@article {pmid40744907,
year = {2025},
author = {Maccioni, L and Brusaferri, L and Barzon, L and Schubert, JJ and Nettis, MA and Cousins, O and Rosenzweig, I and Mizuno, Y and Vicente-Rodríguez, M and Singh, N and Marques, TR and Harrison, NA and Fryer, T and Bullmore, ET and Cash, D and Mondelli, V and Pariante, C and Howes, O and Turkheimer, FE and Loggia, ML and Veronese, M},
title = {A novel blood-free analytical framework for the quantification of neuroinflammatory load from TSPO PET imaging.},
journal = {Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism},
volume = {},
number = {},
pages = {271678X251361261},
doi = {10.1177/0271678X251361261},
pmid = {40744907},
issn = {1559-7016},
abstract = {Positron Emission Tomography (PET) of 18 kDa translocator protein (TSPO) has been investigated as putative marker of neuroinflammation but faces substantial methodological challenges. These include issues with arterial blood sampling for kinetic modeling, the absence of suitable reference regions, genetic polymorphisms affecting tracer affinity, altered blood-to-brain tracer delivery in inflammatory conditions, and high signal variability. This study presents a novel blood-free reference-free method for TSPO PET quantification, leveraging a logistic regression model to estimate the probability of TSPO overexpression across brain regions. Validation was performed on 323 human brain scans from five datasets and three radiotracers. The quantified TSPO topology in healthy controls showed strong concordance with constitutive TSPO gene expression for all tracers. When using [[11]C]PBR28 PET data, the method replicated previous findings in schizophrenia, Alzheimer's disease, chronic pain, and XBD173 blocking. However, model extension to [[18]F]DPA-714 and [[11]C]-(R)-PK11195 revealed small effect sizes and high variability, suggesting the need for tracer-specific model optimization. Finally, validation in a rat model of lipopolysaccharide-induced neuroinflammation confirmed previous evidence of increased brain TSPO uptake after systemic challenge. This novel non-invasive method provides individualized TSPO PET quantification, demonstrating broad applicability across TSPO PET tracers and imaging sites, assuming sufficient training data for model development.},
}

@article {pmid40744774,
year = {2025},
author = {van Dyck, CH},
title = {Editorial: Brain-penetrant antibodies for Alzheimer's disease: The next generation?.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {},
number = {},
pages = {100314},
doi = {10.1016/j.tjpad.2025.100314},
pmid = {40744774},
issn = {2426-0266},
}

@article {pmid40744715,
year = {2025},
author = {Ying, C and He, Y and Guo, Y and Fan, F and Wang, B and Gao, J and Li, Y and Zhang, Y},
title = {Application of Traditional Chinese Medicine in Alzheimer's Disease Treatment: A Focus on the Wnt/[Formula: see text]-Catenin Pathway.},
journal = {The American journal of Chinese medicine},
volume = {},
number = {},
pages = {1-43},
doi = {10.1142/S0192415X25500624},
pmid = {40744715},
issn = {1793-6853},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder primarily characterized by cognitive decline. Its etiology and pathogenesis are complex and multifactorial, with neurotoxicity induced by the abnormal aggregation of amyloid-beta (A[Formula: see text]) protein widely recognized as a central pathological hallmark. Current pharmacological treatments provide only limited symptomatic relief and are often associated with dose-dependent adverse effects. In contrast, Traditional Chinese Medicine (TCM) has garnered growing attention due to its distinctive therapeutic profile, and in particular, its multi-target and multi-pathway synergistic mechanisms. The Wnt/[Formula: see text]-catenin signaling pathway plays a crucial role in intracellular signal transduction and is closely associated with several key pathological processes involved in AD. This review provides a comprehensive analysis of the molecular interplay between the Wnt/[Formula: see text]-catenin signaling pathway and the pathogenesis of AD, as well as a specific focus on how natural compounds, herbal monomers, and classical TCM formulations modulate this pathway. Accumulating evidence suggests that TCM exerts neuroprotective effects by regulating Wnt/[Formula: see text]-catenin signaling to thereby suppress A[Formula: see text] deposition, preserve synaptic structure and tissue homeostasis, modulate cell proliferation and apoptosis, and maintain metabolic and redox homeostasis. Additionally, the review discusses key challenges, such as improving blood-brain barrier permeability and enhancing bioavailability, and outlines future directions involving advanced delivery systems and optimized administration routes. These insights provide a robust scientific foundation for the development of Wnt/[Formula: see text]-catenin-targeted therapies and highlight the potential of TCM in the clinical treatment of AD.},
}

@article {pmid40744685,
year = {2025},
author = {},
title = {Lecanemab (▼Leqembi) for Alzheimer's disease.},
journal = {Drug and therapeutics bulletin},
volume = {63},
number = {8},
pages = {118-124},
doi = {10.1136/dtb.2024.000057},
pmid = {40744685},
issn = {1755-5248},
}

@article {pmid40744499,
year = {2025},
author = {Liu, Y and Weng, Z and Zhai, Z and Xu, Z and Liu, X and Qiang, H and Tian, K and Rao, B and Zhou, G and Guo, Y and Xu, S},
title = {DNA large fragment deleting by compact, sequence-motif-free and specific TaqTth-hpRNA assisted with the microhomology-mediated end joining pathway.},
journal = {Nucleic acids research},
volume = {53},
number = {14},
pages = {},
doi = {10.1093/nar/gkaf723},
pmid = {40744499},
issn = {1362-4962},
support = {BF2024075//Jiangsu Province Advanced Technology Research and Development Program/ ; 82204442//National Natural Science Foundation of China/ ; 32071440//National Natural Science Foundation of China/ ; 82150209//National Natural Science Foundation of China/ ; //Qing Lan Project/ ; 3150120042//China Pharmaceutical University/ ; },
mesh = {*DNA End-Joining Repair ; Humans ; *Gene Editing/methods ; Escherichia coli/genetics ; DNA, Single-Stranded/genetics/metabolism ; DNA Cleavage ; Animals ; Nucleotide Motifs ; },
abstract = {A DNA editing tool TaqTth-hpRNA was developed in this study, composed of a compact recombinant TaqTth nuclease (832 aa) and a simple hairpin-RNA guiding probe (hpRNA). In vitro biochemical studies showed the TaqTth-hpRNA efficiently cleaves artificially synthesized single-stranded DNA without stringent sequence motif like protospacer adjacent motif (PAM). It can also cleave the genomic DNA of Escherichia coli with ∼80% efficiency. The TaqTth-hpRNA cleavage of genomic DNA in mammalian cells generated products with large fragment deletions mediated by the microhomology-mediated end joining pathway. In addition, the cleavage was sensitive to mismatches in targeted regions, which was applied to specific damage of the APPlon mutation in Alzheimer's disease without disrupting the APPwt locus. It is worth mentioning that the APPlon sequence has only one base difference from that of APPwt. The characteristics of small size, no PAM requirement, high specificity, and large deletion products make the TaqTth-hpRNA a potential therapeutic strategy for treating autosomal dominant disorders in the future.},
}

*DNA End-Joining Repair
Humans
*Gene Editing/methods
Escherichia coli/genetics
DNA, Single-Stranded/genetics/metabolism
DNA Cleavage
Animals
Nucleotide Motifs

@article {pmid40744415,
year = {2025},
author = {Park, SY and Setiawan, VW and Crimmins, EM and White, LR and Haiman, CA and Wilkens, LR and Le Marchand, L and Lim, U},
title = {Dietary patterns and risk of Alzheimer's disease and related dementias across five racial and ethnic groups in the Multiethnic Cohort Study.},
journal = {The American journal of clinical nutrition},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.ajcnut.2025.07.020},
pmid = {40744415},
issn = {1938-3207},
abstract = {BACKGROUND: Healthier dietary patterns have been linked to a lower risk of dementia, but data from diverse racial and ethnic populations are limited, particularly to support dietary improvement in older adults.

OBJECTIVE: We examined dietary patterns in relation to late-onset Alzheimer's disease and related dementia (ADRD) risk across five racial and ethnic groups in the Multiethnic Cohort Study.

METHODS: Participants were scored for four pre-defined dietary pattern indices based on their food frequency questionnaire responses at baseline (45-75 years) and at a 10-year follow-up: the alternate Mediterranean diet (aMED), the Dietary Approaches to Stop Hypertension (DASH), the Healthy Eating Index-2015 (HEI-2015), and the Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) diet. Associations between dietary patterns and ADRD were examined using Cox proportional hazards models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs).

RESULTS: Among 92,849 participants with 21,478 cases, higher baseline scores of the four dietary patterns were associated with 4‒9% lower ADRD risk (for aMED, HR 0.91, 95% CI: 0.87, 0.95; for DASH, HR 0.96, 95% CI: 0.92, 1.01; for HEI-2015, HR 0.94, 95% CI: 0.90, 0.98; for MIND, HR 0.91, 95% CI: 0.87, 0.96) over the follow-up, with stronger associations observed in African American, Latino, and White participants than in Japanese American and Native Hawaiian participants. Dietary improvement over 10 years was associated with 11‒25% lower risk across the four indices in a subset of 45,065 participants with 8,360 cases, with similar racial and ethnic differences as observed for baseline diet, but consistently for younger (<60 years at baseline) and older age groups.

CONCLUSIONS: Healthy dietary patterns in mid- to late-life and improvement in older age were associated with a reduced risk of ADRD in a diverse population. The racial and ethnic heterogeneity in the relationships observed warrants further study.},
}

@article {pmid40744389,
year = {2025},
author = {Nelson, VK and Begum, MY and Suryadevara, PR and Madhuri Kallam, SD and Panda, SP and Bodapati, A and Sanga, V and Bishoyi, AK and Ballal, S and Monsi, M and Walia, C and Prasad, GVS and Abomughaid, MM and Shukla, S and Chauhan, P and Jha, NK},
title = {Natural Bioactive Compounds as Modulators of Autophagy: A Herbal Approach to the Management of Neurodegenerative Diseases.},
journal = {European journal of pharmacology},
volume = {},
number = {},
pages = {178003},
doi = {10.1016/j.ejphar.2025.178003},
pmid = {40744389},
issn = {1879-0712},
abstract = {Neurodegenerative diseases (NDs) such as Alzheimer's disease (AD), Parkinson's disease (PD), Polyglutamine (polyQ), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS) disease are a significant health concern that affects millions of people every year worldwide. The main pathological hallmark of various NDs is the formation of misfolded protein aggregation and accumulation of inclusion bodies. These protein aggregates are mainly responsible for producing toxic effects and initiating neuronal cell death, ultimately promoting various NDs. On the other hand, the patients suffering from these kinds of diseases live in impaired conditions, imposing a substantial financial burden on the family. However, the current treatment strategies can only offer temporary relief from the disease symptoms and can't reverse the disease completely. Hence, there is an urgent need for specific and novel drug treatment that can significantly eradicate NDs. Ubiquitin proteasome system (UPS) and autophagy are the two essential intracellular defensive mechanisms that are involved in clearing the protein aggregates, pathogens, and damaged organelles from the cytoplasm and maintaining protein homeostasis. Nevertheless, UPS is inefficient in removing some kinds of organelles and aggregating-prone proteins, specifically in neuronal and glial cells. Under this kind of circumstance, the autophagy mechanism plays a vital role in eliminating the accumulated protein aggregates and other toxic elements from the cytoplasm of the neuronal cells that initiate oxidative stress. However, in NDs, the autophagy function is impaired, and the protein aggregates can't be eliminated effectively. Hence, forced up-regulation of autophagy function by applying various external agents could be a potential therapeutic strategy to control NDs like AD, PD, HD, and ALS. In this review, we focused on different kinds of plant-derived compounds that induce autophagy. We also discussed the role of these plant-derived autophagy modulators in various NDs. In this way, the current review will be a standalone reference to the researchers working in this area.},
}

@article {pmid40744232,
year = {2025},
author = {Lee, HN and Han, CW and Jeong, MS and Jang, SB},
title = {Cryo-EM structure of Amyloid-β and Transthyretin complex and its implications for neuroprotective in neuroblastoma cell lines.},
journal = {Biochemical pharmacology},
volume = {},
number = {},
pages = {117201},
doi = {10.1016/j.bcp.2025.117201},
pmid = {40744232},
issn = {1873-2968},
abstract = {Alzheimer's disease is a severe neurological disorder and the most prevalent form of dementia, characterized by cognitive impairment and hypomnesia. The accumulation and aggregation of Amyloid-β peptides are central to AD pathology, triggering neuroinflammation and neuronal cell death. This study aims to investigate the molecular mechanisms underlying Aβ aggregation and its impact on neuronal function, and to explore potential therapeutic strategies, including peptide-based small molecules, for AD. We analyzed the role of Aβ in neuroinflammation and mitochondrial dysfunction using various in vitro and in vivo models. Structural characterization of the Aβ-TTR complex was performed using cryo-electron microscopy to understand the molecular interactions involved. The study reveals that Aβ aggregation leads to the activation of microglia, increased production of reactive oxygen species, and mitochondrial dysfunction, which contribute to neurodegeneration. Peptide-based small molecules demonstrated high specificity in binding to Aβ, inhibiting its aggregation, and reducing cytotoxicity in neuroblastoma cell lines. The TTR peptide (P2) effectively prevented Aβ-induced cytotoxicity and apoptosis by modulating oxidative stress and mitochondrial dynamics. Structural analysis using cryo-electron microscopy identified key interactions between Aβ and TTR, providing insights into their biological activity. The findings highlight the critical role of Aβ aggregation in AD pathogenesis and underscore the potential of peptide-based small molecules as therapeutic candidates. Understanding the structural mechanisms of Aβ and TTR interactions offers new avenues for developing strategies to prevent neurodegeneration and manage AD more effectively.},
}

@article {pmid40744011,
year = {2025},
author = {Aoki, R and Konno, A and Hosoi, N and Kawabata, H and Hirai, H},
title = {AAV vectors for specific and efficient gene expression in microglia.},
journal = {Cell reports methods},
volume = {},
number = {},
pages = {101116},
doi = {10.1016/j.crmeth.2025.101116},
pmid = {40744011},
issn = {2667-2375},
abstract = {Microglia are crucial targets for therapeutic interventions in diseases like Alzheimer's and stroke, but efficient gene delivery to these immune cells is challenging. We developed an adeno-associated virus (AAV) vector that achieves specific and efficient gene delivery to microglia. This vector incorporates the mIba1 promoter, GFP, miRNA target sequences (miR.Ts), WPRE, and poly(A) signal. Positioning miR.Ts on both sides of WPRE significantly suppressed non-microglial expression, achieving over 90% specificity and more than 60% efficiency in microglia-specific gene expression 3 weeks post-administration. Additionally, this vector enabled GCaMP expression, facilitating real-time calcium dynamics monitoring in microglial processes. Using a blood-brain barrier-penetrant AAV-9P31 capsid variant, intravenous administration resulted in broad and selective microglial GFP expression across the brain. These results establish our AAV vector as a versatile tool for long-term, highly specific, and efficient gene expression in microglia, advancing microglial research and potential therapeutic applications.},
}

@article {pmid40743720,
year = {2025},
author = {Ali, A and Ganeshpurkar, A and Ganeshpurkar, A and Dubey, N},
title = {In Silico Investigation of Ganoderic Acid A Targeting Amyloid-Beta and Tau Protein Aggregation in Alzheimer's Disease.},
journal = {International journal of medicinal mushrooms},
volume = {27},
number = {9},
pages = {85-92},
doi = {10.1615/IntJMedMushrooms.2025059137},
pmid = {40743720},
issn = {1940-4344},
mesh = {*tau Proteins/metabolism/chemistry ; *Alzheimer Disease/drug therapy/metabolism ; *Amyloid beta-Peptides/metabolism/chemistry ; *Lanosterol/analogs & derivatives/pharmacology/chemistry ; Molecular Docking Simulation ; Humans ; Computer Simulation ; Protein Aggregates/drug effects ; Protein Binding ; *Reishi/chemistry ; Heptanoic Acids ; },
abstract = {Alzheimer's disease (AD) represents a significant challenge in neurodegenerative disorders, characterized by the accumulation of amyloid-beta (Aβ) plaques and tau protein tangles in the brain. Current treatments provide symptomatic relief but do not halt disease progression. ganoderic acid A, derived from Ganoderma lucidum, has shown to act as a dual inhibitor of Aβ and tau protein aggregation through in vitro and animal model studies. This study aims to explore the therapeutic potential of ganoderic acid A using in silico methods to predict its binding affinity and mode of interaction with Aβ and tau proteins. Analysis included molecular docking simulations using computational models to evaluate the binding of ganoderic acid A to Aβ and tau proteins. Various tools were employed to predict the binding energy, interaction sites (Autodock), and MD (CABSflex 2.0) of these complexes. Ganoderic acid A demonstrated favorable binding energies and interactions with both Aβ and tau proteins. The compound exhibited potential dual inhibition capabilities by forming stable complexes with critical residues involved in Aβ aggregation and tau protein hyperphosphorylation. The findings suggest that ganoderic acid A holds promise as a dual inhibitor of Aβ and tau protein aggregation in AD. By targeting these key pathological processes, ganoderic acid A may offer therapeutic benefits in halting or slowing disease progression. Confirming these predictions and advancing ganoderic acid A as a possible AD treatment will require additional experimental validation, including in vitro and in vivo research.},
}

*tau Proteins/metabolism/chemistry
*Alzheimer Disease/drug therapy/metabolism
*Amyloid beta-Peptides/metabolism/chemistry
*Lanosterol/analogs & derivatives/pharmacology/chemistry
Molecular Docking Simulation
Humans
Computer Simulation
Protein Aggregates/drug effects
Protein Binding
*Reishi/chemistry
Heptanoic Acids

@article {pmid40743680,
year = {2025},
author = {Wang, C and Wang, Z and Herrero, MT and Xu, T and Chu, F and Zeng, H and Tao, M},
title = {Early diagnosis of mild cognitive impairment and Alzheimer's disease using multimodal feature-based deep learning models in a Chinese elderly population.},
journal = {Asian journal of psychiatry},
volume = {111},
number = {},
pages = {104632},
doi = {10.1016/j.ajp.2025.104632},
pmid = {40743680},
issn = {1876-2026},
abstract = {BACKGROUND: Alzheimer's disease (AD) and mild cognitive impairment (MCI) are progressive neurodegenerative disorders with no effective treatments currently, underscoring the urgent need for early diagnosis. Electroencephalography and event-related potentials (ERP) provide noninvasive, cost-effective methods with high temporal resolution for detecting cognitive decline, while traditional Chinese medicine (TCM) features such as body constitutions have been identified as risk factors for MCI. Recent developments in artificial intelligence (AI) especially deep learning architectures have further improved the diagnostic accuracies of AD and MCI. This study aimed to assess the efficacy of deep learning models based on fused ERP and TCM features in the cross-subject classification of cognitive impairment.

METHODS: Visual oddball ERP tasks under Neutral, Happiness, or Sadness stimulus were conducted among 30 healthy controls (HC, 12 males and 18 females), 30 MCI (10 males and 20 females), and 30 AD (10 males and 20 females) patients. Deep learning models, including EEGNet, Convolutional Neural Network - Long Short-Term Memory, Graph Convolutional Network, (GCN), and multi-scale feature reconstruction GCN, were employed to extract differential entropy features from ERP data, and multilayer perceptron was utilized to extract features from TCM questionnaires. After feature fusion, 10-fold cross-subject binary (HC vs. MCI+AD; MCI vs. AD) and ternary (HC, MCI, AD) classification tasks were performed subsequently.

RESULTS: GCN significantly outperformed other models in all three cross-subject classification tasks. In binary classification tasks distinguishing HC from MCI and AD, GCN achieved accuracies of 90.17 ± 5.58 %, 86.73 ± 2.34 %, and 84.73 ± 4.28 % under Neutral, Happiness, and Sadness, respectively. Similarly, in ternary classification of HC, MCI, and AD, GCN reached the highest accuracy of 72.67 ± 1.89 % under Neutral stimulus.

CONCLUSIONS: Leveraging fused ERP and TCM features, deep learning models have demonstrated robust cross-subject efficacy in the early diagnosis of cognitive decline. Particularly in distinguishing HC from MCI and AD, the performance of GCN was comparable to that of hematological biomarkers. Our study, therefore, highlights a reliable and effective AI-driven methodology for the early diagnosis of cognitive impairment in clinical settings.},
}

@article {pmid40743620,
year = {2025},
author = {Shi, Z and Peng, Q and Sun, S and Xiong, M and Zhu, X and Wang, H and Liu, S and Li, Z and Wang, L and Li, G and Zhan, L},
title = {C/EBP β/AEP pathway mediates hippocampal mitochondrial damage in a mouse model of sepsis encephalopathy.},
journal = {International immunopharmacology},
volume = {163},
number = {},
pages = {115275},
doi = {10.1016/j.intimp.2025.115275},
pmid = {40743620},
issn = {1878-1705},
abstract = {Septic encephalopathy (SE), a neurocritical complication with alarmingly high mortality rates, represents a major diagnostic and therapeutic challenge in intensive care units (ICUs). Current diagnostic protocols rely predominantly on nonspecific clinical symptom assessment, while conventional laboratory biomarkers exhibit insufficient sensitivity for early detection. This diagnostic ambiguity contributes to delayed interventions and unfavorable patient prognoses. Mechanistically, prior studies in Alzheimer's disease (AD) have established that genetic ablation of C/EBP β or AEP (asparagine endopeptidase) mitigates neuroinflammation and disease progression. Intriguingly, our investigation reveals a pathophysiological paradox in SE: Conditional AEP knockout significantly attenuated sepsis-induced hippocampal damage, whereas C/EBP β knockdown unexpectedly exacerbated neuronal injury - findings directly opposing AD-related mechanisms. Notably, this study identifies mitochondrial dysfunction in hippocampal neurons as a previously unrecognized hallmark of SE, characterized by cristae fragmentation and mitochondrial membrane potential collapse. Multimodal analyses further demonstrate that AEP inhibition rescues synaptic plasticity through dual modulation of STat3 signaling and oxidative stress cascades. Importantly, our paradoxical findings regarding C/EBP β suggest context-dependent regulation of neuroinflammation, challenging the prevailing assumption of pathway conservation across neuropathologies. These translational insights not only elucidate the C/EBP β/AEP axis as a novel therapeutic target in SE but also warrant caution against extrapolating AD-derived mechanisms to sepsis-related encephalopathies.},
}

@article {pmid40743521,
year = {2025},
author = {Peterson, CM and St Louis, RM and Flannagan, C},
title = {Enhancing Enrollment and Adherence in Long-Term Wearable Research on Dementia: Qualitative Systematic Review and Meta-Synthesis.},
journal = {JMIR aging},
volume = {8},
number = {},
pages = {e63768},
doi = {10.2196/63768},
pmid = {40743521},
issn = {2561-7605},
mesh = {*Dementia/psychology ; Humans ; *Wearable Electronic Devices ; *Patient Compliance ; Qualitative Research ; },
abstract = {BACKGROUND: With the rapid expansion of wearable technologies, there is increased interest in their utility for passive data collection applications in research on aging. Wearables can be beneficial for research with people with dementia and their families, who have burdens that can make both study participation and reliable data collection more difficult, especially as dementia progresses, but their use also has challenges. Population-specific issues affecting the success of wearables for data collection can include remembering to wear a device, fluctuating acceptance of the device or study participation, and reliance on already strained caregivers.

