; 1RF1AG059009-01//National Health and Medical Research Council/ ; R33 AG062867//National Health and Medical Research Council/ ; 1R01NS119651-01//National Health and Medical Research Council/ ; RF1AG062196//National Health and Medical Research Council/ ; R56AG075744-01A1//National Health and Medical Research Council/ ; /AG/NIA NIH HHS/United States ; //Department of Defense/ ; //California Department of Public Health/ ; //University of Michigan, Siemens, Biogen, Hillblom Foundation/ ; /ALZ/Alzheimer's Association/United States ; //Johnson & Johnson/ ; //Kevin and Connie Shanahan/ ; //Australian Catholic University/ ; //The Stroke Foundation, and the Veterans Administration/ ; },
mesh = {Humans ; *Cognitive Dysfunction/diagnosis/psychology ; Disease Progression ; *Amyloid beta-Peptides/metabolism ; Female ; Male ; *Neuropsychological Tests/statistics & numerical data ; Aged ; *Alzheimer Disease/diagnosis ; Psychometrics ; Longitudinal Studies ; },
abstract = {INTRODUCTION: Cognitive composites offer greater sensitivity to amyloid beta (Aβ)-related decline compared to individual tests for tracking longitudinal cognitive change. We developed and validated data-driven composites from the harmonized Alzheimer's Dementia Onset and Progression in International Cohorts (ADOPIC) study, addressing gaps in psychometric reporting and multi-cohort validation.

METHODS: The study included 1964 cognitively unimpaired (CU) participants at baseline (longitudinal subset = 1110). Principal component analysis-derived domain-specific and general cognitive composites were evaluated for psychometric properties, sensitivity to Aβ-related decline, and mild cognitive impairment (MCI) progression prediction compared to the Alzheimer's Disease Cooperative Study - Preclinical Alzheimer's Cognitive Composite (ADCS-PACC).

RESULTS: Proposed composites demonstrated good to excellent psychometric properties and sensitivity to differentiating CU Aβ trajectories (p < 0.001). General cognition demonstrated longitudinal sensitivity comparable to the ADCS-PACC (d = -0.20) and equivalent classification performance (area under the receiver operating characteristic curve = 0.70). All composites significantly predicted MCI progression (p < 0.001).

DISCUSSION: The composites perform comparably to the ADCS-PACC, developed for CU with Aβ, in longitudinal sensitivity while providing comprehensive psychometric characterization and domain-specific measurement, supporting their utility as outcome measures in preclinical Alzheimer's disease studies.},
}

Humans
*Cognitive Dysfunction/diagnosis/psychology
Disease Progression
*Amyloid beta-Peptides/metabolism
Female
Male
*Neuropsychological Tests/statistics & numerical data
Aged
*Alzheimer Disease/diagnosis
Psychometrics
Longitudinal Studies

@article {pmid42860522,
year = {2026},
author = {Shiferaw, TG and Sarkar, S and Baker, KM and Wooldridge, RS and Binfet, HM and Prozapas, VN and Ogbu, CP and Schepmoes, AA and Attah, IK and Niemeyer, CS and Sprenger, KG and Hassell, JE and Eckel, RH and Melchior, JT and Bruce, KD},
title = {ApoE lipidation state directs immunometabolic reprogramming of human microglia.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {10},
pages = {e71882},
doi = {10.1002/alz.71882},
pmid = {42860522},
issn = {1552-5279},
support = {R01AG079217-01/NH/NIH HHS/United States ; R01NS125591/NS/NINDS NIH HHS/United States ; T32 2T32DK120521-06//Strategic Infrastructure for Research Committee/ ; },
mesh = {Humans ; *Microglia/metabolism ; *Apolipoprotein E4/metabolism ; *Apolipoproteins E/metabolism ; *Lipid Metabolism ; Metabolic Reprogramming ; Mitochondria/metabolism ; Alzheimer Disease/metabolism ; *Apolipoprotein E3/metabolism ; Lipid Droplets/metabolism ; },
abstract = {INTRODUCTION: ApoE ε4 is the strongest genetic risk factor for Alzheimer's disease (AD). Emerging evidence suggests that ApoE4 increases AD risk by disrupting microglial metabolism and function. However, whether ApoE lipidation state contributes to microglial dysfunction remains poorly understood.

