@article {pmid41061696,
year = {2025},
author = {Mao, Y and Cui, M and Jiang, Y and Yu, H and Wang, M and Li, G and Zhang, H and Zhao, C and Shen, Y and Hu, Y and An, Y and Lin, Y and Yuan, Y and Lin, P and Chen, X and Xu, W and Zhao, SM},
title = {AMPKα2 signals amino acid insufficiency to inhibit protein synthesis.},
journal = {Cell metabolism},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.cmet.2025.09.004},
pmid = {41061696},
issn = {1932-7420},
abstract = {The functional difference between the two catalytic subunits, α1 and α2, of AMP-activated protein kinase (AMPK) complexes remains elusive. Herein, we report that AMPKα2 specifically transduces amino acid insufficiency signals to protein synthesis. Low amino acid levels, high protein levels, and reduced phosphorylation of AMPKα threonine 172 (p-T172) are observed in blood samples in patients with Alzheimer's disease (AD) from a cohort of 1,000,000 Chinese individuals. Loss of α2, but not α1, recaptures these observations and induces AD-like cognitive dysfunction in mice. Mechanistically, low amino acid-activated general control nonderepressible 2 (GCN2) specifically phosphorylates α2 at T172 independent of AMP and fructose 1,6-bisphosphate to inhibit protein synthesis. α2-p-T172 loss renders protein over-synthesis and AD-pathologic protein aggregation in cells and in mouse brain. AMPK activators metformin and 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR), as well as branched-chain amino acid (BCAA) or protein restriction, α2-p-T172-dependently prevent AD-like symptoms in mice. We identify AMPKα2 as a specific amino acid abundance detector for protein synthesis.},
}

@article {pmid41061587,
year = {2025},
author = {Kuzu, TD and Brinkmann, E and Bonkhoff, AK and Wunderle, V and Bischof, GN and Giehl, K and Schmieschek, MHT and Onur, OA and Jessen, F and Fink, GR and Drzezga, A and Weiss, PH},
title = {Apraxic deficits in Alzheimer's disease are associated with altered dynamic connectivity in praxis-related networks.},
journal = {Neurobiology of aging},
volume = {157},
number = {},
pages = {36-47},
doi = {10.1016/j.neurobiolaging.2025.09.007},
pmid = {41061587},
issn = {1558-1497},
abstract = {Apraxia is a common symptom in Alzheimer's disease (AD) that reduces autonomy and quality of life. However, the neural basis underlying apraxia in AD, for example, reflected by functional connectivity (FC) alterations, remains unexplored. We investigated static and dynamic FC using resting-state functional imaging in 14 patients with biomarker-confirmed AD pathology and 14 matched healthy participants. FC was estimated as average (static) and short-term (dynamic) connectivity strengths between motor- and praxis-related functional networks. Recurring connectivity patterns were clustered into dynamic states to compute temporal connectivity measures. Connectivity measures were used for correlations with apraxic deficits. In AD patients, static connectivity between visual and inferior parietal networks correlated with apraxic imitation (r = 0.762, PFDR = 0.043) and arm/hand gesture deficits (r = 0.848, PFDR = 0.020), while dynamic connectivity between these networks correlated with apraxic imitation deficits (r = 0.851, PFDR = 0.020). Dynamic FC analysis revealed a segregated and integrated state. AD patients spent more time overall (fraction time, PFDR < 0.001) and remained longer without switching (dwell time, PFDR = 0.004) in the segregated state. Both fraction (ρ = -0.858, PFDR = 0.015) and dwell time (ρ = -0.914, PFDR = 0.003) correlated with apraxic imitation deficits. Connectivity strengths between visual and inferior parietal networks and fraction time in the segregated state predicted apraxic imitation deficits (adjusted R[2] = 0.782, P < 0.001). We conclude that apraxia in AD patients is associated with altered FC in praxis-related networks, suggesting FC as a potential clinical indicator for predicting motor-cognitive deficits.},
}

@article {pmid41061470,
year = {2025},
author = {Rossi, R and Cano, A and Pallarès-Rusiñol, A and Ruiz, A and Martí, M and Pividori, MI},
title = {Electrochemical biosensor for early Alzheimer's detection and patient risk stratification using plasma exosomes.},
journal = {Biosensors & bioelectronics},
volume = {292},
number = {},
pages = {118061},
doi = {10.1016/j.bios.2025.118061},
pmid = {41061470},
issn = {1873-4235},
abstract = {Alzheimer's Disease (AD) is the leading cause of dementia, accounting for 60-70 % of cases worldwide. Early diagnosis remains challenging due to the limitations of current diagnostic tools, which are costly, invasive, and suffer from low patient compliance. Blood-based biomarkers, particularly plasma brain-derived exosomes (BDEs), have emerged as a promising alternative since they carry AD-related molecules and can be isolated non-invasively. In this study, an immunoassay was developed to isolate BDEs using magnetic particles functionalized with an anti-neuroligin-3 (NLGN3) antibody, while the AD-related marker β-secretase (BACE-1) was detected on the captured exosomes. This is the first report combining NLGN3 for for the isolation of BDEs with BACE-1 as a detection target, establishing a novel biomarker panel for AD diagnostics. The assay was evaluated across three readout platforms-optical, chemiluminescent, and electrochemical-with detection limits in the range of 10[4]-10[5] exosomes μL[-1]. Among them, the portable electrochemical platform achieved the improved LOD (1.51 × 10[4] exosomes μL[-1], R[2] = 0.9829). Plasma samples from patients with AD, mild cognitive impairment (MCI), and healthy controls were analyzed, revealing differences in exosomal BACE-1 levels (p < 0.1, t-test). These findings demonstrate, for the first time, an in vitro diagnostic approach based on a portable electrochemical biosensor for early AD detection in plasma through a novel exosomal biomarker panel. Compared to conventional diagnostics, this biosensor offers a non-invasive and cost-effective solution for AD screening, with the potential to support earlier intervention and patient risk stratification.},
}

@article {pmid41061335,
year = {2025},
author = {Shahsavari, F and Eidi, A and Sotoodehnejadnematalahi, F},
title = {Neuroprotective effects of sodium molybdate in a beta-amyloid-induced rat model of Alzheimer's disease: An In Vivo preclinical study.},
journal = {Journal of trace elements in medicine and biology : organ of the Society for Minerals and Trace Elements (GMS)},
volume = {92},
number = {},
pages = {127774},
doi = {10.1016/j.jtemb.2025.127774},
pmid = {41061335},
issn = {1878-3252},
abstract = {BACKGROUND: Molybdenum, as a trace element, exhibits various pharmacological properties, including antioxidant, anti-inflammatory, and free radical-scavenging activities. This study aimed to evaluate the effects of sodium molybdate on neurotoxicity induced by beta-amyloid (Aβ) in adult male Wistar rats.

METHODS: Forty-eight rats were randomly divided into eight groups: Healthy control group, Experimental groups receiving sodium molybdate (0.1, 0.2, and 0.4 mg/kg intragastrically daily), Alzheimer's control group (intrahippocampal injection of Aβ bilaterally), and Alzheimer's experimental groups receiving sodium molybdate (0.1, 0.2, and 0.4 mg/kg intragastrically daily) for 30 consecutive days following Aβ injection. Histopathological changes in the hippocampus were assessed using Hematoxylin and Eosin staining, and amyloid plaques were evaluated via Congo Red staining. The expression levels of GFAP and S100 proteins were investigated by immunohistochemistry, and changes in the expression level of Bax/Bcl2 ratio were evaluated by Real-time PCR in the hippocampus.

FINDINGS: Our results revealed a dose-dependent attenuation of neuronal degeneration, and reduced amyloid plaque formation in the Alzheimer's experimental groups following sodium molybdate administration. Treatment with sodium molybdate at doses of 0.2 and 0.4 mg/kg significantly reduced the levels of both S100 and GFAP proteins (P < 0.05 and P < 0.001 respectively) compared to the Alzheimer's control group. Furthermore, sodium molybdate administration at a dose of 0.1 mg/kg significantly reduced the Bax/Bcl2 expression ratio (P < 0.05), with greater reductions observed at 0.2 and 0.4 mg/kg doses (P < 0.01).

CONCLUSION: The results of this study suggest that sodium molybdate may exert protective effects against neurological disorders caused by Aβ in a rat model of Alzheimer's disease.},
}

@article {pmid41061323,
year = {2025},
author = {Zhang, J and Zhang, L and Sun, X and Yang, Y and Kong, L and Lu, C and Lv, G and Wang, T and Wang, H and Fu, F},
title = {Corrigendum to "Acetylcholinesterase Inhibitors for Alzheimer's Disease Treatment Ameliorate Acetaminophen-Induced Liver Injury in Mice via Central Cholinergic System Regulation" [The Journal of Pharmacology and Experimental Therapeutics 359 (2016) 374-382].},
journal = {The Journal of pharmacology and experimental therapeutics},
volume = {392},
number = {10},
pages = {103699},
doi = {10.1016/j.jpet.2025.103699},
pmid = {41061323},
issn = {1521-0103},
}

@article {pmid41061282,
year = {2025},
author = {Cabreira, V},
title = {Further exploration of functional cognitive impairment in Alzheimer's disease - authors' reply.},
journal = {Journal of the neurological sciences},
volume = {478},
number = {},
pages = {123703},
doi = {10.1016/j.jns.2025.123703},
pmid = {41061282},
issn = {1878-5883},
}

@article {pmid41061266,
year = {2025},
author = {Han, D and Yang, Y},
title = {Exploring the Contributions of Various Acoustic Features in Cantonese Vocal Emotions.},
journal = {Journal of speech, language, and hearing research : JSLHR},
volume = {},
number = {},
pages = {1-12},
doi = {10.1044/2025_JSLHR-24-00677},
pmid = {41061266},
issn = {1558-9102},
abstract = {PURPOSE: The aim of this study was to investigate the acoustic patterns of six emotions and a neutral state in Cantonese speech by focusing on the prosodic modulations that convey emotional content in this tonal language, which has six lexical tones.

METHOD: We employed the extended Geneva minimalistic acoustic parameter set to systematically analyze the acoustic features of 3,474 recordings from the Cantonese Audio-Visual Emotional Speech Database. Linear mixed-effects models were fitted to examine variations in acoustic parameters across emotional states. Decision tree models were used to assess the relative contributions of 22 acoustic parameters in classifying emotions.

RESULTS: By fitting linear mixed-effects models, our results revealed statistically significant variations in most of the acoustic parameters across diverse emotional states. The decision tree models showed the relative contributions of 22 acoustic parameters in the classification of emotions, with spectral parameters accounting for 65.45% of the significance in distinguishing all seven emotional states, significantly exceeding other groups of features.

CONCLUSIONS: Our findings highlight the unique characteristics of emotional expression in Cantonese, in which spectral parameters play a more significant role compared to the frequency-related parameters that are often emphasized in nontonal languages. Our results contribute significantly to understanding vocal emotion expression in tonal languages and are particularly useful for designing emotion-recognition systems and hearing aids that are tailored to tonal language environments. Furthermore, these insights have potential implications for enhancing emotional communication and cognitive training interventions for Cantonese-speaking individuals who use hearing aids or have cochlear implants, are on the autism spectrum, or have Alzheimer's disease.},
}

@article {pmid41061249,
year = {2025},
author = {Wang, B and Zhao, T and Ma, R and Huo, X and Xiong, X and Wu, M and Wang, Y and Liu, L and Zhuang, Z and Wang, B and Shou, J},
title = {Comparative Diagnostic Accuracy of AI-Assisted Fluorine-18 Fluorodeoxyglucose Positron Emission Tomography Versus Structural Magnetic Resonance Imaging in Alzheimer Disease: Systematic Review and Meta-Analysis.},
journal = {JMIR aging},
volume = {8},
number = {},
pages = {e76981},
doi = {10.2196/76981},
pmid = {41061249},
issn = {2561-7605},
mesh = {*Alzheimer Disease/diagnostic imaging/diagnosis ; Humans ; *Fluorodeoxyglucose F18 ; *Positron-Emission Tomography/methods ; *Magnetic Resonance Imaging/methods ; *Artificial Intelligence ; Radiopharmaceuticals ; },
abstract = {BACKGROUND: Neuroimaging is crucial in the diagnosis of Alzheimer disease (AD). In recent years, artificial intelligence (AI)-based neuroimaging technology has rapidly developed, providing new methods for accurate diagnosis of AD, but its performance differences still need to be systematically evaluated.

OBJECTIVE: This study aims to conduct a systematic review and meta-analysis comparing the diagnostic performance of AI-assisted fluorine-18 fluorodeoxyglucose positron emission tomography (18F-FDG PET) and structural magnetic resonance imaging (sMRI) for AD.

METHODS: Databases including Web of Science, PubMed, and Embase were searched from inception to January 2025 to identify original studies that developed or validated AI models for AD diagnosis using 18F-FDG PET or sMRI. Methodological quality was assessed using the TRIPOD-AI (Transparent Reporting of a Multivariable Prediction Model for Individual Prognosis or Diagnosis-Artificial Intelligence) checklist. A bivariate mixed-effects model was employed to calculate pooled sensitivity, specificity, and summary receiver operating characteristic curve area (SROC-AUC).

RESULTS: A total of 38 studies were included, with 28 moderate-to-high-quality studies analyzed. Pooled SROC-AUC values were 0.94 (95% CI 0.92-0.96) for sMRI and 0.96 (95% CI 0.94-0.98) for 18F-FDG PET, demonstrating statistically significant intermodal differences (P=.02). Subgroup analyses revealed that for machine learning, pooled SROC-AUCs were 0.89 (95% CI 0.86-0.92) for sMRI and 0.95 (95% CI 0.92-0.96) for 18F-FDG PET, while for deep learning, these values were 0.96 (95% CI 0.94-0.97) and 0.97 (95% CI 0.96-0.99), respectively. Meta-regression identified heterogeneity arising from study quality stratification, algorithm types, and validation strategies.

CONCLUSIONS: Both AI-assisted 18F-FDG PET and sMRI exhibit high diagnostic accuracy in AD, with 18F-FDG PET demonstrating superior overall diagnostic performance compared to sMRI.},
}

*Alzheimer Disease/diagnostic imaging/diagnosis
Humans
*Fluorodeoxyglucose F18
*Positron-Emission Tomography/methods
*Magnetic Resonance Imaging/methods
*Artificial Intelligence
Radiopharmaceuticals

@article {pmid41060859,
year = {2025},
author = {Du, X and Sun, X and Zeng, M and Tan, W and Li, M},
title = {A Hypergraph Convolutional Network with Explicit High-Order Interaction Information Extraction for Drug Repositioning.},
journal = {IEEE transactions on computational biology and bioinformatics},
volume = {PP},
number = {},
pages = {},
doi = {10.1109/TCBBIO.2025.3619038},
pmid = {41060859},
issn = {2998-4165},
abstract = {Drug repositioning, a promising strategy in drug development, aims to identify new indications for existing drugs, reduce costs, and lower safety risks. Due to their unique advantages in modeling higher-order relations among nodes, hypergraphs and hypergraph neural networks (HGNN) have become increasingly popular in drug repositioning. However, most HGNN-based methods fail to account for the diverse relations generated during the convolution process and do not explicitly model high-order interactions, limiting their ability to capture high-order interaction information adequately. To address these limitations, we propose a hypergraph convolutional network with explicit high-order interaction extraction for drug repositioning, termed HGCNDR. Our model introduces a relation-aware hypergraph convolution operation to handle distinct relation types and an effective strategy using the Hadamard product to model high-order interactions among drugs and diseases, efficiently extracting the resulting high-order interaction information. Specifically, HGCNDR constructs two feature graphs and a hypergraph based on drug similarity features, disease similarity features, and drug-disease association networks. HGCNDR then employs graph convolutional networks to extract embeddings from the feature graphs, while using the relation-aware hypergraph convolution operation and the strategy to extract structural and high-order interaction information embeddings from the hypergraph. Additionally, to preserve the common semantics between the embeddings extracted from the feature graphs and the hypergraph, HGCNDR introduces a consistency constraint. The experimental results demonstrate that HGCNDR has competitive performance compared to several baseline methods. Moreover, case studies on Alzheimer's disease and Breast carcinoma confirm that HGCNDR is able to retrieve more actual drug-disease associations in the top prediction results.},
}

@article {pmid41060400,
year = {2025},
author = {Inoue, Y and Wang, H and Heckman, MG and Ren, Y and White, LJ and Lu, W and Wang, P and Tcw, J and Koga, S and Alnobani, A and DeTure, M and Murray, ME and Petersen, RC and Dickson, DW and Bu, G and Han, X and Kanekiyo, T},
title = {Impact of APOE on cerebrovascular lipid profile in Alzheimer's disease.},
journal = {Acta neuropathologica},
volume = {150},
number = {1},
pages = {39},
pmid = {41060400},
issn = {1432-0533},
support = {22A08//Florida Department of Health Ed and Ethel Moore Alzheimer's Disease Research Program/ ; U19AG069701/GF/NIH HHS/United States ; P30AG062677/GF/NIH HHS/United States ; },
mesh = {Humans ; *Alzheimer Disease/metabolism/genetics/pathology ; Male ; Aged ; Female ; Aged, 80 and over ; *Apolipoproteins E/genetics/metabolism ; *Lipid Metabolism/physiology ; Lipidomics ; Amyloid beta-Peptides/metabolism ; *Brain/metabolism/pathology ; Middle Aged ; Cerebral Amyloid Angiopathy/metabolism/pathology ; },
abstract = {Disturbances within the cerebrovascular system substantially contribute to the pathogenesis of age-related cognitive impairment and Alzheimer's disease (AD). Cerebral amyloid angiopathy (CAA) is characterized by the deposition of amyloid-β (Aβ) in the leptomeningeal and cortical arteries and is highly prevalent in AD, affecting over 90% of cases. While the ε4 allele of apolipoprotein E (APOE) represents the strongest genetic risk factor for AD, it is also associated with cerebrovascular dysregulations. APOE plays a crucial role in brain lipid transport, particularly in the trafficking of cholesterol and phospholipids. Lipid metabolism is increasingly recognized as a critical factor in AD pathogenesis. However, the precise mechanism by which APOE influences cerebrovascular lipid signatures in AD brains remains unclear. In this study, we conducted non-targeted lipidomics on cerebral vessels isolated from the middle temporal cortex of 89 postmortem human AD brains, representing varying degrees of CAA and different APOE genotypes: APOE ε2/ε3 (N = 9), APOE ε2/ε4 (N = 14), APOE ε3/ε3 (N = 21), APOE ε3/ε4 (N = 23), and APOE ε4/ε4 (N = 22). Lipidomics detected 10 major lipid classes with phosphatidylcholine (PC) and phosphatidylethanolamine (PE) being the most abundant lipid species. While we observed a positive association between age and total acyl-carnitine (CAR) levels (p = 0.0008), the levels of specific CAR subclasses were influenced by the APOE ε4 allele. Notably, APOE ε4 was associated with increased PE (p = 0.049) and decreased sphingomyelin (SM) levels (p = 0.028) in the cerebrovasculature. Furthermore, cerebrovascular Aβ40 and Aβ42 levels showed associations with sphingolipid levels including SM (p = 0.0079) and ceramide (CER) (p = 0.024). Weighted correlation network analysis revealed correlations between total tau and phosphorylated tau and lipid clusters enriched for PE plasmalogen and lysoglycerophospholipids. Taken together, our results suggest that cerebrovascular lipidomic profiles offer novel insights into the pathogenic mechanisms of AD, with specific lipid alterations potentially serving as biomarkers or therapeutic targets for AD.},
}

Humans
*Alzheimer Disease/metabolism/genetics/pathology
Male
Aged
Female
Aged, 80 and over
*Apolipoproteins E/genetics/metabolism
*Lipid Metabolism/physiology
Lipidomics
Amyloid beta-Peptides/metabolism
*Brain/metabolism/pathology
Middle Aged
Cerebral Amyloid Angiopathy/metabolism/pathology

@article {pmid41059767,
year = {2025},
author = {Watanabe, H and Whitwell, JL and Bhaskaran, JG and Lowe, VJ and Josephs, KA},
title = {Imposter in the brain: aetiological, clinical and neuroimaging characteristics of Capgras syndrome.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awaf378},
pmid = {41059767},
issn = {1460-2156},
abstract = {Capgras syndrome is a delusional misidentification syndrome characterized by the recurrent belief that someone, usually a family member, has been replaced by an impostor. Although described over a century ago, its etiology, clinical features, and neuroimaging characteristics remain poorly understood due to its rarity. This study aimed to clarify these aspects through the analysis of a large cohort and to explore its clinical implications and underlying mechanisms. We conducted a retrospective cohort study by reviewing medical records of patients diagnosed with Capgras syndrome at the Mayo Clinic (Rochester, Minnesota) over a 28-year period (January 1995-December 2022). Clinical, neuropathological, and neuroimaging data were analyzed. A total of 204 patients were included (median age at onset: 73 years; 44% female). Twelve patients underwent neuropathological examination, all of whom exhibited α-synuclein pathology, including one patient with a clinical diagnosis of Alzheimer's disease (AD). Regarding clinical diagnoses, neurodegenerative diseases were the most common (69%, n=140), with dementia with Lewy bodies (DLB) being predominant (58%, n=118), followed by mixed etiologies ("two-hits") (18%, n=36) and AD (10%, n=21). Psychotic disorders accounted for 9% (n=18) of cases. No case was attributed to a single stroke, although 9% (n=19) involved coexisting cerebrovascular disease in the context of AD or DLB. In DLB, the timing of Capgras syndrome onset varied: it occurred later than cognitive decline and core clinical features (e.g., visual hallucinations, fluctuating cognition, parkinsonism) in both DLB and mild cognitive impairment (MCI)-onset prodromal DLB, but earlier in psychiatric-onset prodromal DLB. In both DLB and AD, Capgras syndrome typically targeted a single spouse, whereas in psychotic disorders, it often involved multiple, non-spousal targets. Depression or anxiety was present in 55% (n=112). Capgras syndrome worsened in the evening or at night (87%, n=45/52), suggesting a link to negative affective states. Among 82 patients with DLB and AD treated with cholinesterase inhibitors, 15% (n=12) showed symptomatic improvement. Neuroimaging with MRI and 18F-fluorodeoxyglucose-PET revealed widespread bilateral cortical involvement and prominent right frontal dysfunction in DLB and AD. Capgras syndrome is associated with DLB and could serve as a potential early diagnostic clue. Recognizing its phenomenological features-the number and type of targeted individuals-can help differentiate between neurodegenerative and psychiatric etiologies. In neurodegenerative diseases, Capgras syndrome may reflect a multifactorial, dynamic process, driven by widespread bilateral cortical dysfunction (particularly involving the right frontal lobe), and psychological factors. Thus, a combined approach involving pharmacological and non-pharmacological interventions may offer effective management strategies.},
}

@article {pmid41059738,
year = {2025},
author = {Osei, GN and Bockarie, A and Akpalu, A and Adueming, PO and Antwi, MH and Appiah, F and Kpelle, L and Donkor, DM and Simpong, DL},
title = {Diagnostic potential of near-infrared spectroscopy in mild cognitive impairment and neurodegenerative disorders: Implications for resource-limited settings.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {10},
pages = {e70769},
doi = {10.1002/alz.70769},
pmid = {41059738},
issn = {1552-5279},
mesh = {Humans ; *Cognitive Dysfunction/diagnosis/diagnostic imaging ; Spectroscopy, Near-Infrared/methods ; *Neurodegenerative Diseases/diagnosis/diagnostic imaging ; Alzheimer Disease/diagnostic imaging/diagnosis ; Brain/diagnostic imaging ; Neuropsychological Tests ; Resource-Limited Settings ; },
abstract = {BACKGROUND: Near-infrared spectroscopy (NIRS) is emerging as a promising tool for early detection of mild cognitive impairment (MCI) and neurodegenerative diseases, especially where advanced imaging is limited.

METHODOLOGY: This systematic review investigates NIRS's diagnostic capabilities. Adhering to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, we conducted a comprehensive review of studies using NIRS for cognitive assessment in MCI and neurodegenerative conditions.

RESULTS/DISCUSSION: NIRS effectively assesses cognitive function, identifying reduced prefrontal connectivity in MCI and subjective cognitive decline (SCD). Interestingly, while SCD patients maintain stronger brain network integrity, NIRS reveals decreased oxyhemoglobin levels in Alzheimer's disease (AD) patients' dorsolateral prefrontal cortex. Combining NIRS with graph analysis, cognitive tasks, and machine learning significantly boosts diagnostic accuracy. Moreover, NIRS can differentiate between neurodegenerative disorders and, with concurrent electroencephalography, offers enhanced understanding of brain connectivity issues in AD. Our findings emphasize NIRS's considerable potential to improve cognitive assessment and neurodegeneration diagnosis.

HIGHLIGHTS: Mild cognitive impairment (MCI) individuals show disruptions in neurovascular coupling and functional connectivity, particularly in the dorsolateral prefrontal cortex during near-infrared spectroscopy (NIRS) assessments. Significant reductions in oxyhemoglobin (HbO2) levels are observed in the dorsolateral prefrontal cortex of amnestic MCI (aMCI) individuals compared to healthy controls. Individuals with subjective cognitive decline (SCD) show lower HbO2 levels than healthy individuals, while aMCI individuals show even more pronounced reductions. The dorsolateral prefrontal cortex is identified as a critical area for Alzheimer's disease (AD) assessment using NIRS, correlating with cognitive performance. Differences in Broca's area activation during language tasks help distinguish behavioral variant frontotemporal dementia from AD, revealing unique cognitive profiles through NIRS.},
}

Humans
*Cognitive Dysfunction/diagnosis/diagnostic imaging
Spectroscopy, Near-Infrared/methods
*Neurodegenerative Diseases/diagnosis/diagnostic imaging
Alzheimer Disease/diagnostic imaging/diagnosis
Brain/diagnostic imaging
Neuropsychological Tests
Resource-Limited Settings

@article {pmid41059714,
year = {2025},
author = {Logue, MW and Labadorf, A and O'Neill, NK and Dickson, DW and Dugger, BN and Flanagan, ME and Frosch, MP and Gearing, M and Jin, LW and Kofler, J and Mayeux, R and McKee, A and Miller, CA and Murray, ME and Nelson, PT and Perrin, RJ and Schneider, JA and Stein, TD and Teich, AF and Tobunluepop, K and Troncoso, JC and Wang, SH and Wang, Z and Wolozin, B and Mez, J and Farrer, LA},
title = {Novel differentially expressed genes and multiple biological pathways for Alzheimer's disease identified in brain tissue from African American donors.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {10},
pages = {e70629},
doi = {10.1002/alz.70629},
pmid = {41059714},
issn = {1552-5279},
support = {R01-AG048927/NH/NIH HHS/United States ; U01-AG058654/NH/NIH HHS/United States ; U54-AG052427/NH/NIH HHS/United States ; U19-AG068753/NH/NIH HHS/United States ; U01-AG062602/NH/NIH HHS/United States ; P30-AG072978/NH/NIH HHS/United States ; U01-081230/NH/NIH HHS/United States ; P01-AG003949/NH/NIH HHS/United States ; P30-AG062677/NH/NIH HHS/United States ; P30-AG062421/NH/NIH HHS/United States ; P30-AG 066507/NH/NIH HHS/United States ; P30-AG066511/NH/NIH HHS/United States ; P30-AG 072972/NH/NIH HHS/United States ; P30-AG066468/NH/NIH HHS/United States ; R01-AG072474/NH/NIH HHS/United States ; RF1-AG066107/NH/NIH HHS/United States ; U24-AG056270/NH/NIH HHS/United States ; P01-AG003949/NH/NIH HHS/United States ; RF1-AG082339/NH/NIH HHS/United States ; RF1-NS118584/NH/NIH HHS/United States ; P30-AG072946/NH/NIH HHS/United States ; P01-AG003991/NH/NIH HHS/United States ; P30-AG066444/NH/NIH HHS/United States ; P01-AG026276/NH/NIH HHS/United States ; P30-AG066462/NH/NIH HHS/United States ; P30-AG072958/NH/NIH HHS/United States ; P30-AG072978/NH/NIH HHS/United States ; 8AZ06//Florida Department of Health/ ; 20A22//Florida Department of Health/ ; },
mesh = {Humans ; *Alzheimer Disease/genetics/pathology/metabolism ; *Black or African American/genetics ; Female ; Male ; Aged ; Genome-Wide Association Study ; *Brain/metabolism/pathology ; Aged, 80 and over ; White People/genetics ; Transcriptome ; Tissue Donors ; Genetic Predisposition to Disease ; Middle Aged ; White ; },
abstract = {INTRODUCTION: Few African American (AA) donors have been included in post mortem Alzheimer's disease (AD) studies compared to European-ancestry (EA) individuals.

METHODS: We generated transcriptome-wide bulk pre-frontal cortex (PFC) gene expression data from 125 AA donors with neuropathologically determined AD and 82 AA controls.

RESULTS: Transcriptome-wide significant differential expression was observed with 482 genes. The most significant, ADAMTS2, showed 1.52 times higher expression in AD cases (p = 2.96x10[-8]). Comparison of findings with those from a recent gene expression study of EA brain donors revealed substantial concordance, including ADAMTS2. Other associations not observed in EA results may be especially relevant to AD risk in the AA population. Examination of AA AD GWAS-implicated variants identified several expression quantitative trait loci.