OBJECTIVE: This study aimed to systematically evaluate contemporary wearables research to describe persons with dementia's experiences with wearables, their desired qualities, and protocol needs to enhance participant buy-in and sustained wearing for better quality dementia research.

METHODS: We used the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) 2020 checklist for systematic reviews and searched 3 scholarly databases using Medical Subject Headings (MeSH) terms for papers published since 2018 featuring the use or discussion of wearable devices for persons with dementia. We screened 1757 abstracts and retained 58 for full-text review.

RESULTS: We present synthesized preferences, barriers, and facilitators to buy-in and adherence to wearables in dementia research. A total of 29 factors were categorized into 4 overarching categories aligned with study development: device selection, protocol considerations, enhancing recruitment, and promoting adherence.

CONCLUSIONS: These findings inform researcher guidelines for wearable device selection and protocol design to enhance the utility of wearables in future longitudinal research featuring persons with dementia and their caregivers.},
}

*Dementia/psychology
Humans
*Wearable Electronic Devices
*Patient Compliance
Qualitative Research

@article {pmid40743478,
year = {2025},
author = {Melikyan, ZA and Al-Darsani, Z and Colcord, KA and Paganini-Hill, A and Jiang, L and Bukhari, SA and Montine, TJ and Kawas, CH and Corrada, MM},
title = {Association of Subjective Memory Complaints With Neuropathologic Changes at Age 90 or Older: The 90+ Study.},
journal = {Neurology},
volume = {105},
number = {4},
pages = {e213948},
doi = {10.1212/WNL.0000000000213948},
pmid = {40743478},
issn = {1526-632X},
mesh = {Humans ; Female ; Male ; Aged, 80 and over ; *Memory Disorders/pathology/psychology/epidemiology ; Longitudinal Studies ; Cross-Sectional Studies ; *Brain/pathology ; *Aging/pathology/psychology ; Cognitive Dysfunction/pathology ; },
abstract = {BACKGROUND AND OBJECTIVES: Subjective memory complaints (SMCs), defined as perception of one's own memory problems, have been associated with Alzheimer disease (AD) neuropathologic changes. Yet, whether SMC is associated with non-AD neuropathologic changes and whether this association is present in both those with normal cognition and those with cognitive impairment is not known. We examined the association of SMC with neurodegenerative and vascular neuropathologic changes in individuals aged 90 and older (oldest old) without dementia at death.

METHODS: We analyzed data from The 90+ Study, an ongoing longitudinal study of aging in Southern California. The study enrolled individuals older than 90 years with evaluations every 6 months and followed until death. Cross-sectional analyses included participants with an SMC evaluation, no dementia at death, and a neuropathologic examination. The predictor, SMC, was defined as a "yes" response to the question from the Geriatric Depression Questionnaire (GDS), "Do you feel you have more problems with memory than most?" at any time during the follow-up. The outcomes were 12 neuropathologic changes, both vascular and neurodegenerative, dichotomized as present/absent. We estimated odds ratio (OR) and 95% CI in the entire group and separately for individuals classified with normal cognition and Cognitive Impairment No Dementia (CIND) at a postmortem case conference using logistic regression adjusted for demographics, GDS minus the SMC item, and Mini-Mental State Examination.

RESULTS: In the 238 participants (mean age at autopsy = 97.5 years, 62% women), 51% had normal cognition at death and 28% reported SMC at some point during follow-up. In the entire group, individuals with SMC had higher odds of atherosclerosis (OR 2.07; 95% CI 1.12-2.83) compared with those without SMC. Among individuals with normal cognition, those with SMC had higher odds of AD neuropathologic change (OR 2.88; 95% CI 1.05-7.92), Lewy Body Disease (OR 3.56; 95% CI 1.07-11.83), and atherosclerosis (OR 3.13; 95% CI 1.21-8.09) compared with no SMC. In individuals with CIND, SMC were not associated with neuropathologic changes.

DISCUSSION: In the oldest old with normal cognition at death SMC were associated with neurodegenerative and vascular neuropathologic changes, suggesting that underlying pathology of SMC is multifactorial.},
}

Humans
Female
Male
Aged, 80 and over
*Memory Disorders/pathology/psychology/epidemiology
Longitudinal Studies
Cross-Sectional Studies
*Brain/pathology
*Aging/pathology/psychology
Cognitive Dysfunction/pathology

@article {pmid40743472,
year = {2025},
author = {Kovaleva, M and Baumberger, BF and Maiga, A and Dietrich, MS and Lauderdale, J and Balas, MC and Maxwell, C},
title = {Experiences of Unpaid Caregivers for Persons With Memory Impairment Navigating Perioperative Care.},
journal = {Journal of trauma nursing : the official journal of the Society of Trauma Nurses},
volume = {},
number = {},
pages = {},
pmid = {40743472},
issn = {1078-7496},
abstract = {BACKGROUND: As the aging population grows, individuals with cognitive impairment face increased challenges and a higher risk of poor outcomes. Although unpaid caregivers provide most of their care and help navigate hospitalizations and surgeries, their experiences in perioperative settings remain poorly understood.

OBJECTIVE: This study explores the experiences of unpaid caregivers of individuals with memory impairment in the perioperative period.

METHODS: This study used a qualitative descriptive approach to explore caregivers' experiences with perioperative care for individuals with cognitive impairment. Semi-structured interviews were conducted with purposefully sampled unpaid caregivers of individuals who had undergone a surgery within the past 6 months at a Southeastern U.S. trauma center (February-April 2021). Conventional content analysis was used to code transcripts and identify themes.

RESULTS: Eight caregivers participated in semi-structured interviews. Caregivers reported being unprepared for postoperative complications, including delirium, cognitive changes, and functional decline. Communication deficits were prominent, with caregivers receiving inadequate information about surgical outcomes and postoperative expectations. Staff demonstrated knowledge gaps regarding dementia care, and 1 instance of verbal abuse toward a patient was reported. Five themes emerged: care recipients' perioperative experiences, caregivers' experiences, healthcare strengths and deficiencies, and improvement recommendations.

CONCLUSION: Caregivers of persons with cognitive impairment face significant challenges during the perioperative period, often unprepared for postoperative complications and lacking adequate communication from healthcare teams. Findings suggest targeted interventions, including preoperative caregiver education about delirium, enhanced communication protocols, and comprehensive hospital staff training on dementia care, could improve outcomes for this growing population requiring surgical intervention.},
}

@article {pmid40743219,
year = {2025},
author = {Dhankhar, A and Khobragade, P and Banerjee, J and Chopra, G and Jacob, S and Dey, AB and Lee, J and Crimmins, E and Thyagarajan, B and Dey, S and Hu, P},
title = {Methodology of community-based venous blood specimen collection for the harmonized diagnostic assessment of dementia for the Longitudinal Aging Study in India (LASI-DAD): Wave 2.},
journal = {PloS one},
volume = {20},
number = {7},
pages = {e0326917},
doi = {10.1371/journal.pone.0326917},
pmid = {40743219},
issn = {1932-6203},
mesh = {Humans ; *Dementia/diagnosis/blood/epidemiology ; India/epidemiology ; Longitudinal Studies ; Male ; Female ; Aged ; *Blood Specimen Collection/methods/standards ; *Aging/blood ; Middle Aged ; Aged, 80 and over ; Biomarkers/blood ; },
abstract = {The prevalence of dementia is on the rise, with 60% of dementia cases existing in low- and middle-income countries. In India, the prevalence was reported to be 7.4%. Since the pathophysiology of dementia is multifactorial, the Harmonized Longitudinal Aging Study in India for the Diagnostic Assessment of Dementia (LASI-DAD) collected data to capture multiple domains, including venous blood specimens (VBS). VBS collection and assays help ascertain the overall health status of an individual, understand disease pathogenesis, and diagnose diseases. In community settings, blood assays also help identify disease trends. However, community VBS collections can often be challenging. Sample quality can be impaired due to individual, environmental, geographical, and pre-analytical processing factors. Therefore, standardization of the process is imperative to ensure biomarker data of high accuracy. LASI-DAD developed a systematic sample collection, shipment, processing, and storage protocol. Multiple checkpoints were in place to monitor sample quality in real time. A phlebotomist was trained from each participating state for specimen collection. All samples were centrally tested for analytes. The overall response rate for blood collection was 71.5%. We collected 17 mL of VBS from 3,252 respondents, who consented to participate. Blood samples were tested for routine analytes, and those specific to Alzheimer's Disease (AD) and AD-related dementias (ADRD). Data was reviewed fortnightly. The median cold chain temperature was 6.2°C and hemolysis was seen in 6.7% of the samples. LASI-DAD standardized and implemented VBS collection while overcoming the challenges faced due to India's diverse socio-demographic, geographical, and environmental conditions. This methodology can serve as a robust tool for VBS handling and ensuring high sample quality for future community-based studies.},
}

Humans
*Dementia/diagnosis/blood/epidemiology
India/epidemiology
Longitudinal Studies
Male
Female
Aged
*Blood Specimen Collection/methods/standards
*Aging/blood
Middle Aged
Aged, 80 and over
Biomarkers/blood

@article {pmid40742839,
year = {2025},
author = {Chen, Q and Wang, J and Wang, G and Hong, Y},
title = {HoloDx: Knowledge- and Data-Driven Multimodal Diagnosis of Alzheimer's Disease.},
journal = {IEEE transactions on medical imaging},
volume = {PP},
number = {},
pages = {},
doi = {10.1109/TMI.2025.3594364},
pmid = {40742839},
issn = {1558-254X},
abstract = {Accurate diagnosis of Alzheimer's disease (AD) requires effectively integrating multimodal data and clinical expertise. However, existing methods often struggle to fully utilize multimodal information and lack structured mechanisms to incorporate dynamic domain knowledge. To address these limitations, we propose HoloDx, a knowledge- and data-driven framework that enhances AD diagnosis by aligning domain knowledge with multimodal clinical data. HoloDx incorporates a knowledge injection module with a knowledge-aware gated cross-attention, allowing the model to dynamically integrate domain-specific insights from both large language models (LLMs) and clinical expertise. A memory injection module with prototypical memory attention further enables consistency preservation across decision trajectories. Through synergistic operation of these components, HoloDx achieves enhanced interpretability while maintaining precise knowledge-data alignment. Evaluations on five AD datasets demonstrate that HoloDx outperforms state-of-the-art methods, achieving superior diagnostic accuracy and strong generalization across diverse cohorts. The source code is released at https://github.com/Qybc/HoloDx.},
}

@article {pmid40742809,
year = {2025},
author = {Shen, Y and Shen, Y and Wang, M and Jin, K and Yang, P and Cao, Z and Zhu, Q and Zhao, Z and Li, H and Han, L and Liu, S and Liao, J and Zhang, J and Fan, X and Wu, D},
title = {A spatial imaging-transcriptomics paradigm for deciphering the molecular basis of microscopic MRI in the normal brain and Alzheimer's disease.},
journal = {Cell reports},
volume = {44},
number = {8},
pages = {116073},
doi = {10.1016/j.celrep.2025.116073},
pmid = {40742809},
issn = {2211-1247},
abstract = {Imaging genomics offers powerful links between genetics and neuroimaging phenotypes, but conventional methods often lack spatial correspondence. We introduce spatial imaging-transcriptomics, a paradigm that directly integrates magnetic resonance imaging (MRI) and spatially resolved transcriptomics (ST) with matched resolution from the same brain through spatially co-registered maps. We apply this framework to wild-type and Alzheimer's disease (AD) mouse models to uncover the molecular underpinnings of diffusion MRI. In the normal brain, fractional anisotropy (FA) correlates with myelination processes and oligodendrocytes, whereas diffusivity indices are associated with neurons. Furthermore, we identified the genetic basis for observed cortical gradients in diffusion tensor imaging (DTI). In the AD mouse model, reduced FA is linked to myelin and oligodendrocyte change and β-amyloid deposition. Critically, imaging-defined disease foci can guide differential gene expression analysis to uncover AD-specific genetic alterations. The spatial imaging-transcriptomics paradigm provides an unprecedented high-resolution bridge between neuroimaging and transcriptomics, benefitting the decipherment of complex molecular events in brain disorders.},
}

@article {pmid40742807,
year = {2025},
author = {Kim, EJ and Park, S and Schuessler, BP and Boo, H and Cho, J and Kim, JJ},
title = {Disruption of hippocampal-prefrontal neural dynamics and risky decision-making in a mouse model of Alzheimer's disease.},
journal = {Cell reports},
volume = {44},
number = {8},
pages = {116081},
doi = {10.1016/j.celrep.2025.116081},
pmid = {40742807},
issn = {2211-1247},
abstract = {This study investigates how amyloid pathology influences hippocampal-prefrontal neural dynamics and decision-making in Alzheimer's disease (AD) using 5XFAD mice, a well-established model system characterized by pronounced early amyloid pathology. Utilizing ecologically relevant "approach food-avoid predator" foraging tasks, we show that 5XFAD mice exhibit persistent risk-taking behaviors and reduced adaptability to changing threat conditions, indicative of impaired decision-making. Multi-regional neural recordings reveal rigid hippocampal CA1 place cell fields, decreased sharp-wave ripple (SWR) frequencies, and disrupted medial prefrontal-hippocampal connectivity, all of which correspond with deficits in behavioral flexibility during spatial risk scenarios. These findings highlight the critical role of SWR dynamics and corticolimbic circuit integrity in adaptive decision-making, with implications for understanding cognitive decline in AD in naturalistic contexts. By identifying specific neural disruptions underlying risky decision-making deficits, this work provides insights into the neural basis of cognitive dysfunction in AD and suggests potential targets for therapeutic intervention.},
}

@article {pmid40742457,
year = {2025},
author = {Sharafshah, A and Motovali-Bashi, M and Blum, K and Lewandrowski, KU and Gold, MS and Keshavarz, P and Thanos, PK},
title = {A GWAS Meta-meta-analysis and In-depth Silico Pharmacogenomic Investigations in Identification of APOE and Other Genes Associated with Pain, Anti-inflammatory, and Immunomodulating Agents in Opioid Use Disorder (OUD) Derived from 14.91 M Subjects.},
journal = {Cellular and molecular neurobiology},
volume = {45},
number = {1},
pages = {76},
pmid = {40742457},
issn = {1573-6830},
mesh = {Humans ; *Genome-Wide Association Study/methods ; *Opioid-Related Disorders/genetics/drug therapy ; *Pain/genetics/drug therapy ; *Apolipoproteins E/genetics ; *Pharmacogenetics/methods ; *Anti-Inflammatory Agents/therapeutic use/pharmacology ; *Immunologic Factors/therapeutic use/pharmacology ; *Computer Simulation ; },
abstract = {This study aimed to integrate genome-wide association studies (GWAS) with pharmacogenomics data to develop personalized pain and inflammatory therapeutics. Despite recent developments in the clinical utilities of pharmacogenomics, it needs more investigations for uncovering the complicated mechanisms of drugs from a genetic standpoint. The research addresses the increasing misuse of opioids during recovery, emphasizing personalized interventions for opioid use disorder (OUD). Key pain-related pathways were analyzed to uncover their interactions. Five GWAS traits, including pain, inflammatory biomarkers, immune system abnormalities, and opioid-related traits, were examined. Candidate genes extracted from GWAS datasets were refined through in silico analyses, including protein-protein interactions (PPIs), TF-miRNA coregulatory interactions, enrichment analysis (EA), and clustering enrichment analysis (CEA). A network of 50 highly connected genes was identified, with APOE emerging as a top candidate due to its role in cholesterol metabolism and opioid-induced lipid effects. Pharmacogenomics analysis highlighted significant gene annotations, including OPRM1, DRD2, APOE, GRIN2B, and GPR98, linking them to opioid dependence, neurological disorders, and lipid traits. Protein interaction analyses further validated these connections, with implications for epigenetic repair. Our findings reveal a strong association between APOE, opioid use, and Alzheimer's disease, suggesting potential for novel recovery strategies. Combining HDL-boosting drugs with pro-dopaminergic regulators like KB220 may help prevent relapse. This study underscores the importance of integrating genetic and pharmacogenomic data to advance personalized therapies.},
}

Humans
*Genome-Wide Association Study/methods
*Opioid-Related Disorders/genetics/drug therapy
*Pain/genetics/drug therapy
*Apolipoproteins E/genetics
*Pharmacogenetics/methods
*Anti-Inflammatory Agents/therapeutic use/pharmacology
*Immunologic Factors/therapeutic use/pharmacology
*Computer Simulation

@article {pmid40742404,
year = {2025},
author = {Chen, X and Zhou, XY and Lan, C and Fu, HJ and Li, ZC and Chen, MY and Wen, YP and Yu, L and Qin, DL and Wu, AG and Wu, JM and Zhou, XG},
title = {Araloside A Induces Raf/MEK/ERK-Dependent Autophagy to Mitigate Alzheimer's and Parkinson's Pathology in Cellular and C. elegans Models.},
journal = {Molecular neurobiology},
volume = {},
number = {},
pages = {},
pmid = {40742404},
issn = {1559-1182},
support = {2024YFHZ0361//The Department of Science and Technology of Sichuan Province/ ; SKL-KF202311//The Open Project Program of State Key Laboratory of Crop Gene Exploration and Utilization in Southwest China/ ; 81801398//the National Natural Science Foundation of China/ ; },
abstract = {Alzheimer's disease (AD) and Parkinson's disease (PD) are characterized by pathological protein aggregation and oxidative stress, leading to progressive neurodegeneration. Enhancing autophagy, the primary intracellular pathway for clearing misfolded proteins, represents a promising therapeutic strategy. In this study, we identify Araloside A (ARA), a triterpenoid saponin derived from Aralia elata, as a potent autophagy inducer that alleviates AD- and PD-related pathology. In neuronal cell models, ARA promotes autophagosome formation, increases LC3-II and Beclin-1 levels, and decreases P62, indicating enhanced autophagic activity. Mechanistic investigations reveal that ARA directly binds to Raf, MEK, and ERK proteins and activates autophagy in a Raf/MEK/ERK-dependent manner. This activation facilitates the clearance of APP, total Tau, phosphorylated Tau, and α-synuclein, thereby reducing cytotoxicity. Furthermore, in transgenic Caenorhabditis elegans models of AD and PD, ARA treatment alleviates protein aggregation and behavioral deficits via ERK-dependent autophagy. Together, these findings identify ARA as a natural compound that enhances autophagic clearance of neurotoxic aggregates via Raf/MEK/ERK pathway activation, offering promising therapeutic insights for neurodegenerative proteinopathies.},
}

@article {pmid40742280,
year = {2025},
author = {Chen, C and Gao, TY and Yi, HW and Zhang, Y and Wang, T and Lou, ZL and Wei, TF and Lu, YB and Li, T and Tang, C and Zhang, WP},
title = {Elevated ubiquitin phosphorylation by PINK1 contributes to proteasomal impairment and promotes neurodegeneration.},
journal = {eLife},
volume = {14},
number = {},
pages = {},
doi = {10.7554/eLife.103945},
pmid = {40742280},
issn = {2050-084X},
support = {2023YFF1204400//National Key Research and Development Program of China/ ; 2021YFF1200900//National Key Research and Development Program of China/ ; 92353304//National Natural Science Foundation of China/ ; 32070666//National Natural Science Foundation of China/ ; },
mesh = {Animals ; Humans ; *Proteasome Endopeptidase Complex/metabolism ; Phosphorylation ; *Protein Kinases/metabolism/genetics ; *Ubiquitin/metabolism ; Mice ; HEK293 Cells ; Neurons/metabolism ; *Neurodegenerative Diseases/metabolism ; Hippocampus ; },
abstract = {Ubiquitin (Ub), a central regulator of protein turnover, can be phosphorylated by PINK1 (PTEN-induced putative kinase 1) to generate S65-phosphorylated ubiquitin (pUb). Elevated pUb levels have been observed in aged human brains and in Parkinson's disease, but the mechanistic link between pUb elevation and neurodegeneration remains unclear. Here, we demonstrate that pUb elevation is a common feature under neurodegenerative conditions, including Alzheimer's disease, aging, and ischemic injury. We show that impaired proteasomal activity leads to the accumulation of sPINK1, the cytosolic form of PINK1 that is normally proteasome-degraded rapidly. This accumulation increases ubiquitin phosphorylation, which then inhibits ubiquitin-dependent proteasomal activity by interfering with both ubiquitin chain elongation and proteasome-substrate interactions. Specific expression of sPINK1 in mouse hippocampal neurons induced progressive pUb accumulation, accompanied by protein aggregation, proteostasis disruption, neuronal injury, neuroinflammation, and cognitive decline. Conversely, Pink1 knockout mitigated protein aggregation in both mouse brains and HEK293 cells. Furthermore, the detrimental effects of sPINK1 could be counteracted by co-expressing Ub/S65A phospho-null mutant but exacerbated by over-expressing Ub/S65E phospho-mimic mutant. Together, these findings reveal that pUb elevation, triggered by reduced proteasomal activity, inhibits proteasomal activity and forms a feedforward loop that drives progressive neurodegeneration.},
}

Animals
Humans
*Proteasome Endopeptidase Complex/metabolism
Phosphorylation
*Protein Kinases/metabolism/genetics
*Ubiquitin/metabolism
Mice
HEK293 Cells
Neurons/metabolism
*Neurodegenerative Diseases/metabolism
Hippocampus

@article {pmid40742252,
year = {2025},
author = {Morgan, TM and Snyder, B},
title = {Pharmacokinetics and Bioavailability of a Novel Rivastigmine Nasal Spray Compared to Rivastigmine Oral Capsule in Healthy Men.},
journal = {Journal of clinical pharmacology},
volume = {},
number = {},
pages = {},
doi = {10.1002/jcph.70086},
pmid = {40742252},
issn = {1552-4604},
support = {AC76937//Lachesis Biosciences and AusIndustry/ ; ACTRN12619001513101//Australian New Zealand Clinical Trials Registry/ ; },
abstract = {To compare the pharmacokinetics, bioavailability, tolerability, and safety of a novel 4 mg rivastigmine nasal spray to 3 mg rivastigmine oral capsule, a single-dose, open-label, randomized, crossover study was conducted in 16 fasted healthy young men (18 to 55 years). Mean (SD) rivastigmine Cmax was 8.39 (6.8) and 13.77 (10.7) ng/mL for oral and nasal, respectively. Rivastigmine AUC0-inf was 19.6 (14.9) and 40.6 (24.4) ng h/mL for oral and nasal, respectively. The ratio of LS means (nasal test / oral reference; 90% C.I.) for rivastigmine Cmax was 185.83% (134.22, 257.28) and for rivastigmine AUC0-inf was 257.35% (197.26, 335.73). Rivastigmine tmax for nasal (0.7 h) was significantly lower than oral (1.2 h, P < .05), however, NAP226-90 tmax for nasal (1.9 h) and oral (1.8 h) were similar. NAP226-90 Cmax was 3.93 (1.1) and 3.01 (0.8) ng/mL for oral and nasal, respectively. NAP226-90 AUC0-inf was 22.9 (5.3) and 23.2 (5.1) ng h/mL for oral and nasal, respectively. Median NAP226-90 to rivastigmine AUC0-inf ratio for nasal (0.55) was significantly lower than oral (1.38, P < .05) because nasal bypassed first-pass metabolism. Both single-dose treatments were safe and well tolerated. Nasal and throat irritation were mostly perceived as mild and transient following nasal administration. The 4 mg rivastigmine nasal spray had 1.5- and 2.0-fold higher dose normalized rivastigmine Cmax and AUC0-inf, respectively, and 2.5-fold lower NAP226-90 to rivastigmine AUC0-inf ratio compared to 3 mg oral capsule. This nasal spray has good potential to improve the local and gastrointestinal tolerability of rivastigmine treatment in Alzheimer's and Parkinson's disease dementia patients.},
}