METHODS: Human microglia were treated with lipid-free (LF) or lipid-bound ApoE3 or ApoE4. Label-free, live-cell holotomography and global proteomics were used to assess isoform- and lipidation-specific effects on lipid droplet (LD) dynamics, mitochondrial morphology, and microglial phenotype.

RESULTS: ApoE4 treatment resulted in fewer but enlarged LDs and increased mitochondrial fragmentation compared to ApoE3, effects that were enhanced by lipid-bound ApoE4. Proteomic analyses revealed a strong type I interferon response in cells exposed to LF-ApoE, which was exacerbated by LF-ApoE4.

DISCUSSION: These findings indicate that lipid-bound ApoE4 drives metabolic reprogramming, whereas LF-ApoE4 promotes inflammatory signaling, identifying ApoE lipidation as a critical modifier of ApoE4-associated AD risk.},
}

Humans
*Microglia/metabolism
*Apolipoprotein E4/metabolism
*Apolipoproteins E/metabolism
*Lipid Metabolism
Metabolic Reprogramming
Mitochondria/metabolism
Alzheimer Disease/metabolism
*Apolipoprotein E3/metabolism
Lipid Droplets/metabolism

@article {pmid42860584,
year = {2026},
author = {Corbali, O and Menon, P and Corbali, HI and Jagannathan, R and Levey, AI},
title = {Diabetes-Associated Cognitive Impairment: Pathophysiology and Emerging Therapies.},
journal = {Annals of clinical and translational neurology},
volume = {},
number = {},
pages = {},
doi = {10.1002/acn3.70487},
pmid = {42860584},
issn = {2328-9503},
abstract = {Diabetes-associated cognitive impairment (DACI) is a common yet underrecognized condition, manifesting along a spectrum from mild cognitive impairment to dementia. DACI encompasses patients who develop vascular dementia (VaD) or Alzheimer's disease (AD) with diabetes as a risk factor; however, in certain patients, particularly those lacking clear VaD or AD features, diabetes may act as a primary driver of neurodegeneration. Mechanistically, DACI can be conceptualized as a neurovascular-metabolic disorder characterized by disruption of the neurovascular unit, impaired cerebral glucose metabolism, brain insulin resistance, and chronic neuroinflammation, contributing to small vessel disease, regional brain atrophy, and accelerated brain aging. In this narrative review, we synthesize current evidence on the clinical and imaging features of DACI, outline key mechanistic pathways linking diabetes to neurodegeneration, and discuss emerging therapeutic strategies, including GLP-1 receptor agonists and SGLT2 inhibitors, with potential neuroprotective effects. Greater recognition of DACI as a neurovascular-metabolic entity may facilitate earlier identification, inform biomarker development, and guide future trials aimed at preserving cognitive function in individuals with diabetes.},
}

@article {pmid42860632,
year = {2026},
author = {Rosahl, M and Kaplan, M and McKniff, M and Callahan, A and Chaturvedi, R and Giovannetti, T},
title = {Preliminary evidence for script generation as an efficient, objective measure of everyday function in older adults.},
journal = {Journal of clinical and experimental neuropsychology},
volume = {},
number = {},
pages = {1-13},
doi = {10.1080/13803395.2026.2743150},
pmid = {42860632},
issn = {1744-411X},
abstract = {INTRODUCTION: Mild difficulties performing everyday activities may emerge early in Alzheimer's disease and Alzheimer's disease-related dementias, creating a need for objective, efficient measures sensitive to subtle functional changes. This study investigated a script generation task (SGT), which required individuals to verbally describe the steps needed to complete familiar everyday activities, as a potential method for detecting mild functional difficulties in older adults with or without mild cognitive impairment (MCI). We examined both human-coded features of script generation and automated linguistic features using natural language processing (NLP).

METHODS: 83 community-dwelling older adults (mean age = 73.59 years; 67% female; 55% White; n = 57 cognitively unimpaired on testing [CU]; n = 26 MCI) completed the SGT, requiring them to describe the steps for four everyday tasks: making toast, preparing instant coffee, making a peanut butter and jelly sandwich, and preparing a lunchbox. SGT performance was scored by human coders for total steps, words, and errors and analyzed using NLP measures of pronoun-to-noun ratio, lexical density, and lexical sophistication. Participants also completed a performance-based test of everyday function (Naturalistic Action Test, NAT), self-report questionnaires regarding everyday function, and cognitive tests.  .