CONCLUSION: This first large-scale AA brain AD gene expression study identified many differentially expressed genes, including ADAMTS2, and supports gene expression as a molecular pathway underlying the impact of several AA AD risk variants.

HIGHLIGHTS: We performed the largest African American brain tissue Alzheimer's disease (AD) gene expression study. Expression differences for 482 genes, notably ADAMTS2, were study-wide significant. Many significant differentially expressed genes are involved in energy metabolism. Several previously known AD-associated variants in African Americans are eQTLs. These results advance knowledge of the genetic basis of AD in the AA population.},
}

Humans
*Alzheimer Disease/genetics/pathology/metabolism
*Black or African American/genetics
Female
Male
Aged
Genome-Wide Association Study
*Brain/metabolism/pathology
Aged, 80 and over
White People/genetics
Transcriptome
Tissue Donors
Genetic Predisposition to Disease
Middle Aged
White

@article {pmid41059602,
year = {2025},
author = {Ryoo, SW and Lin, WZ and Magliocco, A and Ruthirakuhan, M and Wong, YY and Perfetto, SE and Huang, C and Anita, NZ and Arnott, SR and Lang, AE and Symons, S and Hegele, RA and Goubran, M and Ramirez, J and Ottoy, J and Rabin, JS and MacIntosh, BJ and Lanctôt, KL and Liang, N and Cogo-Moreira, H and Taha, AY and Swardfager, W and , },
title = {Metabolic and vascular contributions to dementia: Soluble epoxide hydrolase-derived linoleic acid oxylipins and glycemic status are related to cerebral small vessel disease markers, atrophy, and cognitive performance.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {10},
pages = {e70718},
doi = {10.1002/alz.70718},
pmid = {41059602},
issn = {1552-5279},
support = {PJT-159711/CAPMC/CIHR/Canada ; 446881/CAPMC/CIHR/Canada ; RGPIN-2017-06962//Natural Sciences and Engineering Research Council of Canada/ ; AARG501466//Alzheimer's Association & Brain Canada/ ; 2018-AARGD-591676/ALZ/Alzheimer's Association/United States ; 24AARF-1242638/ALZ/Alzheimer's Association/United States ; project #1008787//National Institute of Food and Agriculture/ ; //Banting and Best Diabetes Centre, University of Toronto/ ; CRC-2020-00353//Canada Research Chairs Program/ ; ER21-16-146//Ontario Ministry of Colleges and Universities/ ; //Centre for Collaborative Drug Research, University of Toronto/ ; BAND3//Weston Brain Institute, Alzheimer's Research UK, Alzheimer's Association, Michael J. Fox Foundation/ ; A2024012F//BrightFocus Foundation/ ; },
mesh = {Humans ; *Epoxide Hydrolases/metabolism ; Male ; Female ; Aged ; *Linoleic Acid/metabolism ; Atrophy/pathology ; *Diabetes Mellitus, Type 2/metabolism/complications ; *Cerebral Small Vessel Diseases/metabolism/pathology ; *Dementia/metabolism/pathology ; Biomarkers/blood ; *Oxylipins/metabolism ; *Cognition/physiology ; Glycated Hemoglobin/metabolism ; Brain/pathology ; Magnetic Resonance Imaging ; Middle Aged ; Blood Glucose/metabolism ; },
abstract = {INTRODUCTION: Type 2 diabetes mellitus (T2DM) is a risk factor for dementia and cerebral small vessel disease, but there remains a need to identify targetable molecular pathways involved in the underlying pathophysiology.

METHODS: In participants with Alzheimer's disease, related dementias, or cerebrovascular diseases, we assessed associations between ratios of unesterified linoleic acid (LA)-derived soluble epoxide hydrolase (sEH) metabolites (diols) and substrates (epoxides), with imaging-derived white matter hyperintensities (WMHs), brain parenchymal fraction (BPF), and cognitive performance. Potential moderation effects by glycemic control (hemoglobin A1c [HbA1c]) were examined.

RESULTS: With elevated HbA1c, greater LA-derived diol/epoxide ratios were associated with greater WMH volume (β [95% CI] = 0.565 [0.100, 1.030], p = 0.017), lower global BPF (β [95% CI] = -0.476 [-0.903, -0.048], p = 0.029), and poorer memory performance (β [95% CI] = -0.603 [-1.070, -0.136], p = 0.012), such that detrimental associations were observed only in T2DM.

DISCUSSION: Cytochrome P450-sEH metabolites may indicate a novel metabolic-vascular contribution to dementia in individuals with T2DM.

ClinicalTrials.gov Identifier NCT04104373.

HIGHLIGHTS: LA-derived sEH metabolite (diol) to substrate (epoxide) ratio was lower in individuals with diabetes. The diol/epoxide ratio with high HbA1c contributed to SVD and brain atrophy. The CYP450-sEH pathway may link metabolic and vascular contributions to dementia. sEH may be a potential therapeutic target in individuals with diabetes.},
}

Humans
*Epoxide Hydrolases/metabolism
Male
Female
Aged
*Linoleic Acid/metabolism
Atrophy/pathology
*Diabetes Mellitus, Type 2/metabolism/complications
*Cerebral Small Vessel Diseases/metabolism/pathology
*Dementia/metabolism/pathology
Biomarkers/blood
*Oxylipins/metabolism
*Cognition/physiology
Glycated Hemoglobin/metabolism
Brain/pathology
Magnetic Resonance Imaging
Middle Aged
Blood Glucose/metabolism

@article {pmid41059583,
year = {2025},
author = {Zeighami, Y and Tremblay, C and Dadar, M},
title = {Sex differences in vulnerability to tau pathology: Impact on cognitive decline.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {10},
pages = {e70634},
doi = {10.1002/alz.70634},
pmid = {41059583},
issn = {1552-5279},
support = {//Canadian Institutes of Health Research (CIHR)/ ; //Natural Sciences and Engineering Research Council of Canada (NSERC)/ ; //Fonds de Recherche du Québec-Santé (FRQS)/ ; },
mesh = {Humans ; Male ; Female ; *Cognitive Dysfunction/pathology/metabolism ; *tau Proteins/metabolism ; Aged ; Longitudinal Studies ; *Sex Characteristics ; Sex Factors ; Aged, 80 and over ; Alzheimer Disease/pathology ; Amyloid beta-Peptides/metabolism ; },
abstract = {INTRODUCTION: Although the link between the presence of amyloid and tau pathologies, neurodegeneration, and cognitive decline in aging individuals is established, it is less clear whether there are sex differences in vulnerability to these pathologies.

METHODS: A total of 1464 participants (7168 longitudinal assessments, 4.77 ± 3.78 years of follow-up) were included from the National Alzheimer's Coordinating Center (NACC) database. Longitudinal mixed effects and mediation models examined the sex differences across cognitive decline trajectories of amyloid (A), tau (T), and neurodegeneration (N) groups.

RESULTS: A[+]T[-] males showed faster cognitive decline compared to A[+]T[-] females (p < 0.005), whereas A[+]T[+] females showed steeper cognitive decline compared to A[+]T[+] males (p < 0.0001). In addition, sex marginally moderated the mediating effect of tau on the relationship between amyloid and cognitive decline (p = 0.046).

DISCUSSION: Sex differences in vulnerability to tau pathology in the presence of amyloid can shape cognitive decline trajectories.

HIGHLIGHTS: A[+]T[-] males showed faster cognitive decline compared to A[+]T[-] females. A[+]T[+] females showed faster cognitive decline compared to A[+]T[+] males. Tau status significantly mediated the relationship between amyloid status and cognitive decline. Sex marginally moderated the mediating relationship between amyloid, tau, and cognitive decline. The findings point to sex differences in the impact of tau pathology on cognition.},
}

Humans
Male
Female
*Cognitive Dysfunction/pathology/metabolism
*tau Proteins/metabolism
Aged
Longitudinal Studies
*Sex Characteristics
Sex Factors
Aged, 80 and over
Alzheimer Disease/pathology
Amyloid beta-Peptides/metabolism

@article {pmid41059577,
year = {2025},
author = {Pedersen, TJ and Lu, R and Toedebusch, C and Hess, A and Richardson, R and Quigley, A and Robinson, CG and Morris, JC and Holtzman, DM and Xiong, C and Gordon, BA and Lucey, BP},
title = {Variability of longitudinal sleep monitoring in amyloid-negative and amyloid-positive cognitively unimpaired and mildly impaired older adults.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {10},
pages = {e70761},
doi = {10.1002/alz.70761},
pmid = {41059577},
issn = {1552-5279},
support = {/NH/NIH HHS/United States ; P01 AG03991/AG/NIA NIH HHS/United States ; P01 AG026276/AG/NIA NIH HHS/United States ; P30 AG066444/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; Male ; Female ; Electroencephalography ; Aged ; Longitudinal Studies ; *Cognitive Dysfunction/physiopathology ; *Sleep/physiology ; *Alzheimer Disease/physiopathology ; *Sleep Wake Disorders ; Aged, 80 and over ; Neuropsychological Tests ; Amyloid beta-Peptides/metabolism ; Self Report ; *Amyloid/metabolism ; },
abstract = {INTRODUCTION: Sleep disturbances are associated with Alzheimer's disease (AD) pathology and cognitive symptoms, but few studies have longitudinally assessed sleep, AD biomarkers, and cognition. Understanding how sleep changes over time in older adults with and without AD pathology is crucial for appropriately designing longitudinal studies of aging and AD.

METHODS: Sleep was measured over ≈3.5 years in older adults using self-reported questionnaires and an at-home single-channel electroencephalography (scEEG) device. Participants also underwent amyloid imaging and cognitive testing. Longitudinal change of multiple sleep parameters was determined and sample sizes estimated for future clinical trials using sleep as an outcome.

RESULTS: In both amyloid groups, EEG spectral power measures demonstrated minimal longitudinal change, whereas self-reported and sleep parameters such as sleep efficiency demonstrated greater variability over time.

DISCUSSION: This study characterized how sleep parameters change in older adults with and without AD pathology, offering important guidance for future longitudinal studies targeting sleep and neurodegeneration.

HIGHLIGHTS: Low variability in electroencephalography (EEG) spectral power metrics, including delta, theta, and alpha power. Greater variability in self-report sleep metrics, including self-reported time to fall asleep and EEG-derived metrics such as sleep duration and N2 sleep. Understanding the variability in sleep measures over time will offer important guidance for designing future longitudinal studies targeting sleep and neurodegeneration.},
}

Humans
Male
Female
Electroencephalography
Aged
Longitudinal Studies
*Cognitive Dysfunction/physiopathology
*Sleep/physiology
*Alzheimer Disease/physiopathology
*Sleep Wake Disorders
Aged, 80 and over
Neuropsychological Tests
Amyloid beta-Peptides/metabolism
Self Report
*Amyloid/metabolism

@article {pmid41059494,
year = {2025},
author = {Allison, EY and Bedi, AM and Rourke, AJ and Mizzi, V and Walsh, JJ and Heisz, JJ and Al-Khazraji, BK},
title = {Resisting decline: the neuroprotective role of resistance exercise in supporting cerebrovascular function and brain health in aging.},
journal = {Frontiers in physiology},
volume = {16},
number = {},
pages = {1606267},
pmid = {41059494},
issn = {1664-042X},
abstract = {Reduced cerebral blood flow (CBF) and cerebrovascular function are critical early-stage biomarkers preceding changes in brain function and structure observed in normal aging and during the onset and progression of Alzheimer's Disease and related dementias (ADRD). Though several interventions attempt to curb the effects of aging and brain neurodegeneration, exercise and lifestyle habits remain one of the most impactful and easily modifiable factors for preserving brain health. Although the effects of aerobic exercise on cerebrovascular function and brain health are well established, resistance training (RT) is rapidly increasing in popularity across all age demographics due to its numerous health benefits. Despite the clear physiological benefits of resistance exercise, its potential efficacy for preserving or improving cerebrovascular and overall brain health remains understudied to date. The aim of this review is to examine the literature pertaining to ways in which resistance exercise may reduce the risk of ADRD and slow age-related decline of brain structures and functions. Additionally, this review seeks to highlight key considerations and challenges regarding the feasibility, adoption, and adherence to resistance exercise in the context of normal aging, mild cognitive impairment, and ADRD.},
}

@article {pmid41059350,
year = {2025},
author = {Zhang, H and Cao, D and Xu, T and Chen, E and Li, G and Chen, Y and Payne, P and Province, M and Li, F},
title = {MosGraphFlow: a novel integrative graph AI model mining signaling targets from multi-omic data.},
journal = {BMC methods},
volume = {2},
number = {1},
pages = {23},
pmid = {41059350},
issn = {3004-8729},
abstract = {UNLABELLED: Multi-omic dataset can better characterize complex cellular signaling pathways from multiple views compared to individual omic data. However, integrative multi-omic data analysis to rank key disease biomarkers and infer core signaling pathways remains an open problem. In this study, we developed a novel graph AI model, mosGraphFlow, for analyzing multi-omic signaling graphs (mosGraphs), 2) analyzed multi-omic mosGraph datasets of Alzheimers' Disease (AD), and 3) developed a visualization tool to facilitate the visualization of identified disease associated signaling biomarkers and network. The comparison results show that the proposed model not only achieves the best classification accuracy but also identifies important AD disease biomarkers and signaling interactions. In the visualization, the signaling sources are highlighted at specific omic levels to facilitate the understanding of disease pathogenesis. The proposed model can also be applied and expanded for other multi-omic data-driven studies. The code of the model is publicly accessible via GitHub: https://github.com/FuhaiLiAiLab/mosGraphFlow.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s44330-025-00041-8.},
}

@article {pmid41059020,
year = {2025},
author = {Lim, KY and Yoon, S and Park, S and Kim, S and Kim, K and Ahn, J and Kim, JP and Kim, HJ and Na, DL and Seo, SW and Kwak, K},
title = {Regional CSF volume quantification using deep learning for comparative analysis of brain atrophy in frontotemporal dementia subtypes.},
journal = {Frontiers in aging neuroscience},
volume = {17},
number = {},
pages = {1631640},
pmid = {41059020},
issn = {1663-4365},
abstract = {INTRODUCTION: Frontotemporal dementia (FTD) encompasses heterogeneous clinical syndromes, and distinguishing its subtypes using imaging remains challenging.

METHODS: We developed a deep learning model to quantify brain atrophy by measuring cerebrospinal fluid (CSF) volumes in key regions of interest (RoIs) on standard MRI scans. In a retrospective study, we analyzed 3D T1-weighted MRI data from 1,854 individuals, including cognitively unimpaired (CU) controls, patients with dementia of the Alzheimer type (DAT), and FTD subtypes: behavioral variant FTD (bvFTD), nonfluent variant primary progressive aphasia (nfvPPA), and semantic variant PPA (svPPA). The model quantified CSF volumes in 14 clinically relevant RoIs and generated age- and sex-adjusted W-scores to express regional atrophy.

RESULTS: Each FTD subtype exhibited a distinct, lateralized atrophy pattern: bvFTD showed widespread bilateral frontal and right-predominant parietal and temporal atrophy; nfvPPA showed left-predominant frontal and parietal atrophy; and svPPA exhibited marked left-lateralized temporal and hippocampal atrophy. All FTD subtypes demonstrated significantly greater CSF expansion in these characteristic regions compared to DAT and CU.

DISCUSSION: This deep learning approach provides a simple, interpretable measure of brain atrophy that differentiates FTD subtypes, requiring only standard MRI with minimal preprocessing, and offers clinical utility.},
}

@article {pmid41058862,
year = {2024},
author = {Yamada, S and Ito, H and Iseki, C and Kondo, T and Yamanaka, T and Tanikawa, M and Otani, T and Ii, S and Ohta, Y and Watanabe, Y and Wada, S and Oshima, M and Mase, M},
title = {Deep learning assessment of disproportionately enlarged subarachnoid-space hydrocephalus in Hakim's disease or idiopathic normal pressure hydrocephalus.},
journal = {Radiology advances},
volume = {1},
number = {3},
pages = {umae027},
pmid = {41058862},
issn = {2976-9337},
abstract = {BACKGROUND: Disproportionately enlarged subarachnoid-space hydrocephalus (DESH) is a key feature of Hakim's disease (synonymous with idiopathic normal pressure hydrocephalus; iNPH). However, it previously had been only subjectively evaluated.

PURPOSE: This study aims to evaluate the usefulness of MRI indices, derived from deep learning segmentation of cerebrospinal fluid (CSF) spaces, for DESH detection and to establish their optimal thresholds.

MATERIALS AND METHODS: This study retrospectively enrolled a total of 1009 participants, including 77 patients diagnosed with Hakim's disease, 380 healthy volunteers, 163 with mild cognitive impairment, 256 with Alzheimer's disease, and 217 with other types of neurodegenerative diseases. DESH, ventriculomegaly, tightened sulci in the high convexities, and Sylvian fissure dilatation were evaluated on three-dimensional T1-weighted MRI by radiologists. The total ventricles, high-convexity part of the subarachnoid space, and Sylvian fissure and basal cistern were automatically segmented using the CSF Space Analysis application (FUJIFILM Corporation). Moreover, DESH, Venthi, and Sylhi indices were calculated based on these 3 regions. The area under the receiver-operating characteristic curves of these indices and region volumes (volume ratios) for DESH detection were calculated.

RESULTS: Of the 1009 participants, 101 (10%) presented with DESH. The DESH, Venthi, and Sylhi indices performed well with 95.0%-96.0% sensitivity and 91.5%-96.8% specificity at optimal thresholds. All patients with Hakim's disease were diagnosed with DESH, despite variations in severity. In patients with Hakim's disease, with or without Alzheimer's disease, the DESH index and total ventricular volume were significantly higher compared to patients with Alzheimer's disease, although the total intracranial cerebrospinal fluid volume was significantly lower.

CONCLUSION: DESH, Venthi, and Sylhi indices, and the volumes and volume ratios of the ventricle and high-convexity part of the subarachnoid space computed using deep learning were useful for the DESH detection that may help to improve the diagnosis of Hakim's disease (ie, iNPH).},
}

@article {pmid41058602,
year = {2025},
author = {Liu, Y and Zhou, Z and Liu, X and Zeng, J and Liu, Q and Xu, T},
title = {An AI-assisted multiplex fluorescence sensing platform for grading diagnosis of Alzheimer's disease.},
journal = {Journal of materials chemistry. B},
volume = {},
number = {},
pages = {},
doi = {10.1039/d5tb01103e},
pmid = {41058602},
issn = {2050-7518},
abstract = {Blood-based biomarkers have become increasingly important for Alzheimer's disease (AD) diagnosis. However, due to individual variations, diagnostic accuracy using a single blood biomarker remains low, making it challenging to implement in large-scale AD screening efforts. Herein, we developed a multiplex fluorescent sensing platform for simultaneously measuring Aβ40, Aβ42, and P-tau181 in the blood, and constructed an artificial intelligence (AI) model. These three biomarkers were analyzed in 60 clinical samples: 15 healthy control, 15 subjective cognitive decline, 15 mild cognitive impairment, and 15 AD samples. The AI model based on these three biomarkers exhibited high predictive accuracy (91%), high positive predictive value (PPV) and low false rate (8.8%). The diagnostic accuracy and PPV of the AI model exceeded 90% for AD grading diagnosis in clinical samples. This study introduces a promising strategy for disease diagnosis and grading based on multi-biomarker analysis.},
}

@article {pmid41058585,
year = {2025},
author = {Kanemoto, H and Suehiro, T and Katakami, S and Koizumi, F and Satake, Y and Taomoto, D and Takeda, K and Kobayashi, M and Yoshiyama, K and Ikeda, M},
title = {Impact of Urinary Incontinence on Idiopathic Normal Pressure Hydrocephalus: A Cross-Sectional Study With Alzheimer's Disease and Dementia With Lewy Bodies.},
journal = {Geriatrics & gerontology international},
volume = {},
number = {},
pages = {},
doi = {10.1111/ggi.70208},
pmid = {41058585},
issn = {1447-0594},
support = {JPMH22GB1002//the Ministry of Health, Labour and Welfare Research/ ; },
abstract = {AIM: This study investigated the impact of urinary incontinence on idiopathic normal pressure hydrocephalus (iNPH) by comparing its characteristics with those of Alzheimer's disease (AD) and dementia with Lewy bodies (DLB).

METHODS: Cognitive impairment, neuropsychiatric symptoms, activities of daily living (ADL), and caregiver burden were compared using data from 107 patients with iNPH, 610 with AD, and 152 with DLB treated at the outpatient clinic of the Department of Psychiatry at the University of Osaka Hospital, through the chi-square and Kruskal-Wallis tests. Multiple regression analysis was performed to investigate factors related to dementia severity and caregiver burden in patients with iNPH.

RESULTS: The iNPH group had milder cognitive impairment and neuropsychiatric symptoms, except for apathy, than the other two groups but showed more dependence on ADL. Patients with iNPH did not differ significantly from those in the other two groups in terms of dementia severity. The caregiver burden was milder in the iNPH group than in the DLB group. In the iNPH group, dementia severity was related to the Mini-Mental State Examination score, urinary incontinence frequency, and apathy, whereas caregiver burden was related to apathy and irritability. Sex, age, and the Timed Up and Go test results were not related to any of these.

CONCLUSIONS: Compared to AD and DLB, iNPH was characterized by urinary incontinence. Although urinary incontinence has not been extensively studied and treated, it may affect daily life more than gait disturbances and cognitive impairments in patients with iNPH.},
}

@article {pmid41058322,
year = {2025},
author = {Huang, CE and Chen, YY and Lu, CH and Yang, YR and Wu, YY and Wu, CH and Tsai, WY and Lin, MH and Tsou, HY and Li, CP and Wang, YH and Chen, CC},
title = {Prevalence and clinical impact of JAK2-CHIP: Association with Parkinsonism and hematologic changes in a population cohort.},
journal = {Journal of the Formosan Medical Association = Taiwan yi zhi},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jfma.2025.09.039},
pmid = {41058322},
issn = {0929-6646},
abstract = {BACKGROUND: JAK2V617F-associated clonal hematopoiesis of indeterminate potential (JAK2-CHIP) has been implicated in cardiovascular disease through inflammatory and thrombotic mechanisms. However, its role in microthromboembolism-related events (miTE-REs), particularly neurodegenerative disorders, remains underexplored.

METHODS: In this retrospective cohort study, we screened 1768 individuals from a health screening population for JAK2V617F using a high-sensitivity qCAST-Duplex PCR assay. To enhance efficiency, we employed a pooled PCR strategy: genomic DNA from 10 samples was combined per reaction. Given the assay's detection limit of 0.01 %, this approach allowed identification of any individual sample with a mutant allele burden (AB) > 0.1 %. Positive pools were deconvoluted and tested individually. Clinical data were analyzed to assess associations between JAK2-CHIP and miTE-REs, including Parkinsonism, dementia, Alzheimer's disease, heart failure, and avascular necrosis. Temporal changes in AB were evaluated in participants with serial blood samples.

RESULTS: JAK2-CHIP was identified in 32 individuals (1.8 %), with prevalence increasing with age. Carriers had a significantly higher prevalence of Parkinsonism than non-carriers (15.6 % vs. 6.3 %, p = 0.035). Carriers with AB ≥1 % had elevated platelet and basophil counts, suggesting subclinical myeloid lineage activation. Among those with serial data, 22.7 % showed clonal expansion, though none developed hematologic malignancy.

CONCLUSION: JAK2-CHIP is associated with increased prevalence of Parkinsonism in otherwise healthy individuals, possibly via microvascular or inflammatory pathways. Elevated platelet and basophil counts among carriers support early functional consequences of this mutation. These findings highlight the clinical relevance of detecting JAK2-CHIP in general populations and underscore its potential as a biomarker for neurologic risk stratification and longitudinal monitoring.},
}

@article {pmid41058018,
year = {2025},
author = {Pascual-Lucas, M and Lacosta, AM and Montañés, M and Canudas, J and Loscos, J and Monleón, I and Allué, JA and Sarasa, L and Fandos, N and Romero, J and Sarasa, M and Torres, M and Whyms, D and Terencio, J and Piñol-Ripoll, G and Boada, M},
title = {Safety, tolerability, immunogenicity, and efficacy of ABvac40 active immunotherapy against Aβ40 in patients with mild cognitive impairment or very mild Alzheimer's disease: A randomized, double-blind, placebo-controlled phase 2 study.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {10},
pages = {e70776},
doi = {10.1002/alz.70776},
pmid = {41058018},
issn = {1552-5279},
support = {//Araclon Biotech-Grifols/ ; },
mesh = {Humans ; Double-Blind Method ; *Alzheimer Disease/therapy/immunology/drug therapy ; Male ; *Amyloid beta-Peptides/immunology ; Female ; Aged ; *Cognitive Dysfunction/therapy/immunology/drug therapy ; *Immunotherapy, Active/methods ; Treatment Outcome ; *Peptide Fragments/immunology ; *Alzheimer Vaccines/therapeutic use/adverse effects ; Middle Aged ; Aged, 80 and over ; },
abstract = {INTRODUCTION: ABvac40 is an investigational active immunotherapy (vaccine) targeting Aβ40. This study assessed the safety and immunogenicity of ABvac40 in patients with amnestic mild cognitive impairment or very mild Alzheimer's disease.

METHODS: AB1601 was a multicenter, randomized, double-blind, placebo-controlled phase 2 study. Patients (n = 124) received five monthly injections plus a 10-month booster of ABvac40 or placebo, with 18-24 months of follow-up. Primary endpoints included safety, tolerability, and immunogenicity. Secondary endpoints assessed immune response, neuropsychological changes, and disease biomarkers.

RESULTS: Treatment-emergent adverse events (TEAEs) and serious TEAEs were comparable between ABvac40 (90.6% and 26.6%) and placebo (93.3% and 26.7%). Amyloid-related imaging abnormalities-hemorrhage (ARIA-H) were similar (12.5% ABvac40; 15.0% placebo), with no ARIA-edema (ARIA-E) or meningoencephalomyelitis. ABvac40 induced a specific, sustained immune response in plasma, with detectable antibodies in CSF.

DISCUSSION: These findings support further investigation of ABvac40 as a potential disease-modifying therapy.

NCT03461276 (ClinicalTrials.gov) HIGHLIGHTS: ABvac40 was safe and well-tolerated in early-stage Alzheimer's disease patients. No amyloid-related imaging abnormalities-edema (ARIA-E) or encephalitis observed; ARIA-hemorrhage (ARIA-H) rates were similar across groups. Specific, sustained immune response to ABvac40 in plasma, with cerebrospinal fluid (CSF) antibody penetration. Cognitive scales and magnetic resonance imaging (MRI) volumetric data favored ABvac40 over placebo. Results support further development of ABvac40 as a disease-modifying therapy.},
}

Humans
Double-Blind Method
*Alzheimer Disease/therapy/immunology/drug therapy
Male
*Amyloid beta-Peptides/immunology
Female
Aged
*Cognitive Dysfunction/therapy/immunology/drug therapy
*Immunotherapy, Active/methods
Treatment Outcome
*Peptide Fragments/immunology
*Alzheimer Vaccines/therapeutic use/adverse effects
Middle Aged
Aged, 80 and over

@article {pmid41058017,
year = {2025},
author = {Tong, H and Capuano, AW and Agarwal, P and Mehta, RI and Sood, A and Bennett, DA and Arvanitakis, Z},
title = {Association of dietary sodium intake with late-life cognitive decline and postmortem neuropathology in community-dwelling older adults.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {10},
pages = {e70706},
doi = {10.1002/alz.70706},
pmid = {41058017},
issn = {1552-5279},
support = {P30AG010161/AG/NIA NIH HHS/United States ; P30AG072975/AG/NIA NIH HHS/United States ; R01AG017917/AG/NIA NIH HHS/United States ; RF1AG059621/AG/NIA NIH HHS/United States ; R01AG074549/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; Male ; Female ; *Cognitive Dysfunction/pathology ; Aged, 80 and over ; Independent Living ; *Sodium, Dietary/adverse effects ; Neuropsychological Tests/statistics & numerical data ; Aged ; *Brain/pathology ; Autopsy ; Cross-Sectional Studies ; Neuropathology ; },
abstract = {INTRODUCTION: Studies link sodium intake to cognition, but most were cross-sectional, and associations with neuropathology remain unclear.

METHODS: 1520 community-dwelling adults (mean age 80.7 years) had annual evaluations (mean follow-up 7.6 years), including 19 neuropsychological tests and a food frequency questionnaires (FFQ). Postmortem neuropathologies were documented in 717 deceased participants. Associations of dietary sodium intake estimated from the FFQ with cognitive decline and neuropathology were examined using adjusted regression models.

RESULTS: Compared to the middle sodium intake quintile (median 2264 mg/day), the lowest quintile (1764 mg/day), but not the highest (2800 mg/day), was associated with faster decline in global cognition, particularly episodic memory and semantic memory. Among the deceased, the lowest quintile was associated with higher immunohistochemistry-based tau tangle density, but not with amyloid burden or infarcts.

DISCUSSION: Low dietary sodium intake is associated with faster cognitive decline and more neuropathology, specifically tangles. Dietary sodium likely plays a role in brain health.