@article {pmid40742251,
year = {2025},
author = {Feng, J and Liu, CW and Peng, J and Hsiao, YC and Chen, D and Jin, C and Lu, K},
title = {Formaldehyde Exposure Induces Systemic Epigenetic Alterations in Histone Methylation and Acetylation.},
journal = {Chemical research in toxicology},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.chemrestox.5c00150},
pmid = {40742251},
issn = {1520-5010},
abstract = {Formaldehyde (FA) is a pervasive environmental organic pollutant and a Group 1 human carcinogen. While FA has been implicated in various cancers, its genotoxic effects, including DNA damage and DNA-protein cross-linking, have proven insufficient to fully explain its role in carcinogenesis, suggesting the involvement of epigenetic mechanisms. Histone post-translational modifications (PTMs) on H3 and H4, which are critical for regulating gene expression, may contribute to FA-induced pathogenesis, as lysine and arginine residues serve as targets for FA-protein adduct formation. This study aimed to elucidate the epigenetic consequences of FA on histone methylation and acetylation patterns through a comprehensive peptide analysis. Human bronchial epithelial cells (BEAS-2B) were exposed to low-dose (0.1 mM) and high-dose (0.5 mM) FA for 1 h, and their histone extracts were analyzed using high-resolution liquid chromatography-tandem mass spectrometry-based proteomics followed by PTM-combined peptide analysis and single PTM site/type comparisons. We identified 40 peptides on histone H3 and 16 on histone H4 bearing epigenetic marks. Our findings revealed that FA exposure induced systemic alterations in H3 and H4 methylation and acetylation, including hypomethylation of H3K4 and H3K79; changes in H3K9, H3K14, H3K18, H3K23, H3K27, H3K36, H3K37, and H3R40; as well as modifications in H4K5, H4K8, H4K12, and H4K16. These FA-induced histone modifications exhibited strong parallels with epigenetic alterations observed in cancers, leukemia, and Alzheimer's disease. This study provides novel evidence of FA-induced epigenetic toxicity, offering new insights into the potential mechanisms underlying FA-driven pathogenesis.},
}

@article {pmid40742248,
year = {2025},
author = {Um Din, N and Maronnat, F and Zolnowski-Kolp, V and Otmane, S and Belmin, J},
title = {Diagnosis accuracy of touchscreen-based testings for major neurocognitive disorders: a systematic review and meta-analysis.},
journal = {Age and ageing},
volume = {54},
number = {7},
pages = {},
doi = {10.1093/ageing/afaf204},
pmid = {40742248},
issn = {1468-2834},
mesh = {Humans ; *Neurocognitive Disorders/diagnosis/psychology ; *Cognition ; *Neuropsychological Tests ; Aged ; Predictive Value of Tests ; *Computers, Handheld ; Reproducibility of Results ; Smartphone ; Male ; Female ; *Mental Status and Dementia Tests ; Aged, 80 and over ; },
abstract = {Facing an increasing prevalence, diagnosis and management of dementia has become a global health challenge. While most cognitive assessments are based on paper tests, the current trend is to digitise them, using new technologies. We aimed to achieve a systematic review on touchscreen-based assessments for neurocognitive disorders. A search on four databases (PubMed, Embase, IEEE Xplore and Web of Science) was performed. Two investigators independently selected the articles and assessed their quality using the QUADAS-2 tool. We included articles whose participants were over 65 years, classified according to the presence/absence of major neurocognitive disorder (M-NCD) determined by conventional assessment of cognition, examined with a novel tool using a touchscreen device (tablet or smartphone). We finally retained 35 articles for the systematic review and 24 for the meta-analysis. Of the 35 articles included in the systematic review, participants had Alzheimer's disease, Parkinson's disease, vascular dementia, Lewy body disease or any type of dementia. Pooled sensitivity and specificity were 0.89 (95% CI: 0.86-0.91) and 0.88 (95% CI: 0.82-0.92), respectively. Performances of self-administered or brief assessment testings were similar to those of assessor-administered or longer duration testings. The major limitation of this review and meta-analysis is the multiplicity and diversity of methods (tools, cognition assessment and type of M-NCD), which make the comparison difficult. We conclude that brief and self-assessment touchscreen-based cognitive tests are appropriate and simple tools to screen major cognitive disorders that can be used in primary care. The study was registered in Prospero (CRD42022358725).},
}

Humans
*Neurocognitive Disorders/diagnosis/psychology
*Cognition
*Neuropsychological Tests
Aged
Predictive Value of Tests
*Computers, Handheld
Reproducibility of Results
Smartphone
Male
Female
*Mental Status and Dementia Tests
Aged, 80 and over

@article {pmid40742102,
year = {2025},
author = {Hirano, K and Egawa, H and Nishihara, S},
title = {The sulfation pattern of glycosaminoglycans in human brain development and neurological disorders such as Alzheimer's disease.},
journal = {American journal of physiology. Cell physiology},
volume = {},
number = {},
pages = {},
doi = {10.1152/ajpcell.00842.2024},
pmid = {40742102},
issn = {1522-1563},
abstract = {Glycosaminoglycans (GAGs) are modified by various sulfotransferases and endosulfatases. The resulting sulfation patterns are formed, influencing numerous functions. Sulfation leads to a strong negative charge on GAGs, inducing specific interactions with proteins such as signaling ligands and pathogenicity factors, impacting cellular functions and disease onset. While a long history of research has greatly advanced our understanding of GAGs and the sulfation patterns in model organisms, studies of human brain development and the pathogenesis of neurological diseases are in their infancy. To elucidate the role of the sulfation patterns in the human brain, it is necessary to determine the interplay of factors such as core proteins, GAG elongation enzymes and sulfotransferases in a hierarchical manner. In recent years, technological advances in, for example, genomic mutation analysis, single cell analysis, and in vitro brain development models, are beginning to inform our understanding of the role of the sulfation patterns in human brain development and neurological disorders such as Alzheimer's disease.},
}

@article {pmid40741986,
year = {2025},
author = {Ding, S and Liu, R and Srivastava, A and Nowakowski, RS and Shen, L and Thompson, PM and Zhang, H and Huang, C},
title = {S-GMAS: Genome-Wide Mediation Analysis With Brain Subcortical Shape Mediators.},
journal = {Human brain mapping},
volume = {46},
number = {11},
pages = {e70297},
doi = {10.1002/hbm.70297},
pmid = {40741986},
issn = {1097-0193},
support = {DMS-2413748//National Science Foundation/ ; U01AG068057/NH/NIH HHS/United States ; RF1AG068191/NH/NIH HHS/United States ; R01AG071470/NH/NIH HHS/United States ; UL1TR002378/NH/NIH HHS/United States ; },
mesh = {Humans ; *Genome-Wide Association Study/methods ; Polymorphism, Single Nucleotide ; Magnetic Resonance Imaging/methods ; *Brain/diagnostic imaging ; *Alzheimer Disease/genetics/diagnostic imaging/pathology ; *Neuroimaging/methods ; *Mediation Analysis ; Male ; },
abstract = {Mediation analysis is widely utilized in neuroscience to investigate the role of brain image phenotypes in the neurological pathways from genetic exposures to clinical outcomes. However, it is still difficult to conduct mediation analyses with whole genome-wide exposures and brain subcortical shape mediators due to several challenges including (i) large-scale genetic exposures, that is, millions of single-nucleotide polymorphisms (SNPs); (ii) nonlinear Hilbert space for shape mediators; and (iii) statistical inference on the direct and indirect effects. To tackle these challenges, this paper proposes a genome-wide mediation analysis framework with brain subcortical shape mediators. First, to address the issue caused by the high dimensionality in genetic exposures, a fast genome-wide association analysis is conducted to discover potential genetic variants with significant genetic effects on the clinical outcome. Second, the square-root velocity function representations are extracted from the brain subcortical shapes, which fall in an unconstrained linear Hilbert subspace. Third, to identify the underlying causal pathways from the detected SNPs to the clinical outcome implicitly through the shape mediators, we utilize a shape mediation analysis framework consisting of a shape-on-scalar model and a scalar-on-shape model. Furthermore, the bootstrap resampling approach is adopted to investigate both global and spatial significant mediation effects. Finally, our framework is applied to the corpus callosum shape data from the Alzheimer's Disease Neuroimaging Initiative.},
}

Humans
*Genome-Wide Association Study/methods
Polymorphism, Single Nucleotide
Magnetic Resonance Imaging/methods
*Brain/diagnostic imaging
*Alzheimer Disease/genetics/diagnostic imaging/pathology
*Neuroimaging/methods
*Mediation Analysis
Male

@article {pmid40741812,
year = {2025},
author = {Yang, M and Tang, X and Iqfath, M and Hernly, E and Unsihuay, D and Manchanda, P and Sharma, K and Qu, Z and Hu, H and Beveridge, C and Chopra, G and Laskin, J},
title = {Multimodal Nano-DESI Mass Spectrometry Imaging Reveals Phospholipids Accumulation in and around Amyloid Plaques in Alzheimer's Disease.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.5c00144},
pmid = {40741812},
issn = {1948-7193},
abstract = {Alzheimer's disease (AD), characterized by β-amyloid plaques, is increasingly recognized by lipid dysregulation as a key factor in its pathology. Mass spectrometry imaging (MSI), a powerful tool for mapping the spatial distribution of biomolecules in tissue sections, is ideally suited for investigating region-specific molecular alterations in diseased animal tissues. Recent MSI advancements have revealed plaque-associated molecular features in the AD brain, highlighting the role of metabolic dysfunction in disease progression. In this study, we developed a novel multimodal MSI approach using nanospray desorption electrospray ionization (nano-DESI) for dual polarity mode lipid and peptide imaging in the brain tissues of 5-7-month-old transgenic familial AD mice (5xFAD), followed by fluorescence imaging of β-amyloid plaques on the same tissue section. Our results revealed the accumulation of several peptides and phospholipids, including phosphatidylethanolamines (PE), phosphatidylinositols (PI), phosphatidylglycerols (PG), and phosphatidylcholines (PC) in and/or surrounding β-amyloid plaques in the hippocampus, isocortex, and thalamus regions of the AD brain. Furthermore, we observed that several fatty acids (FAs) were enhanced in the plaque-enriched subiculum region of the hippocampus. Our results demonstrate the power of the multimodal nano-DESI MSI approach for comprehensive mapping of molecular pathology with high spatial resolution, providing unique insights into disease metabolism and potential biomarkers.},
}

@article {pmid40741711,
year = {2025},
author = {Reagan, AM and MacLean, M and Cossette, TL and Howell, GR},
title = {Retinal vascular dysfunction in the Mthfr[677C>T] mouse model of cerebrovascular disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {8},
pages = {e70501},
doi = {10.1002/alz.70501},
pmid = {40741711},
issn = {1552-5279},
support = {//Diana Davis Spencer Foundation/ ; NS139948/NS/NINDS NIH HHS/United States ; },
mesh = {Animals ; *Methylenetetrahydrofolate Reductase (NADPH2)/genetics/metabolism ; Disease Models, Animal ; *Cerebrovascular Disorders/genetics/pathology ; Mice ; *Retinal Vessels/pathology/physiopathology ; Male ; Female ; Brain/pathology/metabolism ; Retina/pathology ; Mice, Transgenic ; Electroretinography ; Mice, Inbred C57BL ; },
abstract = {INTRODUCTION: Investigations of retinal biomarkers for Alzheimer's disease (AD) and AD and related dementias (ADRD), has increased significantly. We examine retinal vascular health in a mouse containing the ADRD risk variant Mthfr[677C>T] to determine if changes in retina mirror similar changes in cerebrovasculature.

METHODS: Morphology and function of retinal vasculature and neurons were assessed using in vivo imaging, immunohistochemistry, and pattern electroretinography. RNAscope and proteomics were employed to determine Mthfr gene expression and differential protein expression in mice carrying Mthfr[677C>T].

RESULTS: Mice show age- and sex-dependent retinal vascular deficits, displaying similarities to previously published brain data. Mthfr is widely expressed and co-localizes with vascular cell markers. Proteomics identified common molecular signatures across the brain and retina.

DISCUSSION: Results demonstrate that Mthfr-dependent vascular phenotypes occur in brain and retina similarly. These data suggest that assessing age and genetic-driven changes within retinal vasculature represents a minimally invasive method to predict AD-related cerebrovascular damage.

HIGHLIGHTS: Mthfr[677C>T] retinal vascular phenotypes align with cerebrovascular phenotypes. Mthfr[677C>T] brain and retina share Alzheimer's disease (AD)-)relevant differentially expressed proteins. Retinal imaging may provide insight regarding genetic risk for vascular dysfunction.},
}

Animals
*Methylenetetrahydrofolate Reductase (NADPH2)/genetics/metabolism
Disease Models, Animal
*Cerebrovascular Disorders/genetics/pathology
Mice
*Retinal Vessels/pathology/physiopathology
Male
Female
Brain/pathology/metabolism
Retina/pathology
Mice, Transgenic
Electroretinography
Mice, Inbred C57BL

@article {pmid40741702,
year = {2025},
author = {Uchida, Y and Nishimaki, K and Soldan, A and Pettigrew, C and Ho, SG and Moghekar, A and Wang, MC and Miller, MI and Albert, M and Oishi, K},
title = {Change points for dynamic biomarkers in the Alzheimer's disease pathological cascade: A 30-year cohort study.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {8},
pages = {e70544},
doi = {10.1002/alz.70544},
pmid = {40741702},
issn = {1552-5279},
support = {K99AG088363/NH/NIH HHS/United States ; U19AG033655/NH/NIH HHS/United States ; P30AG066507/NH/NIH HHS/United States ; P41RR015241/NH/NIH HHS/United States ; NIAP24-1268927/ALZ/Alzheimer's Association/United States ; },
mesh = {Humans ; *Alzheimer Disease/pathology/cerebrospinal fluid/diagnostic imaging ; *Biomarkers/cerebrospinal fluid ; Male ; Female ; Magnetic Resonance Imaging ; Aged ; Amyloid beta-Peptides/cerebrospinal fluid ; Longitudinal Studies ; Disease Progression ; *Cognitive Dysfunction/pathology/cerebrospinal fluid ; tau Proteins/cerebrospinal fluid ; Brain/pathology/diagnostic imaging ; Cohort Studies ; White Matter/pathology/diagnostic imaging ; Neurofilament Proteins/cerebrospinal fluid ; Aged, 80 and over ; },
abstract = {INTRODUCTION: This study aimed to delineate trajectories of biomarkers-amyloid beta (Aβ), phosphorylated tau, neurodegeneration, and inflammation-and to identify change points along these trajectories.

METHODS: Longitudinal data were collected over 30 years from 349 cognitively unimpaired individuals enrolled in the Biomarkers for Older Controls at Risk for Dementia study. Piecewise regression models were used to identify change points in cerebrospinal fluid biomarkers, brain magnetic resonance imaging volumes, and a composite measure of global cognition.

RESULTS: Eighty-two participants progressed to mild cognitive impairment or dementia during the follow-up period. Change points were identified in years prior to clinical symptom onset: Aβ at -17.1 years, phosphorylated tau at -15.8 years, neurofilament light chain and whole-brain white matter at -11.6 years, and total ventricles at -9.7 years.

CONCLUSION: These findings support the temporal sequence proposed by the dynamic biomarker model of Alzheimer's disease and underscore the significance of white matter degeneration as an early marker for disease progression in the pathological cascade.

HIGHLIGHTS: Data were collected from 349 participants in Biomarkers for Older Controls at Risk for Dementia, a 30-year cohort study. Eighty-two participants progressed to mild cognitive impairment or dementia over an average of 11 to 12 years. Core cerebrospinal fluid biomarkers for Alzheimer's disease began to accelerate 15 to 20 years before clinical onset. Magnetic resonance imaging volumes accelerated with variations across brain structures. Volumetric changes in the white matter and ventricles preceded the hippocampus.},
}

Humans
*Alzheimer Disease/pathology/cerebrospinal fluid/diagnostic imaging
*Biomarkers/cerebrospinal fluid
Male
Female
Magnetic Resonance Imaging
Aged
Amyloid beta-Peptides/cerebrospinal fluid
Longitudinal Studies
Disease Progression
*Cognitive Dysfunction/pathology/cerebrospinal fluid
tau Proteins/cerebrospinal fluid
Brain/pathology/diagnostic imaging
Cohort Studies
White Matter/pathology/diagnostic imaging
Neurofilament Proteins/cerebrospinal fluid
Aged, 80 and over

@article {pmid40741240,
year = {2025},
author = {Li, B and Sun, X and Luo, X and Kan, Y and Wang, W and Wang, T and Wu, C and Hu, Y and Bi, X},
title = {Exploring the mediating role of the plasma lipidome in the pathway from the gut microbiota to dementia: a Mendelian randomization study.},
journal = {Archives of medical science : AMS},
volume = {21},
number = {3},
pages = {964-973},
pmid = {40741240},
issn = {1734-1922},
abstract = {INTRODUCTION: Previous studies have indicated a potential association between the gut microbiota (GM) and dementia; however, the exact cause-and-effect relationships between GM, various types of dementia, and the potential influence of the plasma lipidome as intermediaries are still unclear.

MATERIAL AND METHODS: We used genome-wide association study (GWAS) data to identify GM taxa, plasma lipid species (lipidome), and five types of dementia: Alzheimer's disease (AD), dementia with Lewy bodies (DLB), Parkinson's disease dementia (PDD), frontotemporal dementia (FTD) and vascular dementia (VD). We used Mendelian randomization (MR) to investigate the possible causal connections among the GM, plasma lipidome, and dementias. The inverse variance weighting (IVW) method served as the primary statistical approach. We investigated the role of plasma lipidome as a potential mediating factor in this relationship.

RESULTS: A total of 41 positive and 39 negative causal relationships between genetic susceptibility in the GM taxa or bacterial pathways and dementia, as well as 14 negative causal relationships between the plasma lipidome and dementias, were identified. Additionally, only 1 potential mediation pathway was identified as having a significant mediating effect.

CONCLUSIONS: Our results suggest a link between the GM and the plasma lipidome with five distinct types of dementia, indicating that the phosphatidylcholine (O-16:1_18:2) level could play a role in the pathway from the species Bacteroides coprocola to vascular dementia.},
}

@article {pmid40741133,
year = {2025},
author = {El-Samadi, L and Zahreddine, R and Ziade, JA and El Ghawi, A and Amin, G and Booz, GW and Zouein, FA},
title = {Impact of Myocardial Infarction on Cerebral Homeostasis: Exploring the Protective Role of Estrogen.},
journal = {The journal of cardiovascular aging},
volume = {5},
number = {2},
pages = {},
pmid = {40741133},
issn = {2768-5993},
abstract = {Myocardial infarction (MI), commonly known as a heart attack, results from the rupture of atherosclerotic plaques in coronary arteries, which triggers a series of pathological events including cardiomyocyte death, thrombus formation, and systemic inflammation. These pathological events lead to significant structural and functional changes in the heart, potentially precipitating heart failure. The ramifications of MI extend beyond cardiac dysfunction and impact cerebral health. Accordingly, this review examines the cerebral implications of MI, focusing on how systemic inflammation and reduced cardiac output post-MI affect cerebral blood flow (CBF) and brain function. MI-induced changes in cardiac output can lead to cerebral hypoperfusion, while neuroinflammation and increased blood-brain barrier (BBB) permeability contribute to cognitive decline and neuronal damage, with potential links to Alzheimer's disease (AD). Furthermore, the review explores the role of estrogen in modulating cardiovascular and cerebral health, particularly in post-menopausal women who exhibit distinct cardiovascular risk profiles. Estrogen protects the heart by regulating local renin-angiotensin-aldosterone systems (RAAS) and has significant impacts on brain function. Declining estrogen levels during menopause exacerbate neuroinflammation and cognitive deficits, highlighting the importance of estrogen in maintaining cerebrovascular function. Experimental studies on estrogen replacement therapies, including 17β-estradiol and selective estrogen receptor modulators (SERMs), show potential in mitigating these detrimental effects, enhancing neurogenesis, and improving cognitive outcomes. Estrogen therapy is crucial in preventing cognitive decline and reducing amyloid plaque formation in Alzheimer's models. This review underscores the potential benefits of estrogen therapy in promoting brain recovery post-MI and improving functional outcomes.},
}

@article {pmid40741053,
year = {2025},
author = {Si, X and Wang, Y and Qiu, N and Qian, C and Yang, B and Jin, H and Wang, H and Zhang, X and Xia, J},
title = {Computer-aided discovery of triazolothiadiazoles as DYRK1A-targeted neuroprotective agents.},
journal = {RSC medicinal chemistry},
volume = {},
number = {},
pages = {},
pmid = {40741053},
issn = {2632-8682},
abstract = {Dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) is a promising target for drug discovery against neurological diseases. So far, no DYRK1A inhibitor has been approved for clinical use, partly due to the lack of effective and safe chemotypes. In this study, by using a computer-aided drug design strategy and DYRK1A inhibition assay, we were able to identify a novel DYRK1A inhibitor, i.e., compound Y16-5 (Specs ID: AO-365/43472821) with an IC50 value of 0.29 μM. The molecular docking and molecular dynamics simulations uncovered the binding details of compound Y16-5 that included hydrogen bonds with Leu241, Lys188 and Lys167. According to the kinome analysis, compound Y16-5 was highly selective to DYRK1A. Further cell-based assays have shown that compound Y16-5 could protect human neuroblastoma cell line SH-SY5Y from okadaic acid (OA)-induced injury. In terms of the molecular mechanism, compound Y16-5 decreased tau (pSer396)/tau and Aβ1-42 protein expression highly related to Alzheimer's disease. Further in vitro druglikeness evaluation has demonstrated that (1) compound Y16-5 was not toxic to SH-SY5Y and HL-7702 cells (CC50 > 100 μM), and (2) compound Y16-5 could permeate the blood-brain-barrier, with a permeability value of 31.52 (×10[-6] cm s[-1]). Taken together, we have discovered a potent DYRK1A inhibitor Y16-5 with neuroprotective activity by in silico screening and in vitro bioassays.},
}

@article {pmid40741047,
year = {2025},
author = {Yang, Y and Chen, H and Liu, Q and Niu, Y and Mao, C and Wang, R},
title = {Elucidating molecular pathogenesis and developing targeted therapeutic interventions for cerebrovascular endothelial cell-mediated vascular dementia.},
journal = {Frontiers in aging neuroscience},
volume = {17},
number = {},
pages = {1623050},
pmid = {40741047},
issn = {1663-4365},
abstract = {Vascular dementia (VaD) ranks as the second most prevalent subtype of dementia, surpassed only by Alzheimer's disease (AD). The maintenance of neurological function and cerebral homeostasis critically depends on precisely regulated blood flow within the intricately organized cerebrovascular network. Disruptions in cerebral hemodynamics may impair neurovascular homeostasis, thereby inducing pathophysiological cascades characterized by oxidative stress, neuroinflammation, and neuronal degeneration. Emerging evidence identifies cerebrovascular dysregulation and impaired neurovascular coupling (NVC) as primary pathogenic mechanisms underlying VaD, emphasizing the necessity to elucidate their complex interplay. Cerebrovascular endothelial cells exhibit remarkable heterogeneity, serving dual roles as both architectural components of the blood-brain barrier (BBB) and functional regulators of NVC. Furthermore, pericytes residing abluminal on capillary endothelia demonstrate critical involvement in hemodynamic modulation through contractile regulation of microvascular tone, while concurrently maintaining BBB integrity through dynamic paracrine signaling. This study examines cerebrovascular endothelial-neuronal interactions within the neurovascular unit (NVU) framework, analyzing their bidirectional regulatory mechanisms and therapeutic potential in cognitive dysfunction remediation. The pathophysiological progression of VaD manifests through multiple interdependent pathways, including cerebral hypoperfusion, oxidative stress cascades, neuroinflammatory responses, mitochondrial dysregulation, and electrolyte homeostasis perturbations. Through three interventional axes: (1) BBB fortification strategies; (2) cerebral hemodynamic optimization and NVC enhancement; (3) nanotherapeutic platforms integrating endothelial-specific molecular targets we systematically evaluate endothelial-centric therapeutic paradigms. This multi-modal approach proposes novel mechanistic insights and clinical translation frameworks for VaD management.},
}

@article {pmid40741044,
year = {2025},
author = {Chen, F and Heng, T and Feng, Q and Hua, R and Wu, J and Shi, F and Liao, Z and Qiao, K and Zhang, Z and Miao, J},
title = {Quantitative assessment of brain glymphatic imaging features using deep learning-based EPVS segmentation and DTI-ALPS analysis in Alzheimer's disease.},
journal = {Frontiers in aging neuroscience},
volume = {17},
number = {},
pages = {1621106},
pmid = {40741044},
issn = {1663-4365},
abstract = {BACKGROUND: This study aimed to quantitatively evaluate brain glymphatic imaging features in patients with Alzheimer's disease (AD), amnestic mild cognitive impairment (aMCI), and normal controls (NC) by applying a deep learning-based method for the automated segmentation of enlarged perivascular space (EPVS) and diffusion tensor imaging analysis along perivascular spaces (DTI-ALPS) indices.