RESULTS: After controlling for age, education, and estimated IQ, participants with MCI generated significantly fewer SGT steps than CU participants and used more pronouns relative to nouns, reflecting less specificity in their speech. The ability to generate SGT steps was associated with cognitive tests of episodic memory, and both SGT steps and total words were associated with executive function. Participants who generated more SGT words also completed more steps on the NAT. These associations survived correction for multiple comparisons. By contrast, SGT measures were not significantly associated with self-reported everyday functioning after correction for multiple comparisons.

CONCLUSIONS: Findings provide support for the potential use of the SGT as an objective and efficient measure of mild functional difficulties in older adults. Future work is needed to evaluate the predictive validity of the SGT and to develop automated scoring programs to increase scalability.},
}

@article {pmid42860747,
year = {2026},
author = {Jackson, ML and Sangalang, S and Heyworth, NC and Stradford, J and Lyons-Jones, C and Delaney-Stewart, T and Foster, A and Williams, P and Harris, T and McKinney, W and Baker, C and Thames, AD and Norman, M and Sundermann, EE and Banks, SJ},
title = {A Community's Voice: Community Advisory Boards in ADRD Biomarker Research Among Older Black Women.},
journal = {Journal of the American Geriatrics Society},
volume = {},
number = {},
pages = {},
doi = {10.1111/jgs.70721},
pmid = {42860747},
issn = {1532-5415},
support = {5R01AG077579-02/AG/NIA NIH HHS/United States ; },
abstract = {Alzheimer's Disease and Related Dementias (ADRD) disproportionately affect Black/African American (BAA) women, yet this afflicted population remains underrepresented in ADRD biomarker research. As ADRD blood-based biomarkers become increasingly available, research must prioritize equity and inclusivity to determine their diagnostic specificity in minoritized groups. Community Advisory Boards (CABs) are pivotal in ensuring culturally responsive and community-engaged research. This article outlines the formation, operation, and maintenance of the Black Women: Inflammation and Tau Study (BWITS) CAB, which has played a crucial role in guiding the BWITS Research Team by refining research protocols and safeguarding the cultural contexts of the communities it represents. Motivated by a commitment to the BAA community, we advocate for a transformative shift in ADRD research on minoritized populations, emphasizing the need for CAB input to ensure accountability and the implementation of culturally responsive methods, benefiting both the scientific and target communities.},
}

@article {pmid42860874,
year = {2026},
author = {Gül, A and Yılmaz, F and Topal, F and Özgen, İ and Aydoğmuş, E and Arslanoğlu, H},
title = {In Vitro Antioxidant, Antibacterial, and Cholinesterase-Inhibitory Properties of an Aqueous Euphorbia macroclada Root Extract Obtained by Ultrasound-Assisted Extraction.},
journal = {Chemistry & biodiversity},
volume = {23},
number = {10},
pages = {e71825},
doi = {10.1002/cbdv.71825},
pmid = {42860874},
issn = {1612-1880},
mesh = {*Euphorbia/chemistry ; *Anti-Bacterial Agents/pharmacology/chemistry/isolation & purification ; *Antioxidants/pharmacology/chemistry/isolation & purification ; *Cholinesterase Inhibitors/pharmacology/chemistry/isolation & purification ; Plant Roots/chemistry ; *Plant Extracts/chemistry/pharmacology/isolation & purification ; Microbial Sensitivity Tests ; Acetylcholinesterase/metabolism ; Butyrylcholinesterase/metabolism ; Biphenyl Compounds/antagonists & inhibitors ; Water/chemistry ; *Ultrasonic Waves ; Benzothiazoles/antagonists & inhibitors ; Picrates/antagonists & inhibitors ; Sulfonic Acids/antagonists & inhibitors ; Dose-Response Relationship, Drug ; },
abstract = {In the present study, the aqueous extract obtained from the roots of Euphorbia macroclada via ultrasound-assisted extraction (Ult-ER) was evaluated for its anticholinesterase (AChE and BChE), antioxidant, and antibacterial activities. While the extract exhibited weak inhibition against AChE (IC50: 507.69 ± 17.95 mg/mL), it showed relatively greater inhibitory activity against BChE (IC50: 22.41 ± 0.49 mg/mL). In antioxidant assays, Ult-ER exhibited measurable antioxidant responses, with DPPH and ABTS[+] radical-scavenging capacities of 18.33 ± 0.49 and 119.59 ± 1.86 mg TE/L, respectively. Its Fe[3] [+] and Cu[2] [+] reducing capacities were 128.51 ± 12.57 and 670.33 ± 11.59 mg TE/L, respectively. The total phenolic and flavonoid contents were 84.80 ± 3.31 mg GAE/g and 60.67 ± 2.29 mg QE/g, while the total antioxidant capacity was 9.78 ± 0.44 mg TE/g and 15.62 ± 1.85 mg BHAE/g. In the antibacterial evaluation, Ult-ER at the highest tested concentration of 8 mg/mL exhibited inhibitory activity against all tested strains, including Enterococcus faecalis ATCC 29212, Staphylococcus aureus ATCC 25923, Escherichia coli ATCC 25922, and Pseudomonas aeruginosa ATCC 27853, whereas no detectable inhibition was observed at lower concentrations.},
}