HIGHLIGHTS: The relation of dietary sodium to brain health is not well understood. In this community-based study, FFQs were used to estimate dietary sodium intake. Longitudinal neurocognitive and postmortem neuropathology evaluations were conducted. Among 1520 older adults without known dementia followed annually for 7.6 years, low sodium intake was associated with faster decline in global cognition. Among a subset who died and came to autopsy, low sodium intake was associated with higher tangle density, but not with amyloid burden or infarcts.},
}

Humans
Male
Female
*Cognitive Dysfunction/pathology
Aged, 80 and over
Independent Living
*Sodium, Dietary/adverse effects
Neuropsychological Tests/statistics & numerical data
Aged
*Brain/pathology
Autopsy
Cross-Sectional Studies
Neuropathology

@article {pmid41058004,
year = {2025},
author = {Full, KM and Liu, D and Ibarra-Scurr, DC and Wilkins, CH and Burns, JM and Lewandowski, TM and Vidoni, ED and Jefferson, AL},
title = {Development of a web platform to advance data-driven recruitment for ADRD research.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {10},
pages = {e70722},
doi = {10.1002/alz.70722},
pmid = {41058004},
issn = {1552-5279},
support = {R01-AG034962/NH/NIH HHS/United States ; K24-AG04637/NH/NIH HHS/United States ; P20-AG068082/NH/NIH HHS/United States ; R24-AG063724/NH/NIH HHS/United States ; P30-AG072973/NH/NIH HHS/United States ; IIRG-08-88733/ALZ/Alzheimer's Association/United States ; VR4328//Vanderbilt Institute for Clinical & Translational Research Intramural/ ; UL1-TR000445//Vanderbilt Clinical Translational Science/ ; UL1-TR002243//Vanderbilt Clinical Translational Science/ ; K01AG083223/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *Patient Selection ; *Internet ; *Alzheimer Disease ; *Biomedical Research ; *Dementia ; },
abstract = {INTRODUCTION: To meet increasing investments in research on Alzheimer's disease (AD) and related dementias (ADRD), investigators must efficiently recruit diverse and representative participant samples. To address this challenge, the Vanderbilt Alzheimer's Disease Research Center (ADRC) sought to develop an integrated digital research infrastructure with a web-based platform.

METHODS: In Fall 2021, we partnered with collaborators and developed the Participant Information Tracking and Coordinating Hub (PITCH). PITCH was developed with a novel iterative user-centered design, allowing for continuous platform development and enhancement.

RESULTS: With PITCH we evaluate community-based recruitment strategies, monitor participant progression through the study enrollment pipeline, and simultaneously enrich multiple ADRD studies. The PITCH platform has improved ADRC recruitment efficiency and effectiveness in meeting enrollment goals for two ongoing ADRD cohort studies.

DISCUSSION: With PITCH and data-driven recruitment we will centralize all institutional ADRD research recruitment and successfully enroll more representative samples of research participants.

HIGHLIGHTS: Researchers face challenges recruiting diverse samples with limited recruitment budgets. The Vanderbilt ADRC developed a web platform to enhance recruitment and retention. PITCH builds on previous centralized, data-driven research recruitment models. PITCH has expedited recruitment and study timelines and ensured better inclusion of underrepresented groups.},
}

Humans
*Patient Selection
*Internet
*Alzheimer Disease
*Biomedical Research
*Dementia

@article {pmid41057989,
year = {2025},
author = {Chu, C and Ma, L and Wang, Y and Huynh, ALH and Dunstan, MK and Cui, X and Masters, CL and Goudey, B and Jin, L and Pan, Y},
title = {Predicting severity of cerebral amyloid angiopathy neuropathology: A modeling approach using NACC and ROSMAP data.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {10},
pages = {e70057},
doi = {10.1002/alz.70057},
pmid = {41057989},
issn = {1552-5279},
support = {GNT2007912//National Health and Medical Research Council/ ; GNT2022203//National Health and Medical Research Council/ ; 23AARF-1020292/ALZ/Alzheimer's Association/United States ; },
mesh = {Humans ; *Cerebral Amyloid Angiopathy/pathology/diagnostic imaging/diagnosis ; Male ; Female ; Aged ; Severity of Illness Index ; Alzheimer Disease/pathology ; Aged, 80 and over ; Cohort Studies ; },
abstract = {INTRODUCTION: Cerebral amyloid angiopathy (CAA) is associated with an increased risk of amyloid-related imaging abnormalities (ARIA) in patients with Alzheimer's disease using anti-amyloid beta (Aβ) monoclonal antibody drugs. Here, we developed a tool, CAA risk score (CAARS) to predict the severity of CAA neuropathology.

METHODS: The National Alzheimer's Coordinating Center (NACC) data were used to develop the CAARS, which was then externally validated using the Religious Orders Study and Memory and Aging Project (ROSMAP) data.

RESULTS: The CAARS-4 model achieved a mean area under the receiver-operating characteristic (ROC) curve (AUC-ROC) of 0.71 (95% confidence interval [CI]: 0.69-0.72) and a Harrell's generalized C-index of 0.69 (95% CI: 0.68-0.71) in the NACC cohort validation. It outperformed the baseline models, and the promising performance was validated on ROSMAP participants, demonstrating the robustness and generalizability of the model.

DISCUSSION: CAARS has the potential to predict CAA severity; however, its clinical utility should be evaluated in follow-up studies.

HIGHLIGHTS: Cerebral amyloid angiopathy (CAA) severity can only be confirmed postmortem. CAA is associated with an elevated risk of amyloid-related imaging abnormalities (ARIA). The CAA risk score (CAARS) can stratify CAA risks in living patients. Hypertension and apolipoprotein E (APOE) ε4 are risk factors for CAA. The CAARS has the potential to predict risk of ARIA.},
}

Humans
*Cerebral Amyloid Angiopathy/pathology/diagnostic imaging/diagnosis
Male
Female
Aged
Severity of Illness Index
Alzheimer Disease/pathology
Aged, 80 and over
Cohort Studies

@article {pmid41057930,
year = {2025},
author = {Caillierez, R and Leboullenger, C and Leclercq, S and Besegher, M and Bégard, S and Auger, F and Maurage, CA and Accart, B and Mortelecque, J and Dupré, E and Danis, C and Landrieu, I and Buée, L and Colin, M},
title = {Anti-tau VHH therapy against PHF6: a safe approach to slowing the phenotype of tau pathology.},
journal = {Alzheimer's research & therapy},
volume = {17},
number = {1},
pages = {221},
pmid = {41057930},
issn = {1758-9193},
support = {T-PEP-23-969176//Rainwater Charitable Foundation & Alzheimer's Association/ ; T-PEP-23-969176//Rainwater Charitable Foundation & Alzheimer's Association/ ; TAME, GA101119596//Union-HORIZON-MSCA-2022-DN-01/ ; TAME, GA101119596//Union-HORIZON-MSCA-2022-DN-01/ ; LabEx DISTALZ (Development of Innovative Strategies for a Transdisciplinary Approach to Alzheimer's Disease, ANR-11-LABX-01//French National Research Agency/ ; LabEx DISTALZ (Development of Innovative Strategies for a Transdisciplinary Approach to Alzheimer's Disease, ANR-11-LABX-01//French National Research Agency/ ; StartAIRR BONUS DRESS-2020-023479//French regional funding : Région Hauts de France/ ; StartAIRR BONUS DRESS-2020-023479//French regional funding : Région Hauts de France/ ; FR2054 CNRS//IR INFRANALYTICS FR2054/ ; FR2054 CNRS//IR INFRANALYTICS FR2054/ ; },
mesh = {*tau Proteins/immunology/metabolism/antagonists & inhibitors/genetics ; Animals ; Mice ; *Tauopathies/pathology/metabolism/drug therapy ; Humans ; *Single-Domain Antibodies/therapeutic use ; Mice, Transgenic ; Phenotype ; Brain/metabolism/pathology ; Male ; Disease Models, Animal ; Mice, Inbred C57BL ; Female ; Alzheimer Disease/pathology ; },
abstract = {BACKGROUND: Tauopathies share common features, including tau aggregation, which plays a central role in neurodegeneration. However, these disorders are highly heterogeneous, particularly in the spread of pathological tau species between cells. In Alzheimer's disease, intracellular tau aggregation is followed by a propagation between cells leading to a hierarchical pathway of neurodegeneration, whereas in other tauopathies, such as progressive supranuclear palsy (PSP), pathological tau remains largely confined within neurons and exhibits more limited spread. This variability raises the question of whether tailored treatments for each tauopathy might offer more therapeutic benefit. Hence, we designed two different immunological approaches using single domain antibody fragments, also called VHHs, to target intracellular and extracellular tau. This study aims to first evaluate the safety of these immunological tools on physiological tau and then their potential to slow disease progression.

METHODS: We selected the pro-aggregative tau hexapeptide PHF6 as a common target for the VHHs. These VHHs were cloned in viral vectors allowing to compare two different expression systems: 1) intracytosolic expression to prevent tau accumulation (intraVHH) and 2) secretion into the interstitial fluid, to prevent tau spreading (extraVHH). By stereotactic injection of viral vectors, these VHHs were expressed in the brain of transgenic or wild-type mice and three readouts were studied: behavior, brain imaging and tau lesions.

RESULTS: We validated the correct addressing of intra- and extraVHHs. These two constructs were not associated with adverse effects, even in the absence of tau overexpression, in wild-type mice. Their efficacy was demonstrated in transgenic mouse tau models, either chronic long-term or in acute seeding with injections of human brain homogenates from Alzheimer's disease patients. They both can slow down several pathological effects (i.e. cognitive deficits, cerebral atrophy and neuronal hyperphosphorylation of tau).

CONCLUSIONS: This study is a proof of concept demonstrating that VHHs can be engineered to reduce both intra- and extracellular tau pathologies without major adverse effects, making them of interest for therapeutic applications.},
}

*tau Proteins/immunology/metabolism/antagonists & inhibitors/genetics
Animals
Mice
*Tauopathies/pathology/metabolism/drug therapy
Humans
*Single-Domain Antibodies/therapeutic use
Mice, Transgenic
Phenotype
Brain/metabolism/pathology
Male
Disease Models, Animal
Mice, Inbred C57BL
Female
Alzheimer Disease/pathology

@article {pmid41057918,
year = {2025},
author = {Erichsen, JM and Register, TC and Sutphen, C and Ma, D and Gaussoin, SA and Rudolph, M and Rundle, M and Bateman, JT and Lockhart, SN and Sai, KKS and Whitlow, C and Craft, S},
title = {A phase 2A/B randomized trial of metabolic modulators intranasal insulin and empagliflozin for MCI and early AD.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {10},
pages = {e70704},
doi = {10.1002/alz.70704},
pmid = {41057918},
issn = {1552-5279},
support = {P30 AG072947/AG/NIA NIH HHS/United States ; T32 AG033534/AG/NIA NIH HHS/United States ; //Kulynych Center for Memory and Cognition/ ; //Aptar Pharma/ ; //Kulynych Cente for Memory and and Cognition/ ; T32 AG0333534/AG/NIA NIH HHS/United States ; //National Institute of Aging/ ; PTC-22-975243/ALZ/Alzheimer's Association/United States ; },
mesh = {Humans ; *Glucosides/administration & dosage/therapeutic use ; *Cognitive Dysfunction/drug therapy ; *Benzhydryl Compounds/administration & dosage/therapeutic use ; Male ; Administration, Intranasal ; Female ; *Alzheimer Disease/drug therapy ; *Insulin/administration & dosage/therapeutic use ; Aged ; Double-Blind Method ; *Sodium-Glucose Transporter 2 Inhibitors/administration & dosage/therapeutic use ; Biomarkers/cerebrospinal fluid ; Treatment Outcome ; },
abstract = {INTRODUCTION: Agents targeting metabolic/vascular disorders are promising candidates to treat Alzheimer's disease (AD) and enhance safety and efficacy of other therapies.

METHODS: In a 2×2 factorial double-blinded randomized trial, participants with mild cognitive impairment (MCI), early AD, or who were amyloid positive received intranasal insulin (INI; 40 IU q.i.d.), the sodium-glucose cotransporter-2 inhibitor empagliflozin (10 mg q.d. oral tablet), both, or placebo for 4 weeks. The primary outcome was treatment-related adverse events (TRAEs). Secondary outcomes included the modified Preclinical Alzheimer's Cognitive Composite-5 (mPACC5), fluid biomarkers, cerebral blood flow (CBF), and fractional anisotropy (FA).

RESULTS: TRAEs were mild and similar for all groups. INI increased mPACC5, modulated FA and CBF, and reduced plasma glial fibrillary acidic protein. Empagliflozin lowered cerebrospinal fluid tau and modulated CBF. Both agents moderated immune/inflammatory/neurovascular markers.

DISCUSSION: INI and empagliflozin treatment was safe with promising effects on cognition, fluid, and imaging biomarkers. A longer and larger trial is needed to confirm these results.

CLINICAL TRIAL REGISTRATION: NCT05081219 HIGHLIGHTS: Agents targeting metabolic or vascular disorders are promising candidates to prevent or treat Alzheimer's disease (AD). Intranasal insulin and empagliflozin were safe alone or in combination for mild cognitive impairment/AD. Insulin improved cognition and markers of inflammation and immune function. Empagliflozin reduced markers of vascular injury and neurodegeneration. A longer, larger trial is needed to validate these results.},
}

Humans
*Glucosides/administration & dosage/therapeutic use
*Cognitive Dysfunction/drug therapy
*Benzhydryl Compounds/administration & dosage/therapeutic use
Male
Administration, Intranasal
Female
*Alzheimer Disease/drug therapy
*Insulin/administration & dosage/therapeutic use
Aged
Double-Blind Method
*Sodium-Glucose Transporter 2 Inhibitors/administration & dosage/therapeutic use
Biomarkers/cerebrospinal fluid
Treatment Outcome

@article {pmid41057901,
year = {2025},
author = {Garg, P and Lenk, K and Sundaram, SM},
title = {Small molecule-mediated rapid generation of functional human astrocytes: unveiling AKT1-STAT1/3 signaling in astrocyte development.},
journal = {Stem cell research & therapy},
volume = {16},
number = {1},
pages = {542},
pmid = {41057901},
issn = {1757-6512},
support = {iBrain Graduate School, University of Dusseldorf, Germany//iBrain Graduate School, University of Dusseldorf, Germany/ ; academy of finland//academy of finland/ ; Return home grant//International Society for Neurochemistry/ ; },
mesh = {Humans ; *Astrocytes/metabolism/cytology/drug effects ; *Proto-Oncogene Proteins c-akt/metabolism ; *STAT3 Transcription Factor/metabolism ; Signal Transduction/drug effects ; Cell Differentiation/drug effects ; *STAT1 Transcription Factor/metabolism ; Neural Stem Cells/metabolism/cytology/drug effects ; Induced Pluripotent Stem Cells/metabolism/cytology/drug effects ; },
abstract = {Astrocytes are essential for maintaining brain homeostasis, as they support neurons, regulate synaptic activity, and mediate immune responses within the central nervous system (CNS). Their role in the pathophysiology of various neurological disorders, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), and multiple sclerosis, is increasingly recognized. Thus, differentiation of astrocytes from human induced pluripotent stem cells (hiPSCs) acts as an important tool for studying disease mechanisms and advancing therapeutic development strategies. However, the prolonged time of up to six months required to generate fully mature astrocytes limits their utility, with most protocols yielding only fetal-like astrocytes or relying on artificial transcription factor overexpression. To address this challenge, we developed a small-molecule-based method using PD0325901 (PD), which enables the rapid generation of mature human astrocytes from gliogenic neural stem cells (NSCs) within a short time of 2-3 weeks, without the need for genetic modification. We found that inhibition of MEK1/2 signaling in NSCs via PD resulted in decreased proliferation, upregulation of astrocytic markers, and acquisition of functionally mature astrocytes. Mechanistically, this differentiation process involved AKT1-dependent phosphorylation and activation of STAT1/3 that is the classical pathway for astrocyte differentiation, along with the nuclear loss of the astrocytic transcriptional repressor OLIG2. Overall, our findings present a novel approach for accelerating astrocyte maturation using a small molecule and reveal a key role for AKT1-STAT1/3 signaling in astrocyte development. By significantly shortening the time required to generate mature human astrocytes, this rapid astrocyte differentiation protocol enables more efficient modeling of neurodegenerative diseases and drug screening efforts.},
}

Humans
*Astrocytes/metabolism/cytology/drug effects
*Proto-Oncogene Proteins c-akt/metabolism
*STAT3 Transcription Factor/metabolism
Signal Transduction/drug effects
Cell Differentiation/drug effects
*STAT1 Transcription Factor/metabolism
Neural Stem Cells/metabolism/cytology/drug effects
Induced Pluripotent Stem Cells/metabolism/cytology/drug effects

@article {pmid41057428,
year = {2025},
author = {Azmal, M and Paul, JK and Talukder, OF and Been Haque, ASN and Ghosh, A},
title = {Computational identification of phytochemicals as glycogen synthase kinase 3 beta (GSK3β) inhibitors for therapeutic applications in chronic diseases.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {34882},
pmid = {41057428},
issn = {2045-2322},
mesh = {*Glycogen Synthase Kinase 3 beta/antagonists & inhibitors/chemistry/metabolism ; *Phytochemicals/chemistry/pharmacology/therapeutic use ; Molecular Dynamics Simulation ; Humans ; Molecular Docking Simulation ; *Protein Kinase Inhibitors/pharmacology/chemistry ; Chronic Disease/drug therapy ; },
abstract = {Glycogen synthase kinase-3 beta (GSK-3β) is a serine/threonine kinase implicated in various diseases such as Alzheimer's, diabetes, and cancer, making it a pivotal therapeutic target. This study uniquely integrates a curated phytochemical library with comprehensive ADMET filtering and 200 ns molecular dynamics (MD) simulations to identify stable GSK-3β inhibitors, offering deeper mechanistic and dynamic insights than previous docking-based studies. ADMET profiling shortlisted 49 compounds, with uzarigenin, jatrophone, chrysin, and podolide exhibiting superior binding affinities compared to Tideglusib (-8.53 kcal/mol). Among these, jatrophone displayed the highest binding affinity (9.00 kcal/mol), followed by uzarigenin (8.63 kcal/mol) and podolide (8.60 kcal/mol), indicating stronger interactions with GSK-3β. Molecular dynamics simulations confirmed stability for uzarigenin and podolide over 200 nanoseconds, supported by RMSD, SASA, and Rg analyses. Principal component and covariance analyses revealed strong residue interactions in these complexes. KEGG pathway analysis highlighted the role of GSK-3β inhibitors in Alzheimer's disease, Wnt signaling, and cancer pathways. This study identifies phytochemicals with potential therapeutic applications for neurodegenerative, cancer, and metabolic diseases, warranting further experimental validation.},
}

*Glycogen Synthase Kinase 3 beta/antagonists & inhibitors/chemistry/metabolism
*Phytochemicals/chemistry/pharmacology/therapeutic use
Molecular Dynamics Simulation
Humans
Molecular Docking Simulation
*Protein Kinase Inhibitors/pharmacology/chemistry
Chronic Disease/drug therapy

@article {pmid41057304,
year = {2025},
author = {Paladini, MS and Yang, BA and Torkenczy, KA and Frias, ES and Feng, X and Krukowski, K and Sit, R and Morri, M and Lam, W and Pedoia, V and Tyanova, S and Colonna, M and Nolan, AL and Rosi, S},
title = {Fate mapping of peripherally-derived macrophages after traumatic brain injury in mice reveals a long-lasting population with a distinct transcriptomic signature.},
journal = {Nature communications},
volume = {16},
number = {1},
pages = {8898},
pmid = {41057304},
issn = {2041-1723},
mesh = {Animals ; *Brain Injuries, Traumatic/pathology/genetics/metabolism ; *Macrophages/metabolism ; Male ; Mice ; Female ; *Transcriptome ; Microglia/metabolism ; Brain/pathology/metabolism ; Humans ; Disease Models, Animal ; Mice, Inbred C57BL ; Receptors, CCR2/metabolism/genetics ; Mice, Transgenic ; Alzheimer Disease/genetics/pathology ; Phagocytosis ; Gene Expression Profiling ; },
abstract = {Traumatic brain injury (TBI) is an environmental risk factor for dementia and long-term neurological deficits, posing a significant public health challenge. TBI-induced neuroinflammation involves both brain-resident microglia and peripheral monocyte-derived macrophages (MDMs). Previous research has shown that MDMs contribute to the development of long-term memory deficits, yet their long-term behavior following brain infiltration remains unclear. To address this, our study uses two complementary fate-mapping mouse lines, CCR2-creERT2 and Ms4a3-cre, for precise and lasting tracking of MDMs in vivo. Here we show that MDMs persist in the brain for at least 8 months post-TBI in both male and female mice. MDMs retain phagocytic activity for at least 30 days post-TBI, remain transcriptionally distinct from microglia, and display a gene expression profile associated with aging and disease. Moreover, we identify a core transcriptomic signature of MDMs shared across various mouse models and brain perturbations, which is also enriched in the brain myeloid cells of male subjects with TBI and Alzheimer's disease patients. These findings enhance our understanding of MDMs' dynamics after TBI and inform future targeted myeloid-based therapies.},
}

Animals
*Brain Injuries, Traumatic/pathology/genetics/metabolism
*Macrophages/metabolism
Male
Mice
Female
*Transcriptome
Microglia/metabolism
Brain/pathology/metabolism
Humans
Disease Models, Animal
Mice, Inbred C57BL
Receptors, CCR2/metabolism/genetics
Mice, Transgenic
Alzheimer Disease/genetics/pathology
Phagocytosis
Gene Expression Profiling

@article {pmid41057029,
year = {2025},
author = {Salisbury, DL and Lin, V and Derboghossian, G and Yu, F},
title = {A Comparison of Cardiopulmonary Exercise Testing and Shuttle Walk Test in Older Adults With Amnestic Mild Cognitive Impairment.},
journal = {Journal of aging and physical activity},
volume = {},
number = {},
pages = {1-9},
doi = {10.1123/japa.2025-0074},
pmid = {41057029},
issn = {1543-267X},
abstract = {BACKGROUND/OBJECTIVES: Cardiorespiratory fitness (CRF) has been positively associated with brain volumes and health in older adults and negatively associated with dementia and dementia mortality. Cardiopulmonary exercise testing (CPET) is a gold-standard test for evaluating CRF and for exercise prescription but requires specialized equipment and is time- and resource-intensive. More feasible and valid options for evaluation of CRF are needed. The purpose of this study was to evaluate the validity and relationship of shuttle walk test (SWT) distance with peak oxygen consumption (VO2peak) from cycle ergometer-based CPET in persons with amnestic mild cognitive impairment.

METHODS: This study is a cross-sectional analysis of the baseline data (n = 80) who completed both CPET and SWT from the ACT (aerobic exercise and cognitive training) Trial. Data were analyzed with simple and multiple linear regression.

RESULTS: The study sample was 74.1 (5.7) years old, had 45.0% female representation, and scored 23.2 (2.0) on the Montreal Cognitive Assessment. SWT was positively correlated with VO2peak (r = .57, p < .01). When controlling for age, sex, Montreal Cognitive Assessment, and body mass index, SWT distance remained significantly and positively associated with VO2peak, and explained 6% of the variance in VO2peak (Cohen's ƒ2 = 0.06).

CONCLUSION: This is the first study to investigate the relationship of SWT distance and CPET VO2peak in older adults with amnestic mild cognitive impairment and shows that SWT distance significantly predicts VO2peak. Significance/Implications: Preliminary evidence supports the use of the SWT as a valid assessment of CRF in persons with amnestic mild cognitive impairment.},
}

@article {pmid41057026,
year = {2025},
author = {Lee, J and Kim, J and Lee, K},
title = {Longitudinal Estimation of Adequate Physical Activity Levels to Reduce the Risk of Alzheimer's Disease and Other Dementias in Older Adults With Mild Cognitive Impairment.},
journal = {Journal of physical activity & health},
volume = {},
number = {},
pages = {1-8},
doi = {10.1123/jpah.2025-0355},
pmid = {41057026},
issn = {1543-5474},
abstract = {BACKGROUND: Although previous studies have identified a positive relationship between physical activity (PA) participation and cognitive function in older adults, further research is needed to determine the level of PA necessary to significantly reduce the risk of Alzheimer's disease and related dementias (AD/ADRD), particularly among older adults with mild cognitive impairment.

METHODS: This study used Health and Retirement Study data from 2012 to 2020 (n = 9714 Index = 5) and employed the generalized estimating equations to estimate the odds ratios (OR) of AD/ADRD across various PA levels. Covariates such as age, sex, education, and baseline cognitive function in 2012 were included in the regression model.

RESULTS: Individuals with a PA level of 2.80 experienced a 4.6% reduction in the odds of developing AD/ADRD (B = -0.046, OR = 0.954, 95% CI, 0.946-0.964). Similar significant effects were observed at PA levels of 2.60, 2.40, and 2.20, with ORs of 0.962, 0.967, and 0.970, respectively, all within 95% CI. These findings indicate that maintaining a PA level between 2.20 and 2.80 is significantly associated with a reduced risk of AD/ADRD. Lower PA levels such as 2.00 (OR = 0.974, P = .09) and 1.80 (OR = 0.983, P = .06) showed nonsignificant trends toward risk reduction.

CONCLUSION: Engaging in PA (eg, walking, exercise) more than twice per week significantly reduces the risk of AD/ADRD, whereas less frequent activity showed no statistically significant benefit.},
}

@article {pmid41056883,
year = {2025},
author = {Sarkar, B and Rahman, MT and Mahabubur Rahman, M and Hossen, S and Zhenguo, L and Bhuiyan, NH and Shim, JS},
title = {Amplification of electrochemical signal by moving interdigitated electrode array for highly sensitive detection of Alzheimer's disease markers in blood.},
journal = {Biosensors & bioelectronics},
volume = {292},
number = {},
pages = {118063},
doi = {10.1016/j.bios.2025.118063},
pmid = {41056883},
issn = {1873-4235},
abstract = {Electrochemical biosensors are widely utilized in disease diagnosis due to their high sensitivity, low detection limits, and cost-effectiveness. However, conventional electrochemical ELISA (e-ELISA) measurements face several challenges and limitations, including limited analyte volume, reduced sensitivity, signal instability, and surface fouling. To overcome the limitations, we developed a novel vertically moving sensor system integrated with a laser-induced graphene metal interdigitated array (LIG-MIDA) biosensor modified with carbon nanotubes and silver nanoparticles. The amplitude (4 mm) and speed (8 mm/s) of the sensor movement, as well as the electrode nanoparticle composition (2 % MWCNTs and 10 % AgNPs), were optimized to improve signal amplification and reproducibility. The proposed moving sensor was first demonstrated by measuring p-aminophenol (PAP), which exhibited higher signal stability, lower standard deviations, and a wide linear range (1 mM-10 pM) than the conventional static sensor. The proposed moving sensor achieved detection limits of 0.63 pg/mL for Aβ-40 and 0.78 pg/mL for Aβ-42 in buffer, approximately four times lower than that of the static sensors. Moreover, the proposed sensor was further verified by measuring the Aβ-42 biomarker in real plasma, which showed a similar sensitivity to buffer samples. Therefore, the developed system is clinically applicable for detecting Alzheimer's disease in its early stage.},
}

@article {pmid41056473,
year = {2025},
author = {Crump, C and Wei, J and Vickrey, BG and Edwards, AC and Schulz, PE and Sieh, W and Sundquist, J and Sundquist, K},
title = {Risk of major depression in partners of people with Alzheimer's disease: a national cohort study.},
journal = {Age and ageing},
volume = {54},
number = {10},
pages = {},
doi = {10.1093/ageing/afaf283},
pmid = {41056473},
issn = {1468-2834},
mesh = {Humans ; *Alzheimer Disease/psychology/epidemiology/diagnosis ; Female ; *Depressive Disorder, Major/epidemiology/psychology/diagnosis ; Male ; Aged ; Sweden/epidemiology ; Risk Factors ; Incidence ; Aged, 80 and over ; Middle Aged ; Cohort Studies ; Risk Assessment ; *Spouses/psychology ; *Caregivers/psychology ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) may cause significant psychosocial distress not only in the patient but also their partner. However, long-term risks of major depression in partners of AD patients are largely unknown.

METHODS: A national cohort study was conducted of all 145 289 partners of people diagnosed with all-cause dementia, including 57 113 partners of people diagnosed with AD, in Sweden during 1998-2017, and 1 300 561 population-based controls. Cox regression was used to compute hazard ratios (HRs) for subsequent risk of major depression identified from nationwide outpatient and inpatient diagnoses through 2018, adjusting for sociodemographic factors and prior mental disorders.

RESULTS: The 10-year cumulative incidence of major depression was 5.4% in partners of people with AD, 5.6% in partners of people with all-cause dementia, and 3.9% in controls. The adjusted relative rate of major depression was increased ~1.5-fold in partners of people with AD (HR, 1.53; 95% CI, 1.35-1.72) or all-cause dementia (1.45; 1.34-1.57), compared with controls. These risks were elevated among both women (AD: HR, 1.41; 95% CI, 1.22-1.64; all-cause dementia: 1.36; 1.24-1.50) and men (AD: 1.81; 1.46-2.25; all-cause dementia: 1.73; 1.48-2.01). Risks remained significantly elevated ≥3 years later in both women (1.3- to 1.5-fold) and men (1.5-fold). Risks were generally highest in partners aged ≥85 years.