METHODS: A total of 89 patients with AD, 24 aMCI, and 32 NCs were included. EPVS were automatically segmented from T1WI and T2WI images using a VB-Net-based model. Quantitative metrics, including total EPVS volume, number, and regional volume fractions were extracted, and segmentation performance was evaluated using the Dice similarity coefficient. Bilateral ALPS indices were also calculated. Group comparisons were conducted for all imaging metrics, and correlations with cognitive scores were analyzed.

RESULTS: VB-Net segmentation model demonstrated high accuracy, with mean Dice coefficients exceeding 0.90. Compared to the NC group, both AD and aMCI groups exhibited significantly increased EPVS volume, number, along with reduced ALPS indices (all P < 0.05). Partial correlation analysis revealed strong associations between ALPS and EPVS metrics and cognitive performance. The combined imaging features showed good discriminative performance among diagnostic groups.

CONCLUSION: The integration of deep learning-based EPVS segmentation and DTI-ALPS analysis enables multidimensional assessment of glymphatic system alterations, offering potential value for early diagnosis and translation in neurodegenerative diseases.},
}

@article {pmid40740995,
year = {2025},
author = {Zhang, Y and Zhang, T and Zhao, M and Li, P and Liu, T and Xie, J},
title = {Pharmacological mechanisms and potential clinical applications of Dihydromyricetin in neurological disorders.},
journal = {Frontiers in pharmacology},
volume = {16},
number = {},
pages = {1618623},
pmid = {40740995},
issn = {1663-9812},
abstract = {Neurological disorders (e.g., Alzheimer's disease, Parkinson's disease, and stroke) have complex pathogenesis and affect a substantial proportion of the population; yet, available treatments have poor or limited efficacy, and the patients have a poor prognosis, with high morbidity and mortality. Dihydromyricetin (DHM), a flavonoid compound extracted from plants, has received widespread attention in recent years because of its diverse pharmacological effects. In vitro and in vivo studies have revealed its substantial antioxidant, anti-inflammatory, and neuroprotective properties, making it a promising candidate for the treatment of central nervous system disorders through multiple mechanisms and pleiotropic effects. Therefore, there is an urgent need to develop novel therapeutic strategies. DHM is an attractive candidate for the management of neurological disorders, but there is a lack of a systematic summary of the knowledge status and gaps. Therefore, to address this challenge, we systematically reviewed the pharmacological mechanisms of DHM in central nervous system disorders and its potential applications in related conditions. We analyzed the therapeutic potential and current challenges of DHM to provide a reference for its development and application as a novel therapeutic agent. The review suggests that DHM possesses significant potential for the management of neurological disorders.},
}

@article {pmid40740772,
year = {2025},
author = {Cao, Y and Tang, K and Ma, P and Zhang, R and Yang, Y and Li, T and Zhang, Y and Peng, X},
title = {The role of peripheral innate immune cells in Alzheimer's disease progression.},
journal = {Frontiers in immunology},
volume = {16},
number = {},
pages = {1616939},
pmid = {40740772},
issn = {1664-3224},
mesh = {Humans ; *Alzheimer Disease/immunology/pathology/metabolism/therapy/etiology ; *Immunity, Innate ; Animals ; Disease Progression ; Myeloid-Derived Suppressor Cells/immunology ; Neutrophils/immunology ; },
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder characterized by amyloid-β (Aβ) plaques, neurofibrillary tangles, and chronic neuroinflammation. While microglia and astrocytes dominate CNS immune responses, emerging evidence implicates peripheral innate immune cells (PIICs)-including neutrophils, monocytes, dendritic cells, NK cells, and myeloid-derived suppressor cells (MDSCs)-as critical modulators of AD pathogenesis. This review synthesizes recent advances linking PIIC-related genetic polymorphisms to AD susceptibility and progression. We highlight how PIICs traffic into the brain via chemokine signaling, where they exhibit stage-specific effects: early recruitment may limit Aβ deposition via phagocytosis, whereas chronic infiltration exacerbates neuroinflammation and neuronal death. Paradoxically, some PIICs exert immunosuppressive effects that could be harnessed therapeutically. We further discuss preclinical strategies to modulate PIIC function, such as CCR2 inhibition, neutrophil depletion, and MDSC adoptive transfer. By bridging peripheral and central immunity, this review unveils PIICs as promising targets for next-generation AD therapies, advocating for precision immunomodulation tailored to disease stages.},
}

Humans
*Alzheimer Disease/immunology/pathology/metabolism/therapy/etiology
*Immunity, Innate
Animals
Disease Progression
Myeloid-Derived Suppressor Cells/immunology
Neutrophils/immunology

@article {pmid40740514,
year = {2025},
author = {Wang, J and Mao, Y and Liu, X and Hao, W},
title = {Learning Patient-Specific Spatial Biomarker Dynamics via Operator Learning for Alzheimer's Disease Progression.},
journal = {ArXiv},
volume = {},
number = {},
pages = {},
pmid = {40740514},
issn = {2331-8422},
abstract = {Alzheimer's disease (AD) is a complex, multifactorial neurodegenerative disorder with substantial heterogeneity in progression and treatment response. Despite recent therapeutic advances, predictive models capable of accurately forecasting individualized disease trajectories remain limited. Here, we present a machine learning-based operator learning framework for personalized modeling of AD progression, integrating longitudinal multimodal imaging, biomarker, and clinical data. Unlike conventional models with prespecified dynamics, our approach directly learns patient-specific disease operators governing the spatiotemporal evolution of amyloid, tau, and neurodegeneration biomarkers. Using Laplacian eigenfunction bases, we construct geometry-aware neural operators capable of capturing complex brain dynamics. Embedded within a digital twin paradigm, the framework enables individualized predictions, simulation of therapeutic interventions, and in silico clinical trials. Applied to AD clinical data, our method achieves high prediction accuracy exceeding 90% across multiple biomarkers, substantially outperforming existing approaches. This work offers a scalable, interpretable platform for precision modeling and personalized therapeutic optimization in neurodegenerative diseases.},
}

@article {pmid40740481,
year = {2025},
author = {Avey, DR and Ng, B and Vialle, RA and Kearns, NA and de Paiva Lopes, K and Iatrou, A and De Tissera, S and Vyas, H and Saunders, DM and Flood, DJ and Xu, J and Tasaki, S and Gaiteri, C and Bennett, DA and Wang, Y},
title = {Uncovering plaque-glia niches in human Alzheimer's disease brains using spatial transcriptomics.},
journal = {Molecular neurodegeneration advances},
volume = {1},
number = {1},
pages = {2},
pmid = {40740481},
issn = {3059-4944},
abstract = {BACKGROUND: Amyloid-beta (Aβ) plaques and their associated glial responses are hallmark features of Alzheimer's disease (AD), yet their interactions within the human brain remain poorly defined.

METHODS: We applied spatial transcriptomics (ST) and immunohistochemistry (IHC) to 78 postmortem brain sections from 21 individuals in the Religious Orders Study and Memory and Aging Project (ROSMAP). We paired ST with histological data and stratified spots into major categories of plaque-glia niches based on Aβ, GFAP, and IBA1 intensity. Leveraging published ROSMAP single-nucleus RNA-seq data, we examined differences in gene expression, cellular composition, and intercellular communication across these niches. Neuronal and glial changes were validated by IHC and quantitative analyses. We further characterized glial responses using gene set enrichment analysis (GSEA) with known mouse glial signatures and human AD-associated microglial states. Finally, we used iPSC-derived multicellular cultures and single-cell RNA sequencing (scRNA-seq) to identify cell types that, upon short-term Aβ exposure, recapitulate the glial responses observed in the human spatial data.

RESULTS: Low-Aβ regions, enriched for diffuse plaques, exhibited transcriptomic profiles consistent with greater neuronal loss than high-Aβ regions. High-glia regions showed increased expression of inflammatory and neurodegenerative pathways. Spatial glial responses aligned with established gene modules, including plaque-induced genes (PIGs), oligodendrocyte (OLIG) responses, disease-associated microglia (DAM), disease-associated astrocytes (DAA), and human AD-associated microglial states, indicating that diverse glial phenotypes emerge around plaques and shape the local immune environment. IHC confirmed elevated neuronal apoptosis near low-Aβ plaques and greater CD68 abundance and synaptic loss near glia-high plaques. In vitro, iPSC-derived microglia-but not astrocytes-exposed to Aβ displayed transcriptomic changes that closely mirrored the glial states identified in our ST dataset.

CONCLUSIONS: Our study provides a comprehensive spatial transcriptomic dataset from human AD brain tissue and bridges spatial gene expression with traditional neuropathology. By integrating ST, snRNA-seq, and human multicellular models, we map cellular states and molecular events within plaque-glia niches. This work offers a spatially resolved framework for dissecting plaque-glia interactions and reveals new insights into the cellular and molecular heterogeneity underlying neurodegenerative pathology.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s44477-025-00002-z.},
}

@article {pmid40740460,
year = {2025},
author = {Fu, HX},
title = {Effects of repetitive transcranial magnetic stimulation on electroencephalogram and memory function in patients with mild cognitive impairment.},
journal = {World journal of psychiatry},
volume = {15},
number = {7},
pages = {106761},
pmid = {40740460},
issn = {2220-3206},
abstract = {BACKGROUND: Mild cognitive impairment (MCI) is a high-risk precursor to Alzheimer's disease characterized by declining memory or other progressive cognitive functions without compromising daily living abilities.

AIM: To investigate the efficacy of repetitive transcranial magnetic stimulation (rTMS) in patients with MCI.

METHODS: This retrospective analysis involved 180 patients with MCI who were admitted to The First Hospital of Shanxi Medical University from January 2021 to June 2023. Participants were allocated into the research (n = 98, receiving rTMS) and control groups (n = 82, receiving sham stimulation). Memory tests, cognitive function assessments, event-related potential-P300 tests, and electroencephalogram (EEG) examinations were conducted pre-treatment and post-treatment. Further, memory quotient (MQ), cognitive function scores, and EEG grading results were compared, along with adverse reaction incidences.

RESULTS: Pre-treatment MQ scores, long-term and short-term memory, as well as immediate memory scores, demonstrated no notable differences between the groups. Post-treatment, the research group exhibited significant increases in MQ scores, long-term memory, and short-term memory compared to baseline (P < 0.05), with these improvements being statistically superior to those in the control group. However, immediate memory scores exhibited no significant change (P > 0.05). Further, the research group demonstrated statistically better post-treatment scores on the Revised Wechsler Memory Scale than the control group. Furthermore, post-treatment P300 latency and amplitude improved significantly in the research group, surpassing the control group. EEG grading in the research group improved, and the incidence of adverse reactions was significantly lower than in the control group.

CONCLUSION: Patients with MCI receiving rTMS therapy demonstrated improved memory and cognitive functions and EEG grading and exhibited high safety with fewer adverse reactions.},
}

@article {pmid40740432,
year = {2025},
author = {Zhang, H and Zhang, J and Hsu, CL and Hui, ES and Tse, KH and Mak, HK and Shum, DHK},
title = {Longitudinal effects of sex differences and apolipoprotein E genotype on white matter engagement among elderly.},
journal = {Brain communications},
volume = {7},
number = {4},
pages = {fcaf278},
pmid = {40740432},
issn = {2632-1297},
abstract = {The apolipoprotein E (APOE) ɛ4 allele is the primary genetic risk factor that influences lipid metabolism and contributes to distinctive Alzheimer's disease pathologies, including increased hippocampal atrophy and accelerated cognitive decline. Synaptic dysfunction can occur in APOE4 carriers even before the appearance of any clinical symptoms. Recent evidence has suggested that this genetic risk factor impacts males and females differently. The sex-specific vulnerability for females to cognitive decline, particularly memory, intensifies post-menopause and emphasizes the need for further investigation. White matter abnormalities, APOE4 allele and disruptions in default mode network connectivity serve as early indicators that are crucial for better understanding Alzheimer's disease progression. This study aims to explore relationships between biological sex, APOE4, default mode network-white matter activity and memory function as measured by the Selective Reminding Test. Participants were categorized by risk level on their APOE4 status. Using longitudinal data from the Harvard Aging Brain Study, we examined sex differences in default mode network-white matter engagement among older individuals with and without the APOE4 allele. Our findings demonstrated a significant reduction in default mode network-white matter activity in the right posterior corona radiata in the high-risk group compared to the low-risk group. High-risk females showed reduction in default mode network-white matter activity in the right superior longitudinal fasciculus, which positively correlated with free recall performance, compared to their low-risk counterparts. Unlike females, males showed no significant changes between the low- and high-risk groups. These results underscore the effectiveness of white matter engagement mapping in differentiating longitudinal changes in memory function related to the genetic risk factor APOE4 and biological sex.},
}

@article {pmid40740212,
year = {2025},
author = {Silva, MN and Lula, MD and Felício, LR and Santos, B and Nassif, LS and Borin, MC and Alvares-Teodoro, J and Acurcio, FA and Guerra, AA},
title = {Genetic markers involved in neuroinflammation in Down syndrome: a systematic review.},
journal = {Dementia & neuropsychologia},
volume = {19},
number = {Suppl 1},
pages = {e20240251},
pmid = {40740212},
issn = {1980-5764},
abstract = {UNLABELLED: The immune system plays a fundamental role in protecting human body organs and tissues; however, when exacerbated, it can contribute to the pathology of various conditions. In the central nervous system, immune cell activation, or neuroinflammation, is a key factor in several neurodegenerative diseases. In Down syndrome (DS), the additional copy of chromosome 21 alters gene expression, potentially enhancing inflammatory processes such as neuroinflammation. Therefore, understanding the genetic factors influencing neuroinflammation in DS is essential for identifying biomarkers and therapeutic targets.

OBJECTIVE: Identify genetic markers involved in neuroinflammatory processes in individuals with DS.

METHODS: A comprehensive search was conducted in Medical Literature Analysis and Retrieval System Online (Medline) (United States National Library of Medicine [PubMed]), Embase, Cochrane Library, and Latin American and Caribbean Health Sciences Literature (LILACS) databases, and identified ten relevant studies. These studies assessed and compared gene expression between groups with and without DS associated with neuroinflammation.

RESULTS: Sixty-three genes and 42 genetic markers associated with neuroinflammation in DS were identified. These genes exhibited expression variations that alter inflammatory responses, suggesting a possible link to the progression of neurodegenerative diseases in this population.

CONCLUSIONS: The findings highlight the role of neuroinflammation in neurodegenerative disorders in individuals with DS, especially Alzheimer's disease. Some studies indicated that the triplicated genes SOD1, APP, S100B, TREM2, IFNR1, and IFNR2 are directly related to neuroinflammation. Additionally, elevated levels of pro-inflammatory cytokines, such as IL-1, IL-6, IL-10, IFNγ, and TNF-α, and complement proteins like C1q, C3, and C9 suggest an exacerbated activation of the immune response. However, the roles these genes may play in neurodegenerative diseases and in increasing or reducing neuroinflammation remain controversial.},
}

@article {pmid40740154,
year = {2025},
author = {Waheed, AR and Abdul Razzaq Mshimesh, B},
title = {Evaluating the effectiveness of pterostilbene in improving memory and offering neuroprotection in a rat model of Alzheimer's disease induced by aluminum chloride.},
journal = {Journal of complementary & integrative medicine},
volume = {},
number = {},
pages = {},
pmid = {40740154},
issn = {1553-3840},
abstract = {BACKGROUND AND OBJECTIVES: Alzheimer's disease (AD) is a neurodegenerative disease and is the predominant etiology of dementia. We hypothesize that the naturally occurring pterostilbene (PTE) at doses of 50 and 100 mg/kg would yield dose-dependent neuroprotective effects, reducing cognitive deficits and pathological hallmarks by modulating biomarkers (Amyloid Beta protein (Aβ), Phosphorylated tau protein (P-tau), Brain-Derived Neurotrophic Factor (BDNF), acetylcholinesterase (ACHE), glutamate (GLU)) and a novel synaptic marker neurogranin (NRGN) in rats induced by aluminum chloride (AlCl3). This current research aims to evaluate the neuroprotective effects of pterostilbene (PTE) against neurobehavioral and pathological alterations induced by aluminum chloride (AlCl3) in rats with Alzheimer's.

METHODS: 40 rats were divided into five groups, eight in each group. They received 70 mg/kg of body weight AlCl3 intraperitoneally for 30 days, followed by oral administration of PTE at 50 mg/kg or 100 mg/kg, or donepezil at 1 mg/kg for 14 days. The Y-maze and novel object recognition tests were used for the neurobehavioral evaluation of the rats. This was followed by a biochemical evaluation using ELISA kits to demonstrate the impact of PTE on the levels of Aβ, P-tau, BDNF, NRGN, AChE, and GLU. Additional validations were conducted through histopathological evaluation of the cortex and basal ganglia in the rat brain. Using GraphPad Prism 10, statistical data were obtained by ANOVA and Tukey's multiple comparisons test. The histopathologic score system was determined using the non-parametric Kruskal-Wallis one-way ANOVA k-samples (all pairwise) test.

RESULTS: PTE at 50 mg/kg significantly increases spontaneous alternation percentage (SAP) by 35.7 % and discrimination index (DI) by 79.7 %, while also considerably lowering Aβ by 70.6 %, P-tau by 33.9 %, BDNF by 59.7 %, NRGN by 40 %, ACHE by 28.8 %, and GLU by 28.4 %. Moreover, PTE at 100 mg/kg significantly increases SAP by 42.9 % and DI by 83.4 %, and substantially decreases Aβ by 83.8 %, P-tau by 45.5 %, BDNF by 69 %, NRGN by 42.5 %, ACHE by 69 %, and GLU by 50.9 % compared to the AlCl3 group. Histopathological evaluation of the cortex and basal ganglia in AlCl3-induced rat brains revealed pathological alterations absent in rats treated with PTE.

CONCLUSIONS: This study supports the hypothesis that PTE can reverse memory loss and pathological markers.},
}

@article {pmid40740038,
year = {2025},
author = {Zheng, M and Yang, M and Li, X and Tian, L and Zhou, S and Wang, G and Gao, W},
title = {Attenuation of Tacrine Combined With Rosmarinic Acid.},
journal = {Phytochemical analysis : PCA},
volume = {},
number = {},
pages = {},
doi = {10.1002/pca.70009},
pmid = {40740038},
issn = {1099-1565},
support = {2060302//Key Project at the Central Government Level/ ; ZYYCXTD-D-202005//Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine/ ; 81872956//National Natural Science Foundation of China/ ; 82173929//National Natural Science Foundation of China/ ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is one of the most common forms of dementia among the elderly in the world. With the increase of human life expectancy, its incidence is also increasing year by year. Tacrine (TAC) is the first acetylcholine inhibitor approved for the treatment of AD. Although TAC has obvious anti-AD activity, it was eventually delisted due to acute liver injury caused by its strong hepatotoxicity. Rosmarinic acid (RA) has shown good activity in both neuroprotection and hepatoprotection.

PURPOSE AND STUDY DESIGN: In this study, the combination of RA and TAC was explored, and a high dose of d-galactose was used to build an AD mouse model, which was given at the same time for 4 weeks in order to alleviate TAC hepatotoxicity and enhance the intervention of AD in mice through RA. In particular, we pay attention to the key role of Aβ and microglia in the pathogenesis of AD, so we evaluate the ability of RA combined with TAC in alleviating chronic neuroinflammation induced by Aβ plaque in the brain of AD mice and enhancing the ability of microglia to clear Aβ plaque.