*Euphorbia/chemistry
*Anti-Bacterial Agents/pharmacology/chemistry/isolation & purification
*Antioxidants/pharmacology/chemistry/isolation & purification
*Cholinesterase Inhibitors/pharmacology/chemistry/isolation & purification
Plant Roots/chemistry
*Plant Extracts/chemistry/pharmacology/isolation & purification
Microbial Sensitivity Tests
Acetylcholinesterase/metabolism
Butyrylcholinesterase/metabolism
Biphenyl Compounds/antagonists & inhibitors
Water/chemistry
*Ultrasonic Waves
Benzothiazoles/antagonists & inhibitors
Picrates/antagonists & inhibitors
Sulfonic Acids/antagonists & inhibitors
Dose-Response Relationship, Drug

@article {pmid42861391,
year = {2026},
author = {Zhang, X and Tang, X and Bo, Q and Ma, Y and Shi, F and Hou, H},
title = {Alzheimer's disease diagnosis based on gene selection and cross-tissue validation.},
journal = {Frontiers in genetics},
volume = {17},
number = {},
pages = {1890236},
pmid = {42861391},
issn = {1664-8021},
abstract = {BACKGROUND: Early and accurate diagnosis is critical for intervening in the progression of Alzheimer's disease (AD). However, traditional clinical diagnostic techniques, such as invasive cerebrospinal fluid punctures and expensive neuroimaging, struggle to meet the demands of large-scale early screening.

METHODS: This study proposes a novel transcriptomic-based diagnostic framework named DeepFS, which features an automated gene selection module to filter out redundant noise and identify high-value core gene targets for diagnosis.

RESULTS: DeepFS achieved high-precision identification of AD, yielding an ac-curacy of 89.45% and an AUC value of 0.9647 on brain tissue transcriptomic data. To further explore the methodological generalizability of the framework across different tissue types, we extended DeepFS to a peripheral blood transcriptomic dataset, where it consistently achieved reliable diagnostic classification performance. Furthermore, regarding the brain tissue transcriptomic data, the high-weight genes driven by the gene selection module were integrated with AD brain single-nucleus RNA sequencing data for quantitative analysis at single-cell resolution, further validating the biological efficacy of the module.

CONCLUSION: DeepFS not only exhibits competitive performance in AD diagnostic classification, but can also serve as a valuable prior reference for future AD biomarker research.},
}