CONCLUSIONS: In this large national cohort, partners of people diagnosed with AD or all-cause dementia had ~1.5-fold risks of major depression, which remained elevated several years later. Partners of people with dementia need psychosocial support and long-term follow-up for timely detection and treatment of depression.},
}

Humans
*Alzheimer Disease/psychology/epidemiology/diagnosis
Female
*Depressive Disorder, Major/epidemiology/psychology/diagnosis
Male
Aged
Sweden/epidemiology
Risk Factors
Incidence
Aged, 80 and over
Middle Aged
Cohort Studies
Risk Assessment
*Spouses/psychology
*Caregivers/psychology

@article {pmid41056420,
year = {2025},
author = {Kaskie, B and Bobitt, J and Shah, Y and Khasawinah, S},
title = {Placing Public Health onto the Alzheimer's Disease and Related Dementias Public Policy Platform.},
journal = {The Gerontologist},
volume = {},
number = {},
pages = {},
doi = {10.1093/geront/gnaf224},
pmid = {41056420},
issn = {1758-5341},
abstract = {In 2017, the United States Senate Special Committee on Aging added public health to the Alzheimer's disease and related dementias (ADRD) policy platform by introducing the Building Our Largest Dementia Infrastructure for Alzheimer's Act. Since then, 34 state health departments, seven local, two territorial and one tribal health organization have received a BOLD Program award from the CDC. With the support of the Alzheimer's Association and university-based Centers of Excellence, their efforts have increased public awareness, expanded training of health care providers, linked public health programs and health care systems, and supported programs to reduce the risk for ADRD. In this forum, we draw on examples of federal and state policy making targeting persons living with dementia and demonstrate how iron triangles consisting of advocacy organizations, public servants and policy makers have been critical in building a public policy platform for more than 50 years. We then consider how public health leadership may rely on such iron triangles to expand their role, focusing on the critical role assumed by professional and academic organizations in educating and training those who may help respond to the public health crisis being presented by the booming number of older Americans with ADRD.},
}

@article {pmid41056408,
year = {2025},
author = {Fadel, M and Shean, J and Jackson, E and Harris, JD and Rodríguez, J and Roberts, S},
title = {The Healthy Brain Initiative-Expanding Public Health Capacity to Address Dementia.},
journal = {The Gerontologist},
volume = {},
number = {},
pages = {},
doi = {10.1093/geront/gnaf220},
pmid = {41056408},
issn = {1758-5341},
abstract = {In 2005, Congressional support led to the creation of the Healthy Brain Initiative (HBI) and the collaboration between the Alzheimer's Association and the Centers for Disease Control and Prevention to prioritize brain health in public health practice. Over 20 years, the HBI has developed and implemented the HBI Road Map Series to increase the capacity of health departments to integrate dementia into health departments nationwide, aligning frameworks like the Essential Public Health Services and focusing on health equity across the life course. A growing number of HBI partners now work together to implement public health strategies that promote brain health, address dementia, and support people living with dementia and caregivers. Recognizing opportunities to influence the trajectory of public health action, the HBI prioritizes growing the availability and use of dementia-related public health data and equipping the public health workforce with the knowledge and confidence to make change. This article documents the history and evolution of the HBI, including a description of current efforts and the broader public health context to which it has contributed; efforts of the HBI and partners in national, state, local, territorial, and tribal public health agencies have led to transformative change.},
}

@article {pmid41056389,
year = {2025},
author = {Sharma, M and Deshmukh, S and Thakre, T and Waskar, R and Pardhekar, A},
title = {Ayurvedic Management of Alzheimer's Disease: A Clinical Case Study.},
journal = {Alternative therapies in health and medicine},
volume = {},
number = {},
pages = {},
pmid = {41056389},
issn = {1078-6791},
abstract = {ABSTRACT: Alzheimer's disease is a progressive neurodegenerative disorder that primarily affects memory, cognition, and behavior, often leading to severe functional decline. A 55-year-old male patient came with complaints of confusion in daily activities, forgetting names, misplacing objects, frequent episodes of crying, and loss of communication skills for the past 1 year. He was clinically diagnosed with Alzheimer's Disease. The patient was treated with an Ayurvedic treatment protocol, involving internal administration of Brahmi ghrit, Saraswatarishta with gold, Ashwagandha powder, and Rasona Ksheerpaka, along with Panchakarma therapies including Nasya with Panchendriya taila, Shirobasti, and Abhyanga with Balashwagandha taila. After the treatment, the patient showed marked improvements in memory retention, orientation, and mood stability. This case showed that Ayurvedic interventions aid in slowing cognitive decline and improving daily functioning in Alzheimer's patients, highlighting the need for integrative and individualized treatment approaches in neurodegenerative disorders.

KEYWORDS: neurodegeneration, Alzheimer's disease, Dementia, Ayurvedic medicines, Brahmi ghrit, case report.},
}

@article {pmid41055945,
year = {2025},
author = {Caravaglios, G and Muscoso, EG and Blandino, V and Graziano, F and Guajana, F and Di Maria, G and Vestini, MA and Piccoli, T},
title = {Comparative Analysis of Intracortical Causal Information Flow in Healthy Older Adults and Patients With Amnestic Mild Cognitive Impairment.},
journal = {Clinical EEG and neuroscience},
volume = {},
number = {},
pages = {15500594251385006},
doi = {10.1177/15500594251385006},
pmid = {41055945},
issn = {2169-5202},
abstract = {BackgroundAlzheimer's disease is a neurodegenerative condition characterized by the accumulation of misfolded proteins disrupting connectivity between brain regions. Electroencephalography provides optimal temporal resolution for assessing neuronal communication.ObjectiveTo detect and compare the localization of brain rhythms and the directional flow of oscillatory activity among default mode network nodes during the resting state in patients with amnestic mild cognitive impairment (aMCI) and healthy older adults (HOA).MethodsWe recruited 94 aMCI patients and 66 HOA. We conducted functional localization and connectivity analyses using scalp recordings of neuronal activity, estimated by eLORETA approach. We calculated the effective connectivity by applying the isolated effective coherence method, allowing the frequency decomposition of the directional flow of oscillatory activity between pairs of brain regions. Eight brain regions from the default mode network were selected.ResultsAlthough trends in spectral power were noted, no statistically significant differences were found between groups. Concerning iCOH analysis, both groups showed increased information flow from the posterior to the anterior nodes. Specifically, the precuneus was dominant in transmitting information to the anterior nodes of the DMN. Furthermore, aMCI patients had lower effective connectivity values than HOA.ConclusionsiCOH analysis effectively profiles default mode nodes during the resting state, adding information on both localization and directionality of information flow, as well as the involved EEG oscillations. Furthermore, it is well-suited to detect between-group connectivity differences, suggesting its usefulness as a biomarker in the prodromal clinical stage of AD.},
}

@article {pmid41055934,
year = {2025},
author = {Yu, J and Yu, Y and Li, M and Liu, Z and Yang, F},
title = {Development and validation of a predictive nomogram for mild cognitive impairment in middle-aged and elderly populations: A multi-module analysis integrating air quality and sociodemographic factors.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251378520},
doi = {10.1177/13872877251378520},
pmid = {41055934},
issn = {1875-8908},
abstract = {BackgroundGrowing evidence links air pollution to mild cognitive impairment (MCI), yet existing models often overlook environmental exposures. We developed a novel MCI nomogram integrating air pollution, sociodemographic, and clinical predictors for Chinese adults ≥ 45 years.ObjectiveTo develop and validate a personalized MCI risk assessment tool incorporating sociodemographic, clinical, and environmental factors.MethodsUsing the 2015 CHARLS cohort (n = 7702), we built two MCI prediction models with city- and county-level air pollution exposures. Model performance was assessed via discrimination (C-index, ROC), calibration, clinical utility (decision curves), predictive performance (net reclassification improvement, NRI and integrated discrimination improvement, IDI).ResultsThis study analyzed 7702 participants, randomly split into training (n = 5391) and validation (n = 2311) groups. Uni-variate analysis identified MCI risk in age ≥75 years, private medical insurance, married individuals and males. Multivariate analysis in Model 2 identified 13 key factors associated with MCI, among them age ≥75 years (OR = 5.437, 95%CI: 3.524-8.388, p < 0.001), private medical insurance (OR = 4.994, 95%CI: 2.340-11.337, p = 0.002), being mental disorders (OR = 2.210, 95%CI: 1.217-4.014, p < 0.001), males (OR = 0.638, 95%CI: 0.493-0.824, p = 0.04), PM10 (OR = 1.059, 95%CI: 1.051-1.067, p < 0.001) and PM2.5 (OR = 1.025, 95%CI: 1.013 -1.038, p < 0.001) as strongest predictors. Model 2 outperformed Model 1 with higher discrimination, better calibration, greater clinical utility and improved accuracy.ConclusionsThe validated nomogram enables individualized MCI risk stratification, supporting targeted community prevention strategies.},
}

@article {pmid41055851,
year = {2025},
author = {Gautam, AS and Akhtar, MZ and Uttamrao, LV and Kumari, N and Pandey, SK and Dey, M and Singh, RK},
title = {Intranasal Aβ1-42 Exposure Led To Neurobehavioral Alteration, Neuroinflammatory and Neurodegenerative Molecular Biomarkers in Mice Brain.},
journal = {Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology},
volume = {20},
number = {1},
pages = {83},
pmid = {41055851},
issn = {1557-1904},
mesh = {Animals ; *Amyloid beta-Peptides/administration & dosage/toxicity ; Mice ; *Peptide Fragments/administration & dosage/toxicity/metabolism ; Administration, Intranasal ; Biomarkers/metabolism ; *Brain/metabolism/drug effects/pathology ; Male ; *Neuroinflammatory Diseases/chemically induced/metabolism/pathology ; *Alzheimer Disease/metabolism/chemically induced/pathology ; *Behavior, Animal/drug effects ; Disease Models, Animal ; Oxidative Stress/drug effects ; tau Proteins/metabolism ; },
abstract = {In this study, we aimed to evaluate the AD structural hallmarks along with brain biomarkers and neurobehavioral alterations in a repeated intranasal Aβ1-42 exposure mouse model. This model is a simple, non-invasive, and less stressful method and may allow direct access of Aβ to the brain. The results of this study showed a dose-dependent increase in the level of Aβ1-42 deposition, tau phosphorylation, neuroinflammatory and oxidative stress biomarkers in brain tissue, along with learning and memory deficits in mice. This model may be suitable for evaluating the biochemical, structural, functional histological alterations, along with the neurobehavioral deficits mimicking AD.},
}

Animals
*Amyloid beta-Peptides/administration & dosage/toxicity
Mice
*Peptide Fragments/administration & dosage/toxicity/metabolism
Administration, Intranasal
Biomarkers/metabolism
*Brain/metabolism/drug effects/pathology
Male
*Neuroinflammatory Diseases/chemically induced/metabolism/pathology
*Alzheimer Disease/metabolism/chemically induced/pathology
*Behavior, Animal/drug effects
Disease Models, Animal
Oxidative Stress/drug effects
tau Proteins/metabolism

@article {pmid39605467,
year = {2025},
author = {Singh, V and Rochakim, N and Ferraresso, F and Garg, K and Choudhury, A and Kastrup, CJ and Ahn, HJ},
title = {Aquaporin-4 and Caveolin-1 as Mediators of Fibrinogen-Driven Cerebrovascular Pathology in Cerebral Amyloid Angiopathy.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2024.11.11.623066},
pmid = {39605467},
issn = {2692-8205},
support = {R01 NS104386/NS/NINDS NIH HHS/United States ; RF1 AG078245/AG/NIA NIH HHS/United States ; },
abstract = {UNLABELLED: Cerebral Amyloid Angiopathy (CAA), characterized by amyloid-β (Aβ) accumulation within perivascular spaces (PVS), contributes to vascular damage and inflammation in Alzheimer's disease (AD). Despite its significance, the mechanisms driving Aβ deposition in PVS and the resulting vascular pathology remain poorly understood. Growing evidence suggests that fibrinogen, the main component in blood clots, interacts with Aβ and exacerbates inflammation in AD. Fibrinogen also co-deposits with Aβ in the PVS of CAA-positive vessels in the brains of hereditary CAA patients. However, the mechanisms by which fibrinogen contributes to cerebrovascular impairment remain poorly understood. To investigate this, we used TgSwDI transgenic mice, which develop robust CAA pathology, and observed a significant increase in fibrin(ogen) extravasation and colocalization with Aβ in the PVS. Moreover, we observed a significant aquaporin-4 (AQP4) depolarization in CAA-laden blood vessels of TgSwDI mice, which correlated with fibrin(ogen)-Aβ colocalization. Given AQP4 crucial role in Aβ clearance through glymphatic pathway, its depolarization may disrupt critical Aβ clearance, thereby exacerbating CAA pathology. Additionally, Caveolin-1, a protein involved in non-specific transcytosis across the endothelium, significantly increased with age in TgSwDI mice and correlated with fibrin(ogen) extravasation. To further explore the relationship between fibrin(ogen) and these cerebrovascular alterations, we depleted fibrinogen in TgSwDI mice using siRNA approach. This intervention resulted in decreased CAA, restored polarized expression of AQP4, reduced caveolin-1 levels, attenuated microglial activation, and improved spatial memory in fibrinogen-depleted TgSwDI mice. These findings suggest that targeting fibrinogen could be a promising strategy for mitigating CAA pathology and its associated cerebrovascular pathology.

SIGNIFICANCE STATEMENT: Our study uncovers the mechanism by which fibrin(ogen)-Aβ colocalization exacerbates CAA pathology. Our findings highlight the potential link between fibrinogen/ fibrin(ogen)-Aβ colocalization and AQP4 depolarization thereby exacerbating CAA pathology. The age-dependent increase of endothelial caveolin-1 could facilitate fibrin(ogen) extravasation, assisting the later to binds to Aβ in the perivascular space which ultimately induce microglial neuroinflammation and AQP4 depolarization, thus exacerbating CAA pathology. Furthermore, fibrinogen depletion could mitigate CAA severity, reduce microglial activation, restore AQP4 polarization and memory impairment. These results suggest that targeting fibrinogen and caveolin-1-mediated transcytosis may offer new strategies to address CAA-associated cerebrovascular pathology.},
}

@article {pmid41058864,
year = {2024},
author = {Sohn, B and Chung, SJ and Lee, JR and Hwang, D and Xie, W and Chan, LL and Choi, YS and , and , and , },
title = {[18]F-FDG-PET-based deep learning for predicting cognitive decline in non-demented elderly across the Alzheimer's disease clinical spectrum.},
journal = {Radiology advances},
volume = {1},
number = {3},
pages = {umae021},
pmid = {41058864},
issn = {2976-9337},
abstract = {BACKGROUND: With disease-modifying treatments for Alzheimer's disease (AD), prognostic tools for the pre-dementia stage are needed. This study aimed to evaluate the prognostic value of an [18]F-fluorodeoxyglucose-positron emission tomography ([18]F-FDG-PET)-based deep-learning (DL) model in the pre-dementia stage of mild cognitive impairment (MCI) and normal cognition (NC).

MATERIALS AND METHODS: A [18]F-FDG-PET-based DL model was developed to classify diagnosis of AD-dementia vs NC using AD Neuroimaging Initiative (ADNI) and Japanese-ADNI (J-ADNI) datasets (n = 756), which provided the degree of similarity to AD-dementia. The prognostic value of the DL output for cognitive decline was assessed in the ADNI MCI (n = 663), J-ADNI MCI (n = 129), and Harvard Aging Brain Study (HABS) NC (n = 274) participants using Cox regression and calculating the integrated area under the time-dependent ROC curves (iAUC), along with clinical information and [18]F-FDG-PET standardized uptake value ratio (SUVR). Subgroup analysis in the amyloid-positive ADNI MCI participants was performed using Cox regression and calculating the area under the time-dependent ROC (tdAUC) curves at 4-year follow-up to assess prognostic value of DL output over clinical information, [18]F-FDG-PET SUVR, and amyloid PET Centiloids.

RESULTS: DL output remained independently prognostic among other factors in all three datasets (P < .05 for all by Cox regression). By adding DL output to other prognostic factors, prediction significantly improved in ADNI-MCI (iAUC differences 0.020 [0.007-0.034] before and after adding DL output) and improved without statistical significance in J-ADNI (0.020 [-0.005 to 0.044], and HABS-NC sets (0.059 [-0.003 to 0.126]). DL output showed independent (P = .002 by Cox regression) and significant added prognostic value (tdROC difference 0.019 [<0.001-0.036]) over clinical information, [18]F-FDG-PET SUVR, and Centiloids in the amyloid-positive ADNI MCI participants.

CONCLUSION: The [18]F-FDG-PET-based DL model demonstrated the potential to improve cognitive decline prediction beyond clinical information, and conventional measures from [18]F-FDG-PET and amyloid PET and may prove useful for clinical trial recruitment and individualized management.},
}

@article {pmid41059393,
year = {2024},
author = {Choi, YS and Ngam, PI and Lee, JR and Hwang, D and Tan, EK and , and , and , and , },
title = {Deep learning-based amyloid PET harmonization to predict cognitive decline in non-demented elderly.},
journal = {Radiology advances},
volume = {1},
number = {2},
pages = {umae019},
pmid = {41059393},
issn = {2976-9337},
abstract = {BACKGROUND: The robustness of conventional amyloid PET harmonization across tracers has been questioned.

PURPOSE: To evaluate deep learning-based harmonization of amyloid PET in predicting conversion from cognitively unimpaired (CU) to mild cognitive impairment (MCI) and MCI to Alzheimer's disease (AD).

MATERIALS AND METHODS: We developed an amyloid PET-based deep-learning model to classify participants with a clinical diagnosis of AD-dementia vs CU across different tracers from the Alzheimer's Disease Neuroimaging Initiative (ADNI), Japanese ADNI, and Australian Imaging, Biomarker, and Lifestyle cohorts (n = 1050). The model output [deep learning-based probability of Alzheimer's disease-dementia (DL-ADprob)], with other prognostic factors, was evaluated for predicting cognitive decline in ADNI-MCI (n = 451) and Harvard Aging Brain Study (HABS)-CU (n = 271) participants using Cox regression and area under time-dependent receiver operating characteristics curve (tdAUC) at 4-year follow-up. Subgroup analyses were performed in the ADNI-MCI group for conversion from amyloid-positive to AD and from amyloid negative to positive. Intraclass correlation coefficient (ICC) of DL-ADprob between tracers was calculated in the Global Alzheimer's Association Interactive Network dataset (n = 155).

RESULTS: DL-ADprob was independently prognostic in both ADNI-MCI (P < .001) and HABS-CU (P = .048) sets. Adding DL-ADprob to other factors increased prognostic performances in both ADNI-MCI (tdAUC 0.758 [0.721-0.792] vs 0.782 [0.742-0.818], tdAUC difference 0.023 [0.007-0.038]) and HABS-CU (tdAUC 0.846 [0.755-0.925] vs 0.870 [0.773-0.943], tdAUC difference 0.022 [-0.004 to 0.053]). DL-ADprob was independently prognostic in amyloid-positive (P < .001) and amyloid-negative subgroups (P = .007). DL-ADprob showed incremental prognostic value in amyloid-positive (tdAUC 0.666 [0.623-0.713] vs 0.706 [0.657-0.755], tdAUC difference 0.039 [0.016-0.064]), but not in amyloid-negative (tdAUC 0.818 [0.757-0.882] vs 0.816 [0.751-0.880], tdAUC difference -0.002 [-0.031 to 0.029]) subgroup. The pairwise ICCs of DL-ADprob between Pittsburgh compound B and florbetapir, florbetaben, and flutemetamol, respectively, ranged from 0.913 to 0.935.

CONCLUSION: Deep learning-based harmonization of amyloid PET improves cognitive decline prediction in non-demented elderly, suggesting it could complement conventional amyloid PET measures.},
}

@article {pmid38014269,
year = {2025},
author = {Kapadia, M and Betjemann, AM and Cottam, MA and Mashayekhi, M and Silver, HJ and Hasty, AH and Caslin, HL},
title = {Single cell RNA-sequencing suggests a novel lipid-associated mast cell population following weight cycling.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2023.11.12.566786},
pmid = {38014269},
issn = {2692-8205},
abstract = {We previously demonstrated that weight cycled mice have increased adipose mast cells compared to obese mice by single cell RNA-sequencing. Here, we aimed to confirm and elucidate these changes. Interestingly, we did not detect an increase in total mast cell numbers in weight cycled mice by Toluidine blue or flow cytometry, however, further subcluster analysis of our dataset showed that our initial mast cell cluster consisted of two unique populations. One population had very high expression of classical mast cell markers and another had elevated lipid handling and antigen presentation genes with a concomitant reduction in classical mast cell genes. This new "lipid-associated" mast cell cluster accounted for most of the mast cells in the weight cycled group. We induced a similar phenotype in vitro using repeated exposure to adipose tissue conditioned media to mimic weight gain and weight regain. Upon repeated exposure to adipose tissue conditioned media, bone marrow-derived mast cells had increased lipid droplets and reduced expression of cKit and FcεR1 compared to control cells. Moreover, we analyzed mast cells in a pilot study of subcutaneous adipose tissue from four obese, prediabetic women. We found two mast cell populations that appear similar to the murine populations detected by sequencing. The population with reduced cKit and FcεR1 was significantly correlated with weight variance. Together, these data suggest that weight cycling may induce a unique population of mast cells similar to lipid-associated macrophages, which have been shown to play a role in diverse diseases from obesity and atherosclerosis to Alzheimer's disease. Future studies will focus on isolation of these cells from mice and humans to better determine their lineage, differentiation, and functional roles.},
}

@article {pmid41059414,
year = {2023},
author = {Flatt, JD and Cicero, EC},
title = {Advancing equity in Alzheimer's disease and mental health research for LGBTQIA+ older adults.},
journal = {Nature. Mental health},
volume = {1},
number = {6},
pages = {385-387},
pmid = {41059414},
issn = {2731-6076},
abstract = {LGBTQIA+ older adults are under-represented in Alzheimer's disease and mental health research. Here we highlight the current research evidence, social and policy influences, and ways healthcare and research professionals can improve equity in research and healthcare.},
}

@article {pmid41055498,
year = {2025},
author = {Schoonheim, MM},
title = {Juxtacortical White Matter Staging as a Correlate of Progression in Alzheimer Disease.},
journal = {Radiology},
volume = {317},
number = {1},
pages = {e252559},
doi = {10.1148/radiol.252559},
pmid = {41055498},
issn = {1527-1315},
}

@article {pmid41055495,
year = {2025},
author = {Zhang, J and Yang, X and Wang, Y and Xu, X and Zheng, Y and Huang, Q and Wang, W and Xu, W and Guan, Y and Liu, J and Deng, Y and Xie, F and Li, B},
title = {Identifying Distinct Spatiotemporal Patterns of Juxtacortical Microstructure in Alzheimer Disease Using Diffusion MRI-derived Free Water Fraction.},
journal = {Radiology},
volume = {317},
number = {1},
pages = {e243423},
doi = {10.1148/radiol.243423},
pmid = {41055495},
issn = {1527-1315},
mesh = {Humans ; Aged ; Female ; *Alzheimer Disease/diagnostic imaging/pathology/metabolism ; Male ; Aged, 80 and over ; Prospective Studies ; Middle Aged ; *Diffusion Magnetic Resonance Imaging/methods ; Positron-Emission Tomography/methods ; Adult ; *Brain/diagnostic imaging/pathology ; Amyloid beta-Peptides/metabolism ; Water ; Cognitive Dysfunction/diagnostic imaging ; },
abstract = {Background The free water fraction (FWF) is a potential imaging marker in Alzheimer disease (AD). Purpose To evaluate juxtacortical FWF, its association with neuropathologic severity, and its spatiotemporal pattern using MRI and PET in participants with AD or normal cognition. Materials and Methods This secondary analysis of a prospective study was conducted from November 2021 to July 2024, including diffusion MRI to assess FWF, fluorine 18 ([18]F) florbetapir PET to assess amyloid-β (Aβ), and [18]F-MK-6240 PET to assess tau accumulation. Two independent subtype and stage inference (SuStaIn) models analyzed only juxtacortical FWF change or integrated FWF and Aβ. Results A total of 359 participants (mean age, 69 years ± 8 [SD]; age range, 40-86 years; 223 female) were included (161 with normal cognition, 85 with mild cognitive impairment due to AD, and 113 with dementia due to AD). Compared with controls, participants with AD had increased FWF (false discovery rate [FDR]-corrected P < .001 to P = .049), which was associated with higher global cortical Aβ and tau deposition (P < .001 to P = .04 for Aβ; P < .001 to P = .01 for tau; all FDR-corrected). The first SuStaIn model identified two distinct spatiotemporal trajectories of FWF: The orbitofrontal-first subtype had smaller left and right hippocampus volumes (left, b = -0.1 and P = .007; right, b = -0.08 and P = .03) and worse cognitive performance (verbal fluency test, b = -0.21 and P = .01; shape-trail test part A, b = 0.16 and P < .001) compared with the precuneus-first subtype. The second SuStaIn model integrating FWF and Aβ identified two subtypes: The amyloid-first subtype had higher levels of amyloid deposition in the cortex (b = -0.3 and P < .001), whereas the FWF-first subtype had lower left cortical thickness (b = -0.05 and P = .01) and worse cognitive performance (verbal fluency test, b = -0.17 and P = .02; shape-trail test part A, b = 0.20 and P < .001). Conclusion Juxtacortical FWF was higher in participants with AD compared with cognitively normal controls and associated with Aβ, tau, and neurodegeneration biomarkers. Distinct spatiotemporal progression patterns of FWF had distinct cognitive performance profiles. Clinical trial registration no. NCT05623124 © RSNA, 2025 Supplemental material is available for this article. See also the editorial by Schoonheim in this issue.},
}

Humans
Aged
Female
*Alzheimer Disease/diagnostic imaging/pathology/metabolism
Male
Aged, 80 and over
Prospective Studies
Middle Aged
*Diffusion Magnetic Resonance Imaging/methods
Positron-Emission Tomography/methods
Adult
*Brain/diagnostic imaging/pathology
Amyloid beta-Peptides/metabolism
Water
Cognitive Dysfunction/diagnostic imaging

@article {pmid41055405,
year = {2025},
author = {Shan, C and Cong, R and Xu, X and Li, Y and Tian, Y and Cao, W and Zhao, W and Miao, L and Teng, J and Huang, N and Chen, J},
title = {APP ubiquitination by VHL protein is essential for MVB sorting and lysosomal degradation.},
journal = {Journal of molecular cell biology},
volume = {},
number = {},
pages = {},
doi = {10.1093/jmcb/mjaf033},
pmid = {41055405},
issn = {1759-4685},
abstract = {Amyloid precursor protein (APP), a type I transmembrane protein, is closely related to the pathogenesis of Alzheimer's disease (AD). Amyloid beta (Aβ) is generated by sequential processing of APP in the Golgi apparatus and endosomes, and its toxicity leads to neuron dysfunction and neurodegeneration. APP is selectively shuttled between intracellular membrane compartments and ultimately transported into lysosomes. However, the mechanisms underlying APP sorting signals and lysosomal degradation are largely unclear. In this study, we show that the von Hippel‒Lindau protein (VHL), a subunit of an E3 ligase, recognizes the cytoplasmic domain of APP and mediates its ubiquitination. VHL-mediated ubiquitination facilitates the sorting of membrane APP into intraluminal vesicles of multivesicular bodies (MVBs) and subsequent degradation in lysosomes. Therefore, the loss of VHL accelerates Aβ plaque deposition and memory deficits in AD model mice. Our findings reveal the role of VHL in restricting AD pathogenesis through ubiquitination-dependent MVB sorting and lysosomal degradation of APP.},
}

@article {pmid41055317,
year = {2025},
author = {Li, J and Sun, W and Wang, X and Ding, F and Li, L and Lin, X and Zhao, Y},
title = {Astaxanthin Suppresses Amyloid-Beta-Induced Toxicity in AD Transgenic Caenorhabditis elegans via Promoting Skn-1-Dependent Proteasomal Activity.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.5c00130},
pmid = {41055317},
issn = {1948-7193},
abstract = {Astaxanthin is a ketocarotenoid that exhibits a variety of bioactivities, including neuroprotection, but the detailed mechanisms by which astaxanthin exerts neuroprotection remain unclear. In the present study, the effects of astaxanthin on amyloid-beta (Abeta)-induced toxicity were investigated in a Caenorhabditis elegans (C. elegans) model of Alzheimer's disease (AD). It is demonstrated that astaxanthin treatment significantly alleviated the Abeta-induced paralytic phenotype in AD C. elegans while reducing the production of reactive oxygen species and restoring the level of glutathione. Further analyses revealed that astaxanthin treatment resulted in a decrease in Abeta accumulation in AD C. elegans. Moreover, astaxanthin restored the proteasomal activity in AD C. elegans by elevating the expression of genes encoding the central subunits of the 20S proteasome. Therefore, astaxanthin might reduce Abeta accumulation via promoting proteasomal function. In addition, astaxanthin treatment increased the expression of skinhead-1 (skn-1), while knockdown of skn-1 expression by RNA interference diminished the inhibition of astaxanthin on Abeta-induced toxicity in AD C. elegans. The elevation of the expression of proteasome subunit genes and the enhancement of proteasomal activity by astaxanthin were also dependent on SKN-1. Overall, these findings indicated that astaxanthin exerted its protection against Abeta-induced toxicity in AD C. elegans via maintaining redox balance and promoting SKN-1-mediated proteasomal activity.},
}

@article {pmid41055255,
year = {2025},
author = {Li, Y and Xie, L and Khandelwal, P and Wisse, LEM and Brown, CA and Prabhakaran, K and Tisdall, MD and Mechanic-Hamilton, D and Detre, JA and Das, SR and Wolk, DA and Yushkevich, PA},
title = {Automatic Segmentation of Medial Temporal Lobe Subregions in Multi-Scanner, Multi-Modality Magnetic Resonance Imaging of Variable Quality.},
journal = {Hippocampus},
volume = {35},
number = {6},
pages = {e70036},
doi = {10.1002/hipo.70036},
pmid = {41055255},
issn = {1098-1063},
support = {R01-AG069474/NH/NIH HHS/United States ; RF1-AG056014/NH/NIH HHS/United States ; P30-AG072979/NH/NIH HHS/United States ; R01-AG070592/NH/NIH HHS/United States ; },
mesh = {Humans ; *Temporal Lobe/diagnostic imaging ; *Magnetic Resonance Imaging/methods ; Male ; Female ; Aged ; Aged, 80 and over ; Longitudinal Studies ; *Image Processing, Computer-Assisted/methods ; *Multimodal Imaging/methods ; Middle Aged ; Alzheimer Disease/diagnostic imaging ; },
abstract = {Volumetry of subregions in the medial temporal lobe (MTL) computed from automatic segmentation in MRI can track neurodegeneration in Alzheimer's disease. However, poor quality MR images can lead to unreliable segmentation of MTL subregions. Considering that different MRI contrast mechanisms and field strengths (jointly referred to as "modalities" here) offer distinct advantages in imaging different parts of the MTL, we developed a multi-modality segmentation model using both 7T and 3T structural MRI to obtain robust segmentation in poor-quality images. MRI modalities including 3T T1-weighted, 3T T2-weighted, 7T T1-weighted and 7T T2-weighted (7T-T2w) of 197 participants were collected from a longitudinal aging study at the Penn Alzheimer's Disease Research Center. Among them, 7T-T2w was used as the primary modality, and all other modalities were rigidly registered to the 7T-T2w. A model derived from nnU-Net took these registered modalities as input and outputted subregion segmentation in 7T-T2w space. 7T-T2w images most of which had high quality from 25 selected training participants were manually segmented to train the multi-modality model. Modality augmentation, which randomly replaced certain modalities with Gaussian noise, was applied during training to guide the model to extract information from all modalities. The multi-modality model delivered good performance regardless of 7T-T2w quality, while the single-modality model under-segmented subregions in poor-quality images. The multi-modality model generally demonstrated stronger discrimination of A + MCI versus A-CU. Intra-class correlation and Bland-Altman plots demonstrate that the multi-modality model had higher longitudinal segmentation consistency in all subregions while the single-modality model had low consistency in poor-quality images. The multi-modality MRI segmentation model provides an improved biomarker for neurodegeneration in the MTL that is robust to image quality. It also provides a framework for other studies which may benefit from multimodal imaging.},
}

Humans
*Temporal Lobe/diagnostic imaging
*Magnetic Resonance Imaging/methods
Male
Female
Aged
Aged, 80 and over
Longitudinal Studies
*Image Processing, Computer-Assisted/methods
*Multimodal Imaging/methods
Middle Aged
Alzheimer Disease/diagnostic imaging

@article {pmid41055091,
year = {2025},
author = {Beiglary, S and Feng, Y and Wang, N and Ghaeili, N and Jao, YL and Liao, YJ and Li, Y and Wang, J},
title = {Using Wearable Sensors to Measure and Predict Personal Circadian Lighting Exposure in Nursing Home Residents: Model Development and Validation.},
journal = {JMIR aging},
volume = {8},
number = {},
pages = {e72338},
doi = {10.2196/72338},
pmid = {41055091},
issn = {2561-7605},
mesh = {*Nursing Homes ; Humans ; *Lighting ; *Wearable Electronic Devices ; *Circadian Rhythm/physiology ; Aged ; Male ; Female ; Aged, 80 and over ; Machine Learning ; Calibration ; Dementia ; },
abstract = {BACKGROUND: Lighting, especially circadian lighting, significantly affects people with dementia, influencing sleep patterns, daytime alertness, and behavioral symptoms such as agitation. Since individuals experience and respond to light differently, measuring personal lighting exposure is essential for understanding its impact on health. Without individual data, the connection between lighting and health outcomes remains unclear. Wearable sensors provide a practical way to track personal light exposure, helping researchers better assess its effects on circadian rhythms and overall well-being.