RESULTS: The results show that the combination of RA and TAC has the best intervention effect on AD compared with the single use of the two drugs, and it is basically positively correlated with RA dose. RA + TAC significantly improved body weight, organ index, and behavioral state of AD mice. Further analysis showed that RA + TAC enhanced the antioxidant level of hippocampus and serum of AD mice, alleviated the pathological damage of hippocampus, significantly improved cholinergic system, reduced the expression levels of AB plaque and neurotoxic Aβ1-41 and Aβ1-42 in the brain, and significantly increased the level of neuroprotective protein trigger receptor expressed on myeloid cells 2 (TREM2), which mediated the phagocytosis of microglia. More importantly, the combination therapy of RA and TAC decreased the expression of M1 microglia marker (ionized calcium-binding adapter molecule 1 [Iba-1]), increased the expression of M2 microglia marker Arg-1, and promoted the release of anti-inflammatory compounds. In addition, RA + TAC also inhibited the mRNA expression of TLR4 and NF-κB related to neuroinflammation. In the aspect of liver function, RA reduced cell death mediated by Caspase-3 by regulating the expression of bcl-2/bax, alleviated TAC-induced liver injury in mice, and made the serum indexes of ALT, AST, ALP, TBIL, and γ-GT reflecting liver function closer to the normal range.

CONCLUSION: The combination of RA and TAC shows the potential to reduce the hepatotoxicity of TAC and is expected to enhance its therapeutic effect on AD.},
}

@article {pmid40739971,
year = {2025},
author = {Oh, JH and Seo, J and Park, HJ},
title = {Cause of death statistics in 2022 in the Republic of Korea.},
journal = {Ewha medical journal},
volume = {48},
number = {3},
pages = {e46},
doi = {10.12771/emj.2025.00689},
pmid = {40739971},
issn = {2234-2591},
abstract = {PURPOSE: This study aimed to describe mortality trends in the Republic of Korea in 2022 by analyzing total deaths, crude and age-standardized mortality rates, as well as age- and sex-specific patterns and changes in cause-specific mortality. The analysis updates previous reports with newly available data from 2022.

METHODS: A repeated cross-sectional analysis was performed using nationwide death certificate data collected through municipal administrative offices. Deaths occurring in 2022 were aggregated from reports filed over a 16-month period, spanning January 2022 to April 2023. Causes of death were classified according to the World Health Organization's International Classification of Diseases. Quality assurance was ensured through administrative record linkage across 22 databases and validation using an independent infant mortality survey. Descriptive statistics were employed to summarize the findings.

RESULTS: In 2022, Korea recorded 372,939 deaths (the highest annual total since 1983), corresponding to a crude death rate of 727.6 per 100,000 population. This increase contributed to a net population decline of 123,751. Mortality rates rose across most age groups, with particularly marked increases among those aged 1-9 and those aged 80 or older. Coronavirus disease 2019 (COVID-19) became the third leading cause of death (31,280 deaths; 61.0 per 100,000), driven largely by the Omicron variant and heightened infection rates among older adults. Pancreatic cancer overtook stomach cancer in the mortality rankings. There were sharp increases in deaths attributed to Alzheimer's disease and diabetes. Although deaths from intentional self-harm declined, suicide remained a significant cause of death among younger individuals.

CONCLUSION: Korea experienced a record-high mortality rate in 2022, largely due to the impacts of COVID-19 and ongoing population aging. Notable shifts in cause-specific mortality were observed, including increases in deaths from Alzheimer's disease, diabetes, and pancreatic cancer, underscoring evolving public health challenges.},
}

@article {pmid40739944,
year = {2025},
author = {Hardy, J},
title = {Alzheimer's Disease: Treatment Challenges for the Future.},
journal = {Journal of neurochemistry},
volume = {169},
number = {8},
pages = {e70176},
doi = {10.1111/jnc.70176},
pmid = {40739944},
issn = {1471-4159},
mesh = {*Alzheimer Disease/drug therapy/therapy/metabolism ; Humans ; Animals ; Amyloid beta-Peptides/metabolism/immunology/antagonists & inhibitors ; },
abstract = {The approvals of the first anti-amyloid antibodies for the treatment of Alzheimer's disease have changed both the clinical and research landscape for the disease. These antibodies, lecanemab and donanemab, mark a turning point for our understanding of the disease pathogenesis and for the treatment of this prevalent disorder. This review discusses what they imply for disease pathogenesis and what is needed to progress from the current imperfect therapies toward safe and better, disease halting therapies. The research over the next period will involve drug development, largely aimed at reducing the side effects of the anti-amyloid therapies, biomarker and genetic research to try and identify patients earlier in the disease process, and neuropathological research in individuals who have received treatment to try and understand the pathological substrates of the continuing clinical decline in the disease.},
}

*Alzheimer Disease/drug therapy/therapy/metabolism
Humans
Animals
Amyloid beta-Peptides/metabolism/immunology/antagonists & inhibitors

@article {pmid40739894,
year = {2025},
author = {Kruse, P and Eichler, A and Klukas, L and Lenz, M},
title = {A synapse perspective on the function of the amyloid precursor protein.},
journal = {Science progress},
volume = {108},
number = {3},
pages = {368504251360728},
doi = {10.1177/00368504251360728},
pmid = {40739894},
issn = {2047-7163},
mesh = {*Amyloid beta-Protein Precursor/metabolism/genetics ; Humans ; *Synapses/metabolism/pathology ; *Alzheimer Disease/metabolism/pathology ; Animals ; Neuronal Plasticity ; Protein Processing, Post-Translational ; },
abstract = {The amyloid precursor protein (APP) is a transmembrane protein widely expressed throughout the brain, where it plays critical roles in both physiological and pathological states. APP undergoes complex post-translational processing by various secretases, a process that can lead to amyloid plaque formation via its amyloidogenic pathway. Consequently, APP has been extensively studied in the context of Alzheimer's disease (AD). However, emerging evidence highlights its physiological functions and the diverse roles of its cleavage fragments. This review explores the dual role of APP and its fragments, focusing on their contributions to synaptic structure, function, and plasticity. We summarize the mechanisms by which APP and its fragments influence synaptic dynamics and plasticity in the hippocampal CA1 region. These insights underline the importance of APP beyond amyloidogenesis, emphasizing its role in fundamental neurobiological processes and potential implications for understanding early AD-related synaptic dysfunction.},
}

*Amyloid beta-Protein Precursor/metabolism/genetics
Humans
*Synapses/metabolism/pathology
*Alzheimer Disease/metabolism/pathology
Animals
Neuronal Plasticity
Protein Processing, Post-Translational

@article {pmid40739885,
year = {2025},
author = {Parveen, K and Ross, JA and van der Wurp, H and Balzer-Geldsetzer, M and Berg, D and Deuschl, G and Gasser, T and Hilker-Roggendorf, R and Kalbe, E and Liepelt-Scarfone, I and Mollenhauer, B and Riedel, O and Röske, S and Schulz, JB and Spottke, A and Storch, A and Trenkwalder, C and Kassubek, J and Witt, K and Dodel, R and Wüllner, U and Ramirez, A and Dalmasso, MC},
title = {Progression to Parkinson's dementia is not modulated by genetic risk variants for Alzheimer's or Parkinson's disease.},
journal = {Journal of Parkinson's disease},
volume = {},
number = {},
pages = {1877718X251356512},
doi = {10.1177/1877718X251356512},
pmid = {40739885},
issn = {1877-718X},
abstract = {Parkinson's disease (PD) is marked by motor symptoms and often accompanied by mild cognitive impairment (PD-MCI), affecting up to 50% of patients and preceding PD dementia (PDD). Genetic factors may influence this progression, yet the underlying mechanisms remain unclear. This study investigated genetic factors influencing the progression from PD-MCI to PDD using polygenic risk scores (PRS). A genome-wide association study (GWAS) was conducted using data from the LANDSCAPE study. Multivariable Cox regression, Kaplan-Meier survival analysis, and concordance statistics assessed the relationship between PRS and PDD progression. No significant association was found between PD PRS and the risk of developing PDD.},
}

@article {pmid40739848,
year = {2025},
author = {Ding, J and Sun, B and Gao, Y and Gu, C and Zhang, J and Wang, L and Zheng, J and Xia, B and Qi, X},
title = {APOE4 Exacerbates Cerebral Tau Pathology Through Cholesterol-Induced Degradation of Phosphatase in Atherosclerosis.},
journal = {CNS neuroscience & therapeutics},
volume = {31},
number = {8},
pages = {e70536},
doi = {10.1111/cns.70536},
pmid = {40739848},
issn = {1755-5949},
support = {Guizhou Teaching and Technology [2023] 015//Department of Education of Guizhou Province/ ; QKHJC-ZK [2023]YB 316//Guizhou Provincial Science and Technology Projects/ ; 2021ZD0201100//Science Innovation 2030 - Brain Science and Brain-Inspired Intelligence Technology Major Project/ ; 2021ZD0201103//Science Innovation 2030 - Brain Science and Brain-Inspired Intelligence Technology Major Project/ ; 82260263//National Natural Science Foundation of China/ ; Qiankehe Platform Talents-CXTD [2023] 003//Guizhou Provincial Science and Technology Program Project Grant/ ; Qian Science Foundation-ZK [2023] 328//Guizhou Provincial Basic Research Program (Natural Science)/ ; [2025] 521//Guizhou Provincial Basic Research Program (Natural Science)/ ; Qianjiaoji [2024] 93//Guizhou Provincial Education Department Young Scientific Talent/ ; },
mesh = {Animals ; *Apolipoprotein E4/genetics/metabolism ; *Cholesterol/metabolism ; *tau Proteins/metabolism ; Mice ; Humans ; Mice, Transgenic ; *Atherosclerosis/pathology/metabolism/genetics ; Male ; Mice, Inbred C57BL ; *Protein Phosphatase 2/metabolism ; Female ; *Brain/pathology/metabolism ; Alzheimer Disease/pathology/metabolism ; Diet, High-Fat/adverse effects ; Gene Knock-In Techniques ; },
abstract = {BACKGROUND: Apolipoprotein epsilon4 allele (APOE4) is a common risk factor for atherosclerosis (AS) and neurodegenerative diseases like Alzheimer's disease (AD), but whether and how APOE4 induces AD-like neuropathies in the brain of AS pathology remains poorly characterized.

METHODS: By combining postmortem AS human brains and APOE4 knock-in mice, we examined the effects of APOE4 on tau and related neuropathological changes in the brain of AS. Behavioral and pathological observations were used to evaluate the protective effects of facilitating cholesterol transport in APOE4 AS mice.

RESULTS: Here, we showed that APOE4 carriers exhibited higher AD-like phosphorylated Tau (p-Tau) levels in AS postmortem brains. Knocking in human APOE4 in high fat diet-fed mice induced AS pathology and coupled AS and AD. APOE4 promoted cerebral cholesterol content, which could trigger protein phosphatase 2A (PP2A) degradation. We further demonstrated cholesterol could facilitate the ubiquitination of PP2A B and PP2A C, which were regulatory and catalytic subunits of PP2A respectively, leading to PP2A B and PP2A C degradation through the ubiquitin-proteasome system. Reduced PP2A B and PP2A C resulted in cerebral Tau hyperphosphorylated at multiple AD-associated sites. The APOE4 AS mice exhibited an AD-like phenotype, including synaptic degeneration, blood-brain barrier breakdown, glial activation, and cognitive impairment simultaneously. Pharmacologically facilitating cholesterol transport alleviated neuropathologies in APOE4 AS mice.

CONCLUSION: Altogether, these results suggested a role of the APOE4 in linking AS with Tau neuropathology, which might increase the risk of related neurodegenerative diseases for AS patients.},
}

Animals
*Apolipoprotein E4/genetics/metabolism
*Cholesterol/metabolism
*tau Proteins/metabolism
Mice
Humans
Mice, Transgenic
*Atherosclerosis/pathology/metabolism/genetics
Male
Mice, Inbred C57BL
*Protein Phosphatase 2/metabolism
Female
*Brain/pathology/metabolism
Alzheimer Disease/pathology/metabolism
Diet, High-Fat/adverse effects
Gene Knock-In Techniques

@article {pmid40739693,
year = {2025},
author = {Pathak, R and Chandra, P and Sachan, N},
title = {Unveiling the Health Potential of Myricetin: Bio-accessibility, Safety Considerations, and Therapeutic Mechanisms.},
journal = {Current pharmaceutical design},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113816128369420250707163438},
pmid = {40739693},
issn = {1873-4286},
abstract = {Myricetin, a naturally occurring flavanol, has gained significant attention due to its diverse pharmacological properties, including antioxidant, anti-inflammatory, anticancer, antidiabetic, and neuroprotective effects. Found abundantly in various plant families, such as Myricaceae, Anacardiaceae, and Polygonaceae, Myricetin exerts its therapeutic effects by modulating key cellular pathways, including Nrf2/HO-1, MAPK, and PI3K/Akt signaling. This review systematically evaluates Myricetin's bioaccessibility, pharmacokinetics, and therapeutic potential, highlighting its role in modulating oxidative stress, inhibiting tumor proliferation, and protecting against neurodegenerative diseases. Despite its promising benefits, Myricetin exhibits limited bioavailability due to poor aqueous solubility and extensive phase II metabolism (glucuronidation and sulfation). Additionally, Myricetin interacts with cytochrome P450 enzymes (CYP3A4, CYP2C9, CYP2D6), potentially altering drug metabolism and increasing the risk of drug interactions. Toxicological studies indicate an LD50 of 800 mg/kg in mice, with potential hepatic and renal toxicity at high doses, mainly due to redox cycling and quinone formation. While Myricetin shows excellent radical-scavenging properties, it may act as a pro-oxidant in the presence of metal ions, leading to oxidative stress and cellular damage. This review underscores the need for advanced formulation strategies to enhance bioavailability and mitigate toxicity risks. Future clinical investigations are essential to establish optimal therapeutic dosages, assess long-term safety, and validate Myricetin's potential as a nutraceutical and therapeutic agent in chronic diseases.},
}

@article {pmid40739680,
year = {2025},
author = {Rose, DK and Pfund, G and Lee, JK and Liu, AJ and Benitez, A and Fani, N and Walker, KA and Mielke, MM and Bateman, JR},
title = {Adverse childhood experiences influence markers of neurodegeneration risk in older adults.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {8},
pages = {e70523},
doi = {10.1002/alz.70523},
pmid = {40739680},
issn = {1552-5279},
support = {P30AG072947/AG/NIA NIH HHS/United States ; 1R38AG065762/AG/NIA NIH HHS/United States ; U24AG021886//Alzheimer's Disease Center Fluid Biomarker Initiative/ ; P30AG028716//Duke-UNC Alzheimer's Disease Research Center/ ; },
mesh = {Humans ; Male ; Female ; *Adverse Childhood Experiences ; Aged ; Biomarkers/blood ; Middle Aged ; Mental Status and Dementia Tests/statistics & numerical data ; White Matter/diagnostic imaging ; Glial Fibrillary Acidic Protein/blood ; Risk Factors ; Brain/diagnostic imaging ; Neurofilament Proteins/blood ; },
abstract = {INTRODUCTION: Adverse childhood experiences (ACEs) disrupt brain development and increase vulnerability to Alzheimer's disease and related dementias (ADRD). We explored how ACEs impact neuroimaging, plasma biomarkers, and cognition in older adults.

METHODS: Data from 214 participants aged ≥ 55 years were analyzed using linear and logistic regression, adjusting for demographic covariates.

RESULTS: Financial need associated negatively with Montreal Cognitive Assessment scores (β = -0.10, p = 0.011). Lower mean diffusivity across white matter tracts associated with parental violence (β = -0.01, p = 0.03). Lower glial fibrillary acidic protein associated with parental intimidation (β = -0.07, p = 0.01) and parental violence (β = -0.18, p = 0.006). Family problems and separation (β = -0.16, p = 0.003), financial need (β = -0.1, p = 0.04), and parental intimidation (β = -0.05, p = 0.01) inversely associated with neurofilament light chain.

DISCUSSION: Findings challenge the notion that ACEs uniformly accelerate neurodegeneration. Longitudinal studies are needed to determine whether these results reflect resilience, survivorship, or cohort-specific factors influencing ADRD risk.

HIGHLIGHTS: Adverse childhood experiences (ACEs) may elicit compensatory neural responses in aging. Financial need was associated with lower global cognition (Montreal Cognitive Assessment scores). Some ACEs (e.g., financial need, parental intimidation) linked to lower plasma neurofilament light chain. Parental violence linked to lower glial fibrillary acidic protein and mean diffusivity values, implying intact white mattery integrity.},
}

Humans
Male
Female
*Adverse Childhood Experiences
Aged
Biomarkers/blood
Middle Aged
Mental Status and Dementia Tests/statistics & numerical data
White Matter/diagnostic imaging
Glial Fibrillary Acidic Protein/blood
Risk Factors
Brain/diagnostic imaging
Neurofilament Proteins/blood

@article {pmid40739673,
year = {2025},
author = {Zheng, X and Yuan, W and Li, L and Ma, H and Zhu, M and Li, X and Feng, X},
title = {Targeting proprotein convertase subtilisin/kexin type 9 (PCSK9) to tackle central nervous system diseases: role as a promising approach.},
journal = {European journal of medical research},
volume = {30},
number = {1},
pages = {690},
doi = {10.1186/s40001-025-02937-1},
pmid = {40739673},
issn = {2047-783X},
mesh = {Humans ; *Proprotein Convertase 9/metabolism/genetics ; *PCSK9 Inhibitors/therapeutic use ; *Central Nervous System Diseases/drug therapy/metabolism ; Animals ; },
abstract = {Atherosclerosis-associated disease (ASD) represents a complex pathological condition, characterized by the formation of atherosclerotic plaques within the arterial walls, encompassing cholesterol depositions, which is primarily attributed to elevated levels of low-density lipoprotein-cholesterol (LDL-C). A log-linear association between the absolute magnitude of LDL-C exposure and ASD risk has been widely studied. High levels of LDL-C have been acknowledged as the predominant culprit. The previous research findings have demonstrated that PCSK9 inhibitors (PCSK9i) can remarkably diminish the risk of ASD. The current research has primarily focused on the relevance of PCSK9 to the cardiovascular system and lipid metabolism; however, an increasing body of evidence shows that PCSK9 is pivotal in pathogenic processes in other organ systems. Yet, PCSK9's impact on the brain is complex and not fully clarified, although several recent studies emphasize a putative role of its impact on various neurodegenerative disorders. Among neurological disorders, not only stroke but neurogenesis, neural cell differentiation, central LDL receptor metabolism, neural cell apoptosis, neuroinflammation, alcohol use disorder (AUD), amyotrophic lateral sclerosis(ALS), and Alzheimer's Disease (AD) are related to PCSK9. PCSK9 expression in brain is low but greatly upregulated in neurological disorders. Therefore, PCSK9 is a promising pathway for the treatment of central nervous diseases. This review comprehensively describes evidence from the previous research on the effects of PCSK9i on the central nervous system, with a focus on the clinical potential of PCSK9i. We anticipate that this review will generate data that will help biomedical researchers or clinical workers develop treatments for the neurological diseases based on PCSK9i.},
}

Humans
*Proprotein Convertase 9/metabolism/genetics
*PCSK9 Inhibitors/therapeutic use
*Central Nervous System Diseases/drug therapy/metabolism
Animals

@article {pmid40739660,
year = {2025},
author = {Liu, F and Liu, Y and Feng, Y and Zhao, J and Wang, M and Ye, M and Zhang, Y and Gan, X and Pan, Q and Shen, J},
title = {Folate mediates cognitive impairment of aged people with periodontitis.},
journal = {Nutritional neuroscience},
volume = {},
number = {},
pages = {1-13},
doi = {10.1080/1028415X.2025.2536038},
pmid = {40739660},
issn = {1476-8305},
abstract = {BACKGROUND: Periodontitis is associated with poorer cognitive function. It remains unclear whether folate plays a crucial role in periodontitis-promoted cognitive impairment (CI) in the elderly population.

METHODS: Data for this cross-sectional population-based study were obtained from the National Health and Nutrition Examination Survey (NHANES), 2011-2014 database. Associations between periodontitis and cognitive scores, exogenous folate (dietary intake folate equivalents and dietary supplement folate), and endogenous folate (folate from serum and red blood cells) levels were estimated by propensity score weighted regression models. Natural effect models were applied to estimate the mediation effect of folate for the periodontitis-cognition relationship.

RESULTS: Out of the 1966 participants, 869 (44.2%) had periodontitis. The periodontitis group has lower cognitive scores and dietary supplement, serum total, and RBC folate levels. The mediation effect of dietary supplement folate for the periodontitis-general cognition score association was significant, with mediation proportions of 8.4%. The mediation effects of serum total folate and RBC folate for periodontitis-general cognition score were both significant, with mediation proportions of 9.1%. Notably, periodontitis cases with dietary supplement folate or high dietary intake folate had significantly higher general cognition scores than those of periodontitis cases without dietary supplement folate or with low dietary intake folate.

CONCLUSIONS: Dietary folate supplementation may serve as a modifiable strategy to slow periodontitis-related cognitive decline in older adults, with serum and RBC levels functioning as key biomarkers of its potential effect.},
}

@article {pmid40739579,
year = {2025},
author = {He, D and Bao, Y and Yuan, S and Wang, Y and Cai, J and Xu, F and Chang, T and Zhang, P and Yue, M and Pan, X and Hao, H and Zheng, Q},
title = {Integrated plasma and red blood cell membrane lipidomics analysis unveils novel biomarker panel for Alzheimer's disease.},
journal = {Alzheimer's research & therapy},
volume = {17},
number = {1},
pages = {178},
doi = {10.1186/s13195-025-01830-7},
pmid = {40739579},
issn = {1758-9193},
support = {BK20161587//the Natural Science Foundation of Jiangsu Province/ ; 81930109 and 82321005//the National Natural Science Foundation of China/ ; 2021YFA1301300//the Major State Basic Research Development Program of China/ ; G20582017001//Overseas Expertise Introduction Project for Discipline Innovation/ ; SKLNMZZ202402//the Project of State Key Laboratory of Natural Medicines, China Pharmaceutical University/ ; SZSM202301035//Sanming Project of Medicine in Shenzhen/ ; BG2024045//Major Science and Technology Project of Jiangsu Province/ ; },
mesh = {Humans ; *Alzheimer Disease/blood/diagnosis ; *Lipidomics ; Biomarkers/blood ; Male ; Female ; Aged ; *Erythrocyte Membrane/metabolism/chemistry ; Cognitive Dysfunction/blood ; Aged, 80 and over ; Middle Aged ; Lipids/blood ; },
abstract = {BACKGROUND: Discovering new biomarkers for Alzheimer's disease (AD) are significant for early diagnosis and monitoring disease's progression. Blood-based lipid biomarkers, particularly from red cell membranes, offer a non-invasive alternative, providing insights into AD progression and potential therapeutic targets.

METHODS: This study innovatively incorporates red cell membrane (RCM) lipids, which reflect chronic physiological alterations and are linked to AD pathogenesis. A comprehensive lipid detection platform was employed to analyze lipid profiles from 156 individuals, including normal subjects, those with amnestic mild cognitive impairment, and AD patients. Differential lipids were identified and validated to be AD-associated by correlation analysis and big data analysis. Multi-dimensional criteria were applied to select potential lipid biomarkers.

RESULTS: PLS-DA revealed distinct lipidomic profiles between groups, with RCM samples showing superior separation. 138 differentially expressed lipids were identified and enriched in AD-related pathways, many uniquely associated with the RCM. Six lipids were selected as a potential biomarker panel for AD based on multi-dimensional criteria.