@article {pmid42861417,
year = {2026},
author = {Guan, Y and Gu, P and Guo, D and Huang, L and Lian, D and Zhang, C and Feng, J and Peng, H},
title = {Multipath interaction network of annexin A2: multifaceted regulation and translational perspectives in neurological diseases.},
journal = {Frontiers in genetics},
volume = {17},
number = {},
pages = {1916220},
pmid = {42861417},
issn = {1664-8021},
abstract = {Annexin A2 (Anxa2) is a Ca[2+]-dependent phospholipid-binding protein whose functions are shaped by dynamic membrane association, post-translational regulation, and interactions with diverse molecular partners. Rather than acting as a conventional pathway-specific regulator, Anxa2 appears to operate within a multipath interaction network that links membrane organization, cytoskeletal remodeling, vesicular trafficking, extracellular proteolysis, and cellular stress responses. This Review examines how these interconnected functions contribute to neurological diseases, including Parkinson's disease, Alzheimer's disease, ischemic stroke, traumatic brain injury, and glioma. We critically evaluate evidence connecting Anxa2 with Phosphatidylinositol 3-kinase/Protein Kinase B (PI3K/AKT), mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK), Nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-κB), and Transforming Growth Factor-beta (TGF-β) related signaling and distinguish direct molecular interactions from pathway-dependent or secondary signaling changes. Current evidence suggests that many Anxa2-associated signaling outputs may arise from changes in membrane trafficking, receptor organization, protein handling, and cellular state rather than from direct control of individual signaling cascades. This network-based view also provides a framework for interpreting apparently divergent effects of Anxa2 across neuronal, glial, endothelial, immune, and tumor contexts. From a translational perspective, Anxa2 is therefore a promising but challenging target: its broad physiological functions argue against indiscriminate inhibition and instead favor disease-, cell-, and interaction-specific modulation. Defining the molecular architecture and context-specific operation of Anxa2-centered networks will be essential for determining its value as a biomarker and therapeutic target in neurological disease.},
}

@article {pmid42861666,
year = {2026},
author = {Ding, L and Zheng, M and Wang, S and Liu, W and Liang, Y and Xie, S and Yang, T and Sheng, D and Wang, S and Sheng, J and Jia, J and , },
title = {Cross-cohort NULISAseq identifies tau-anchored CSF and plasma-specific signatures across the amyloid-positive Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {10},
pages = {e71915},
doi = {10.1002/alz.71915},
pmid = {42861666},
issn = {1552-5279},
support = {STI2030-Major Projects - 2021ZD0201802//National Key Research and Development Program of China/ ; CX23YZ15//Chinese Institutes for Medical Research/ ; U20A20354//National Natural Science Foundation of China/ ; U19 AG024904/AG/NIA NIH HHS/United States ; W81XWH-12-2-0012//U.S. Department of Defense (DOD ADNI)/ ; },
mesh = {Humans ; *Alzheimer Disease/cerebrospinal fluid/blood ; *tau Proteins/cerebrospinal fluid/blood ; Female ; Biomarkers/cerebrospinal fluid/blood ; Male ; Aged ; Proteomics ; Amyloid beta-Peptides/cerebrospinal fluid/blood ; Cohort Studies ; },
abstract = {INTRODUCTION: ATN-stratified cerebrospinal fluid (CSF) proteomic signals may partly reflect classifier tau immunoassays; reproducible non-tau signals and CSF-plasma differences remain unclear.

METHODS: We profiled CSF from 60 A[+] Beijing patients with Alzheimer's disease (AD) and 875 A[+] Alzheimer's Disease Neuroimaging Initiative (ADNI) participants using the NULISAseq CNS Disease Panel. Differential expression was assessed using a false discovery rate (FDR) < 0.05 and |log2FC|≥0.5 across three ATN contrasts. We also analyzed ADNI plasma, protein-cognition correlations, tau-adjusted associations, and nested models comparing non-tau proteins with tau biomarkers.

RESULTS: Eight CSF proteins met the cross-cohort criterion within at least one matched contrast: pTau-217, pTau-181, pTau-231, MAPT, SMOC1, MDH1, VSNL1, and FABP3. NULISA tau correlated with INNOTEST (ρ = 0.75-0.85) and Elecsys (ρ = 0.65-0.68). T and N classifications agreed for 94.6% of ADNI participants (κ = 0.880); after adjustment for CSF pTau-217, all 12 associations involving the four non-tau proteins retained their direction and FDR support. In CSF, Elecsys p-tau181 and NULISA tau-family analytes had the strongest cognitive correlations (mean |ρ| = 0.35 and 0.29-0.34, respectively), followed by FABP3 (0.24). Adding the four-protein block after tau increased cross-validated R[2] across all three cross-sectional outcomes in models without diagnosis (+0.0101 to +0.0265), most clearly for the Alzheimer's Disease Assessment Scale-Cognitive Subscale, 13-item version (ADAS-Cog13); diagnosis-conditioned models showed no stable increment beyond tau and clinical characteristics. In plasma, pTau-217 was the only analyte that met both thresholds in all three contrasts.