OBJECTIVE: This study aims to develop and validate both calibration and predictive models using wearable lighting sensors to assess individual circadian lighting exposure accurately. By leveraging machine learning techniques and empirical data, we seek to establish a reliable method for health care researchers and practitioners to investigate and optimize lighting conditions for improved circadian health in nursing homes, especially for residents with dementia.

METHODS: A combination of controlled laboratory experiments and on-site data collection was conducted using professional spectrophotometer measurements as ground truth. Calibration models were developed for photopic lux and correlated color temperature, while predictive models estimated circadian metrics such as circadian stimulus. The sensors and the developed models were implemented in a real-world health care research project about bright light therapy intervention at 2 assisted-living facilities.

RESULTS: The calibration models for photopic lux and correlated color temperature demonstrated strong accuracy, with an adjusted R² of 0.858 and 0.982, respectively, ensuring reliable sensor measurements. Predictive models for circadian stimulus were developed using both simple regression and machine learning techniques. The random forest model outperformed linear regression, achieving an adjusted R² of 0.915 and a cross-validation R² of 0.857, demonstrating high generalization capability. Upon the implementation of these models, significant individual variations in circadian light exposure were found in the study, highlighting the significance of customized lighting evaluations. These results confirm the effectiveness of wearable sensors, combined with the developed calibration and predictive modeling, in accurately assessing personal circadian light exposure and supporting lighting-related health care research.

CONCLUSIONS: This study introduces an effective and scalable approach to circadian light assessment using wearable sensors and predictive modeling. By replacing labor-intensive and costly spectrometer measurements, the proposed methodology enables continuous, cost-effective monitoring in health care environments. However, challenges related to sensor wearability, durability, and user compliance were identified, underscoring the need for further sensor design refinements. Future research should focus on refining sensor integration, expanding case studies, and developing adaptive lighting interventions to enhance circadian health in vulnerable populations.},
}

*Nursing Homes
Humans
*Lighting
*Wearable Electronic Devices
*Circadian Rhythm/physiology
Aged
Male
Female
Aged, 80 and over
Machine Learning
Calibration
Dementia

@article {pmid41055040,
year = {2025},
author = {Alexandersen, CG and Bassett, DS and Goriely, A and Chaggar, P},
title = {Neuronal activity and amyloid-β promote tau seeding in the entorhinal cortex in Alzheimer's disease.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awaf374},
pmid = {41055040},
issn = {1460-2156},
abstract = {The entorhinal cortex is the first region to develop tau pathology in Alzheimer's disease and primary age-related tauopathy, yet the reasons for this selective vulnerability remain unclear. We developed a computational model in which neuronal activity and amyloid-β (Aβ) modulate tau transport, hypothesizing that this mechanism explains entorhinal vulnerability to early tau pathology. The model combines structural connectivity with either neuronal activity (measured by heading hierarchy okayfluorodeoxyglucose, FDG PET) or amyloid-β burden (measured by Aβ PET). We analyzed Alzheimer's Disease Neuroimaging Initiative (ADNI) data comprising 527 FDG PET scans (mean age 71.8 years; 174 cognitively normal, 293 mild cognitive impairment, 60 Alzheimer's disease) and 1,244 Aβ PET scans (mean age 72.4 years; 501 cognitively normal, 588 mild cognitive impairment, 155 Alzheimer's disease). From these, 253 FDG-tau and 453 Aβ-tau PET pairs were used in regression analyses. Key results were replicated in the Harvard Aging Brain Study (HABS; 300 FDG, 348 Aβ, 116 FDG-tau, and 255 Aβ-tau pairs). Both FDG- and Aβ-based models consistently identified the entorhinal cortex as a primary tau seeding region in ADNI (FDG: z ≈ 4.6-4.9, p < 0.0066; Aβ: z ≈ 4.0-8.7, p ≤ 0.011) and in HABS (FDG: z = 5.7, p = 0.030; Aβ: z = 6.0, p = 0.0018). Simple linear regression showed modest associations between model-derived seeding and empirical entorhinal tau in ADNI (FDG: β = 6.7, p = 0.0039; Aβ: β = 11.3, p < 0.001), which remained significant after adjustment for age, sex, and APOE4 status (FDG: β = 7.1, p < 0.001; Aβ: β = 9.7, p < 0.001). Aβ-based associations replicated in HABS (β = 3.3, p < 0.001), while FDG-based correlations were not detectable in this predominantly cognitively normal cohort (β = -0.43, p = 0.80; power = 49%). These findings support a mechanistic role for neuronal activity and amyloid-β in initiating tau pathology, with the entorhinal cortex consistently emerging as highly vulnerable. Our computational model reliably identifies this region as the epicenter of pathology, supporting the idea that brain-wide patterns of neuronal activity and amyloid burden determine where tau pathology begins.},
}

@article {pmid41054805,
year = {2025},
author = {Teipel, S and Singh, D and Dubbelman, MA and Pan, G and Tang, Y and König, A},
title = {Early detection of Alzheimer's disease: From multiplex assays and imaging to point of care devices and AI-based functional monitoring.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251383339},
doi = {10.1177/13872877251383339},
pmid = {41054805},
issn = {1875-8908},
abstract = {The advent of disease-modifying treatments and risk-reduction strategies in the clinic have increased the demand for biomarkers for early disease detection, prediction of clinical course of disease, individual risk prediction and monitoring of treatment effects. The studies in this special issue span ultra-sensitive fluid assays and automated laboratory platforms, structural and molecular neuroimaging, electrophysiology, digital cognitive and behavioral monitoring, multi-omics, neuromodulation, and the computational frameworks necessary to integrate these diverse data.},
}

@article {pmid41054216,
year = {2025},
author = {Sánchez de Muniain, L and Escalada, P and Ramírez, MJ and Solas, M},
title = {Astrocytes as Metabolic Sensors Orchestrating Energy-Driven Brain Vulnerability in Alzheimer's Disease.},
journal = {Journal of neurochemistry},
volume = {169},
number = {10},
pages = {e70252},
doi = {10.1111/jnc.70252},
pmid = {41054216},
issn = {1471-4159},
support = {PID2021-128737NB-I00//MCIN/AEI/10.13039/501100011033/ ; },
mesh = {*Alzheimer Disease/metabolism/pathology ; Humans ; *Astrocytes/metabolism/pathology ; *Energy Metabolism/physiology ; *Brain/metabolism/pathology ; Animals ; Oxidative Stress/physiology ; },
abstract = {Alzheimer's disease (AD), the leading neurodegenerative disorder linked to aging, emerges within a paradoxical metabolic landscape. Despite rising cellular energy demands due to accumulated damage and stress, overall energy expenditure remains stable or declines with age. The brain, acting as the central regulator, responds to hypermetabolic signals from aged tissues by activating energy-conserving mechanisms. In this scenario, astrocytes, strategically located between blood vessels and neurons, play a pivotal role as energy sensors, adapting to systemic stress and modulating brain metabolism. This review explores how astrocytes undergo metabolic reprogramming in the early stages, potentially becoming maladaptive over time, fueling neuroinflammation, oxidative stress, and accelerating AD. By understanding astrocyte energetics, we uncover new avenues for biomarkers and therapies that could transform AD treatment.},
}

*Alzheimer Disease/metabolism/pathology
Humans
*Astrocytes/metabolism/pathology
*Energy Metabolism/physiology
*Brain/metabolism/pathology
Animals
Oxidative Stress/physiology

@article {pmid41054161,
year = {2025},
author = {Li, Z and Wang, T and Ou, X},
title = {Overactive bladder and cognitive impairment in adults aged 60 and over: A cross-sectional study.},
journal = {Medicine},
volume = {104},
number = {40},
pages = {e44544},
doi = {10.1097/MD.0000000000044544},
pmid = {41054161},
issn = {1536-5964},
mesh = {Humans ; *Urinary Bladder, Overactive/epidemiology/psychology/complications ; Male ; Female ; Aged ; Cross-Sectional Studies ; Middle Aged ; *Cognitive Dysfunction/epidemiology/etiology ; Aged, 80 and over ; United States/epidemiology ; Nutrition Surveys ; Neuropsychological Tests ; },
abstract = {The elderly frequently experience a prevalent condition known as overactive bladder (OAB). There have been indications of a possible association with a decrease in cognitive function. This research examined the association between OAB and cognitive abilities in the older population. For this research, we gathered information from the National Health and Nutrition Examination Survey from 2011 to 2014. Multiple linear regression analysis was utilized to examine the relationship between OAB and cognitive performance in older individuals in the United States. Cognitive abilities were assessed through the digit symbol substitution test (DSST), the animal fluency test (AFT), and the Consortium to Establish a Registry for Alzheimer's Disease (CERAD). The study comprised 2807 older adults who were 60 years old or older. In the initial crude model (Model 1), OAB exhibited a significant association with cognitive decline. The β-coefficients for the CERAD.word learning AFT and the DSST were -1.60 (95% confidence interval [95% CI]: -2.10, -1.10), -1.71 (95% CI: -2.13, -1.28), and -7.85 (95% CI: -9.16, -6.54), respectively. Furthermore, after adjustments (Model 3), the relationship persisted unchanged (CERAD.word learning: β = -0.62, P = .0099; AFT: β = -0.57, P = .0042; DSST: β = -2.84, P < .0001). In conclusion, our study, which involved a nationally representative cohort of elderly individuals from the United States, revealed a positive association between OAB and cognitive decline.},
}

Humans
*Urinary Bladder, Overactive/epidemiology/psychology/complications
Male
Female
Aged
Cross-Sectional Studies
Middle Aged
*Cognitive Dysfunction/epidemiology/etiology
Aged, 80 and over
United States/epidemiology
Nutrition Surveys
Neuropsychological Tests

@article {pmid41054101,
year = {2025},
author = {Hu, W and Liu, X and Zhang, P},
title = {Rapid eye movement sleep behavior disorder (RBD) and neurodegenerative diseases: A bidirectional 2-sample Mendelian randomization study.},
journal = {Medicine},
volume = {104},
number = {40},
pages = {e44816},
doi = {10.1097/MD.0000000000044816},
pmid = {41054101},
issn = {1536-5964},
support = {2024NSFSC1608//Science and Technology Plan Project of Sichuan Province,/ ; 2024HX019)//Horizontal project of Sichuan Provincial People's Hospital/ ; 2024HX018//Horizontal project of Sichuan Provincial People's Hospital/ ; },
mesh = {Humans ; Mendelian Randomization Analysis ; *REM Sleep Behavior Disorder/genetics/epidemiology ; Polymorphism, Single Nucleotide ; *Neurodegenerative Diseases/genetics/complications/epidemiology ; Genome-Wide Association Study ; Parkinson Disease/genetics ; Amyotrophic Lateral Sclerosis/genetics ; Alzheimer Disease/genetics ; Frontotemporal Dementia/genetics ; Lewy Body Disease/genetics ; },
abstract = {Observational studies have documented association between rapid eye movement sleep behavior disorder (RBD) and neurodegenerative diseases, but the causal relationship remains to be established. In this study, we utilized a bidirectional 2-sample Mendelian randomization (MR) approach to assess the potential causal connection between RBD and 6 neurodegenerative conditions, including Alzheimer disease (AD), amyotrophic lateral sclerosis (ALS), dementia with Lewy bodies (DLB), frontotemporal dementia (FTD), multiple system atrophy (MSA), and Parkinson disease (PD). Inverse variance weighting (IVW) was performed as the main MR analysis, and additional 4 MR methods were performed to reinforce the robustness of the final MR estimates. Sensitivity analyses were conducted to detect possible heterogeneity or pleiotropy. Ten single-nucleotide polymorphisms (SNPs) for RBD, 54 SNPs for AD, 11 SNPs for ALS, 4 SNPs for DLB, 3 SNPs for MSA, and 12 SNPs for PD were selected as instrumental variables in this study. No suitable instrumental variables for FTD could be identified from genome-wide association studies dataset using a threshold of P < 5 × 10-8. Genetically predicted RBD was causally associated with an increased risk of PD (IVW: odds ratios = 1.093, 95% confidence intervals = [1.031-1.159], P = .003). In the reverse MR analysis, genetically predicted PD was found to be causally increased the incidence of RBD (IVW: odds ratios = 1.758, 95% confidence intervals = [1.355-2.281], P = 2.176 × 10-5). No heterogeneity or pleiotropy was observed in Cochran Q test, MR-Egger intercept test, or MR-PRESSSO Global test in the determination of the above 2 MR analyses. However, this bidirectional MR study did not identify any causal relationship between RBD and AD, ALS, DLB, FTD, and MSA. This MR study supported a bidirectional causal relationship between RBD and PD, mutually increasing the incidence of each. However, current genetic evidence did not support causal associations between RBD and AD, ALS, DLB, FTD, and MSA in either direction. However, these null findings should be interpreted with caution due to the limited sample sizes of the genome-wide association studies summary data used, highlighting the need for larger genetic studies to investigate these relationships further.},
}

Humans
Mendelian Randomization Analysis
*REM Sleep Behavior Disorder/genetics/epidemiology
Polymorphism, Single Nucleotide
*Neurodegenerative Diseases/genetics/complications/epidemiology
Genome-Wide Association Study
Parkinson Disease/genetics
Amyotrophic Lateral Sclerosis/genetics
Alzheimer Disease/genetics
Frontotemporal Dementia/genetics
Lewy Body Disease/genetics

@article {pmid41054040,
year = {2025},
author = {Zheng, W and Wang, Y and Zhu, E and Xu, R and Zhu, L},
title = {Association between different types of lung cancer and neurodegenerative diseases: A two-sample Mendelian randomization study.},
journal = {Medicine},
volume = {104},
number = {40},
pages = {e45048},
doi = {10.1097/MD.0000000000045048},
pmid = {41054040},
issn = {1536-5964},
mesh = {Humans ; *Lung Neoplasms/genetics/epidemiology ; Mendelian Randomization Analysis ; Genome-Wide Association Study ; *Parkinson Disease/genetics/epidemiology ; *Alzheimer Disease/genetics/epidemiology ; *Carcinoma, Squamous Cell/genetics/epidemiology ; *Neurodegenerative Diseases/epidemiology/genetics ; },
abstract = {Previous observational studies demonstrated that lung cancer and both Alzheimer disease (AD) and Parkinson disease (PD) may be related. However, the results of different studies are still controversial, possibly due to differences in the types of lung cancer examined. To date, no research has discussed it further yet. In this study, Mendelian randomization (MR) analysis was employed to investigate the relationship between different types of lung cancer and neurodegenerative diseases. We extracted data sets related to the exposure (lung cancer) and outcomes (AD/PD) from the Integrative Epidemiology Unit open Genome-Wide Association Study project. Then, we carried out two-sample MR analyses to explore the connection between lung cancer and both AD and PD. We also conducted sensitivity analyses on positive results from the MR analysis to make sure the results were accurate. Our two-sample MR analyses revealed that lung squamous cell carcinoma (LUSC) is negatively related to AD (OR = 0.935, 95% CI [0.892-0.980], P = .005). According to the sensitivity and heterogeneity analyses, no heterogeneity (P = .223) and pleiotropy (P = .548) were observed in this positive result. Thus, the findings were reliable. The IVW findings suggested that LUSC and PD did not significantly correlate (OR = 0.920, 95% CI [0.778-1.089], P = .332). Similarly, there was no obvious connection between lung adenocarcinoma and AD (OR = 0.968, 95% CI [0.915-1.025], P = .270) and PD (OR = 0.981, 95% CI [0.851-1.130], P = .787), according to IVW results. Results of two-sample MR analyses revealed that LUSC and a decreased risk of AD may be related.},
}

Humans
*Lung Neoplasms/genetics/epidemiology
Mendelian Randomization Analysis
Genome-Wide Association Study
*Parkinson Disease/genetics/epidemiology
*Alzheimer Disease/genetics/epidemiology
*Carcinoma, Squamous Cell/genetics/epidemiology
*Neurodegenerative Diseases/epidemiology/genetics

@article {pmid41053953,
year = {2025},
author = {Arciuolo, V and D'Aria, F and Caruso, MR and Calvino, MM and Amato, J and Lazzara, G and Milioto, S and Giancola, C and Cavallaro, G and Pagano, B},
title = {Therapeutic Oligonucleotides for Neurodegenerative Diseases: Aptamer Strategies and Clay Nanoparticle-Based Delivery.},
journal = {Chemical record (New York, N.Y.)},
volume = {},
number = {},
pages = {e2500126},
doi = {10.1002/tcr.202500126},
pmid = {41053953},
issn = {1528-0691},
support = {//Ministero dell'Università e della Ricerca/ ; P2022C5PWY//European Union - Next Generation EU/ ; },
abstract = {Aptamers have emerged as promising therapeutic oligonucleotides (TOs) due to their structural adaptability, high binding affinity, and remarkable specificity toward diverse biological targets. Among them, G-quadruplex-forming aptamers stand out for their unique secondary structures and distinct chemical properties. Their potential in neurodegenerative diseases such as Alzheimer's, Parkinson's, and Huntington's lies in their ability to inhibit protein aggregation and modulate pathogenic pathways. However, their application is hindered by enzymatic degradation and limited membrane permeability. To overcome these issues, chemical modifications, such as backbone and sugar alterations, and nanomaterial-based delivery strategies have been developed. Notably, clay nanoparticles, such as halloysite nanotubes and montmorillonite, have gained attention as effective carriers for TOs, enhancing their structural stability and bioavailability. This review discusses recent advancements in aptamer-based TOs, with a focus on G-quadruplex-forming oligonucleotides, their therapeutic potential in neurodegenerative diseases, and innovative nanocarrier systems that can improve their stability and targeted delivery. Finally, it highlights current challenges and future directions in the chemical design and formulation of aptamer-based therapeutics for targeted applications.},
}

@article {pmid41053874,
year = {2025},
author = {Malpetti, M and Rathore, S and Iaccarino, L and La Joie, R and Tronchin, G and Wessels, AM and Sims, JR and Pontecorvo, MJ and Shcherbinin, S and Rabinovici, GD},
title = {Regional tau PET patterns predict prospective domain-specific cognitive decline in early symptomatic Alzheimer's disease.},
journal = {Alzheimer's research & therapy},
volume = {17},
number = {1},
pages = {220},
pmid = {41053874},
issn = {1758-9193},
support = {ARUK-RADF2021A-010//Race Against Dementia Alzheimer's Research UK/ ; PD/2020/02//Parke Davis Exchange Fellowship in Biomedical Sciences/ ; NIHR203312//NIHR Cambridge Biomedical Research Centre/ ; P30-AG062422, R35 AG072362, U01-AG057195, U01-AG082350//NIH/NIA/ ; },
mesh = {Humans ; *Alzheimer Disease/diagnostic imaging/metabolism/psychology ; *Positron-Emission Tomography ; Male ; Female ; *tau Proteins/metabolism ; *Cognitive Dysfunction/diagnostic imaging/metabolism/psychology ; Aged ; Neuropsychological Tests ; Magnetic Resonance Imaging ; *Brain/diagnostic imaging/metabolism ; Longitudinal Studies ; Aged, 80 and over ; Prospective Studies ; Middle Aged ; },
abstract = {BACKGROUND: Tau-PET binding patterns are heterogenous, with regional binding showing strong cross-sectional correlations with domain-specific cognitive performance and longitudinal correlations with prospective neurodegeneration. Here we evaluated whether regional patterns of baseline tau-PET predict prospective longitudinal decline in specific cognitive domains in early symptomatic Alzheimer's disease (AD), including participants from clinical trial cohorts.

METHODS: 731 amyloid-positive participants with a clinical diagnosis of mild cognitive impairment (MCI) or mild AD dementia underwent a flortaucipir F 18 PET (FTP-PET), structural MRI, and neuropsychological testing with the AD Assessment Scale-Cognitive Subscale (ADAS-Cog). Cognitive assessment was repeated after 9-18 or 12-24 months. Sub-scale annualized w-scores at each time point were combined as composite scores according to domains, including episodic memory, semantic memory, executive function, language and praxis. Latent growth curve models were applied to longitudinal composite scores to estimate the rate of annual decline (slope) in each participant. Standardized uptake value ratio (SUVR) images were created using cerebellar crus as the reference region. Regional and voxel-wise correlation analyses were implemented to identify baseline FTP-PET patterns and MRI grey matter volumes associated with longitudinal changes in each cognitive domain, and to evaluate whether MRI mediates the association between FTP-PET and cognitive decline.

RESULTS: Differential FTP-PET signal patterns showed significant negative associations with domain-specific annual rates of decline. Higher temporo-parietal FTP-PET SUVR was associated with faster decline in episodic memory, while higher left anterior temporal SUVR was associated with faster decline in semantic memory. FTP-PET signal in a left-dominant fronto-temporal pattern was associated with faster decline in language, while FTP-PET signal in a right-dominant fronto-parietal pattern was associated with faster decline in praxis. Executive decline showed limited spatial associations with FTP-PET. Overall, regional and voxel-wise analyses identified similar pairwise associations between FTP-PET signal and domain-specific longitudinal decline. Baseline MRI showed weaker associations with domain-specific cognitive decline than FTP-PET, and did not mediate the predictive effect of the latter.

CONCLUSION: Differential regional tau-PET signal patterns were associated with domain-specific cognitive decline in MCI and early AD dementia. Tau-PET may be a useful precision medicine tool to support individualized predictions of cognitive decline trajectories in early symptomatic AD.},
}

Humans
*Alzheimer Disease/diagnostic imaging/metabolism/psychology
*Positron-Emission Tomography
Male
Female
*tau Proteins/metabolism
*Cognitive Dysfunction/diagnostic imaging/metabolism/psychology
Aged
Neuropsychological Tests
Magnetic Resonance Imaging
*Brain/diagnostic imaging/metabolism
Longitudinal Studies
Aged, 80 and over
Prospective Studies
Middle Aged

@article {pmid41053791,
year = {2025},
author = {Kim, D and Highland, HM and Smit, RAJ and Hysong, MR and Buchanan, VL and Young, KL and Zhao, C and Spracklen, CN and Kilpeläinen, TO and Guo, B and Darst, BF and Cai, Y and Wang, Z and Lundin, J and Berndt, SI and Manson, JE and Marouli, E and Lange, L and Lange, E and Fornage, M and Gignoux, CR and Haiman, CA and Rich, SS and Buyske, S and Loos, RJF and Kooperberg, C and Peters, U and Avery, CL and Gordon-Larsen, P and Graff, M and Raffield, LM and North, KE},
title = {Genetic underpinnings of the heterogeneous impact of obesity on lipid levels and cardiovascular disease.},
journal = {Genome medicine},
volume = {17},
number = {1},
pages = {113},
pmid = {41053791},
issn = {1756-994X},
support = {903805//American Heart Association/ ; NNF22OC0074128//Novo Nordisk Foundation Center for Basic Metabolic Research/ ; Intramural Research Program/CP/NCI NIH HHS/United States ; R01HL142302/HL/NHLBI NIH HHS/United States ; R01DK122503/DK/NIDDK NIH HHS/United States ; R01HD057194//Eunice Kennedy Shriver National Institute of Child Health and Human Development/ ; R01HG010297/HG/NHGRI NIH HHS/United States ; },
mesh = {Humans ; *Obesity/genetics/complications/blood ; *Cardiovascular Diseases/genetics/etiology/blood ; Genome-Wide Association Study ; Body Mass Index ; Male ; Female ; Middle Aged ; *Lipids/blood ; Mendelian Randomization Analysis ; Genetic Predisposition to Disease ; Multifactorial Inheritance ; Polymorphism, Single Nucleotide ; Triglycerides/blood ; },
abstract = {BACKGROUND: Obesity is thought to increase cardiovascular disease (CVD) risk partly through dyslipidemia. Yet, obesity's effects on dyslipidemia are not uniform. Understanding the shared genetic basis between obesity and lipid traits can provide insight into this heterogeneity and its implications for CVD risk.

METHODS: We examined local genetic correlations between three lipid measures [high-density lipoprotein cholesterol (HDL), low-density lipoprotein cholesterol (LDL), and triglycerides (TG)] and body mass index (BMI) using genome-wide association study summary statistics from European ancestry UK Biobank participants. We identified genomic loci with opposing genetic effects on obesity and dyslipidemia risk (protective BMI-lipid loci) and those with concordant directions for both obesity and dyslipidemia risk (adverse BMI-lipid loci). Gene-based association analyses were used to prioritize potential causal genes. We then constructed polygenic risk scores for BMI (PRSBMI) based on protective and adverse loci and assessed their associations with BMI, lipid levels, CVD, and related traits in the diverse Population Architecture using Genomics and Epidemiology (PAGE) study. PheWAS was performed in the All of Us cohort. Mendelian randomization (MR) was conducted to assess the causal impact of protective/adverse loci on cardiometabolic outcomes. Finally, we investigated the associations with fat distribution traits using MRI-based fat measures in the UK Biobank.

RESULTS: Among 2495 regions, we identified 789 HDL, 26 LDL, and 494 TG loci with significant local genetic correlation with BMI (including overlapping loci). Of these, 3 HDL, 10 LDL, and 8 TG loci showed protective correlations. Gene-based analyses prioritized 18 candidate causal genes. The protective PRSBMI(+)HDL(+) was associated with higher BMI but favorable lipid profiles and reduced CVD risk in PAGE. PheWAS revealed protective associations with hyperlipidemia, atrial fibrillation, and Alzheimer's disease. MR supported the favorable causal effects of these protective loci on several cardiometabolic outcomes. Notably, protective PRSBMI(+)TG(-) was uniquely associated with decreased visceral-to-abdominal subcutaneous adipose tissue ratio.