CONCLUSIONS: RCM shows broader lipidomic relevance and stronger biomarker potential compared to plasma. Integrating RCM lipids with plasma analysis enhances AD diagnostics and highlights the potential of RCM as an underexplored biomarker resource.},
}

Humans
*Alzheimer Disease/blood/diagnosis
*Lipidomics
Biomarkers/blood
Male
Female
Aged
*Erythrocyte Membrane/metabolism/chemistry
Cognitive Dysfunction/blood
Aged, 80 and over
Middle Aged
Lipids/blood

@article {pmid40739333,
year = {2025},
author = {Farombi, T and Arulogun, O and Nichols, M and Olorunsogbon, OF and Ogunronbi, M and Oyedola, O and Cadmus, E and Ojebuyi, B and Sanni, TA and Mutiso, V and Uthman, M and Sule, AG and Gumikiriza-Onoria, JL and Onunka, GC and Calys-Tagoe, B and Dinku, T and Amaechi, IA and Ogunyemi, AO and Onibon, OY and Ukpabi, DE and Ezin, HO and Gyabaah, S and Afolaranmi, T and Adeleye, O and Coleman, N and Mwombeki, I and Andrea, D and Damasceno, A and Bello, A and Wahab, K and Musyimi, C and Ndetei, D and Nwani, P and Njamnshi, WY and Elugbadebo, O and Obiako, R and Olowoyo, P and Zewde, YZ and Ayele, BA and Okubadejo, N and Osaigbovo, G and Sarfo, F and Akpalu, A and Kamada, L and Baiyewu, O and Noeline, N and Ogundele, AT and Njamnshi, AK and Iwuozo, E and Adoukonou, T and Boshe, J and Paddick, SM and Nwazor, EO and Osemwegie, N and Ikanga, J and Seshadri, S and Owolabi, M and Richard, W and Byrd, G and Kalaria, RN and Ogunniyi, A and Pericak-Vance, M and Akinyemi, R},
title = {The role of community advisory boards in enhancing recruitment and retention in Alzheimer's disease and related dementia research in Africa: Experience from the READD-ADSP study.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {8},
pages = {e70529},
doi = {10.1002/alz.70529},
pmid = {40739333},
issn = {1552-5279},
support = {U54HG007479//The SIREN study/ ; U19AG074865//The National Institute of Aging/National Institutes of Health/ ; R01AG072547//The National Institute of Aging/National Institutes of Health/ ; GBHI ALZ UK-21-24204//The Alzheimer Association/ ; FLR/R1/191813//The UK Royal Society/African Academy of Sciences/ ; FCG/R1/201034//The UK Royal Society/African Academy of Sciences/ ; R01NS107900//The Systematic Investigation of Blacks with Stroke using Genomics (SIBS Genomics) Study/ ; U01HG010273//African Neurobiobank for Precision Stroke Medicine ELSI Project/ ; },
mesh = {Humans ; *Alzheimer Disease/genetics ; *Advisory Committees ; *Patient Selection ; Africa ; *Dementia/genetics ; Qualitative Research ; *Biomedical Research ; },
abstract = {INTRODUCTION: The Recruitment and Retention of Alzheimer's Disease Diversity Genetic Cohorts in the Alzheimer's Disease Sequencing Project (READD-ADSP) was established to bridge the gap in Alzheimer's disease and related dementias (ADRD) research in Africa. We examined the role of Community Advisory Boards (CABs) in improving participant recruitment and retention in ADRD research in Africa, by exploring how culturally sensitive engagement, community trust-building, and stakeholder involvement influence research participation.

METHODS:  A multi-site, multi-phased qualitative study approach that involved establishment of CABs, initial planning meetings and community engagement cum recruitment activities.

RESULTS:  Twenty-one CABs (141 members) were established across 14 study sites in 9 African Dementia Consortium (AfDC) member countries. Co-creation planning meetings, culturally sensitive outreaches for brain health, dementia awareness creation, and recruitment were held.

DISCUSSION:  Establishing CABs within the READD-ADSP project has proven instrumental in co-creating culturally appropriate and community-centered strategies for recruitment and retention in ADRD research in Africa.

HIGHLIGHTS: The Recruitment and Retention of Alzheimer's Disease Diversity Genetic Cohorts in the Alzheimer's Disease Sequencing Project (READD-ADSP) project utilizes a community-engaged research (CER) framework to develop a community engagement program and establish Community Advisory Boards (CABs) to enhance participant recruitment and retention. There is a need to standardize CER practices and promote context-sensitive and culturally appropriate CE activities across African Dementia Consortium (AfDC) sites to ensure cultural sensitivity and enhance recruitment and retention. The project seeks to empower CABs to promote national dementia policies by collaborating with policy-makers and advancing equitable dementia scienced and care in Africa.},
}

Humans
*Alzheimer Disease/genetics
*Advisory Committees
*Patient Selection
Africa
*Dementia/genetics
Qualitative Research
*Biomedical Research

@article {pmid40739300,
year = {2025},
author = {Hosseininasabnajar, F and Kakinami, L and , },
title = {The longitudinal effects of global and regional brain measurements on cognitive abilities.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {27846},
doi = {10.1038/s41598-025-08152-6},
pmid = {40739300},
issn = {2045-2322},
mesh = {Humans ; Male ; Aged ; *Cognition/physiology ; Female ; Longitudinal Studies ; *Brain/diagnostic imaging/pathology ; *Alzheimer Disease/diagnostic imaging/pathology/physiopathology ; *Cognitive Dysfunction/diagnostic imaging/pathology/physiopathology ; Magnetic Resonance Imaging ; Aged, 80 and over ; Neuroimaging ; },
abstract = {Loss of brain tissues and cognitive abilities are natural processes of aging, but longitudinal studies are limited. We explored the longitudinal association between global and regional brain measures with cognitive abilities among individuals with normal cognitive status, mild cognitive impairment, and Alzheimer's Disease, including those with stable or progressive cognitive status, from the Alzheimer's Disease Neuroimaging Initiative. Follow-up was conducted approximately every six months for two to three years to classify participants by their cognitive status (n = 814). Mixed effects models were used to measure the longitudinal association between global and regional brain measures with cognitive abilities assessed by the Alzheimer's Disease Assessment cognition sub-scale after controlling for covariates. While whole brain volume (controlling for head size) affected the rate of cognition changes among those with mild cognitive impairment or Alzheimer's, other volumetric and thickness measures (hippocampus volume, ventricles volume, and entorhinal cortex thickness) had differential effects on cognition, but not on the speed of their changes. Results highlight the potential importance of different brain regions on cognition, but perhaps not on the rate of change and should be further investigated.},
}

Humans
Male
Aged
*Cognition/physiology
Female
Longitudinal Studies
*Brain/diagnostic imaging/pathology
*Alzheimer Disease/diagnostic imaging/pathology/physiopathology
*Cognitive Dysfunction/diagnostic imaging/pathology/physiopathology
Magnetic Resonance Imaging
Aged, 80 and over
Neuroimaging

@article {pmid40739178,
year = {2025},
author = {Taylor, S and Dunn, L and Udeh-Momoh, C and Abbott, K and Giannakopoulou, P and Middleton, L and Robinson, O and Kalsi, J and Kafetsouli, D and Ford, J},
title = {Technology readiness among UK-based cognitively unaffected older adults during the COVID-19 pandemic: potential implications for decentralised alzheimer's disease prevention trials.},
journal = {BMC geriatrics},
volume = {25},
number = {1},
pages = {563},
pmid = {40739178},
issn = {1471-2318},
mesh = {Humans ; Female ; *COVID-19/epidemiology/prevention & control ; Male ; *Alzheimer Disease/prevention & control/psychology/epidemiology ; Aged ; *Telemedicine ; United Kingdom/epidemiology ; Aged, 80 and over ; Surveys and Questionnaires ; Pandemics ; SARS-CoV-2 ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) remains a global health and socioeconomic burden. Telemedicine has been more widely used since the beginning of the COVID-19 pandemic and may be an effective strategy to mitigate the rising costs associated with AD. This study aimed to assess technology readiness among older adults at risk of developing dementia, with the goal of informing the design and delivery of technology-based approaches in AD prevention research.

METHODS: Cognitively unaffected older adults (n = 226) from the CHARIOT PRO Substudy were invited to complete the CHARIOT Technology Questionnaire (CTQ). CTQ assessed technology experiences and attitudes, including 'technology readiness' via the Technology Readiness Index (TRI).

RESULTS: Female participants scored, on average, lower TRI (M = 27.50, SD = 6.87) compared to males (M = 29.50, SD = 6.02). Furthermore, age predicted levels of technology readiness. Exploratory factor analysis determined two factors: "Technology Competence" (Factor 1) and "Technology Trepidation" (Factor 2). Gender differences were found for "Technology Competence" (but not "Technology Trepidation"), and age predicted "Technology Trepidation" (but not "Technology Competence").

DISCUSSION: Differences in gender, age, "Technology Competence", and "Technology Trepidation" may highlight those who need additional study and/or support in remote-based AD dementia prevention trials.

CONCLUSIONS: COVID-19 has accelerated our adoption of 'digitalisation' in AD dementia research. A deeper understanding of the barriers to technology readiness may help inform future AD research studies.

TRIAL REGISTRATION: The CHARIOT PRO SubStudy is registered with clinicaltrials.gov (NCT02114372).},
}

Humans
Female
*COVID-19/epidemiology/prevention & control
Male
*Alzheimer Disease/prevention & control/psychology/epidemiology
Aged
*Telemedicine
United Kingdom/epidemiology
Aged, 80 and over
Surveys and Questionnaires
Pandemics
SARS-CoV-2

@article {pmid40738837,
year = {2025},
author = {Giovannucci, TA and Arber, C and Wray, S},
title = {Reconstructing Alzheimer's disease one cell type at a time using in vitro tricultures.},
journal = {Trends in neurosciences},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.tins.2025.07.010},
pmid = {40738837},
issn = {1878-108X},
abstract = {In a recent study, Lish and colleagues used a fully human-based, induced pluripotent stem cell (iPSC)-derived triculture model of neurons, astrocytes, and microglia to delineate non-cell autonomous contributions to familial Alzheimer's disease (AD). This approach offers a versatile platform to explore early disease mechanisms, dissect cell-cell interactions, and support the development of targeted therapeutic or biomarker strategies.},
}

@article {pmid40738791,
year = {2025},
author = {Roy, A and Dawson, VL and Dawson, TM},
title = {From metabolism to mind: The expanding role of the GLP-1 receptor in neurotherapeutics.},
journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics},
volume = {},
number = {},
pages = {e00712},
doi = {10.1016/j.neurot.2025.e00712},
pmid = {40738791},
issn = {1878-7479},
abstract = {GLP-1 receptor agonists (GLP-1RAs), initially approved for diabetes and obesity, are now under investigation for neuroprotective effects in a range of neurological disorders. These agents, whose receptors are widely expressed in brain regions involved in cognition and metabolism, modulate neurotransmitter release and promote neurogenesis. While preclinical studies consistently demonstrate benefits in models of Alzheimer's disease, Parkinson's disease, multiple sclerosis, and amyotrophic lateral sclerosis (ALS), clinical trial outcomes have been variable, largely owing to heterogeneity in study populations and trial design. Newer agents, such as NLY01 and tirzepatide, are under development to enhance central nervous system penetration and efficacy. Although GLP-1RAs are generally safe in metabolic conditions, their use in neurological diseases requires careful monitoring and patient selection. Future directions include developing reliable biomarkers, implementing precision medicine strategies, and exploring the use of combination therapies to maximize therapeutic potential.},
}

@article {pmid40738658,
year = {2025},
author = {Petrella, JR and Liu, AJ and Wang, LA and Doraiswamy, PM},
title = {AI-Assisted Detection of Amyloid-related Imaging Abnormalities (ARIA): Promise and Pitfalls.},
journal = {AJNR. American journal of neuroradiology},
volume = {},
number = {},
pages = {},
doi = {10.3174/ajnr.A8946},
pmid = {40738658},
issn = {1936-959X},
abstract = {The advent of anti-amyloid therapies (AATs) for Alzheimer's disease (AD) has elevated the importance of MRI surveillance for amyloidrelated imaging abnormalities (ARIA) such as microhemorrhages and siderosis (ARIA-H) and edema (ARIA-E). We report a literature review and early quality assurance experience with an FDA-cleared assistive AI tool intended for detection of ARIA in MRI clinical workflows. The AI system improved sensitivity for detection of subtle ARIA-E and ARIA-H lesions but at the cost of a reduction in specificity. We propose a tiered workflow combining protocol harmonization and expert interpretation with AI overlay review. AI-assisted ARIA detection is a paradigm shift that offers great promise to enhance patient safety as disease-modifying therapies for AD gain broader clinical use; however, some pitfalls need to be considered.ABBREVIATIONS: AAT＝ anti-amyloid therapy; ARIA＝ amyloid-related imaging abnormalities, ARIA-H = amyloid-related imaging abnormality-hemorrhage, ARIA-E = amyloid-related imaging abnormality-edema.},
}

@article {pmid40738461,
year = {2025},
author = {Haque, A and Montalbano, M and Khan, S and Puangmalai, N and Bhatt, N and Shchankin, N and Jerez, C and Kayed, R},
title = {Characterization of conformation-specific antibodies TOMA-1 and TTCM-1 for recombinant tau monomer and amplified brain derived tau oligomer.},
journal = {Biochimica et biophysica acta. Molecular basis of disease},
volume = {},
number = {},
pages = {167995},
doi = {10.1016/j.bbadis.2025.167995},
pmid = {40738461},
issn = {1879-260X},
abstract = {Tauopathies are a set of neurodegenerative diseases characterized by the pathological accumulation of aggregated tau in the brain. Recent breakthrough evidence has revealed the existence of different strains of tau oligomer (TauO) which direct the different pathological presentation of individual tauopathies. Extensive research efforts have been devoted to search for specific antibodies or drug candidates which target TauO to serve as promising alternatives to treat Alzheimer's disease (AD) in future. To screen for the antibodies which are able to bind with amplified brain derived tau oligomer (aBDTO), we have investigated the binding parameters of the tau oligomer-specific monoclonal antibody-1 (TOMA-1) and toxic tau conformation-specific monoclonal antibody-1 (TTCM-1) with the recombinant tau monomer (rTauM) and aBDTO using isothermal titration calorimetry (ITC). TOMA-1 specifically recognizes the amino acid sequences 367-386, 382-401 and 367-386 and TTCM-1 specifically recognizes the amino acid sequence 307-326 of rTauM and aBDTO, respectively. Our results demonstrated that both TOMA-1 and TTCM-1 have a high binding affinity with aBDTO compared to rTauM. We also observed that higher the binding affinity of the antibody to the aBDTO, lower was the toxicity of the aBDTO and vice versa. Our study taken together presents both TOMA-1 and TTCM-1 to be potential immunotherapeutic agents against AD.},
}

@article {pmid40738457,
year = {2025},
author = {Chowdhury, S and Gupta, BD and Ghosh, S and Gayen, S and Kar, A and Mukherjee, PK and Haldar, PK},
title = {Metabolite profiling and neuroprotective potential of Clitoria ternatea L. through in-vitro and in-vivo experimental models.},
journal = {Fitoterapia},
volume = {},
number = {},
pages = {106772},
doi = {10.1016/j.fitote.2025.106772},
pmid = {40738457},
issn = {1873-6971},
abstract = {INTRODUCTION: Alzheimer's disease is a growing concern in the global population, affecting learning, memory and causes neurodegeneration. Clitoria ternatea L. (Fabaceae), is used traditionally to treat cognitive dysfunction by improving memory.

AIM OF THE STUDY: This study focuses on the metabolite profiling and evaluation of the neuroprotective potential of C. ternatea L. extracts in the in-vitro enzyme inhibition model and in-vivo anti-Alzheimer model.

MATERIALS AND METHODS: The in-vitro cholinesterase enzyme inhibitory potential of CT root, flower, and combination extract was assessed by Ellman's method. Metabolite profiling of combination extract was done followed by in-vivo neurobehavioral study. Biochemical parameters related to neurological dysfunction were evaluated in brain tissues along with histopathological changes.

RESULT: The combination extract exhibited the most potent Acetylcholinesterase and Butyrylcholinesterase inhibitory activity with IC50 81.91 ± 0.19 μg/mL & and 91.48 ± 0.23 μg/mL respectively as compare to CTF & CTR extract. The UHPLC-Q-TOF-MS identified 26 phytoconstituents, including Malvidin, Delphinidin, Taraxerol, Clitorinolactone etc. The In-vivo study demonstrated memory enhancement with dose 200 mg/kg body weight. No significant histopathological changes were found in high dose of combination treated group, whereas little changes were found in low dose.

CONCLUSION: C. ternatea L. flower and root extract in combination was found to be more efficacious for the management of neurological dysfunction and memory impairment and this is due to the synergistic interaction of phytomolecules present in the extract. Further, ex-vivo evaluation along with the regulation of key genes and pathways could be done to establish the mechanism of action.},
}

@article {pmid40738263,
year = {2025},
author = {Bostick, JW and Connerly, TJ and Thron, T and Needham, BD and de Castro Fonseca, M and Kaddurah-Daouk, R and Knight, R and Mazmanian, SK},
title = {Genotype and microbiome shape immunity in a sex-specific manner in mouse models of Alzheimer's disease.},
journal = {Brain, behavior, and immunity},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.bbi.2025.07.028},
pmid = {40738263},
issn = {1090-2139},
abstract = {Preclinical studies have revealed that the microbiome broadly affects immune responses and deposition and/or clearance of amyloid-beta (Aβ) in mouse models of Alzheimer's disease (AD), but whether, and how, the microbiome shapes central and peripheral immune profiles in AD models remains unknown. We examined adaptive immune responses in two mouse models containing AD-related genetic predispositions (3xTg and 5xFAD) in the presence or absence of the microbiome to determine if it promotes dysregulated immune responses and cognition in AD. T and B cells were altered in central nervous system (CNS)-associated lymph nodes and systemic immune tissues between genetic models and wildtype mice, with earlier signs of heightened immune activity in females. Systemic immune responses were modulated by the microbiome and differed by sex. Further, the absence of a microbiome in germ-free mice resulted in increased cognitive deficits, primarily in males. These data reveal sexual dimorphism in early signs of immune activity and microbiome effects, and highlight how sex and the microbiome shape responses in mouse models of AD.},
}

@article {pmid40737826,
year = {2025},
author = {Khan, S and Iqbal, T and Hussain, R and Alshehri, FF and Shehri, ZSA and Gomha, SM and Zaki, MEA and Kashtoh, H},
title = {Computationally guided design and synthesis of pyrimidine-oxazole hybrids as novel antidiabetic agents: kinetic and molecular interaction studies.},
journal = {Computational biology and chemistry},
volume = {119},
number = {},
pages = {108602},
doi = {10.1016/j.compbiolchem.2025.108602},
pmid = {40737826},
issn = {1476-928X},
abstract = {Diabetes mellitus (DM) is one of the complex and chronic endocrine diseases often characterized by high blood glucose level. Diabetes is due to either pancreases not producing insulin which convert excess of blood glucose to glycogen, or the cell of body becoming unresponsive to insulin's effect. Primary symptom of DM includes blurry vision, excess urination and slow healing sores but if not diagnosed earlier and treated, it is associated with some severe secondary impairment like cardiovascular diseases, diabetic neuropathy, diabetic nephropathy and Alzheimer's diseases etc. The focus of current research work is to design and synthesized a novel pyrimidine based oxazole derivatives (1-10) having promising anti-diabetic activity. These derivatives were synthesized by using reagent grade starting material i.e. 4-chloro-6-methylpyrimidin-2-amine. Structural conformation of the synthesized derivative was acquired by [1]H-NMR and [13]C-NMR and their molecular weight were confirmed by HREI-MS. These compound exhibit moderate to excellent biological potential against α-amylase and α-glucosidase in comparison to standard acarbose IC50= 10.50 ± 0.20 μM and IC50= 10.80 ± 0.10 μM. Among these derivatives, analog 8 having IC50= 5.20 ± 0.10 μM against α-amylase and IC50= 5.70 ± 0.10 μM against α-glucosidase emerged as a most potent compound of the series with excellent inhibitory potency of target enzyme. The biological interaction of the newly synthesized derivatives was studied through molecular docking to assess their enzyme inhibition potency. Furthermore, the molecular dynamic (MD) simulation, density functional theory (DFT) studies are also performed in order to assess their structural conformational changes, stability and reactivity under dynamic environment. Absorption distribution metabolism excretion and toxicity (ADMET) analysis showed that these potent compounds have no toxicological effect.},
}

@article {pmid40737816,
year = {2025},
author = {Laurell, AA and Shah, SN and Rahmati, M and O'Brien, JT and Underwood, BR},
title = {Hypothalamic imaging in Alzheimer's disease and Lewy body dementia: A systematic review and meta-analysis.},
journal = {Neurobiology of aging},
volume = {155},
number = {},
pages = {87-99},
doi = {10.1016/j.neurobiolaging.2025.07.011},
pmid = {40737816},
issn = {1558-1497},
abstract = {Symptoms related to sleep, weight, and endocrine dysfunction are common in Alzheimer's disease (AD) and Lewy body dementia (LBD). The cause of these symptoms is not known, but they may be related to hypothalamic neurodegeneration. We performed a systematic search of MEDLINE and EMBASE for studies using MRI or PET imaging to examine the hypothalamus in AD or LBD. The Newcastle-Ottawa scale was used to assess the risk of bias. A random-effects meta-analysis was conducted using the standardised mean difference (SMD) in hypothalamic volume, and a narrative synthesis was used to examine associations between hypothalamic imaging and sleep, weight, and endocrine function. We screened 8891 articles which identified 22 studies for inclusion in the narrative synthesis of which 6 were suitable for meta-analysis. 86 % had a low to moderate risk of bias. People with mild-moderate AD had a smaller hypothalamus compared to controls (SMD=-0.49[-0.86,-0.13],p = 0.018;I[2]=67 %[21.5 %-86.1 %];n = 454(AD),715(controls)), and had differences in hypothalamic metabolism and connectivity. Two studies in LBD found lower grey matter and serotonin transporter binding in the hypothalamus compared to controls. Hypothalamic differences in AD were associated with male sex, worse sleep, lower bone mineral density and plasma levels of sex hormones. Body mass index was not associated with hypothalamic volume in AD, although further studies are needed. Lower hypothalamic volume is seen in AD and this may influence sleep and endocrine function. A better understanding of hypothalamic degeneration may help elucidate how pathology relates to symptoms in AD and LBD and reveal new targets for intervention.},
}