DISCUSSION: CSF NULISAseq identified a reproducible tau-associated signature across A[+] cohorts that extended beyond the tau family. The four non-tau proteins extend the molecular profile associated with tau-defined disease state and merit further evaluation for biological stratification in independent cohorts.},
}

Humans
*Alzheimer Disease/cerebrospinal fluid/blood
*tau Proteins/cerebrospinal fluid/blood
Female
Biomarkers/cerebrospinal fluid/blood
Male
Aged
Proteomics
Amyloid beta-Peptides/cerebrospinal fluid/blood
Cohort Studies

@article {pmid42861684,
year = {2026},
author = {Lahlou, S and Ismail, Z and Smith, EE and Dang-Vu, TT and Badhwar, A},
title = {Vascular brain injury modifies the relationship between sleep duration, cognition, and white matter hyperintensity burden in the Alzheimer's disease continuum.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {10},
pages = {e71838},
doi = {10.1002/alz.71838},
pmid = {42861684},
issn = {1552-5279},
support = {//Fonds de Recherche du Québec - Santé (FRQS)/ ; //Fonds de soutien à la recherche pour les neurosciences du vieillissement/ ; //Fondation Courtois/ ; //FRQS Chercheurs boursiers/ ; CNA-137794/CAPMC/CIHR/Canada ; CNA-163902/CAPMC/CIHR/Canada ; CND-193575/CAPMC/CIHR/Canada ; BCA 527734/CAPMC/CIHR/Canada ; //Gordie Howe CARES/ ; //UK National Institute for Health and Care Research Exeter Biomedical Research Centre/ ; //Vascular Training Platform/ ; },
mesh = {Humans ; *Alzheimer Disease/pathology/diagnostic imaging/complications/physiopathology ; *White Matter/pathology/diagnostic imaging ; Male ; Female ; *Sleep Duration ; Magnetic Resonance Imaging ; Aged ; *Cognition/physiology ; *Cognitive Dysfunction/pathology ; Aged, 80 and over ; Brain/pathology ; Cohort Studies ; },
abstract = {INTRODUCTION: Self-reported sleep duration is associated with dementia-risk and vascular brain injury markers, including white matter hyperintensities (WMHs), yet how additional cerebrovascular pathology alters these relationships remains unclear.

METHOD: In a deeply phenotyped cohort (735) including healthy and Alzheimer's disease (AD) continuum individuals (subjective and mild cognitive impairment [MCI], dementia [AD], MCI and AD with high vascular burden [+V]), sleep was assessed using the Pittsburgh Sleep Quality Index. Individuals were classified as WMH-only or WMH+ (WMHs with microbleeds, infarcts, or cerebral amyloid angiopathy). Linear models tested interactions between sleep duration, WMH+ status, and diagnostic group on WMH burden and cognition.

RESULTS: In MCI+V and AD, WMH+ significantly amplified the association between shorter sleep and greater WMH burden. In AD, longer sleep related to better cognition in WMH+ but worse cognition in WMH-only (exploratory).

DISCUSSION: Additional vascular brain injury modifies how sleep relates to WMH burden and cognition across the AD continuum, highlighting the importance of moving beyond WMHs alone.},
}

Humans
*Alzheimer Disease/pathology/diagnostic imaging/complications/physiopathology
*White Matter/pathology/diagnostic imaging
Male
Female
*Sleep Duration
Magnetic Resonance Imaging
Aged
*Cognition/physiology
*Cognitive Dysfunction/pathology
Aged, 80 and over
Brain/pathology
Cohort Studies