CONCLUSIONS: Identifying and validating genomic loci with shared genetic signals between BMI and lipid levels further supports the importance of genetics in defining the heterogeneous impact of obesity on dyslipidemia and CVD.},
}

Humans
*Obesity/genetics/complications/blood
*Cardiovascular Diseases/genetics/etiology/blood
Genome-Wide Association Study
Body Mass Index
Male
Female
Middle Aged
*Lipids/blood
Mendelian Randomization Analysis
Genetic Predisposition to Disease
Multifactorial Inheritance
Polymorphism, Single Nucleotide
Triglycerides/blood

@article {pmid41053519,
year = {2025},
author = {Amiri, M and Afshary, H and Bezaatpour, A and Hatamikia, S and Wei, J and Boukherroub, R and Szunerits, S},
title = {A critical review on neurodegenerative biomarker diagnostics: where is the field heading to?.},
journal = {Analytical and bioanalytical chemistry},
volume = {},
number = {},
pages = {},
pmid = {41053519},
issn = {1618-2650},
abstract = {Neurodegenerative diseases (NDD), a collection of disorders with different underlying causes and clinical presentations, are recognized as a major area of concern of our society today. The most common NDD are Parkinson's disease (PD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and Huntington's disease, each one of them being characterized by the progressive degradation of nerve cells and accumulation of misfolded and aggregated proteins in the affected brain region. Diagnosing NDD is challenging, due to the heterogeneity of the disease and the overlap of symptoms. Yet, early detection and accurate diagnosis are crucial for effective NDD management. With the emergence of disease-modifying therapies for AD, monitoring disease progression and treatment success is becoming essential. The future of NND diagnostics is focusing on developing less invasive, cost-effective strategies that enable early NDD identification and detection with improved patient outcomes. The integration of biotechnology and nanotechnology is seen as crucial for advancing the analytical science aspect of NDD. The creation of these innovative tools and methodologies is on the verge of enabling new possibilities for clinical diagnostics, but is also faced with several hurdles that will be critically evaluated.},
}

@article {pmid41053434,
year = {2025},
author = {Renganathan, A and Minaya, MA and Broder, M and Alfradique-Dunham, I and Miller, RL and Dhavale, DD and Moritz, M and Bhagat, R and Marsh, J and Verbeck, A and Galasso, G and Starr, E and Agard, DA and Kotzbauer, PT and Cruchaga, C and Karch, CM},
title = {A novel lncRNA FAM151B-DT regulates degradation of aggregation prone proteins.},
journal = {Molecular psychiatry},
volume = {},
number = {},
pages = {},
pmid = {41053434},
issn = {1476-5578},
support = {NS110890//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; NS123985//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; NS110436//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; NS097799//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; AG083215//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; },
abstract = {Neurodegenerative diseases share common features of protein aggregation along with other pleiotropic traits, including shifts in transcriptional patterns, neuroinflammation, disruption in synaptic signaling, mitochondrial dysfunction, oxidative stress, and impaired clearance mechanisms like autophagy. However, key regulators of these pleiotropic traits have yet to be identified. Here, we used transcriptomics, mass spectrometry, and biochemical assays to define the role of a novel lncRNA on tau pathophysiology. We discovered a long non-coding RNA (lncRNA), FAM151B-DT, that is reduced in a stem cell model of frontotemporal lobar dementia with tau inclusions (FTLD-tau) and in brains from FTLD-tau, progressive supranuclear palsy, Alzheimer's disease, and Parkinson's disease patients. We show that silencing FAM151B-DT in vitro is sufficient to enhance tau and α-synuclein aggregation. To begin to understand the mechanism by which FAM151B-DT mediates tau aggregation and contributes to several neurodegenerative diseases, we deeply characterized this novel lncRNA and found that FAM151B-DT resides in the cytoplasm where it interacts with tau, α-synuclein, HSC70, and other proteins involved in protein homeostasis. When silenced, FAM151B-DT blocks autophagy, leading to the accumulation of tau and α-synuclein. Importantly, we discovered that increasing FAM151B-DT expression is sufficient to promote autophagic clearance of phosphorylated tau and α-synuclein, and reduce tau and α-synuclein aggregation. Overall, these findings pave the way for further exploration of FAM151B-DT as a promising molecular target for several neurodegenerative diseases.},
}

@article {pmid41053038,
year = {2025},
author = {Ficchì, S and Cauzzi, E and La Barbera, L and De Paolis, ML and Loffredo, G and Spoleti, E and Ferrari, I and Saba, L and Biamonte, F and Nobili, A and Krashia, P and D'Amelio, M},
title = {Optogenetic stimulation of midbrain dopaminergic neurons rescues hippocampal synaptic plasticity deficits in a mouse model of Alzheimer's disease.},
journal = {Translational psychiatry},
volume = {15},
number = {1},
pages = {371},
pmid = {41053038},
issn = {2158-3188},
support = {AARG-21-851219/ALZ/Alzheimer's Association/United States ; },
mesh = {Animals ; *Alzheimer Disease/physiopathology/therapy ; *Dopaminergic Neurons/physiology ; *Optogenetics ; Disease Models, Animal ; Mice ; *Mesencephalon/physiopathology ; *Neuronal Plasticity/physiology ; *Hippocampus/physiopathology ; Mice, Inbred C57BL ; Mice, Transgenic ; Oxidopamine ; *Long-Term Potentiation/physiology ; Male ; Synaptic Transmission ; },
abstract = {We previously demonstrated that the Tg2576 mouse model of Alzheimer's Disease (AD) exhibits degeneration of midbrain dopaminergic neurons, resulting in reduced dopamine (DA) outflow in the hippocampus. These impairments temporally coincide with synaptic plasticity deficits at CA3-CA1 synapses. Notably, systemic administration of dopaminergic agents/drugs rescues the hippocampal deficits in Tg2576 mice. However, whether direct stimulation of the remaining midbrain dopaminergic neurons can restore glutamatergic transmission and rescue plasticity dysfunctions in the context of AD remains unexplored. Here, using both 6-hydroxydopamine (6-OHDA) neurotoxic lesion and optogenetic stimulation in C57BL/6N and DATCre/Tg2576 mice, respectively, we demonstrate that midbrain DA is essential for hippocampal High-Frequency Stimulation-induced Long-Term Potentiation (HFS-LTP) in CA3-CA1 synapses. Indeed, lesioning midbrain DA neurons with 6-OHDA abolishes HFS-LTP and impairs novel object recognition memory. Conversely, optogenetic activation of the midbrain-hippocampal dopaminergic pathway in DATCre/Tg2576 mice enhances glutamatergic transmission and rescues plasticity deficits. Our results highlight the phase-specific role of DA in HFS-LTP, since 6-OHDA lesion affects the late but not the early phase, aligning with prior studies on D1/D5 receptor involvement in protein synthesis-dependent plasticity. Furthermore, we provide novel insights into midbrain DA neuron regulation, demonstrating that phasic, but not prolonged, optogenetic stimulation effectively engages DA neuron activity, restoring hippocampal function in Tg2576 mice. Notably, phasic DA release induces "DA-LTP" via D1/D5 receptors, and restores HFS-LTP in CA3-CA1 synapses of AD mice, underscoring a potential compensatory mechanism counteracting plasticity deficits induced by DA neuron degeneration in Tg2576 mice. These findings support targeting the dopaminergic midbrain as a promising strategy for AD treatment, complementing pharmacological and non-invasive neuromodulatory approaches.},
}

Animals
*Alzheimer Disease/physiopathology/therapy
*Dopaminergic Neurons/physiology
*Optogenetics
Disease Models, Animal
Mice
*Mesencephalon/physiopathology
*Neuronal Plasticity/physiology
*Hippocampus/physiopathology
Mice, Inbred C57BL
Mice, Transgenic
Oxidopamine
*Long-Term Potentiation/physiology
Male
Synaptic Transmission

@article {pmid41053035,
year = {2025},
author = {Huang, D and Long, Y and Yang, Y and Wu, J and Yang, J and Huang, Y and Li, Y and Liu, P and Yuan, M and Song, X and Tan, X and Zheng, P and Zhang, J},
title = {Impairments of spatial memory retrieval via medial mammillary body dysfunction in Alzheimer's disease model.},
journal = {Translational psychiatry},
volume = {15},
number = {1},
pages = {353},
pmid = {41053035},
issn = {2158-3188},
support = {32400850//National Natural Science Foundation of China (National Science Foundation of China)/ ; 2022M710989//China Postdoctoral Science Foundation/ ; },
mesh = {*Alzheimer Disease/physiopathology/complications ; Animals ; *Mammillary Bodies/physiopathology ; *Spatial Memory/physiology ; Disease Models, Animal ; Mice ; Optogenetics ; Male ; *Memory Disorders/physiopathology ; Neurons/physiology ; Mice, Transgenic ; Thalamus/physiopathology ; *Mental Recall/physiology ; },
abstract = {Alzheimer's disease (AD) patients and AD mouse models usually have cognitive impairments, such as significant spatial memory deficits, which are coupled with dysregulation in the structure and function of neural circuits. The medial mammillary body (MM) is associated with spatial memory, and its dysfunction emerges in early AD. However, the link between spatial memory deficits and MM dysfunction remains unclear. Here, by combining c-Fos mapping with optogenetic stimulation, we found the MM was involved in the retrieval of object-location memory. Furthermore, using viral tracing, we demonstrated the axonopathy of MM neurons in the thalamus in the early stages of AD mouse model. Fiber photometry revealed that neuronal activity of MM neurons showed distinct responses to objects in different locations. However, neuronal activity was significantly reduced during the object-location memory retrieval phase in AD mice. Activating MM neurons in AD mice through optogenetic manipulation rescues the object-location memory impairment. Together, our results highlight the importance of MM dysfunction in AD, which may serve as a foundation for further exploration of new targets in AD.},
}

*Alzheimer Disease/physiopathology/complications
Animals
*Mammillary Bodies/physiopathology
*Spatial Memory/physiology
Disease Models, Animal
Mice
Optogenetics
Male
*Memory Disorders/physiopathology
Neurons/physiology
Mice, Transgenic
Thalamus/physiopathology
*Mental Recall/physiology

@article {pmid41053017,
year = {2025},
author = {Zhang, Q and Lo, H and Song, Y and Feng, L and You, H and Chen, X and Wang, Y and Pan, X},
title = {LRRK2 deficiency mitigates amyloid β deposition-mediated pathology in a murine Alzheimer's disease model by reprogramming microglia.},
journal = {Translational psychiatry},
volume = {15},
number = {1},
pages = {375},
pmid = {41053017},
issn = {2158-3188},
support = {82071175//National Natural Science Foundation of China (National Science Foundation of China)/ ; 2023J011519//Natural Science Foundation of Fujian Province (Fujian Provincial Natural Science Foundation)/ ; },
mesh = {Animals ; *Leucine-Rich Repeat Serine-Threonine Protein Kinase-2/genetics/deficiency ; *Microglia/metabolism/pathology ; *Alzheimer Disease/pathology/genetics/metabolism/immunology ; Mice ; Disease Models, Animal ; *Amyloid beta-Peptides/metabolism ; *Plaque, Amyloid/pathology/metabolism ; Hippocampus/pathology/metabolism ; Mice, Transgenic ; Mice, Knockout ; Male ; Brain/pathology/metabolism ; },
abstract = {Leucine-rich repeat kinase 2 (LRRK2), primarily expressed in microglia, is responsible for the modulation of innate immune responses and associated with various immunological disorders. Available evidence documents that though as the predominant etiological factor for familial Parkinson's disease, LRRK2 mutations rarely occur in Alzheimer's disease (AD) and that LRRK2 polymorphism is potentially associated with late-onset AD. However, the role of LRRK2 in AD immunopathogenesis remains unknown. In this study, we investigated the impact of LRRK2 deficiency on cognitive function, Aβ plaque accumulation, and plaque-associated neuropathology in AD mice. The results revealed that compared with the 5xFAD mice, the 8-month-old 5xFAD;LRRK2[-/-] mice reported improved learning and memory, reduced cerebral and hippocampal Aβ plaque burden, and decreased microglia and astrocytes within the central region of hippocampal Aβ plaques. The 5xFAD;LRRK2[-/-] mice also showed a decrease in several complement and proinflammatory cytokines in the brain, indicating an altered microglial phenotype. Furthermore, the absence of LRRK2 prevented synaptic loss and restored the disrupted equilibrium between excitatory and inhibitory synapses in the 5xFAD mice. These findings suggest that LRRK2 may play an essential role in Aβ plaque pathology, glial responses to plaques, and neuronal dysfunction in the brain of the 5xFAD mice and that a genomic transgene-blockade of LRRK2 may reprogram the microglial responsivity, thus mitigating the neuropathological and behavioral deficits in AD mice. The 5xFAD;LRRK2[-/-] mice reduced cognitive impairment in the Morris water maze test compared with the 5xFAD mice. The protective effect of LRRK2 inhibition is not dependent on the APP production process or Aβ degradation. Conversely, 5xFAD;LRRK2[-/-] mice enhanced microglial phagocytosis, reducing Aβ aggregation and glial activation. Additionally, compared with the 5xFAD, the 5xFAD;LRRK2[-/-] mice exhibited preserved synaptic structure, characterized by higher PSD95 expression, lower C1qa/C3 expression in both excitatory and inhibitory synapses, upregulated VGLUT1 expression, and downregulated VGAT expression.},
}

Animals
*Leucine-Rich Repeat Serine-Threonine Protein Kinase-2/genetics/deficiency
*Microglia/metabolism/pathology
*Alzheimer Disease/pathology/genetics/metabolism/immunology
Mice
Disease Models, Animal
*Amyloid beta-Peptides/metabolism
*Plaque, Amyloid/pathology/metabolism
Hippocampus/pathology/metabolism
Mice, Transgenic
Mice, Knockout
Male
Brain/pathology/metabolism

@article {pmid41052990,
year = {2025},
author = {Liu, WZ and Huang, LY and Chi, S and Ma, YH and Tan, CC and Tan, L and , and Xu, W},
title = {The blood lipidome fatty acid profile predicts the disease risk and clinical phenotypes of Alzheimer's disease: associations from two prospective cohort studies.},
journal = {Translational psychiatry},
volume = {15},
number = {1},
pages = {373},
pmid = {41052990},
issn = {2158-3188},
support = {tsqn202211375//Taishan Scholar Project of Shandong Province/ ; tsqn202312391//Taishan Scholar Project of Shandong Province/ ; },
mesh = {Humans ; *Alzheimer Disease/blood/genetics/pathology/diagnosis ; Male ; Female ; Middle Aged ; Aged ; *Fatty Acids/blood ; Prospective Studies ; Adult ; Aged, 80 and over ; Hippocampus/pathology ; Biomarkers/blood ; Phenotype ; Risk Factors ; Lipidomics ; United Kingdom ; },
abstract = {The relationship between fatty acids and Alzheimer's Disease (AD) risk has been an area of growing interest but remains insufficiently understood. This study aimed to develop and validate a fatty acid score (FAS) derived from blood fatty acid levels and explore its association with AD risk. We analyzed 148,308 UK Biobank participants (age 37-73; mean 55.96 years) with a mean follow-up of 12.3 years (maximum 16), and 1193 ADNI subjects (age 55-90; mean 73.50 years) with a mean follow-up of 4.2 years (maximum 8). Lasso regression was used to construct the FAS based on UKB, and Cox regression and linear regression was employed to assess the relationships of FAS with AD risk, cognition, hippocampal volume, and/or cerebrospinal fluid markers in both cohorts. Stratified effects by APOE ε4 status were examined. Causal mediation, proteomic, and bioinformatic analyses were performed to reveal potential mechanisms. Higher FAS was associated with increased AD risk in both cohorts (UKB: HR = 1.298, 95% CI 1.183-1.423, P < 0.001; ADNI: HR = 1.413, 95% CI 1.105-1.808, P = 0.006). In UKB, higher FAS was linked to reduced hippocampal volume (P < 0.001), and in ADNI, it was associated with faster hippocampal atrophy (P = 0.002) and cognitive decline (P < 0.001). These associations were stronger in APOE ε4 carriers. Hippocampal volume partly mediated the link between FAS and cognitive decline. Proteomic analyses demonstrated that the protein expression levels of Adhesion G protein-coupled receptor G1 (ADGRG1), Chitinase-3-like protein 1 (CHI3L1), RNA-binding FOX-1 homolog 3 (RBFOX3), and Growth differentiation factor 15 (GDF15) could mediate the effect of FAS on AD risk. The enriched pathways include cytokine activity, neurotrophic signaling, and pathways related to nervous system development. Blood levels of fatty acid could aid in AD prediction, but further research is needed to confirm causality.},
}

Humans
*Alzheimer Disease/blood/genetics/pathology/diagnosis
Male
Female
Middle Aged
Aged
*Fatty Acids/blood
Prospective Studies
Adult
Aged, 80 and over
Hippocampus/pathology
Biomarkers/blood
Phenotype
Risk Factors
Lipidomics
United Kingdom

@article {pmid41052979,
year = {2025},
author = {Cantero, JL and Atienza, M and Podlesniy, P and Puigròs, M and Trullas, R},
title = {Salivary mitochondrial DNA is associated with biomarkers of Alzheimer's disease in cognitively normal older adults.},
journal = {Translational psychiatry},
volume = {15},
number = {1},
pages = {355},
pmid = {41052979},
issn = {2158-3188},
support = {PID2023-149270OB-I00//Ministerio de Economía y Competitividad (Ministry of Economy and Competitiveness)/ ; PID2023-153168OB-I00//Ministerio de Economía y Competitividad (Ministry of Economy and Competitiveness)/ ; },
mesh = {Humans ; *DNA, Mitochondrial/metabolism ; *Alzheimer Disease/metabolism/diagnosis ; Biomarkers/metabolism/blood ; Aged ; Female ; Male ; *Amyloid beta-Peptides/metabolism/blood ; *Saliva/chemistry/metabolism ; tau Proteins/blood ; Positron-Emission Tomography ; Aged, 80 and over ; Neurofilament Proteins/blood ; Middle Aged ; },
abstract = {A significant body of evidence suggests that mitochondrial dysfunction plays a key role in the development and progression of Alzheimer's disease (AD). However, the absence of peripheral biomarkers for mitochondrial dysfunction limits its clinical applicability. Mitochondrial DNA (mtDNA) copy number, a proxy for mitochondrial function, has shown promise in detecting early stages of AD and predicting AD risk in cerebrospinal fluid (CSF) and blood, respectively. Surprisingly, recent studies have identified mtDNA molecules in human saliva, but their relationship with AD remains unexplored. Here, we investigated potential associations between salivary mtDNA copy number and cortical amyloid-β (Aβ) load measured with PET, and blood AD markers measured with ultrasensitive single molecule array (SIMOA) assays, in cognitively normal older adults. We found that salivary mtDNA copy number was positively correlated with cortical Aβ burden and plasma levels of tau phosphorylated at threonine 181 (pTau-181), and negatively correlated with general cognitive ability. It is worth noting that salivary mtDNA was not significantly associated with other blood-based AD biomarkers, including Aβ1-40, Aβ1-42, neurofilament-light chain (NfL), or glial fibrillary acidic protein (GFAP). Additionally, plasma pTau-181 levels moderated the association between salivary mtDNA and Aβ accumulation in the inferior temporal lobe, while Aβ load in the occipital cortex mediated the association between plasma pTau-181 and salivary mtDNA. Together, these findings represent the first evidence linking salivary mtDNA to well-established AD biomarkers in normal aging, suggesting that salivary mtDNA may serve as a potential non-invasive biomarker for identifying individuals at risk for developing AD in the general population.},
}

Humans
*DNA, Mitochondrial/metabolism
*Alzheimer Disease/metabolism/diagnosis
Biomarkers/metabolism/blood
Aged
Female
Male
*Amyloid beta-Peptides/metabolism/blood
*Saliva/chemistry/metabolism
tau Proteins/blood
Positron-Emission Tomography
Aged, 80 and over
Neurofilament Proteins/blood
Middle Aged

@article {pmid41052971,
year = {2025},
author = {Chen, J and Xiang, P and Duro-Castano, A and Cai, H and Guo, B and Liu, X and Yu, Y and Lui, S and Luo, K and Ke, B and Ruiz-Pérez, L and Gong, Q and Tian, X and Battaglia, G},
title = {Rapid amyloid-β clearance and cognitive recovery through multivalent modulation of blood-brain barrier transport.},
journal = {Signal transduction and targeted therapy},
volume = {10},
number = {1},
pages = {331},
pmid = {41052971},
issn = {2059-3635},
support = {769798 CheSSTag//EC | EU Framework Programme for Research and Innovation H2020 | H2020 Priority Excellent Science | H2020 European Research Council (H2020 Excellent Science - European Research Council)/ ; },
mesh = {Animals ; *Blood-Brain Barrier/metabolism/drug effects ; *Amyloid beta-Peptides/genetics/metabolism ; Mice ; *Alzheimer Disease/genetics/drug therapy/pathology/metabolism ; Humans ; *Low Density Lipoprotein Receptor-Related Protein-1/genetics ; *Cognition/drug effects ; Receptors, LDL/genetics ; Disease Models, Animal ; Transcytosis ; },
abstract = {The blood‒brain barrier (BBB) is a highly selective permeability barrier that safeguards the central nervous system (CNS) from potentially harmful substances while regulating the transport of essential molecules. Its dysfunction is increasingly recognized as a pivotal factor in the pathogenesis of Alzheimer's disease (AD), contributing to the accumulation of amyloid-β (Aβ) plaques. We present a novel therapeutic strategy that targets low-density lipoprotein receptor-related protein 1 (LRP1) on the BBB. Our design leverages the multivalent nature and precise size of LRP1-targeted polymersomes to modulate receptor-mediated transport, biasing LRP1 trafficking toward transcytosis and thereby upregulating its expression to promote efficient Aβ removal. In AD model mice, this intervention significantly reduced brain Aβ levels by nearly 45% and increased plasma Aβ levels by 8-fold within 2 h, as measured by ELISA. Multiple imaging techniques confirmed the reduction in brain Aβ signals after treatment. Cognitive assessments revealed that treated AD mice exhibited significant improvements in spatial learning and memory, with performance levels comparable to those of wild-type mice. These cognitive benefits persisted for up to 6 months post-treatment. This work pioneers a new paradigm in drug design, where function arises from the supramolecular nature of the nanomedicine, harnessing multivalency to elicit biological action at the membrane trafficking level. Our findings also reaffirm the critical role of the BBB in AD pathogenesis and demonstrate that targeting the BBB can make therapeutic interventions significantly more effective. We establish a compelling case for BBB modulation and LRP1-mediated Aβ clearance as a transformative foundation for future AD therapies.},
}

Animals
*Blood-Brain Barrier/metabolism/drug effects
*Amyloid beta-Peptides/genetics/metabolism
Mice
*Alzheimer Disease/genetics/drug therapy/pathology/metabolism
Humans
*Low Density Lipoprotein Receptor-Related Protein-1/genetics
*Cognition/drug effects
Receptors, LDL/genetics
Disease Models, Animal
Transcytosis

@article {pmid41052930,
year = {2025},
author = {Emami Naeini, S and Bhandari, B and Hill, B and Perez-Morales, N and Rogers, HM and Khodadadi, H and Young, N and Maciel, LM and Yu, JC and Hess, DC and Morgan, JC and Lopes Salles, É and Wang, LP and Baban, B},
title = {Rethinking Alzheimer's: Harnessing Cannabidiol to Modulate IDO and cGAS Pathways for Neuroinflammation Control.},
journal = {eNeuro},
volume = {},
number = {},
pages = {},
doi = {10.1523/ENEURO.0114-25.2025},
pmid = {41052930},
issn = {2373-2822},
abstract = {Alzheimer's disease (AD) has traditionally been associated with amyloid-β plaques, but growing evidence underscores the role of neuroinflammation in disease progression. The autoinflammatory hypothesis of AD suggests chronic immune dysfunction contributes to neuronal damage, making immune modulation a promising therapeutic strategy.Cannabidiol (CBD), a phytocannabinoid with anti-inflammatory properties, may offer therapeutic potential. This study investigates how CBD independently influences two key neuroinflammatory regulators in AD: the Indoleamine 2,3-dioxygenase (IDO) pathway and the cyclic GMP-AMP synthase (cGAS) pathway. Though mechanistically distinct, both shape CNS immune responses. Targeting these immune-metabolic axes provides a mechanistic alternative to amyloid- or tau-based approaches by addressing upstream drivers of neuroinflammation and immune dysregulation. Using the male 5XFAD transgenic AD mouse model, we administered CBD via inhalation and assessed IDO and cGAS expression using flow cytometry, immunofluorescence, and gene expression analysis. We evaluated cytokine levels and used STRING-based bioinformatics to identify CBD-target interactions. CBD treatment significantly reduced IDO and cGAS expression, correlating with decreased pro-inflammatory cytokines, including TNF-α, IL-1β, and IFN-γ. Bioinformatics identified potential interactions between CBD and immune targets such as AKT1, TRPV1, and GPR55. These targets were prioritized based on their roles in neuroinflammatory signaling and high-confidence interactions with CBD. AKT1 regulates inflammatory signaling and cell survival, TRPV1 modulates nociception and neuroinflammation, and GPR55 influences immune cell activation. These findings support CBD as a potential monotherapy or adjunctive treatment for AD by targeting distinct neuroinflammatory pathways, including IDO and cGAS. Further studies are warranted to fully explore its therapeutic potential.Significance statement This study highlights the therapeutic potential of cannabidiol (CBD) in targeting neuroinflammation, a major driver of Alzheimer's disease (AD) progression. By modulating the IDO and cGAS pathways-critical regulators of CNS immune responses-CBD reduces pro-inflammatory cytokines and ameliorates immune dysfunction. These findings support the emerging autoinflammatory hypothesis of AD, which posits that chronic inflammation underlies neuronal damage. The IDO/cGAS signaling axis, located at the intersection of innate immunity and metabolic regulation, remains underexplored in AD and represents a key intervention point to disrupt neuroinflammatory loops. This study positions CBD as a promising mono- or adjunctive therapy and reinforces the need to consider multi-targeted strategies that address upstream immune mechanisms in neurodegenerative disease.},
}

@article {pmid41052554,
year = {2025},
author = {Xu, Z and Yan, X and Xia, P and Zhu, Y and Chen, Y and Guo, C and Li, H},
title = {Insights into the coaggregation mechanisms of amyloid-α and amyloid-β.},
journal = {International journal of biological macromolecules},
volume = {},
number = {},
pages = {148086},
doi = {10.1016/j.ijbiomac.2025.148086},
pmid = {41052554},
issn = {1879-0003},
abstract = {The aggregation of amyloid-β protein (Aβ) into oligomers and amyloid fibrils is a critical event in the pathogenesis of Alzheimer's disease (AD). Notably, previous studies have suggested that cross-interactions between amyloid-α protein (Aα) and Aβ could provide a novel therapeutic strategy for AD. However, the physical mechanism of Aα co-assembly with Aβ during the early stage remains elusive due to the fast aggregation speed. Herein, to investigate the effect of Aα on Aβ assembly, we performed molecular dynamics (MD) simulations on Aα/Aβ mixed heterooctamer and Aα/Aβ isolated homooctamer systems. Based on the currently observed patterns of Aα/Aβ mixed heterooctamer, we proposed that the most stable pattern is the (Aα2Aβ2)2 system featuring two chains of Aα adjacent to two chains of Aβ in each layer. Our results demonstrate that Aα induced Aβ to form more β-sheet content in the 17-42 segment. Structural analysis reveals that the intra-layer salt bridge and the inter-layer hydrophobic interactions play crucial roles in the co-assembly process of Aα and Aβ. Our work dissects the Aα/Aβ co-assembly mechanisms at the atomic level, which will contribute to a deeper understanding of the pathogenesis of AD.},
}

@article {pmid41052547,
year = {2025},
author = {Ajoolabady, A and Kim, B and Abdulkhaliq, AA and Ren, J and Bahijri, S and Tuomilehto, J and Borai, A and Khan, J and Pratico, D},
title = {Dual role of microglia in neuroinflammation and neurodegenerative diseases.},
journal = {Neurobiology of disease},
volume = {},
number = {},
pages = {107133},
doi = {10.1016/j.nbd.2025.107133},
pmid = {41052547},
issn = {1095-953X},
abstract = {Microglia are the principal innate immune cells of the central nervous system, playing cardinal roles in regulating immunity and mediating neuroinflammation - a chronic inflammatory response occurring in the brain and spinal cord. Microglia exhibit a dual role in this process: they can suppress neuroinflammation through anti-inflammatory polarization or inhibition of proinflammatory intracellular signaling, or conversely, they can exacerbate neuroinflammation via activation of proinflammatory pathways and phenotypes. This seemingly binary behavior is further complicated by a network of internal and external molecular effectors that influence microglial polarization and function, guiding them toward either neuroprotection or neurotoxicity. In this narrative review, we aimed to elucidate the dual role of microglia in neuroinflammation, particularly in the context of neurodegenerative diseases and other brain pathologies. Special emphasis is placed on the most recent findings related to key proteins such as TREM2 (triggering receptor expressed on myeloid cells 2) and HMGB1 (high mobility group box 1 protein). By examining the molecular mechanisms and pathways involving these proteins, we highlight promising therapeutic targets for modulating neuroinflammation and advancing developing novel treatment strategies for neurodegenerative and other brain-related disorders.},
}

@article {pmid41052542,
year = {2025},
author = {Hansen, N and Wiltfang, J},
title = {[Disease-modifying therapy with lecanemab for early Alzheimer's dementia].},
journal = {Fortschritte der Neurologie-Psychiatrie},
volume = {},
number = {},
pages = {},
doi = {10.1055/a-2681-4558},
pmid = {41052542},
issn = {1439-3522},
abstract = {Alzheimer's disease (AD) is a severe and progressive neurodegenerative disease of the brain that has so far been treated with symptomatic drug and non-drug therapies as standard treatment. Following the approval of the monoclonal anti-amyloid antibody by the FDA, AD therapy has changed, as this therapy has made it possible to attenuate the biological disease process of AD. Lecanemab has been recommended by the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) for approval in patients with early AD under two conditions. Firstly, homozygous ApoE4 carriers and secondly, patients receiving oral anticoagulants should not receive lecanemab. The following narrative review explains the mechanism of action, safety and side effects of lecanemab. Furthermore, risk factors for side effects are described. Finally, the first experiences with lecanemab are reported and the efficacy and financial aspects are discussed. Lecanemab leads to a temporary reduction in amyloid-ß deposits and to a benefit that can be reflected in everyday competence, cognition and quality of life and can be described as a breakthrough in AD's therapy due to its demonstrable biological and clinical efficacy.},
}

@article {pmid41052405,
year = {2025},
author = {Cerino, ES and McCoy, MC and Martinez, M and Seaton, TJ and Dopson, R and Anderson, TJ and Porter, G and Shannon, FR and Livingston, RA and Black, AD and Mogle, J and Lucero, L and McCarthy, MJ},
title = {Supporting Individuals With Cognitive Impairment and Family Members in Rural Communities: Protocol for a Mixed Methods Digital Health Study.},
journal = {JMIR research protocols},
volume = {14},
number = {},
pages = {e77958},
doi = {10.2196/77958},
pmid = {41052405},
issn = {1929-0748},
mesh = {Humans ; *Cognitive Dysfunction/diagnosis/therapy/psychology ; *Rural Population ; Arizona ; *Family/psychology ; Male ; Female ; Telemedicine ; Caregivers/psychology ; Aged ; Surveys and Questionnaires ; Research Design ; Digital Health ; },
abstract = {BACKGROUND: The health and economic burdens of Alzheimer disease and related dementias (ADRD) are exacerbated for people living in rural social contexts who experience geographic barriers to care. There are currently few resources specifically designed to support socioculturally diverse rural ADRD care dyads, including early detection of potential precursors to ADRD such as mild cognitive impairment (MCI) and subjective cognitive decline (SCD).