@article {pmid40737743,
year = {2025},
author = {Liu, J and Liu, K and Cui, X and Ji, Y and Ding, Z and Chang, Z and Zhang, J and Wang, X and Liu, Y},
title = {From gut to brain: donepezil and nimodipine combination therapy improves cognitive deficits in Alzheimer's disease via gut microbiota and metabolites.},
journal = {Biochemical and biophysical research communications},
volume = {778},
number = {},
pages = {152418},
doi = {10.1016/j.bbrc.2025.152418},
pmid = {40737743},
issn = {1090-2104},
abstract = {Donepezil (DNP) is often combined with nimodipine (NMD) for the treatment of Alzheimer's disease (AD). However, its underlying mechanisms remain poorly understood. This study integrated pharmacodynamics, microbiomics, and fecal metabolomics analysis to explore the therapeutic potential and mechanism of DNP + NMD in AD. The results showed that DNP + NMD significantly reduced the contents of serum inflammatory cytokines interleukin-6 (IL-6), IL-1β, and tumor necrosis factor-α (TNF-α) as well as the contents of nitric oxide synthase (NOS), glycogen synthase kinase-3β (GSK-3β) and acetylcholinesterase (AChE) in the hippocampus, alleviated neuronal damage in hippocampal tissues and effectively improved cognitive deficits of AD rats. Furthermore, DNP + NMD greatly increased the relative abundance of beneficial bacteria (Lactobacillus and Prevotellaceae_Prevotella) and decreased the relative abundance of harmful bacteria (Ruminococcus and Akkermansia). Fecal metabolomic analyses indicated that DNP + NMD regulated 28 fecal differential metabolite levels mainly through six key pathways, including linoleic acid metabolism, arachidonic acid metabolism, unsaturated fatty acid biosynthesis, steroid hormone biosynthesis, saturated fatty acid biosynthesis, primary bile acid biosynthesis, pantothenic acid biosynthesis, and coenzyme A biosynthesis pathway. Moreover, Spearman's correlation analysis revealed significant associations between affected metabolites and specific gut microbes. In general, our research sheds light that DNP + NMD exerts a neuroprotective effect against AD by ameliorating the gut microbiota and fecal metabolic disorders, uncovering novel mechanistic insights and therapeutic targets for AD intervention.},
}

@article {pmid40737487,
year = {2025},
author = {Zhang, M and Kim, Y and Bosworth, A and T C W, J and Nih, LR and Kisler, K and Sagare, AP and Rust, R},
title = {Brain pericytes derived from human pluripotent stem cells retain vascular and phagocytic functions under hypoxia.},
journal = {Stem cells (Dayton, Ohio)},
volume = {},
number = {},
pages = {},
doi = {10.1093/stmcls/sxaf055},
pmid = {40737487},
issn = {1549-4918},
abstract = {The integrity and function of the blood-brain barrier (BBB) are largely regulated by pericytes. Pericyte deficiency leads to BBB breakdown and neurological dysfunction in major neurological disorders including stroke and Alzheimer's disease (AD). Transplantation of pericytes derived from induced pluripotent stem cells (iPSC-PC) has been shown to restore the BBB and improve functional recovery in mouse models of stroke and pericyte deficiency. However, the molecular profile and functional properties of iPSC-PC under hypoxic conditions, similar to those found in ischemic and neurodegenerative diseases remain largely unexplored. Here, we demonstrate that iPSC-PC under severe hypoxia retain essential functional properties, including key molecular markers, proliferation rates, and the ability to migrate to host brain vessels via function-associated PDGFRB-PDGF-BB signaling. Additionally, we show that iPSC-PC exhibit similar clearance of amyloid beta (Aβ) neurotoxins from AD mouse brain sections under both normoxic and hypoxic conditions. These findings suggest that iPSC-PC functions are largely resilient to hypoxia, highlighting their potential as a promising cell source for treating ischemic and neurodegenerative disorders.},
}

@article {pmid40737431,
year = {2025},
author = {D'Oliveira Albanus, R and Finan, GM and Brase, L and Sweeney, N and Kim, TY and Chen, S and Ryoo, Y and Park, J and Guo, Q and Kannan, A and Acquarone, M and You, SF and Novotny, BC and Mace, EM and Ribeiro Pereira, PM and Morris, JC and Holtzman, DM and McDade, E and Farlow, M and Chhatwal, JP and Benitez, BA and Piccio, L and Perrin, RJ and Sutherland, GT and Ma, Q and Karch, CM and Kim, DY and Tanzi, RE and Fu, H and Harari, O and Kim, TW},
title = {Systematic analysis of cellular cross-talk reveals a role for SEMA6D-TREM2 regulating microglial function in Alzheimer's disease.},
journal = {Science translational medicine},
volume = {17},
number = {809},
pages = {eadx0027},
doi = {10.1126/scitranslmed.adx0027},
pmid = {40737431},
issn = {1946-6242},
mesh = {Humans ; *Alzheimer Disease/metabolism/pathology/genetics ; *Membrane Glycoproteins/metabolism/genetics ; *Receptors, Immunologic/metabolism/genetics ; *Microglia/metabolism/pathology ; *Semaphorins/metabolism/genetics ; Gene Regulatory Networks ; Brain/pathology/metabolism ; Neurons/metabolism/pathology ; *Cell Communication ; Plaque, Amyloid/pathology/metabolism ; Male ; Female ; Induced Pluripotent Stem Cells/metabolism ; Intercellular Signaling Peptides and Proteins ; },
abstract = {Cellular cross-talk, mediated by membrane receptors and their ligands, is crucial for brain homeostasis and can contribute to neurodegenerative diseases such as Alzheimer's disease (AD). To find cross-talk dysregulations involved in AD, we reconstructed cross-talk networks from single-nucleus transcriptional profiles of 67 clinically and neuropathologically well-characterized controls and AD brain donors from the Knight Alzheimer Disease Research Center and the Dominantly Inherited Alzheimer Network cohorts. We predicted a role for TREM2 and additional AD risk genes mediating neuron-microglia cross-talk in AD. We identified a gene network mediating neuron-microglia cross-talk through TREM2 and neuronal SEMA6D, which we predicted is disrupted in late AD stages. Using spatial transcriptomics on the human brain, we observed that the SEMA6D-TREM2 cross-talk gene network is activated near Aβ plaques and SEMA6D-expressing cells. Using tissue immunostaining of human brains, we found that SEMA6D colocalizes with Aβ plaques and TREM2-activated microglia. In addition, we found that plaque-proximal SEMA6D abundance decreased with the disease stage, which correlated with a reduction in microglial activation near plaques. These findings suggest that the loss of SEMA6D signaling impairs microglial activation and Αβ clearance. To validate this hypothesis, we leveraged TREM2 knockout human induced pluripotent stem cell-derived microglia and observed that SEMA6D induces microglial activation and Aβ plaque phagocytosis in a TREM2-dependent manner. In summary, we demonstrate that characterizing cellular cross-talk networks can yield insights into AD biology, provide additional context to understand AD genetic risk, and find previously unknown therapeutic targets and pathways.},
}

Humans
*Alzheimer Disease/metabolism/pathology/genetics
*Membrane Glycoproteins/metabolism/genetics
*Receptors, Immunologic/metabolism/genetics
*Microglia/metabolism/pathology
*Semaphorins/metabolism/genetics
Gene Regulatory Networks
Brain/pathology/metabolism
Neurons/metabolism/pathology
*Cell Communication
Plaque, Amyloid/pathology/metabolism
Male
Female
Induced Pluripotent Stem Cells/metabolism
Intercellular Signaling Peptides and Proteins

@article {pmid40737409,
year = {2025},
author = {Zou, F and Liu, Y and Luo, Y and Xu, T},
title = {A wearable spatiotemporal controllable ultrasonic device with amyloid-β disaggregation for continuous Alzheimer's disease therapy.},
journal = {Science advances},
volume = {11},
number = {31},
pages = {eadw1732},
doi = {10.1126/sciadv.adw1732},
pmid = {40737409},
issn = {2375-2548},
mesh = {*Alzheimer Disease/therapy/metabolism/pathology ; Animals ; *Amyloid beta-Peptides/metabolism/chemistry ; Mice ; Disease Models, Animal ; *Wearable Electronic Devices ; Microglia/metabolism ; Humans ; Brain/metabolism/pathology ; Plaque, Amyloid/metabolism ; *Ultrasonic Therapy/instrumentation ; Mice, Transgenic ; *Protein Aggregates ; },
abstract = {The rising prevalence of Alzheimer's disease (AD) due to an aging population has made the search for effective treatments more urgent than ever. Previous studies have demonstrated that continuous ultrasound can depolymerize amyloid proteins, offering potential relief from AD. In this study, we present a portable, fully integrated wearable ultrasound system designed to promote amyloid protein depolymerization. The system comprises a flexible honeycomb ultrasonic array patch, a flexible printed circuit, and an interactive terminal control system to facilitate the treatment process. Our results demonstrate that the system effectively reduces amyloid proteins in the brain, improves cognitive function in a familial Alzheimer's disease (FAD) mouse model, enhances microglial phagocytosis of amyloid-β plaques, and shifts microglia polarization from M1 to M2. These changes contribute to a mitigated inflammatory environment in the brain. This innovative approach may pave the way for noninvasive, personalized treatments for AD, potentially transforming therapeutic strategies in neurodegenerative disorders.},
}

*Alzheimer Disease/therapy/metabolism/pathology
Animals
*Amyloid beta-Peptides/metabolism/chemistry
Mice
Disease Models, Animal
*Wearable Electronic Devices
Microglia/metabolism
Humans
Brain/metabolism/pathology
Plaque, Amyloid/metabolism
*Ultrasonic Therapy/instrumentation
Mice, Transgenic
*Protein Aggregates

@article {pmid40737296,
year = {2025},
author = {Shrestha, RLS and M C, S and Tamang, A and Poudel, M and Parajuli, N and Shrestha, A and Shrestha, T and Bharati, S and Maharjan, B and Marasini, BP and Adhikari Subin, J},
title = {Evaluating the inhibitory efficacy of Oxalis phytocompounds on monoamine oxidase B: An integrated approach targeting age related neurodegenerative diseases through molecular docking and dynamics simulations.},
journal = {PloS one},
volume = {20},
number = {7},
pages = {e0329168},
doi = {10.1371/journal.pone.0329168},
pmid = {40737296},
issn = {1932-6203},
mesh = {*Monoamine Oxidase/metabolism/chemistry ; Molecular Docking Simulation ; *Monoamine Oxidase Inhibitors/chemistry/pharmacology ; Molecular Dynamics Simulation ; Humans ; *Phytochemicals/pharmacology/chemistry ; *Neurodegenerative Diseases/drug therapy/enzymology ; Protein Binding ; Ligands ; },
abstract = {Monoamine oxidase B (MAO-B) serves as a critical target in the management of neurodegenerative diseases (NDDs) such as Alzheimer's and Parkinson's due to its role in regulating oxidative stress and dopamine metabolism. In this context, phytochemicals from Oxalis species, known for their neuroprotective properties, were explored for their potential MAO-B inhibitory activity using computational approach. Plant-derived compounds, offering a better safety profile than synthetic drugs and greater cost-effectiveness, present a promising avenue for developing alternative therapeutic strategies. Molecular docking (MD), molecular dynamics simulations (MDS), and binding free energy calculations were employed to evaluate the inhibitory potential of Oxalis phytochemicals against MAO-B (PDB ID: 4A79). Stable ligand-protein complexes with optimal docking scores were selected, and key parameters from molecular dynamics trajectories, including binding stability and interactions, were analyzed to identify high potential inhibitors of MAO-B for therapeutic development. Results showed beta-sitosterol (-11.92 kcal/mol), squalene (-11.89 kcal/mol), etretinate (-11.46 kcal/mol), rhoifolin (-11.44 kcal/mol), and swertisin (-11.13 kcal/mol) demonstrated superior binding affinities compared to the native ligand (-11.12 kcal/mol). Three additional compounds; phloridzin (-11.10 kcal/mol), rhapontin (-11.02 kcal/mol), and diosmetin 7-O-beta-D-glucopyranoside (-10.96 kcal/mol) exhibited better binding than reference drugs. The predominant interactions between protein and ligand were hydrophobic, with hydrogen bonds and Pi-stacking enhancing the complexes' stability. The evaluation based on geometrical and thermodynamic metrics derived from 200 ns MDS, identified rhoifolin, beta-sitosterol, and swertisin as promising MAO-B inhibitors. Minimal translational and rotational movements of these ligands within the catalytic site of MAO-B under quasi-physiological conditions suggested effective inhibition. Preserved thermodynamic feasibility reinforced these findings. ADMET analysis identified squalene and beta-sitosterol as CNS active candidates with favorable pharmacokinetics, while etretinate, rhoifolin, and swertisin may act as peripheral modulators, requiring optimization for improved CNS delivery. Further experimental validation of efficacy, pharmacokinetics, and safety is recommended to advance the therapeutic potential of these hit candidates.},
}

*Monoamine Oxidase/metabolism/chemistry
Molecular Docking Simulation
*Monoamine Oxidase Inhibitors/chemistry/pharmacology
Molecular Dynamics Simulation
Humans
*Phytochemicals/pharmacology/chemistry
*Neurodegenerative Diseases/drug therapy/enzymology
Protein Binding
Ligands

@article {pmid40737129,
year = {2025},
author = {Talbot, EP and Lee, YS and Dinata, E and Yoon, S and Roh, S and Tietze, J},
title = {Cognitive decline, depression, and protective factors among middle aged and older Indigenous women.},
journal = {Social work in health care},
volume = {},
number = {},
pages = {1-22},
doi = {10.1080/00981389.2025.2535286},
pmid = {40737129},
issn = {1541-034X},
abstract = {This study investigated the direct relationship between cognitive decline and depressive symptoms among Indigenous women aged 40 to 70 from a Northern Plains tribe, examining the indirect associations between cognitive decline and depressive symptoms through the importance of religious and spiritual beliefs and the frequency of exercise. Data from 133 participants were analyzed using path analysis, which included the PHQ-9 and the Alzheimer's Disease 8 scale. Results indicate a significant link between cognitive decline and depressive symptoms, with 39.1% showing probable depressive symptoms. The importance of religious and spiritual beliefs was negatively associated with depressive symptoms, while exercise was positively associated with depressive symptoms. However, there was no indirect effect between cognitive decline and depressive symptoms through either the importance of religious and spiritual beliefs or the frequency of exercise. These findings highlight the importance of cognitive health and resilience factors.},
}

@article {pmid40736876,
year = {2025},
author = {Núñez-Cortés, R and Calatayud, J and Calonge-Pascual, S and Andersen, LL and Bláfoss, R and López-Gil, JF and López-Bueno, R},
title = {Dose-Response Association of Handgrip Strength With Alzheimer's Disease: A Longitudinal Study Involving 85,979 Adults.},
journal = {International journal of geriatric psychiatry},
volume = {40},
number = {8},
pages = {e70137},
doi = {10.1002/gps.70137},
pmid = {40736876},
issn = {1099-1166},
support = {QLK6-CT-2001-00360//The SHARE data collection has been funded by the European Commission/ ; SHARE-I3: RII-CT-2006-062193//The SHARE data collection has been funded by the European Commission/ ; COMPARE: CIT5-CT-2005-028857//The SHARE data collection has been funded by the European Commission/ ; SHARELIFE: CIT4-CT-2006-028812//The SHARE data collection has been funded by the European Commission/ ; SHARE-PREP: GA N°211909//The SHARE data collection has been funded by the European Commission/ ; SHARE-LEAP: GA N°227822//The SHARE data collection has been funded by the European Commission/ ; SHARE M4: GA N°261982//The SHARE data collection has been funded by the European Commission/ ; DASISH: GA N°283646//The SHARE data collection has been funded by the European Commission/ ; SHARE-DEV3: GA N°676536//Horizon 2020/ ; SHARE-COHESION: GA N°870628//Horizon 2020/ ; SERISS: GA N°654221//Horizon 2020/ ; SSHOC: GA N°823782//Horizon 2020/ ; U01_AG09740-13S2//DG Employment, Social Affairs and Inclusion. Additional funding from the German Ministry of Education and Research, the Max Planck Society for the Advancement of Science, the U.S. National Institute/ ; P01_AG005842//DG Employment, Social Affairs and Inclusion. Additional funding from the German Ministry of Education and Research, the Max Planck Society for the Advancement of Science, the U.S. National Institute/ ; P01_AG08291//DG Employment, Social Affairs and Inclusion. Additional funding from the German Ministry of Education and Research, the Max Planck Society for the Advancement of Science, the U.S. National Institute/ ; P30_AG12815//DG Employment, Social Affairs and Inclusion. Additional funding from the German Ministry of Education and Research, the Max Planck Society for the Advancement of Science, the U.S. National Institute/ ; R21_AG025169//DG Employment, Social Affairs and Inclusion. Additional funding from the German Ministry of Education and Research, the Max Planck Society for the Advancement of Science, the U.S. National Institute/ ; Y1-AG-4553-01//DG Employment, Social Affairs and Inclusion. Additional funding from the German Ministry of Education and Research, the Max Planck Society for the Advancement of Science, the U.S. National Institute/ ; IAG_BSR06-11//DG Employment, Social Affairs and Inclusion. Additional funding from the German Ministry of Education and Research, the Max Planck Society for the Advancement of Science, the U.S. National Institute/ ; OGHA_04-064//DG Employment, Social Affairs and Inclusion. Additional funding from the German Ministry of Education and Research, the Max Planck Society for the Advancement of Science, the U.S. National Institute/ ; HHSN271201300071C/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *Hand Strength/physiology ; Female ; Male ; Longitudinal Studies ; Aged ; *Alzheimer Disease/epidemiology/physiopathology ; Middle Aged ; Europe/epidemiology ; Israel/epidemiology ; Aged, 80 and over ; Incidence ; Risk Factors ; },
abstract = {OBJECTIVE: To investigate the dose-response relationship between handgrip strength and incidence of Alzheimer's disease (AD) in middle-aged and older adults.

DESIGN: Longitudinal study.

PATIENTS AND METHODS: A longitudinal study was conducted in people over 50 years old in 27 European countries and Israel. Data were collected from waves 1, 2, 4, 5, 6, 7 and 8 of the Survey of Health, Ageing and Retirement in Europe (SHARE) between February 2004 and January 2021. Handgrip strength was measured with a hand dynamometer. AD was self-reported based on previous diagnosis. Dose-response associations were assessed by restricted cubic splines.

RESULTS: A total of 85,979 (55.8% female) participants were followed for a median of 9.3 years. Over this time, 3324 (3.9%) developed AD. In the adjusted model, for participants < 65 years, those in the middle third of handgrip strength showed a lower risk of AD compared to the lower third (HR = 0.63, 95% CI: 0.47-0.84), as well as participants in the upper third (HR = 0.63, 95% CI: 0.47-0.85). The spline model determined that the minimum and optimal doses of handgrip strength for a significant reduction in the risk of AD for those aged < 65 years were 54 kg (HR = 0.99; 95% CI: 0.08-0.99) and 56 kg (HR = 0.27; 95% CI: 0.08-0.91), respectively. Among those aged ≥ 65 years, the minimum and optimal doses were 31 kg (HR = 0.69; 95% CI: 0.48-0.99) and 49 kg (HR = 0.57; 95% CI: 0.43-0.76), respectively.

CONCLUSION: Higher levels of handgrip strength showed a lower risk of developing AD, among adults aged 50 years and over. However, the dose-response relationship is limited to specific ranges according to age group. We identified a range between 54 and 56 kg years and a range between 31 and 49 kg as suitable to prevent AD in adults aged 50-64 and ≥ 65 years, respectively. Routine assessment of hand grip strength can help healthcare professionals identify people at increased risk of AD. Strength-based interventions could provide a practical strategy to support cognitive health and reduce the risk of dementia in clinical practice.},
}

Humans
*Hand Strength/physiology
Female
Male
Longitudinal Studies
Aged
*Alzheimer Disease/epidemiology/physiopathology
Middle Aged
Europe/epidemiology
Israel/epidemiology
Aged, 80 and over
Incidence
Risk Factors

@article {pmid40736688,
year = {2025},
author = {Tossetta, G and Fantone, S and Olivieri, F and Mazzucchelli, R and Togni, L and Santarelli, A and Marzioni, D and Rippo, MR},
title = {Effect of natural compounds on NRF2/KEAP1 signaling in periodontitis: a potential use to prevent age-related disorders.},
journal = {Molecular biology reports},
volume = {52},
number = {1},
pages = {771},
doi = {10.1007/s11033-025-10878-5},
pmid = {40736688},
issn = {1573-4978},
mesh = {*NF-E2-Related Factor 2/metabolism ; Humans ; *Periodontitis/metabolism/drug therapy ; *Kelch-Like ECH-Associated Protein 1/metabolism ; Signal Transduction/drug effects ; Animals ; Reactive Oxygen Species/metabolism ; Aging ; Neurodegenerative Diseases/prevention & control/metabolism ; Inflammation/metabolism ; },
abstract = {40% of the population over 60 years of age is affected by periodontitis which is characterized by chronic inflammation, periodontal damage and alveolar bone resorption. The nuclear factor erythroid 2-related factor 2 (NFE2L2 or NRF2)/ Kelch-like ECH-Associated Protein 1 (KEAP1) (NRF2/KEAP1) signaling pathway plays a key role in periodontitis modulating redox balance and periodontium inflammation. However, NRF2 expression decreases in gingival tissues of severe periodontitis patients while Reactive Oxygen Species (ROS) levels are increased during periodontitis. ROS and lipopolysaccharide (LPS) produced by gram-negative bacteria favor the production of inflammatory cytokines, then causing periodontal inflammation and favoring alveolar bone loss (due to excessive osteoclast formation and activation). Periodontitis has also been associated to the development of age-related neurodegenerative diseases such as Alzheimer's and Parkinson's diseases since the increased cytokines levels and the bacteria themselves present in the periodontium can easily reach the brain due to their anatomical proximity. Thus, periodontitis could be considered a risk factor for the development of Alzheimer's and Parkinson's diseases. In this review we explored the role of NRF2/KEAP1 signaling activation in in vitro and in vivo models of periodontitis to suggest potential treatments of periodontitis and avoid/delay the development of age-related neurodegenerative diseases.},
}

*NF-E2-Related Factor 2/metabolism
Humans
*Periodontitis/metabolism/drug therapy
*Kelch-Like ECH-Associated Protein 1/metabolism
Signal Transduction/drug effects
Animals
Reactive Oxygen Species/metabolism
Aging
Neurodegenerative Diseases/prevention & control/metabolism
Inflammation/metabolism