@article {pmid42861699,
year = {2026},
author = {Exalto, LG and van Alphen, JL and Barkhof, F and Teunissen, C and Vijverberg, EGB and Aarsland, D and Lemstra, AW},
title = {Dementia with Lewy bodies and amyloid pathology: Eligible for anti-amyloid treatment or not?.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {10},
pages = {e71907},
doi = {10.1002/alz.71907},
pmid = {42861699},
issn = {1552-5279},
mesh = {Humans ; *Lewy Body Disease/drug therapy/pathology ; *Alzheimer Disease/drug therapy/pathology ; *Amyloid beta-Peptides/metabolism ; },
abstract = {In the future, treatment of dementia will be personalized, targeted to contributing pathologies, rather than the clinical syndrome. Anti-amyloid drugs for Alzheimer's disease are the first approved drugs; however, the impact of co‑pathology on the treatment effects remains incomplete. Currently, only patients with a clinical diagnosis of Alzheimer's disease are eligible for these new drugs, but could they also be beneficial when amyloid is present in other neurodegenerative diseases? For example, roughly 50% of patients with dementia with Lewy bodies are amyloid-positive. In this perspective, we discuss the theoretical benefits and challenges of anti-amyloid drugs in patients with a clinical diagnosis of dementia with Lewy bodies and concomitant Alzheimer's disease pathology. We show that a significant portion of newly diagnosed dementia with Lewy bodies patients could be eligible. We advocate for the systematic collection of efficacy and safety data using innovative strategies to achieve adequate statistical power.},
}

Humans
*Lewy Body Disease/drug therapy/pathology
*Alzheimer Disease/drug therapy/pathology
*Amyloid beta-Peptides/metabolism

@article {pmid42861749,
year = {2026},
author = {Gigi, GP and Prema, S},
title = {Benzimidazole-based Multi-target Directed Ligands: A Comprehensive Review of Therapeutic Potential in Alzheimer's disease.},
journal = {Mini reviews in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113895575491724260908101357},
pmid = {42861749},
issn = {1875-5607},
abstract = {Alzheimer's Disease (AD) is a multifactorial neurodegenerative disorder characterized by progressive cognitive decline. Current treatments provide only symptomatic relief and fail to halt disease progression, underscoring the urgent need for disease-modifying interventions. The complex interplay among amyloid-β aggregation, tau hyperphosphorylation, cholinergic dysfunction, oxidative stress, metal dyshomeostasis, and neuroinflammation necessitates multi-target therapeutic strategies. Benzimidazole analogues have emerged as a promising scaffold in this context, owing to their structural flexibility, broad pharmacological activity, and demonstrated multi-target capability. This review critically analyses recent developments in the design, synthesis, and biological evaluation of benzimidazole-based compounds as potential anti-Alzheimer's agents. Particular emphasis is placed on structure-activity relationships governing interactions with key AD-relevant targets, including acetylcholinesterase (AChE), butyrylcholinesterase (BChE), β-secretase (BACE1), tau-related protein kinases, and metal chelation relevant to amyloid pathology. The neuroprotective, antioxidant, and anti-inflammatory properties of these derivatives are also discussed in the context of their potential disease-modifying relevance. The advantages of benzimidazole-based Multi-target Directed Ligands (MTDLs) over conventional single-target approaches are highlighted, particularly their capacity to address multiple pathological hallmarks of AD simultaneously. Key limitations, including pharmacokinetic challenges and the absence of clinical validation, are critically evaluated to provide a balanced perspective. Overall, this review establishes benzimidazole analogues as promising lead structures in AD drug discovery and aims to guide future medicinal chemistry efforts toward more effective, disease-modifying therapies.},
}

@article {pmid42861801,
year = {2026},
author = {Alpana, and Dewangan, HK},
title = {Crossing the Blood-brain Barrier: Emerging Nanotechnological Approaches for Neurodegenerative Disease Therapy.},
journal = {Current neurovascular research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672026454704261001071449},
pmid = {42861801},
issn = {1875-5739},
abstract = {Neurodegenerative disorders such as Parkinson's Disease (PD), Alzheimer's Disease (AD), Amyotrophic Lateral Sclerosis (ALS), and Huntington's Disease (HD) are characterized by progressive neuronal degeneration and severe therapeutic limitations due to the Blood-Brain Barrier (BBB). Recent advances in nanotechnology have enabled the development of nanoscale drug delivery systems capable of improving BBB penetration and enhancing therapeutic efficacy. This review discusses recent progress in Lipid Nanoparticles (LNPs), polymeric nanoparticles, exosomes, magnetic nanoparticles, gold nanoparticles, graphene quantum dots, and RNAloaded nanocarriers for brain-targeted delivery. Special emphasis is placed on receptor-mediated transcytosis, intranasal delivery, magnetic targeting, and ionizable lipid nanoparticle systems for nucleic acid delivery. Recent nanoformulations including curcumin-loaded nanoparticles, siRNA- loaded lipid nanoparticles, dopamine-loaded liposomes, and lactoferrin-functionalized polymeric nanoparticles are critically compared based on BBB penetration, therapeutic efficacy, toxicity, and translational potential. Furthermore, current clinical challenges including nanotoxicity, pharmacokinetics, large-scale manufacturing, and regulatory barriers are discussed. Nanotechnology- based therapeutics represent a promising strategy for improving diagnosis and treatment of neurodegenerative disorders and may facilitate the future development of precision nanomedicine.},
}