OBJECTIVE: The primary objective of the Northern Arizona Memory Study (NAZMS) is to develop culturally informed and scalable resources to identify and support rural families at risk for ADRD. The purpose of this study is to introduce the NAZMS protocol and discuss its role in addressing dementia risk and promoting cognitive health in rural communities.

METHODS: This dyadic study will use a mixed methods, digital health approach. A sample of rural care dyads with MCI or SCD will be screened and recruited through partnerships with community centers across Northern Arizona. Consenting dyads will complete semistructured interviews to answer questions about technology preferences for monitoring symptoms and engaging in remotely delivered interventions. Next, care dyads will complete separate baseline questionnaires assessing dyadic (eg, experiences with caregiving or care receiving) and health factors. Participants with cognitive impairment will then complete a 14-day mobile protocol of brief end-of-day surveys and cognitive assessments delivered via study-provided smartphones.

RESULTS: Data from the qualitative interviews will provide dyad preferences for intervention development. Data from the quantitative protocol will specify for whom (ie, between-person) and on which days (ie, within-person) modifiable factors are related to better cognitive health in everyday life.

CONCLUSIONS: This study will take a mixed methods, digital health approach to supporting rural families at risk for ADRD by understanding intervention preferences and identifying the modifiable protective and risk factors that influence cognitive health in everyday life. The findings are expected to directly support rural Arizonans and respond to national priorities in ADRD research for the development of community-based disease education programs and the use of digital assessments of cognitive health and well-being.},
}

Humans
*Cognitive Dysfunction/diagnosis/therapy/psychology
*Rural Population
Arizona
*Family/psychology
Male
Female
Telemedicine
Caregivers/psychology
Aged
Surveys and Questionnaires
Research Design
Digital Health

@article {pmid41052384,
year = {2025},
author = {Shields, KE},
title = {Uninformed Consent In An Alzheimer's Clinical Trial.},
journal = {Health affairs (Project Hope)},
volume = {44},
number = {10},
pages = {1317-1320},
doi = {10.1377/hlthaff.2025.00314},
pmid = {41052384},
issn = {2694-233X},
mesh = {Humans ; *Alzheimer Disease/drug therapy ; *Informed Consent/psychology ; *Clinical Trials as Topic ; Female ; Male ; Aged ; },
abstract = {An Alzheimer's drug trial participant experiences serious adverse effects and feels inadequately informed about the drug's risks.},
}

Humans
*Alzheimer Disease/drug therapy
*Informed Consent/psychology
*Clinical Trials as Topic
Female
Male
Aged

@article {pmid41052375,
year = {2025},
author = {Edwards, NC and Lao, P and Alshikho, MJ and Mazen, J and Huber, B and Hale, C and Berroa, J and Morel, N and Pacheco, A and Walker, S and Herman, M and Gutierrez, J and Wilcock, DM and Simoes, S and Manly, JJ and Brickman, AM},
title = {Alzheimer Disease, Vascular Disease, and Blood-Brain Barrier Permeability Biomarkers in Middle-Aged Adults.},
journal = {Neurology},
volume = {105},
number = {9},
pages = {e214220},
doi = {10.1212/WNL.0000000000214220},
pmid = {41052375},
issn = {1526-632X},
mesh = {Humans ; Female ; *Alzheimer Disease/blood/diagnostic imaging ; Male ; Middle Aged ; Biomarkers/blood ; *Blood-Brain Barrier/metabolism/diagnostic imaging ; Amyloid beta-Peptides/blood ; tau Proteins/blood ; Magnetic Resonance Imaging ; Placenta Growth Factor/blood ; *Cerebrovascular Disorders/blood/diagnostic imaging ; Glial Fibrillary Acidic Protein/blood ; Neurofilament Proteins/blood ; Vascular Endothelial Growth Factor A/blood ; },
abstract = {BACKGROUND AND OBJECTIVES: Cerebrovascular disease (CVD) influences Alzheimer disease (AD) risk and progression, but the link between vascular disease and AD pathophysiology remains unclear, particularly in midlife when the impact of CVD on AD risk may be strongest. This study examined the relationship of recently validated vascular cognitive impairment (VCI) plasma biomarker concentrations that reflect aspects of blood-brain barrier dysfunction with MRI markers of CVD and AD plasma biomarker concentrations.

METHODS: The study included middle-aged participants from the Offspring Study of Racial and Ethnic Disparities in AD who had MRI and plasma biomarker data available. Biomarker concentrations of vascular endothelial growth factor (VEGF) family members (VEGF-D, placental growth factor [PlGF], and basic fibroblast growth factor [bFGF]) were measured using the Meso Scale Discovery platform. β-Amyloid (Aβ42, Aβ40), phosphorylated tau 181 (p-tau181), astrocytosis (glial fibrillary acidic protein [GFAP]), and neurodegeneration (neurofilament light chain [NfL]) biomarkers were measured with Simoa immunoassays. White matter hyperintensity (WMH) volumes were derived from T2-weighted MRI scans. Bivariate relationships of WMH, Aβ42/Aβ40 ratio, p-tau181, GFAP, and NfL with VEGF biomarkers were tested, and path analyses examined potential causal pathways linking each VEGF biomarker concentration to WMH and GFAP, as well as their downstream associations with tau pathology and neurodegeneration.

RESULTS: We analyzed data from 488 participants (mean [SD] age = 54.3 [10.5]; 66.8% women). Higher PlGF levels were associated with older age (R [CI] = 0.25 [0.17-0.33]); greater WMH volume (R [CI] = 0.2 [0.11-0.29]); and higher levels of GFAP (R [CI] = 0.11 [0.02-0.2]), p-tau181 (R [CI] = 0.12 [0.03-0.21]), and NfL (R [CI] = 0.19 [0.1-0.27]). Higher VEGF-D was associated with increased GFAP (R [CI] = 0.11 [0.02-0.19]) and NfL (R [CI] = 0.16 [0.07-0.25]) levels. bFGF concentration was associated with a lower Aβ42/40 ratio (R [CI] = -0.1 [-0.19 to -0.02]) and higher p-tau181 levels (R [CI] = 0.13 [0.04-0.21]). The best fitting path model showed that PlGF had an indirect effect on GFAP levels mediated by WMH. GFAP subsequently had a direct positive effect on p-tau181, which in turn had a positive effect on NfL levels. VEGF-D and bFGF levels also had a positive direct effect on NfL.

DISCUSSION: The findings suggest that permeability of the blood-brain barrier is linked to AD pathophysiology, contributes to cerebrovascular lesions observed on MRI, and is associated with neuroinflammation in middle age.},
}

Humans
Female
*Alzheimer Disease/blood/diagnostic imaging
Male
Middle Aged
Biomarkers/blood
*Blood-Brain Barrier/metabolism/diagnostic imaging
Amyloid beta-Peptides/blood
tau Proteins/blood
Magnetic Resonance Imaging
Placenta Growth Factor/blood
*Cerebrovascular Disorders/blood/diagnostic imaging
Glial Fibrillary Acidic Protein/blood
Neurofilament Proteins/blood
Vascular Endothelial Growth Factor A/blood

@article {pmid41051912,
year = {2025},
author = {Hickman, LB and Pandey, B and Fish, A and Bandla, M and Husein, A and Allas, C and Kottakota, H and Herzog, L and Vossel, K and Stern, JM},
title = {Late-onset epilepsy of unknown etiology is more treatment-responsive than acquired lesional late-onset epilepsy.},
journal = {Epilepsia open},
volume = {},
number = {},
pages = {},
doi = {10.1002/epi4.70156},
pmid = {41051912},
issn = {2470-9239},
support = {UE5 NS065723-16/NS/NINDS NIH HHS/United States ; R01 NS033310/NS/NINDS NIH HHS/United States ; R01 AG058820/NS/NINDS NIH HHS/United States ; R01 AG075955/NS/NINDS NIH HHS/United States ; R56 AG074473/NS/NINDS NIH HHS/United States ; UH2 AG083254/NS/NINDS NIH HHS/United States ; },
abstract = {OBJECTIVE: Late-onset epilepsy of unknown etiology (LOEU) carries an elevated risk of dementia, suggesting that it may represent an early manifestation of neurodegenerative or cerebrovascular disease. Direct comparisons between LOEU and acquired lesional late-onset epilepsy (LOE) may elucidate clinical features specific to LOEU.

METHODS: We performed a retrospective chart review of patients with LOE, with first documented seizure at age 55 or older, whose evaluation included an epilepsy-protocol brain MRI and/or inpatient video-EEG evaluation. Etiology was determined from neuroimaging lesions and medical history. Patients without an identified etiology were categorized as LOEU. Analyses were performed controlling for sex, age of onset, and epilepsy duration.

RESULTS: We identified 75 LOEU (mean onset: 64.9 years, 38.7% female) and 57 acquired lesional LOE cases with etiologies including cortical stroke, hemorrhage, neoplasm, trauma, or infection (mean onset: 66.5 years, 36.8% female). LOEU was less likely to have a history of status epilepticus (6.7% vs. 21.1%, aOR: 0.28, p < 0.03) or to have undergone inpatient video-EEG monitoring (13.3% vs. 24.6%, aOR: 0.34, p < 0.04). LOEU was prescribed fewer ASMs compared to acquired lesional LOE (aOR: 0.43, p < 0.02), and LOEU patients prescribed multiple ASMs had lower average 12-month seizure frequency than acquired lesional LOE (median: 0.2 vs. 1.0, p < 0.01). LOEU had lower rates of vascular comorbidities than acquired lesional LOE, though rates of subsequent dementia were not significantly different (5-year risk: 16.6% vs. 17.7%). An exploratory cluster analysis demonstrated an LOEU subgroup with older onset, higher prevalence of white matter hyperintensities, cerebral atrophy, epileptiform discharges, and greater epilepsy severity.

SIGNIFICANCE: LOEU was associated with fewer proxies for epilepsy severity, signifying that LOEU is more often treatment-responsive than acquired lesional LOE. LOEU has lower rates of comorbid vascular disease compared to acquired lesional LOE, suggesting that occult cerebrovascular disease is not overrepresented in LOEU relative to other forms of LOE.

PLAIN LANGUAGE SUMMARY: People who develop epilepsy after age 55 without a known cause usually respond well to treatment and need fewer antiseizure medications than people with epilepsy from a known brain injury. In this study, they had fewer hospital stays for seizure monitoring and fewer vascular problems. Dementia risk was high in patients with late-onset epilepsy, both when the cause was known and when it was unknown. Late-onset epilepsy without a known cause is often less severe but still needs regular monitoring for memory and thinking problems.},
}

@article {pmid41051722,
year = {2025},
author = {Mohan Kumar, D and Talwar, P},
title = {Amyloid-β, Tau, and α-Synuclein Protein Interactomes as Therapeutic Targets in Neurodegenerative Diseases.},
journal = {Cellular and molecular neurobiology},
volume = {45},
number = {1},
pages = {84},
pmid = {41051722},
issn = {1573-6830},
support = {SG20240107//Vellore Institute of Technology, Vellore, India/ ; },
mesh = {*tau Proteins/metabolism ; *alpha-Synuclein/metabolism ; Humans ; *Neurodegenerative Diseases/metabolism/drug therapy ; *Amyloid beta-Peptides/metabolism ; Protein Interaction Maps ; },
abstract = {Alzheimer's and Parkinson's disease are the most prevalent neurological diseases. Amyloid-β, tau, and α-synuclein proteins are known to be implicated in neurodegenerative disease (NDD). Elucidation of precise therapeutic targets remains a challenge. Therefore, the identification of interactomes of amyloid-β precursor protein (APP), microtubule-associated protein tau (MAPT), and α-synuclein (SNCA) proteins is of great interest, aimed at unraveling novel targets. An integrated analysis was employed to identify direct interactors as therapeutic targets, considering protein-protein interactions and subsequent network analysis. Further, it was proposed to identify hub proteins, intended targets, regulatory factors, disease-gene associations, functional enrichment analyses of the protein interactors interfered with gene ontologies and disease-driving pathways. Protein interactome centered on APP, MAPT, and SNCA identified the top hundred high-confidence protein-protein interactions that revealed BACE1, PSEN1, SORL1, GSK3B, CDK5, SNCAIP, PRKN, and APOE as physical and functional protein interactors. The top ten hub proteins were ranked based on multiple centrality measures and topological algorithms. Further, the integrated network of all three protein interactomes contained distinct nodes with edges. Interestingly, regulatory mechanisms have revealed possible regulatory modules, including cleavage, phosphorylation, and ubiquitination. Top interacting proteins were enriched in several ontology terms, such as regulation of neuronal apoptotic processes, amyloid beta fibril formation, and tau protein binding. Pathway analysis mapped the pathways of neurodegeneration-multiple disease, with a significant level of interacting proteins. Finally, the most comprehensive interactome associated with NDD provides insights into protein interactors, regulating the mechanisms of key proteins that can serve as novel therapeutic targets.},
}

*tau Proteins/metabolism
*alpha-Synuclein/metabolism
Humans
*Neurodegenerative Diseases/metabolism/drug therapy
*Amyloid beta-Peptides/metabolism
Protein Interaction Maps

@article {pmid41051689,
year = {2025},
author = {Azam, HMH and Mumtaz, M and Rödiger, S and Schierack, P and Hussain, N and Aisha, A},
title = {MicroRNAs in neurodegenerative diseases: from molecular mechanisms to clinical biomarkers, detection methods and therapeutic strategies-advances and challenges.},
journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology},
volume = {},
number = {},
pages = {},
pmid = {41051689},
issn = {1590-3478},
abstract = {Neurodegenerative diseases (NDDs) pose significant challenges in early detection and treatment due to their complex pathophysiology and heterogeneous clinical presentations. MicroRNAs (miRNAs), small noncoding RNAs that regulate gene expression, have emerged as promising diagnostic biomarkers and therapeutic targets in NDDs. Pathological examination of affected tissues reveals early synaptic dysfunction, protein misfolding, and neuroinflammation occur prior to overt clinical symptoms, highlighting the importance of sensitive diagnostics approaches in prodromal stages. This review summarizes for researchers on the role of miRNAs in NDDs by examining their diagnostic potential in biofluids such as blood and cerebrospinal fluid, and their therapeutic applicability through inhibition or replacement strategies. Literature from peer-reviewed databases was assessed with a focus on recent advances in molecular detection platforms, computational modeling of miRNA-mRNA interactions, and preclinical/clinical investigations.More than 2600 human miRNAs have been identified, collectively regulating over half of mammalian protein-coding genes. Quantitative methodologies, particularly reverse transcription quantitative PCR (RT-qPCR), enable reliable miRNA profiling, facilitating early diagnosis and prognosis of NDDs. Therapeutic strategies, including antagomirs, mimics, sponges and viral or non-viral delivery systems, show promise in modulating disease pathways. However, significant challenges remain, including variability in miRNA extraction and quantification protocols, off-target effects, delivery barriers across the blood brain barrier and limited reproducibility across studies. MiRNAs represent a class of molecular tools with potential to transform diagnostics and therapeutics in NDDs. Future research should prioritize methodological standardization, validation in large multicenter cohorts, and improved computational approaches to elucidate miRNA-mediated regulatory networks in NDDs. Replication studies and translational research are essential harnessing the the full clinical utility of miRNAs in the management of Alzheimer disease, Parkinson disease and other NDDs. Graphical Abstract.},
}

@article {pmid41051550,
year = {2025},
author = {Yang, T},
title = {Molecular Mechanisms of EDC-Induced Alzheimer's Disease and of Traditional Chinese Medicine Active Substances in Treating AD and Antagonizing EDC-Induced Effects.},
journal = {Neurochemical research},
volume = {50},
number = {5},
pages = {319},
pmid = {41051550},
issn = {1573-6903},
mesh = {*Alzheimer Disease/chemically induced/drug therapy/metabolism ; Molecular Docking Simulation/methods ; *Medicine, Chinese Traditional/methods ; Humans ; *Drugs, Chinese Herbal/therapeutic use/pharmacology ; Animals ; Network Pharmacology ; Ginsenosides/therapeutic use/pharmacology ; Protein Interaction Maps/drug effects ; },
abstract = {AD, a progressive neurodegenerative disorder, imposes an increasingly heavy burden on global public health, with its pathogenesis remaining incompletely understood. Meanwhile, EDCs-widely present in the environment, food, and consumer products-have emerged as a significant public health concern due to their diverse health risks, including potential contributions to neurodegenerative processes such as AD by disrupting neurohomeostasis. Furthermore, as natural compounds, ginsenosides and other AS have been the focus of numerous studies exploring their role in treating AD, thanks to their advantages of multi-target properties and low side effects. However, the specific molecular pathways through which EDCs induce AD, as well as the mechanisms by which AS may counteract EDC-induced toxicity and intervene in AD, remain unclear. Against this background, this study sought to: (1) explore the molecular pathways through which EDCs may induce AD by disrupting neurohomeostasis; (2) preliminarily investigate the potential of AS in treating AD and antagonizing EDC-induced AD at the molecular level. To achieve these goals, we integrated network toxicology, network pharmacology, and molecular docking to construct a multi-dimensional interaction network among EDCs, AD, and AS. By establishing intersecting target sets for EDCs-AD and AS-AD, core targets were identified via topology analysis of protein-protein interaction (PPI) networks. GO and KEGG enrichment analyses highlighted key pathways, including serotonergic synapse and neuroactive ligand-receptor interaction. Molecular docking further explored interactions between EDCs/AS and core target proteins. The results suggest that EDCs may drive neurodegeneration in AD by impairing synaptic function, while AS may counteract these effects by enhancing synaptic activity, stabilizing membrane microenvironments, inhibiting Aβ aggregation, alleviating neuroinflammation, and restoring metabolic homeostasis. Further analysis indicated that AS exhibit stronger binding ability to core targets compared to EDCs, implying a potential antagonistic effect of AS against EDCs. This study provides insights into the molecular mechanisms underlying EDC-induced AD and establishes a multi-target theoretical framework for AS-mediated antagonism of EDC toxicity, offering a reference for the prevention and treatment of neurodegenerative diseases.},
}

*Alzheimer Disease/chemically induced/drug therapy/metabolism
Molecular Docking Simulation/methods
*Medicine, Chinese Traditional/methods
Humans
*Drugs, Chinese Herbal/therapeutic use/pharmacology
Animals
Network Pharmacology
Ginsenosides/therapeutic use/pharmacology
Protein Interaction Maps/drug effects

@article {pmid41051494,
year = {2025},
author = {Das, M and Debnath, S and Sar, S and Kumar, V and Dey, RK and Meena, AK and Roy, S and Bolleddu, R and Babu, G},
title = {HPTLC, GC-MS profiling, and biological activity comparison of Cinnamomum zeylanicum Blume (stem bark) essential oil between Indian and African varieties.},
journal = {Naunyn-Schmiedeberg's archives of pharmacology},
volume = {},
number = {},
pages = {},
pmid = {41051494},
issn = {1432-1912},
abstract = {Cinnamomum zeylanicum Blume, known for its medicinal and culinary value, was analyzed for comparative phytochemical profiling and antioxidant potential between Indian (Shillong, Kolkata) and African (Tanzania) stem bark varieties. Using HPTLC and GC-MS, the essential oils revealed key variations in chemical constituents, notably the exclusive presence of eugenol in the Tanzanian variety and higher cinnamaldehyde dimethyl acetal content. Physicochemical and organoleptic differences reflected geographic influence. Antioxidant studies using DPPH and FRAP assays confirmed superior activity in the Tanzanian sample, with the lowest IC50 (22.05 µg/ml) and highest FRAP value (579 µM). Phytochemical screening confirmed the presence of multiple bioactive compounds in the samples. These results underscore the significance of geographical origin in the quality and efficacy of medicinal plants, supporting the need for standardization protocols. This study provides a robust framework for evaluating regional variations in C. zeylanicum, enhancing its pharmacological validation and ensuring authenticity in herbal formulations. Molecular docking study with eugenol revealed strong binding affinity of eugenol with protein targets PTP1B, PPARγ, PPARδ, and PPARα in diabetes, and with BACE1 in Alzheimer's disease.},
}

@article {pmid41051385,
year = {2025},
author = {Xie, D and Zheng, Q and Lv, J and Zhang, Q and Cui, Z and Huang, S and Yu, W and Chen, B and Que, W and Fu, S and Xi, Y and Chen, J and Ye, X and Chen, S and Zhao, H and Yamamoto, T and Koyama, H and Wang, X and Cheng, J},
title = {Uric Acid Functions as an Endogenous Modulator of Microglial Function and Amyloid Clearance in Alzheimer's Disease.},
journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
volume = {},
number = {},
pages = {e10270},
doi = {10.1002/advs.202510270},
pmid = {41051385},
issn = {2198-3844},
support = {2022Y4007//Fujian Provincial Industry-University-Research Collaborative Innovation Project Plan/ ; U01 AG024904/AG/NIA NIH HHS/United States ; W81XWH-12-2-0012//DOD ADNI/ ; 2020J01018//Natural Science Foundation of Fujian Province/ ; 82260163//National Natural Science Foundation of China/ ; 82370895//National Natural Science Foundation of China/ ; 82271451//National Natural Science Foundation of China/ ; },
abstract = {Epidemiological studies have linked uric acid (UA), the end product of purine metabolism in humans, with reduced Alzheimer's disease (AD) risk. Decreased serum UA levels are observed in AD patients versus age-matched controls, while upstream purine metabolites remained unchanged. In 5×FAD mice, two months of UA supplementation improved cognitive function and reduced amyloid plaque burden. Mechanistically, UA enhances microglial amyloid-β (Aβ) phagocytosis and induces transcriptional reprogramming in AD mouse microglia, characterized by upregulated phagocytic pathways and attenuated inflammatory responses. UA treatment restored the recycling of Aβ receptors CD36 and TREM2 in microglia, enhanced lysosomal biogenesis, and facilitated Aβ degradation. These findings identify UA as a critical endogenous modulator of microglial Aβ processing and suggest exploring UA supplementation as a therapeutic strategy for AD.},
}

@article {pmid41051312,
year = {2025},
author = {Karlsson, L and Janelidze, S and Barthélemy, NR and Horie, K and Therriault, J and Gaetani, L and Bellomo, G and Schindler, SE and Vogel, J and Arvidsson, I and Åström, K and Gordon, BA and Raji, CA and Benzinger, TLS and Morris, JC and Nilsson, J and Brinkmalm, A and Palmqvist, S and Stomrud, E and Salvadó, G and Pichet Binette, A and Di Filippo, M and Parnetti, L and Rosa-Neto, P and Blennow, K and Bateman, RJ and Mattsson-Carlgren, N and Hansson, O},
title = {Reference proteins to improve Core 1 and Core 2 Alzheimer's disease CSF and plasma biomarkers.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awaf375},
pmid = {41051312},
issn = {1460-2156},
abstract = {Concentration-based fluid biomarkers represent an informative and cost-effective way to detect and monitor Alzheimer's disease (AD) pathology. However, non-AD-related inter-individual variation in biofluids can also affect biomarker concentrations. Here, we investigated whether normalization of cerebrospinal fluid (CSF) and plasma biomarkers to reference proteins, such as amyloid-β40 (Aβ40) and non-phosphorylated mid-region tau (np-tau), improves their robustness and reliability of representing AD pathology load. Using the Swedish BioFINDER-2 cohort (n=1702, 50.7% male, mean [SD] age 68.4 [12.2] years), we compared the associations between tau/Aβ-PET load and fluid biomarkers alone versus in a ratio with a reference protein (Aβ40 or np-tau) in univariate linear regression models. Fluid biomarkers included CSF and plasma measures of p-tau217, p-tau181, p-tau205, np-tau181-190, np-tau195-210, np-tau212-221, Aβ42, Aβ40, and CSF MTBR-tau243, SNAP-25, neurogranin, YKL-40, sTREM2, and plasma eMTBR-tau243. Biomarkers were measured with mass spectrometry assays and/or immunoassays. In addition, we performed validation and extended analyses, comparing for example group-level diagnostic differences and longitudinal biomarker trajectories, in three independent prospective cohorts: BioFINDER-1, Knight Alzheimer Disease Research Center (ADRC), and Translational Biomarkers in Aging and Dementia (TRIAD), as well as in an Italian multiple sclerosis cohort. CSF Aβ40 normalization significantly strengthened the associations of several core CSF AD biomarkers, including CSF MTBR-tau243, p-tau isoforms and synaptic biomarkers, with tau-PET (ΔR[2]=0.064-0.24) and Aβ-PET (ΔR[2] = 0.016-0.28). Normalization to CSF np-tau mainly improved concordance with Aβ-PET (ΔR[2] = -0.0059-0.19). The strongest association with tau-PET was observed for MTBR-tau243/Aβ40 (R[2] = 0.78, compared to 0.65 for non-normalized MTBR-tau243), and with Aβ-PET for p-tau217/np-tau (R[2] = 0.65, compared to 0.46 for non-normalized p-tau217). Plasma biomarker associations with tau-PET improved when using normalization to plasma Aβ40 or np-tau (ΔR[2] = 0.004-0.14), with the strongest effect for eMTBR-tau243/np-tau (R[2] = 0.72 versus 0.60). Associations with Aβ-PET were enhanced with np-tau normalization (ΔR[2] = 0.018-0.16, strongest for p-tau217/np-tau: R[2] = 0.62 versus 0.53). The results were replicated in Knight ADRC and TRIAD. Furthermore, longitudinal analyses showed that Aβ40 normalization typically reduced inter-individual rather than intra-individual variability over time. Normalization did not enhance group-level differences in inflammatory CSF biomarkers in AD, nor did it improve biomarker associations in the multiple sclerosis cohort. In conclusion, normalization of CSF and plasma biomarkers to reference proteins, such as Aβ40 or np-tau, enhances their association with brain tau and Aβ pathology, making already high-performing AD fluid biomarkers even more accurate.},
}

@article {pmid41051231,
year = {2025},
author = {Paul, S and Guruprasad, L},
title = {Hexagonal Boron Nitride Nanoparticles for Inhibition of Small Fragment Tau Aggregation.},
journal = {The journal of physical chemistry. B},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.jpcb.5c04935},
pmid = {41051231},
issn = {1520-5207},
abstract = {The aberrant folding of the Tau protein is correlated with several neurodegenerative diseases, such as Alzheimer's and other tauopathies. Recent studies on the neurotoxic species of Tau have identified some smaller nucleating domains of the full-length protein to initiate Tau aggregation and are shown as potential therapeutic targets in Tau pathology. Two hexapeptides, namely, PHF6 ([306]VQIVYK[311]) and PHF6* ([275]VQIINK[280]), have been recognized as the most important aggregation-prone Tau fragments among all. Currently, low-dimensional nanomaterials have shown a plethora of applications in bionanomedicine, including the treatment of amyloid diseases. Hexagonal boron nitride (h-BN) nanoparticles, analogous to carbon nanomaterials, have become potential candidates in this field due to their lower cytotoxicity compared to carbon nanoparticles and biocompatibility. In this study, we have explored the aggregation pattern of PHF6 and PHF6* and the effects of a two-dimensional (2D) h-BN nanosheet (BNNS) on these peptide oligomerizations. Atomistic simulations reveal that the PHF6-PHF6 homomer aggregation is highly favored due to the aromatic π-π interaction between the Tyr residues; furthermore, the heteromeric interaction between PHF6 and PHF6* is stronger than the self-association of PHF6* homomers. In the presence of BNNS, the peptides get absorbed on the nanosurface through weak hydrophobic interactions and aromatic π-π stacking and remain in their monomeric random coil structure. Also, the h-BN nanosheet can destabilize the preformed oligomers of the hexapeptides, hence providing a new direction toward the use of h-BN and other related nanomaterials as potential antiaggregating agents against amyloid deposition.},
}

@article {pmid41051061,
year = {2025},
author = {Dhillon, A and Fazal, J},
title = {Risk Factors for Dementia in a Sample of Patients From a Quaternary Care Hospital Network in the United Arab Emirates: A Case-control Study.},
journal = {Alzheimer disease and associated disorders},
volume = {},
number = {},
pages = {},
doi = {10.1097/WAD.0000000000000691},
pmid = {41051061},
issn = {1546-4156},
abstract = {BACKGROUND: Data on risk factors for dementia in the MENA region and specifically in the UAE are limited.