@article {pmid42861804,
year = {2026},
author = {Borah, D and Devroy, P and Bala, A},
title = {Neuroimmune Dynamics of the Microglia-astrocyte Axis: Implications for Neurodegenerative Disorders as a Double-edged Sword.},
journal = {Current neuropharmacology},
volume = {},
number = {},
pages = {},
doi = {10.2174/011570159X507671260924120425},
pmid = {42861804},
issn = {1875-6190},
abstract = {INTRODUCTION: Maintaining homeostasis in the Central Nervous System (CNS) requires constant, bidirectional molecular interactions between microglia and astrocytes. This intercellular communication, mediated by cytokines, extracellular vesicles, purinergic signals, and connexin hemichannels, synchronizes immune surveillance, neurogenesis, and synaptic pruning under physiological conditions. However, this interaction can drive persistent neuroinflammation in chronic Neurodegenerative Disorders (NDDs) such as Multiple Sclerosis (MS), Parkinson's Disease (PD), and Alzheimer's Disease (AD).

METHODS: Gene disease association analyses and review of existing literature were employed to identify shared glial regulators and molecular mediators across multiple neurodegenerative disorders, supported by schematic diagrams illustrating intercellular signaling dynamics Results: Deregulated astrocytes sustain microglial activation, creating self-amplifying inflammatory loops, while activated M1 microglia induce the conversion of astrocytes into neurotoxic A1 astrocytes via factors such as IL-1α, TNF-α, and complement C1q. Important mediators, such as prostaglandins, IL-1β, and IL-18, further contribute to demyelination, astrogliosis, and excitotoxicity. A convergent glial activation axis identifies shared regulators across several neurodegenerative disorders, including TREM2, GRN, LRRK2, and BDNF.

DISCUSSION: Active research targeting reactive astrogliosis and microglial reprogramming towards homeostatic phenotypes shows therapeutic promise. Nevertheless, CNS immune complexity, translational challenge, and inter-patient immunological variability underscore the need for individualized, combinatorial therapeutic strategies and human-relevant experimental models.

CONCLUSION: The microglia-astrocyte axis plays a dual role in neuro-immune homeostasis and neurodegeneration, representing critical therapeutic targets for NDDs and requiring further mechanistic and translational investigation.},
}

@article {pmid42861812,
year = {2026},
author = {Nour, H and Mounadi, N and Chtita, S},
title = {In silico Exploration of the Therapeutic Potential of Phytocannabinoids.},
journal = {Mini reviews in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113895575510188260922092929},
pmid = {42861812},
issn = {1875-5607},
abstract = {Plant-derived cannabinoids exhibit remarkable structural diversity and have attracted increasing attention as bioactive compounds. Recent in silico studies have explored how these compounds interact with molecular targets involved in neurodegenerative, metabolic, oncological, and viral diseases. This review summarizes the available data on molecular docking, molecular dynamics (MD), and ADMET analysis published from 2023 to 2026 for selected phytocannabinoids. Analysis of the reviewed publications suggests that compounds such as Δ9-THC, CBN, THCV, and THCA are predicted to bind to numerous proteins implicated in disease pathogenesis, including acetylcholinesterase, butyrylcholinesterase, EGFR, BRAF/TGF-β, α-amylase, and SARS-CoV-2 Mpro. However, the docking scores obtained by different computational protocols are not directly comparable. Similarly, stable MD trajectories and favorable ADMET predictions provide computational evidence but do not guarantee the biological efficacy and safety of the studied compounds. This review highlights the importance of integrating molecular docking, molecular dynamics, pharmacokinetic prediction, and experimental validation. It also identifies methodological gaps and proposes a stepwise experimental strategy to validate the most promising computational hypotheses.},
}