METHODS: A case-control study of dementia patients and age-matched controls identified over 10 years at a quaternary care hospital network in Abu Dhabi. Historic data on cardiovascular, neurological, psychiatric, and nutritional risk factors were collected for patients and controls.

RESULTS: A total of 281 dementia patients (mean age 74.9 ± 9.2 y, 46.3% females) and 281 age-matched controls (mean age 74.3 ± 4.6 y, 55.9% females) were included. Patients with dementia were more likely to have heart failure, cerebrovascular disease, chronic anemia, chronic kidney disease, Parkinson disease, other neurodegenerative changes, mood disorders, psychotic disorders, and vitamin D deficiency, and less likely to have hyperlipidemia compared with controls. On logistic regression, only cerebrovascular disease (OR: 6.578, 95% CI: 2.163-20.004, P = 0.001) and mood disorders (OR: 10.046, 95% CI: 2.255-44.751, P = 0.002) were significantly and independently associated with dementia, while hyperlipidemia was protective (OR: 0.531, 95% CI: 0.360-0.783, P = 0.001).

CONCLUSION: Cerebrovascular disease and mood disorders are potential risk factors for dementia in the MENA region, while a protective role for hyperlipidemia warrants further investigation.},
}

@article {pmid41051040,
year = {2025},
author = {Agarwal, U and Paliwal, S and Yadav, V and Pannu, A and Tonk, RK and Verma, S},
title = {Pathological Insights into Neurodegenerative and Neurodevelopmental Disorders: Perspectives for the Development of Novel Treatment Approaches.},
journal = {CNS & neurological disorders drug targets},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118715273402657250905055635},
pmid = {41051040},
issn = {1996-3181},
abstract = {Neurodegenerative and neurodevelopmental disorders represent a significant global health burden, characterized by progressive neuronal dysfunction and loss. Both diseases, despite their diverse etiologies and mechanisms, share a complex interplay of genetic, environmental, and biological factors. Neurodegenerative diseases are caused by multiple factors, including aging, mitochondrial dysfunction, oxidative stress, inflammation, genetic mutations, and protein misfolding. In contrast, neurodevelopmental disorders are primarily influenced by epigenetic alterations, neurotransmitter imbalances, early brain damage, environmental factors, and genetic variations. Despite extensive research, effective treatments remain unavailable due to the complexity of their pathologies and the biochemical pathways involved. A deep understanding of the complexities and individual differences associated with these disorders is crucial for developing effective treatments. In this background, this review provides a comprehensive overview of neurodegenerative and neurodevelopmental disorders, including their clinical symptoms, etiology, pathogenesis, underlying mechanisms, potential drug targets, reported drugs, advanced treatment options, and challenges in the drug discovery process. This comprehensive literature review was conducted using databases such as PubMed and Scopus, focusing on research published up to April 2025. By understanding the complexities of these disorders, researchers can develop novel therapeutic approaches, including potential drugs and advanced treatment methods, to mitigate their devastating impact.},
}

@article {pmid41050965,
year = {2025},
author = {Watson, JA and Knoedler, S and von Reibnitz, D and Zurfluh, CE and Imholz, C and Esposito, G and Schreiner, SJ and Gousopoulos, E and Cai, A and Kollarik, S and Giovanoli, P and Baumann, C and Lindenblatt, N},
title = {Brain Drain for Brain Gain: Potential Applications of Robotic-assisted Lymphatic Microsurgery in the Management of Neurological Disorders.},
journal = {Plastic and reconstructive surgery. Global open},
volume = {13},
number = {10},
pages = {e7191},
pmid = {41050965},
issn = {2169-7574},
abstract = {BACKGROUND: The central nervous system (CNS) was long believed to be devoid of lymphatic drainage. However, the discovery of the glymphatic system and meningeal lymphatics has revolutionized our understanding of cerebrospinal fluid homeostasis and neuroimmune interactions. The glymphatic system facilitates perivascular cerebrospinal fluid-interstitial fluid exchange and promotes neurotoxic waste clearance, whereas meningeal lymphatics serve as conduits between the CNS and peripheral lymphatic circulation. Dysfunction in these lymphatic efflux pathways has been implicated in the pathogenesis of neurological disorders such as Alzheimer disease, Parkinson disease, traumatic brain injury, and intracranial hemorrhage, where impaired waste removal contributes to protein aggregation, neuroinflammation, and hence, disease onset and progression.

METHODS: Recent preliminary evidence suggests that surgical modulation of lymphatic drainage may offer novel therapeutic avenues for these disorders, with lymphatic microsurgery, particularly deep cervical lymphovenous anastomosis (LVA), proposed as an innovative procedure to enhance CNS lymphatic outflow. The first case reports in Alzheimer disease patients demonstrated not only the operative feasibility of LVA but also postoperative cognitive improvements. Despite these promising findings, systematic (pre)clinical studies remain scarce, calling for further research.

RESULTS: This article examined the role of the brain lymphatic system in neurological disorders and discussed the potential of lymphatic microsurgery as a novel therapeutic intervention. We also highlight ongoing clinical trials and potential future innovations, including surgical robotic assistance, and report on 2 cases of deep neck LVA for central lymphatic disorders.

CONCLUSIONS: By combining neurolymphatic research with surgical advances, LVAs have the potential to redefine therapeutic paradigms in CNS disorder management.},
}

@article {pmid41050964,
year = {2025},
author = {Zhou, Z and Chen, X and Kou, W and Meng, F and Yu, L and Wen, J and Boey, J and Shah, V and Malagón, P},
title = {Modified Dynamic Lymphaticovenular Anastomosis for Surgical Management of Alzheimer Disease.},
journal = {Plastic and reconstructive surgery. Global open},
volume = {13},
number = {10},
pages = {e7082},
pmid = {41050964},
issn = {2169-7574},
abstract = {Alzheimer disease (AD) is a neurodegenerative disorder that frequently results in progressive cognitive decline. Despite the extensive research conducted on AD, there is presently no solution available due to its increasing prevalence. Recent research has suggested cervical lymphaticovenular anastomosis (LVA) as a therapeutic strategy to improve lymphatic outflow and potentially reduce AD symptoms. We established an amended LVA protocol to mitigate the risk of venous reflux, a prevalent issue associated with the original LVA methodology. A 64-year-old man of Chinese descent exhibited the typical signs and symptoms of AD. The absence of substantial progress with standard medical treatment led to the consideration of LVA. We used a lower limb vein graft for the LVA, anastomosing it to the cervical lymphatic vessels and external jugular vein. The cognitive function of the patient got better after LVA, as shown by higher Mini Mental State Examination and Montreal Cognitive Assessment scores. Fewer β-amyloid and tau protein deposits were observed on positron emission tomography/computed tomography scans. No adverse occurrences or issues were observed. The success in this case demonstrated the potential role of LVA in the management of AD. However, further thorough research is required to evaluate the efficacy of our technique.},
}

@article {pmid41050948,
year = {2025},
author = {Dogan, C and Miller, CE and Jefferis, T and Saranti, M and Tempesta, AJ and Schofield, AJ and Palaniappan, R and Bowman, H},
title = {Headache-specific hyperexcitation sensitises and habituates on different time scales: An event related potential study of pattern-glare.},
journal = {Neuroimage. Reports},
volume = {5},
number = {3},
pages = {100271},
pmid = {41050948},
issn = {2666-9560},
abstract = {Cortical hyperexcitability is a key pathophysiological feature in several neurological disorders, including migraine, epilepsy, tinnitus, and Alzheimer's disease. We examined the temporal characteristics of Event Related Potentials (ERPs) in a healthy population using the Pattern Glare Test, a diagnostic tool used to assess patients with sensitivity to cortical hyperexcitability. In pre-experiment questionnaires, participants reported their susceptibility to a range of symptoms. A factor analysis over these responses identified three variables, with the one we investigate in this paper loading strongly on headache symptoms, e.g. headache frequency. We investigated two timeframes: habituation over the course of the entire experiment and sensitization over the course of a sequence of stimulus presentations. We found evidence of hyperexcitability at electrodes over visual cortex, for the aggravating stimulus (grating of ∼3 cycles/deg). Participants higher on the headache factor exhibited a higher degree of habituation and sensitization, with evidence that the level of sensitization habituated through the course of the experiment. These findings suggest that the same experimental paradigm and analysis should be performed on a clinically diagnosed population.},
}

@article {pmid41050943,
year = {2025},
author = {Huff, AJ and Park, J and Montero-Hernandez, S and Park, L and Lee, C and Pollonini, L and Ahn, H},
title = {Functional near-infrared spectroscopy (fNIRS) detects brain changes for apathy and pain in patients with Alzheimer's disease and related dementias: An exploratory study.},
journal = {Neuroimage. Reports},
volume = {5},
number = {3},
pages = {100266},
pmid = {41050943},
issn = {2666-9560},
abstract = {Alzheimer's Disease and Related Dementias (ADRD) are degenerative and progressive in nature and are often accompanied by chronic pain and neuropsychiatric symptoms, which can be early signs and aggravators of ADRD. This exploratory study explores the relationship between self-reported pain, neuropsychiatric symptoms, and pain-evoked cortical hemodynamic changes measured using functional near-infrared spectroscopy (fNIRS) in the prefrontal and primary motor and somatosensory brain cortices bilaterally, stratified by high or low cognitive function in individuals with ADRD. This study analyzed baseline data of 40 individuals with mild to moderate ADRD with knee osteoarthritis. Baseline data from 40 individuals with mild to moderate ADRD and knee osteoarthritis were analyzed. Measures included self-reported pain, depression, and apathy, along with fNIRS-derived cerebral hemodynamic responses to sub-threshold thermal pain stimulation across five brain regions. The study revealed significant negative correlations for oxyhemoglobin and apathy in the right prefrontal cortex associated with low cognitive function (p = .04) and significant positive correlations for oxyhemoglobin and apathy in the right somatosensory region (p = .04) and for oxyhemoglobin and pain in the medial prefrontal cortex (p = .04) associated with higher cognitive function. Study findings suggest that fNIRS may provide valuable biomarkers for apathy and depression in individuals with ADRD and chronic osteoarthritic pain, with differential patterns based on cognitive function, suggesting neuropsychiatric symptoms may manifest differently depending on the patient's cognitive status. Future studies should explore its utility in larger, diverse samples and clinical interventions targeting neuropsychiatric symptoms.},
}

@article {pmid41050842,
year = {2025},
author = {Sun, Z and Cao, H},
title = {Regression analysis of multiplicative hazards model with time-dependent coefficient for sparse longitudinal covariates.},
journal = {Journal of nonparametric statistics},
volume = {},
number = {},
pages = {},
pmid = {41050842},
issn = {1048-5252},
abstract = {We study the multiplicative hazards model with intermittently observed longitudinal covariates and time-varying coefficients. For such models, the existing ad hoc approach, such as the last value carried forward, is biased. We propose a kernel weighting approach to get an unbiased estimation of the non-parametric coefficient function and establish asymptotic normality for any fixed time point. Furthermore, we construct the simultaneous confidence band to examine the overall magnitude of the variation. Simulation studies support our theoretical predictions and show favorable performance of the proposed method. A data set from Alzheimer's Disease Neuroimaging Initiative study is used to illustrate our methodology.},
}

@article {pmid41050829,
year = {2025},
author = {Christianson, K and Prabhu, M and Popp, ZT and Rahman, MS and Drane, J and Lee, M and Lathan, C and Lin, H and Au, R and Sunderaraman, P and Hwang, PH},
title = {Adherence timescale impacts completion rates of high-frequency mobile cognitive assessments among older adults.},
journal = {Exploration of medicine},
volume = {6},
number = {},
pages = {},
pmid = {41050829},
issn = {2692-3106},
abstract = {AIM: Mobile technology enables frequent, remote cognitive assessments, introducing new methodological opportunities and challenges. The study evaluated the feasibility of a high-frequency cognitive assessment schedule among older adults, in terms of total assessments and adherence to a prescribed schedule.

METHODS: Thirty-three older adults were recruited from the Boston University Alzheimer's Disease Research Center (mean age = 73.5 years; 27.3% cognitively impaired; 57.6% female; 81.8% White, 18.2% Black). Participants downloaded the DANA Brain Vital mobile application on their own mobile devices during a remote study visit, and were provided a schedule with seventeen assessments to complete over one year at varying frequencies. The first segment contained three subsegments to be completed within one week, the second segment consisted of weekly subsegments spanning three weeks, and the third and fourth segments consisted of monthly subsegments spanning five and six months, respectively. Three adherence types were defined to reflect incrementally broader adherence timescales: subsegment adherence (strict adherence to each prescribed assessment period), segment adherence (completing the required number of assessments within each broader segment), and cumulative adherence (completing the total number of assessments irrespective of timing).

RESULTS: Completion rates differed depending on the adherence timescale and corresponding adherence type. Using the strictest adherence definition (subsegment adherence), completion rates declined (from 93.9% to 72.7%, p = 0.05) during the fourth segment. However, when a broader adherence timescale was applied, completion rates did not decline. Overall completion rates increased as adherence timescale parameters were broadened from subsegment adherence (60.6%) to segment adherence (78.8%), to cumulative adherence (90.9%).

CONCLUSIONS: Older adults, including those with cognitive impairment, are able to complete remote cognitive assessments at a high-frequency, but may not necessarily adhere to prescribed schedules. Future high-frequency studies should consider adherence as a potential behavioral variable to complement cognitive test data, while recognizing the potential influence of adherence timescale on interpreting completion rates.},
}

@article {pmid41050469,
year = {2025},
author = {Wang, Y and Liu, T and He, Y and Tang, Y and Tan, P and Huang, L and Huang, D and Wen, T and Shao, L and Wang, J and Wang, Y and Han, Z},
title = {Identifying Alzheimer's disease-related pathways based on whole-genome sequencing data.},
journal = {Computational and structural biotechnology journal},
volume = {27},
number = {},
pages = {4132-4144},
pmid = {41050469},
issn = {2001-0370},
abstract = {Alzheimer's disease (AD) is a highly inheritable neurodegenerative disorder for which pathway-specific genetic profiling provides insights into its key biological mechanisms and potential treatment targets. Traditional disease-pathway analyses for AD have certain limitations, such as environmental interference and arbitrary sample division. We present a comprehensive framework that starts with genome data, avoiding these drawbacks and offering intrinsic pathway-specific genetic profiling for AD. Whole genome sequencing data from 173 individuals were used to quantify transcriptomes in 14 brain regions, estimate individual-level pathway variant scores, and analyze AD risk for each patient. These results were combined to identify AD-related pathways and quantify their interactions. The predicted expression levels were consistent with previous findings, and the estimated AD risk showed a significant correlation with Braak/Thal scores. A total of 3798 pathways were identified as potentially associated with AD, with about 19.7 % previously reported. The pathways identified as AD risk related primarily address six core biological themes, including: Immunity and inflammation, Metabolism, Protein homeostasis, DNA/RNA and Epigenetics, Synapse and structure, Cell cycle. Specifically, key pathways, such as NF-κB signaling and GSK3β activation, were linked to AD pathogenesis. The interactions among pathways highlighted shared gene functions in AD. In summary, we provided an effective framework for disease-pathway analysis, revealing the interdependence or compensatory effects of pathways in AD.},
}

@article {pmid41050397,
year = {2025},
author = {Liu, W and Zhao, Y and Liu, T and Wang, Y and Yin, D and Zou, S and Zou, C and Zhang, Z and Zhi, H and Wang, Y},
title = {Kaixin San Jiawei granule improves cognitive function and alleviates neuronal damage in Alzheimer's disease via multi-component and multi-target mechanisms.},
journal = {Frontiers in pharmacology},
volume = {16},
number = {},
pages = {1650534},
pmid = {41050397},
issn = {1663-9812},
abstract = {BACKGROUND: Kaixin San Jiawei Granule (KSG) is a traditional Chinese medicine formulation derived from classical prescriptions. Although it has shown promise in treating Alzheimer's disease (AD), its precise mechanisms of action remain unclear. This study aimed to systematically investigate the molecular mechanisms underlying KSG's therapeutic effects on AD through an integrative approach combining network pharmacology with experimental validation.

METHODS: An in vivo AD model was established in male KM mice via intraperitoneal injection of scopolamine. Cognitive function was assessed using the Morris water maze, and hippocampal levels of acetylcholine (ACh), acetylcholinesterase (AChE), glutathione peroxidase (GSH-Px), and reactive oxygen species (ROS) were measured using ELISA. In vitro, PC12 cells were exposed to Aβ25-35 to induce apoptosis. Immunofluorescence staining, Western blotting, and qPCR were used to assess the expression of amyloid-beta (Aβ), apoptosis-related protein caspase-3, and inflammatory cytokines (TNF-α, IL-1β). Active components of KSG and their potential targets and pathways were identified using mass spectrometry and network pharmacology, while partial validation was performed using molecular docking and Western blotting.

RESULTS: In vivo, KSG significantly alleviated scopolamine-induced cognitive deficits in mice. Treatment increased hippocampal levels of ACh and GSH-Px while reducing AChE and ROS. In vitro, KSG mitigated Aβ25-35-induced cytotoxicity in PC12 cells, decreased Aβ accumulation, and downregulated the expression of TNF-α and IL-1β. However, KSG had no significant effect on telomerase activity, telomere length, or the expression of the telomere-associated protein POT1. Mass spectrometry and network pharmacology analyses identified genistein, quercetin, and apigenin as key active compounds with TP53, AKT1, PTGS2, and CNR2 identified as core targets. Molecular docking validation confirmed the favorable binding activity between them. The calcium signaling, PI3K-Akt, and MAPK pathways emerged as the primary enriched pathways.

CONCLUSION: KSG improves cognitive function and attenuates Aβ-induced neuronal damage in AD through multi-component, multi-target synergistic mechanisms. These effects appear to be mediated by modulation of the cholinergic system, inhibition of oxidative stress and inflammation, and suppression of neuronal apoptosis. These findings provide a theoretical basis and experimental support for developing novel AD therapies based on traditional Chinese medicine.},
}

@article {pmid41050058,
year = {2025},
author = {Ma, M and Deng, C and Liu, Y and Cao, Q and Liu, F and Zhang, Y},
title = {A hypergraph neural network for prioritizing Alzheimer's disease risk genes.},
journal = {Frontiers in genetics},
volume = {16},
number = {},
pages = {1668200},
pmid = {41050058},
issn = {1664-8021},
abstract = {Identifying the complex genetic architecture of Alzheimer's disease (AD) is critical for understanding its pathophysiology. While network-based computational methods assist in this task, they primarily model simple pairwise gene interactions and fail to capture the higher-order associations of genes that drive complex diseases. To address this limitation, we introduce HyperAD, a novel hypergraph neural network framework designed to predict AD risk genes by explicitly modeling these higher-order associations of genes. HyperAD constructs a hypergraph in which functional gene sets from databases such as MSigDB form hyperedges, and uses a two-stage hypergraph message passing neural network to extract high-order association information from the hypergraph. Comprehensive evaluations demonstrate that HyperAD significantly outperforms state-of-the-art methods. We validate the prediction results of HyperAD through multiple lines of evidence. HyperAD-predicted genes are enriched in AD-related biological processes and have significant associations with known related genes in terms of sequence similarity, protein interaction, and miRNA. In addition, their protein expression levels are significantly altered in the brains of AD patients, and they contain both known risk sites and new, high-confidence candidate genes. HyperAD provides a more accurate and biologically insightful tool for prioritizing genes and unraveling the complex genetic landscape of AD.},
}

@article {pmid41049948,
year = {2025},
author = {Lawongsa, K and Kumjan, S},
title = {Prevalence and Determinants of Dementia Among Older Adults Attending Outpatient Clinics in a Tertiary Care Hospital in Thailand: A Secondary Data Analysis.},
journal = {Cureus},
volume = {17},
number = {9},
pages = {e91454},
pmid = {41049948},
issn = {2168-8184},
abstract = {BACKGROUND: Dementia is an increasing public health concern, particularly in aging societies. While most prevalence estimates in Thailand are derived from community-based studies, less is known about the burden and risk factors of dementia in tertiary care outpatients, who often present with multimorbidity.

METHODS: We conducted a retrospective cross-sectional study using secondary data from patients aged ≥60 years attending internal medicine, neurology, and geriatric outpatient clinics of Phramongkutklao Hospital, a tertiary hospital in Bangkok, Thailand, between January 1 and December 31, 2024. Dementia was identified using a hierarchical algorithm incorporating International Classification of Diseases, Tenth Revision (ICD-10) diagnostic codes, prescriptions for anti-dementia medications, and cognitive test results, with sensitivity analyses using stricter definitions. Independent variables included demographic characteristics, vascular and non-vascular comorbidities, medication use, and laboratory results. Prevalence was calculated with 95% confidence intervals (CI). Poisson regression with robust variance estimation was used to calculate crude and adjusted prevalence ratios (aPR) for associated factors.

RESULTS: Of 4,100 older adults, 512 had dementia (12.5%). Alzheimer's disease was the most frequent subtype, accounting for 278 cases (54.3% of dementia; 6.8% of the total sample). In univariable analysis, dementia was associated with age ≥80 years, female sex, low education, hypertension, diabetes mellitus, stroke/transient ischemic attack (TIA) history, depression, and an Anticholinergic Cognitive Burden (ACB) score ≥3. After adjustment, age ≥80 years remained the strongest determinant (aPR 2.41, 95% CI 1.92-3.01). Female sex (aPR 1.28, 95% CI 1.07-1.53), education ≤6 years (aPR 1.64, 95% CI 1.33-2.01), hypertension (aPR 1.21, 95% CI 1.02-1.43), diabetes mellitus (aPR 1.27, 95% CI 1.07-1.52), stroke/TIA (aPR 1.89, 95% CI 1.52-2.35), depression (aPR 1.48, 95% CI 1.16-1.90), and ACB score ≥3 (aPR 1.36, 95% CI 1.09-1.70) were all independently associated with dementia.

CONCLUSION: Dementia was common among tertiary care outpatients, with prevalence higher than community-based estimates. Advanced age, female sex, low education, vascular comorbidities, depression, and anticholinergic medication burden were significant correlates. These findings highlight the need for routine screening, aggressive vascular risk factor management, and medication review in tertiary care settings to mitigate the burden of dementia.},
}

@article {pmid41049759,
year = {2025},
author = {Meden, A and Žnidaršič, N and Knez, D and Wang, Y and Xu, Z and Yang, H and Zhang, W and Pišlar, A and Perdih, A and Brezar, SK and Grgurevič, N and Pajk, S and Sun, H and Gobec, S},
title = {Pleiotropic prodrugs for both symptomatic and disease-modifying treatment of Alzheimer's disease.},
journal = {Acta pharmaceutica Sinica. B},
volume = {15},
number = {9},
pages = {4807-4828},
pmid = {41049759},
issn = {2211-3835},
abstract = {The inherent complexity of Alzheimer's disease (AD) and failed clinical trials have spiked the interest in multifunctional ligands that target at least two key disease-associated macromolecules in AD pathology. Here we present a focused series of pleiotropic N-carbamoylazole prodrugs with dual mechanism of action. Pseudo-irreversible inhibition of the first therapeutic target, human butyrylcholinesterase (hBChE), enhances cholinergic transmission, and thereby provides symptomatic treatment, same as the standard therapeutics in use for AD. Simultaneously, this step also functions as a metabolic activation that liberates a nanomolar selective α 2-adrenergic antagonist atipamezole, which blocks pathological amyloid β (Aβ)-induced and noradrenaline-dependent activation of GSK3β that ultimately leads to hyperphosphorylation of tau, thus achieving a disease-modifying effect. Lead compound 8 demonstrated long-term pseudo-irreversible hBChE inhibition, metabolic activation in human plasma, blood-brain barrier permeability, and p.o. bioavailability in mice. Multi-day in vivo treatment with 8 in an Aβ-induced AD murine model revealed a significant alleviation of cognitive deficit that was comparable to rivastigmine, the current drug of choice for AD therapy. Furthermore, decreased GSK3β activation and lowered tau phosphorylation were observed in APP/PS1 mice. This surpasses the symptomatic-only treatment with cholinesterase inhibitors, as it directly blocks an essential pathological cascade in AD. Therefore, these multifunctional α 2-adrenergic antagonists-butyrylcholinesterase inhibitors, exemplified by lead compound 8, present an innovative, small molecule-based, disease-modifying approach to treatment of AD.},
}

@article {pmid41049755,
year = {2025},
author = {Yang, Y and Diao, Y and Jiang, L and Li, F and Chen, L and Ni, M and Wang, Z and Fang, H},
title = {A computational medicine framework integrating multi-omics, systems biology, and artificial neural networks for Alzheimer's disease therapeutic discovery.},
journal = {Acta pharmaceutica Sinica. B},
volume = {15},
number = {9},
pages = {4411-4426},
pmid = {41049755},
issn = {2211-3835},
abstract = {The translation of genetic findings from genome-wide association studies into actionable therapeutics persists as a critical challenge in Alzheimer's disease (AD) research. Here, we present PI4AD, a computational medicine framework that integrates multi-omics data, systems biology, and artificial neural networks for therapeutic discovery. This framework leverages multi-omic and network evidence to deliver three core functionalities: clinical target prioritisation; self-organising prioritisation map construction, distinguishing AD-specific targets from those linked to neuropsychiatric disorders; and pathway crosstalk-informed therapeutic discovery. PI4AD successfully recovers clinically validated targets like APP and ESR1, confirming its prioritisation efficacy. Its artificial neural network component identifies disease-specific molecular signatures, while pathway crosstalk analysis reveals critical nodal genes (e.g., HRAS and MAPK1), drug repurposing candidates, and clinically relevant network modules. By validating targets, elucidating disease-specific therapeutic potentials, and exploring crosstalk mechanisms, PI4AD bridges genetic insights with pathway-level biology, establishing a systems genetics foundation for rational therapeutic development. Importantly, its emphasis on Ras-centred pathways-implicated in synaptic dysfunction and neuroinflammation-provides a strategy to disrupt AD progression, complementing conventional amyloid/tau-focused paradigms, with the future potential to redefine treatment strategies in conjunction with mRNA therapeutics and thereby advance translational medicine in neurodegeneration.},
}

@article {pmid41049748,
year = {2025},
author = {Abdelhameed, A and Feng, J and Hu, X and Li, F and Lundin, S and Schulz, PE and Tao, C},
title = {AI-powered model for accurate prediction of MCI-to-AD progression.},
journal = {Acta pharmaceutica Sinica. B},
volume = {15},
number = {9},
pages = {4427-4437},
pmid = {41049748},
issn = {2211-3835},
abstract = {Alzheimer's disease (AD) remains a formidable challenge in modern healthcare, necessitating innovative approaches for its early detection and intervention. This study aimed to enhance the identification of individuals with mild cognitive impairment (MCI) at risk of developing AD. Leveraging advances in computational power and the extensive availability of healthcare data, we explored the potential of deep learning models for early prediction using medical claims data. We employed a bidirectional gated recurrent unit (BiGRU) deep learning model for predictive modeling of MCI progression across various prediction intervals, extending up to five years post-initial MCI diagnosis. The performance of the BiGRU model was rigorously compared with several machine-learning model baselines to evaluate its efficacy. Using a robust cross-validation methodology, the BiGRU emerged as the top-performing model, achieving an Area Under the Receiver Operating Characteristic Curve (AUC-ROC) of 0.833 (95% CI: 0.822, 0.843), an Area Under the Precision-Recall Curve (AUC-PR) of 0.856 (95% CI: 0.845, 0.867), and an F1-Score of 0.71 (95% CI: 0.694, 0.724) for a five-year prediction interval. The results indicate that BiGRU, utilizing longitudinal claims data, reliably predicts MCI-to-AD progression over a lengthy interval following the initial MCI diagnosis, offering clinicians a valuable tool for targeted risk identification and stratification.},
}