@article {pmid40736492,
year = {2025},
author = {Grad, R and Ebell, MH},
title = {Top 20 Research Studies of 2024 for Primary Care Physicians.},
journal = {American family physician},
volume = {112},
number = {1},
pages = {34-41},
pmid = {40736492},
issn = {1532-0650},
mesh = {Humans ; Anti-Bacterial Agents/therapeutic use ; *Physicians, Primary Care ; COVID-19 ; *Primary Health Care ; SARS-CoV-2 ; },
abstract = {This article summarizes the top 20 research studies of 2024 identified as POEMs (patient-oriented evidence that matters). Based on a network meta-analysis, the oral antibiotics most likely to be effective for community-acquired pneumonia are telithromycin (not available in the United States), azithromycin, amoxicillin-clavulanate, and the quinolones levofloxacin and nemonoxacin (not available in the United States). The oral antivirals molnupiravir and nirmatrelvir-ritonavir reduce hospitalizations in immunocompromised patients with COVID-19. In average-risk infants, a single dose of nirsevimab reduces hospitalizations due to respiratory syncytial virus. Amoxicillin with or without clavulanate is more effective than placebo for children with symptoms of acute sinusitis. Benzyl benzoate 25% is highly effective for scabies in adolescents and adults. Lactobacillus-containing probiotics reduce the incidence of recurrent urinary tract infections (UTIs) in premenopausal women with frequent UTIs. Low-dose amitriptyline is effective as second-line therapy for irritable bowel syndrome. For patients with uncomplicated gallstones, conservative management is a reasonable option. Sodium-glucose cotransporter-2 (SGLT-2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists are better than older drugs at improving patient-oriented outcomes for type 2 diabetes. Continuous or intermittent glucose monitoring is minimally effective for control of type 2 diabetes and can be harmful. Phentermine-topiramate and GLP-1 receptor agonists are the most effective drugs for promoting weight loss. Semaglutide is effective for secondary prevention of cardiovascular disease in people with obesity and no diabetes. SGLT-2 inhibitors and GLP-1 receptor agonists decrease cardiovascular death in older adults with type 2 diabetes and heart failure. Beta blockers do not prevent subsequent events after myocardial infarction in patients with preserved ejection fraction. For patients who do not quit smoking after a trial of varenicline or combined nicotine replacement therapy, a higher dose of either drug can increase quit rates. e-Cigarettes increase abstinence from smoking, but long-term vaping is a consequence for some. Oral naltrexone and acamprosate are safe and effective treatments for alcohol use disorder. Cognitive behavior therapy can reduce fatigue attributed to long COVID. New monoclonal antibodies for Alzheimer disease are harmful, expensive, and minimally effective. Clinicians may choose to deliver bad news in person or by telephone, using their judgment or patient preference to decide which is best for the patient.},
}

Humans
Anti-Bacterial Agents/therapeutic use
*Physicians, Primary Care
COVID-19
*Primary Health Care
SARS-CoV-2

@article {pmid40736488,
year = {2025},
author = {Johnston, EM and Lounsbery, JL},
title = {Benzgalantamine (Zunveyl) for the Treatment of Mild to Moderate Alzheimer Disease.},
journal = {American family physician},
volume = {112},
number = {1},
pages = {22-23},
pmid = {40736488},
issn = {1532-0650},
}

@article {pmid40736371,
year = {2025},
author = {Chen, KY and Ross, JS and Cohen, AB and Karlawish, J and Oh, ES and Gupta, R},
title = {Demographic Data Supporting FDA Authorization of AI Devices for Alzheimer Disease and Related Dementias.},
journal = {JAMA},
volume = {},
number = {},
pages = {},
doi = {10.1001/jama.2025.12779},
pmid = {40736371},
issn = {1538-3598},
}

@article {pmid40736363,
year = {2025},
author = {Kang, X and Lin, J and Zhao, K and Yan, S and Chen, P and Wang, D and Yao, H and Zhou, B and Yu, C and Wang, P and Liao, Z and Chen, Y and Zhang, X and Han, Y and Lu, J and Liu, Y and , and , },
title = {Structural MRI-based Computer-aided Diagnosis Models for Alzheimer Disease: Insights into Misclassifications and Diagnostic Limitations.},
journal = {Radiology. Artificial intelligence},
volume = {},
number = {},
pages = {e240508},
doi = {10.1148/ryai.240508},
pmid = {40736363},
issn = {2638-6100},
abstract = {"Just Accepted" papers have undergone full peer review and have been accepted for publication in Radiology: Artificial Intelligence. This article will undergo copyediting, layout, and proof review before it is published in its final version. Please note that during production of the final copyedited article, errors may be discovered which could affect the content. Purpose To examine common patterns among different computer-aided diagnosis (CAD) models for Alzheimer's disease (AD) using structural MRI data and to characterize the clinical and imaging features associated with their misclassifications. Materials and Methods This retrospective study utilized 3258 baseline structural MRIs from five multisite datasets and two multidisease datasets collected between September 2005 and December 2019. The 3D Nested Hierarchical Transformer (3DNesT) model and other CAD techniques were utilized for AD classification using 10-fold cross-validation and cross-dataset validation. Subgroup analysis of CAD-misclassified individuals compared clinical/neuroimaging biomarkers using independent t tests with Bonferroni correction. Results This study included 1391 patients with AD (mean age, 72.1 ± 9.2 years, 757 female), 205 with other neurodegenerative diseases (mean age, 64.9 ± 9.9 years, 117 male), and 1662 healthy controls (mean age, 70.6 ± 7.6 years, 935 female). The 3DNesT model achieved 90.1 ± 2.3% crossvalidation accuracy and 82.2%, 90.1%, and 91.6% in three external datasets. Further analysis suggested that false negative (FN) subgroup (n = 223) exhibited minimal atrophy and better cognitive performance than true positive (TP) subgroup (MMSE, FN, 21.4 ± 4.4; TP, 19.7 ± 5.7; PFWE < 0.001), despite displaying similar levels of amyloid beta (FN, 705.9 ± 353.9; TP, 665.7 ± 305.8; PFWE = 0.47), Tau (FN, 352.4 ± 166.8; TP, 371.0 ± 141.8; PFWE = 0.47) burden. Conclusion FN subgroup exhibited atypical structural MRI patterns and clinical measures, fundamentally limiting the diagnostic performance of CAD models based solely on structural MRI. ©RSNA, 2025.},
}

@article {pmid40736114,
year = {2025},
author = {Gonçalves, AE and Spigariol, O and Silva, LMD and Rego, YF and Herrera-Arozamena, C and Rodríguez-Franco, MI and Fátima, Â and Doring, TH and Araujo, LA and Macedo, MLR and Saba, S and Rafique, J and Oliveira, AS and Souza, MM},
title = {New Tacrine Dimers Alleviate the Intracellular Amyloid-β-induced Cognitive Disturbance and Oxidative Stress in Mice.},
journal = {Anais da Academia Brasileira de Ciencias},
volume = {97Suppl. 2},
number = {Suppl. 2},
pages = {e20241163},
doi = {10.1590/0001-3765202520241163},
pmid = {40736114},
issn = {1678-2690},
mesh = {Animals ; *Oxidative Stress/drug effects ; *Tacrine/pharmacology/pharmacokinetics/chemistry ; *Amyloid beta-Peptides ; Mice ; *Alzheimer Disease/drug therapy ; Disease Models, Animal ; Male ; *Neuroprotective Agents/pharmacology ; *Cognitive Dysfunction/drug therapy ; Dimerization ; },
abstract = {This study aimed to investigate in vivo and ex-vivo the effects of tacrine dimers (TD1, TD2, TD3 and TD4) in mice with Alzheimer's disease (AD) induced by amyloid peptide (Aβ42) and, respectively, evaluated in behavioral tests of cognition, oxidative stress and neuroinflammation. All dimers reduced the cognitive deficit caused by Aβ42, oxidative stress and neuroinflammation, especially the compound TD4. By ADMET analysis (SwissADME and pkCSM 2.10 platforms), TD4 exhibited favorable pharmacokinetic properties with the control drug. The results suggest a therapeutic potential for AD for these compounds, given their distinct cognitive and neuroprotective effects in AD models induced by Aβ42.},
}

Animals
*Oxidative Stress/drug effects
*Tacrine/pharmacology/pharmacokinetics/chemistry
*Amyloid beta-Peptides
Mice
*Alzheimer Disease/drug therapy
Disease Models, Animal
Male
*Neuroprotective Agents/pharmacology
*Cognitive Dysfunction/drug therapy
Dimerization

@article {pmid40735987,
year = {2025},
author = {Ergin, AD},
title = {Nanotechnological Approaches for Mitochondrial Targeting in Neurodegenerative Diseases.},
journal = {Current topics in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115680266397447250723073446},
pmid = {40735987},
issn = {1873-4294},
abstract = {OBJECTIVES: Mitochondria are dynamic organelles essential for energy metabolism and cellular homeostasis, playing critical roles in ATP production, calcium regulation, redox balance, and apoptosis. However, mitochondrial dysfunction is a central factor in the pathogenesis of neurodegenerative diseases, including Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease, and Parkinson's disease. Given the essential role of mitochondria in neuronal survival, targeted therapeutic strategies that restore mitochondrial function have gained significant attention. This review explores the latest advances in mitochondrial-targeted therapies and their potential applications in neurodegenerative diseases.

METHODS: A comprehensive literature review was conducted on mitochondrial-targeted therapeutic strategies, with a focus on nanotechnology-based drug delivery systems. The analysis includes various nanoparticle-based approaches, such as liposomes, DQAsomes, and polymeric nanoparticles, which have demonstrated high biocompatibility, controlled drug release, and enhanced mitochondrial targeting efficiency. Additionally, mitochondria-penetrating peptides and delocalized lipophilic cations (DLCs) are discussed for their role in improving drug localization within mitochondria and overcoming biological barriers, including the blood-brain barrier (BBB).

RESULTS: Recent research shows the potential of mitochondrial-targeted antioxidants, peptides, and biocompatible nanocarriers in arranging mitochondrial dysfunction and protecting neurons from oxidative damage. Various nanoparticle-based drug delivery systems have demonstrated the ability to selectively target mitochondria, improving drug bioavailability, therapeutic efficacy, and neuroprotective outcomes in neurodegenerative diseases.

CONCLUSION: Mitochondria-targeted therapies provide promising avenues for disease-modifying treatments aimed at preserving neuronal integrity and delaying disease progression. The unique properties of nanoparticles, such as their ability to enhance drug stability, facilitate controlled release, and achieve precise mitochondrial localization, make them valuable tools for neurodegenerative disease therapy. Future research should focus on optimizing delivery systems, validating clinical applicability, and exploring interdisciplinary approaches to accelerate translation into effective treatments.},
}

@article {pmid40735986,
year = {2025},
author = {Akocak, S and Lolak, N and Ammara, A and Güler, ÖÖ and Supuran, CT},
title = {Exploring the Carbonic Anhydrase Activation Properties of 4-arylazo-3,5- diamino-1H-pyrazoles against hCA I, II, IV, and VII isoenzymes.},
journal = {Current topics in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115680266373008250723064558},
pmid = {40735986},
issn = {1873-4294},
abstract = {INTRODUCTION: CAs serve as crucial enzymes involved in a variety of physiological processes, including brain metabolism and cognitive function. hCA VII, a brain-associated isoform, plays an important role in modulating cerebral metabolism. Activating hCA VII may provide therapeutic benefits in Alzheimer's disease and other neurodegenerative or age-related illnesses. This study proposes to add to the growing interest in CAAs by developing innovative drugs with selective activation characteristics that target brain-associated CA isoforms.

METHOD: A series of 4-arylazo-3,5-diamino-1H-pyrazoles have been produced by reacting aniline and aniline derivatives with a malononitrile solution at 0-5 °C, resulting in compounds 1(a-m). Then, arylazo malononitrile compounds were added with hydrazine monohydrate to obtain 4- arylazo-3,5-diamino-1H-pyrazole derivatives 2(a-m). The activity of the synthesized compounds was examined on human CA isoforms I, II, IV, and VII to determine activation potency and selectivity.

RESULTS: The synthesized compounds demonstrated a wide spectrum of strong micromolar activation on human CA isoforms, with particularly encouraging results for hCA VII. The discovered activators showed a high selectivity profile for the brain-associated hCA VII isoform, indicating their potential use in neurological methods of therapy.

DISCUSSION: Among the most compelling findings of this study is the unprecedented potency of several synthesized derivatives, particularly 2i and 2m, in selectively activating hCA VII far beyond the benchmark histamine, positioning them as promising pharmacological candidates for addressing CA-related neurological disorders.

CONCLUSION: The research successfully discovered potent and selective CAAs with specific activity against hCA VII, a key enzyme in brain metabolism. These outcomes offer novel possibilities for developing medicinal products for neurological disorders and provide critical molecules for further study into CAAs. Furthermore, the study advances our understanding of enzyme activation kinetics and gives significant insights into the future of enzyme-based treatment research.},
}

@article {pmid40735980,
year = {2025},
author = {Agarwal, U and Tonk, RK and Verma, S},
title = {Pathogens Association with Alzheimer Disease: Emerging Concepts and New Perspectives.},
journal = {Current gene therapy},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115665232389348250722073721},
pmid = {40735980},
issn = {1875-5631},
abstract = {Alzheimer's Disease (AD) represents a significant global health challenge, distinguished by a complex pathology that involves the accumulation of abnormal proteins in the brain, leading to neuronal loss and brain atrophy. Recent research has indicated a potential association between various pathogens and the development of AD, suggesting that infectious pathogens may play a role in its pathology. The study focuses on the exploration of pathogens linked to AD. It aims to enhance the understanding of the disease's etiopathogenesis, which refers to the causes and development of the condition. The findings from this analysis have the potential to contribute to improved diagnostic methods and treatment strategies for AD. Overall, the manuscript highlights the importance of exploring infectious pathogens relating to neurodegenerative disorders. This comprehensive literature review was conducted using databases such as PubMed and Scopus, focusing on research published up to March 2025. Articles were searched based on keywords related to reviews and research exploring the association/link between different pathogens and AD, emerging interventions, preventive strategies, and limitations in study design. This study indicates that various viruses, bacteria, and fungi are significant contributors to the condition, while parasites and prions play a lesser role. Notably, the variability in pathogen species among patients could provide insights into the evolution and severity of clinical symptoms associated with the disease. Additionally, some studies propose that after modification, certain fungi may actually reduce the amyloid burden in Alzheimer's patients. However, it is crucial to emphasize that there is currently no definitive evidence supporting the notion that treating infections alone can prevent or cure AD. The prevention and treatment of pathogens, including viruses, bacteria, and fungi, as well as infectious prions, may play a significant role in reducing the risk of AD. Effective management of these pathogens can help to control and prevent further damage in individuals who have already been diagnosed with AD. There is a pressing need for additional pre-clinical and clinical research to deepen the understanding of the pathophysiological connections between pathogens and AD.},
}

@article {pmid40735976,
year = {2025},
author = {Gunasekaran, TI and Sanchez, D and Reyes-Dumeyer, D and Ventura, R and Morales, C and Alshikho, M and Lee, AJ and Lantigua, RA and Gu, Y and Honig, LS and Vardarajan, BN and Brickman, AM and Mayeux, R},
title = {Frequency of Microvascular Pathology and Hippocampal Atrophy on Magnetic Resonance Imaging in a Community Study of Alzheimer's Disease with Blood-Based Biomarkers.},
journal = {Annals of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1002/ana.70006},
pmid = {40735976},
issn = {1531-8249},
abstract = {OBJECTIVE: Blood-based biomarkers for Alzheimer's disease (AD), representing antemortem indicators of AD pathophysiology, have greatly improved the accuracy of diagnosis. However, these biomarkers may not capture a frequent coincident pathology, such as cerebrovascular disease.

METHODS: We measured plasma amyloid-β40, amyloid-β42, total tau, tau phosphorylated at threonine 181, tau phosphorylated at threonine 217, glial fibrillary acidic protein, and neurofilament light chain in 685 multiancestral individuals who had clinical assessments and brain magnetic resonance imaging. The cohort was represented by individuals of European, African American, and Caribbean Hispanic ancestry. Participants were then classified as biomarker-positive or -negative for AD based on previously established cutoffs: 2.65 pg/mL for, tau phosphorylated at threonine 181 and 0.39 pg/mL for tau phosphorylated at threonine 217. We used magnetic resonance images to compare white matter hyperintensity volume (WMH), silent brain infarcts, microhemorrhages, and hippocampus volume across groups by their clinical diagnosis and biomarker status.

RESULTS: In the P-tau181 group (n = 685), 70 individuals (10.2%) had dementia or amnestic mild cognitive impairment. A total of 40 (57%) were biomarker-positive for AD, and 30 were classified as other dementia. Among 615 without dementia, 265 (40.3%) were preclinical AD, and 348 (50.8%) were biomarker-negative controls. In the tau phosphorylated at threonine 217 group (n = 535), 54 (10.1%) had dementia or amnestic mild cognitive impairment, including 33 biomarker-positive for AD and 21 with other dementia, whereas 183 (38.0%) were preclinical AD and 298 (61.9%) were biomarker-negative controls. Across both classifications, biomarker-positive for AD and other dementia individuals showed greater WMH volumes, more infarcts, and smaller hippocampus. However, P-tau217 positivity was more sensitive to WMH volume differences, whereas tau phosphorylated at threonine 181 better captured hippocampal atrophy and silent brain infarcts. Interestingly, ethnic differences may also influence detection of changes in WMH volumes, hippocampal volume, and infarcts in relation to specific biomarkers.

INTERPRETATION: The results indicate that cerebrovascular disease is consistently involved in dementia either directly or as a coincident pathology in AD. These results underscore the need to incorporate both blood-based biomarkers and structural imaging in the evaluation of patients with dementia. ANN NEUROL 2025.},
}

@article {pmid40735840,
year = {2025},
author = {Xu, J and Hörner, M and Atienza, EB and Manibarathi, K and Nagel, M and Hauser, S and Admard, J and Casadei, N and Ossowski, S and Schuele, R},
title = {Long-read RNA-sequencing reveals transcript-specific regulation in human-derived cortical neurons.},
journal = {Open biology},
volume = {15},
number = {7},
pages = {250200},
doi = {10.1098/rsob.250200},
pmid = {40735840},
issn = {2046-2441},
support = {//DFG-funded NGS Competence Center/ ; //European Reference Network for Rare Neurological Diseases/ ; //Else Kröner-Fresenius-Stiftung/ ; //National Institutes of Health (NIH)/ ; //National Institute of Neurological Disorders and Stroke (NINDS)/ ; //Bundesministerium für Bildung und Forschung (BMBF)/ ; },
mesh = {Humans ; *Neurons/metabolism/cytology ; *Sequence Analysis, RNA/methods ; *Transcriptome ; Induced Pluripotent Stem Cells/metabolism/cytology ; Gene Expression Profiling/methods ; *Gene Expression Regulation ; Fibroblasts/metabolism/cytology ; *Cerebral Cortex/cytology/metabolism ; Alternative Splicing ; },
abstract = {Long-read RNA sequencing has transformed transcriptome analysis by enabling comprehensive mapping of full-length transcripts, providing an unprecedented resolution of transcript diversity, alternative splicing and transcript-specific regulation. In this study, we employed nanopore long-read RNA sequencing to profile the transcriptomes of three cell types commonly used to model brain disorders, human fibroblasts, induced pluripotent stem cells and stem cell-derived cortical neurons, identifying extensive transcript diversity with 15 072 transcripts in stem cell-derived cortical neurons, 13 048 in fibroblasts and 12 759 in induced pluripotent stem cells. Our analyses uncovered 35 519 differential transcript expression events and 5135 differential transcript usage events, underscoring the complexity of transcriptomic regulation across these cell types. Importantly, by integrating differential transcript expression and usage analyses, we gained deeper insights into transcript dynamics that are not captured by gene-level expression analysis alone. Differential transcript usage analysis highlighted transcript-specific changes in disease-relevant genes such as APP, KIF2A and BSCL2, associated with Alzheimer's disease, neuronal migration disorders and degenerative axonopathies, respectively. This added resolution emphasizes the significance of transcript-level variations that often remain hidden in traditional differential gene expression analyses. Overall, our work provides a framework for understanding transcript diversity in both pluripotent and specialized cell types, which can be used to investigate transcriptomic changes in disease states in future work. Additionally, this study underscores the utility of differential transcript usage analysis in advancing our understanding of neurodevelopmental and neurodegenerative diseases, paving the way for identifying transcript-specific therapeutic targets.},
}

Humans
*Neurons/metabolism/cytology
*Sequence Analysis, RNA/methods
*Transcriptome
Induced Pluripotent Stem Cells/metabolism/cytology
Gene Expression Profiling/methods
*Gene Expression Regulation
Fibroblasts/metabolism/cytology
*Cerebral Cortex/cytology/metabolism
Alternative Splicing

@article {pmid40735627,
year = {2025},
author = {Jehangir, H},
title = {Mislabelling, misclassification, misinterpretation: A critical appraisal of mortality trends in Alzheimer's and ischemic heart disease.},
journal = {International journal of cardiology. Cardiovascular risk and prevention},
volume = {26},
number = {},
pages = {200464},
pmid = {40735627},
issn = {2772-4875},
}

@article {pmid40735445,
year = {2025},
author = {Khan, W and Khan, MS and Qasem, SN and Ghaban, W and Saeed, F and Hanif, M and Ahmad, J},
title = {An explainable and efficient deep learning framework for EEG-based diagnosis of Alzheimer's disease and frontotemporal dementia.},
journal = {Frontiers in medicine},
volume = {12},
number = {},
pages = {1590201},
pmid = {40735445},
issn = {2296-858X},
abstract = {The early and accurate diagnosis of Alzheimer's Disease and Frontotemporal Dementia remains a critical challenge, particularly with traditional machine learning models which often fail to provide transparency in their predictions, reducing user confidence and treatment effectiveness. To address these limitations, this paper introduces an explainable and lightweight deep learning framework comprising temporal convolutional networks and long short-term memory networks that efficiently classifies Frontotemporal dementia (FTD), Alzheimer's Disease (AD), and healthy controls using electroencephalogram (EEG) data. Feature engineering has been conducted using modified Relative Band Power (RBP) analysis, leveraging six EEG frequency bands extracted through power spectrum density (PSD) calculations. The model achieves high classification accuracies of 99.7% for binary tasks and 80.34% for multi-class classification. Furthermore, to enhance the transparency and interpretability of the framework, SHAP (SHapley Additive exPlanations) has been utilized as an explainable artificial intelligence technique that provides insights into feature contributions.},
}

@article {pmid40735383,
year = {2025},
author = {Luca, A and Luca, M and Ferri, R and Barbanti, M and Malaguarnera, R and Pecorino, B and Scollo, P and Serretti, A},
title = {Medical Comorbidities in Alzheimer's Disease: An Autopsy Confirmed Study with a Focus on Sex-Differences?.},
journal = {Clinical neuropsychiatry},
volume = {22},
number = {3},
pages = {207-214},
pmid = {40735383},
issn = {2385-0787},
abstract = {OBJECTIVE: Systemic comorbidities are common in Alzheimer's disease (AD) and may influence disease progression, severity, and management. Aim of the study was to assess the prevalence of comorbid medical conditions in a large cohort of AD patients, focusing on sex differences.

METHOD: AD patients from the NIMH Alzheimer Disease Genetics Initiative were enrolled. Data on multimorbidity, demographics, disease characteristics, and clinical assessments were collected from interviews, medical records, and examinations. Univariate and multivariate logistic regression models were performed to identify possible associations between comorbidities and sex. Subgroup analysis was performed for patients with autopsy-confirmed AD.

RESULTS: Four hundred and twenty-four AD patients (295 women; mean age: 78.4±8.3 years) were included. Men had a higher prevalence of heart disease, diabetes, chronic obstructive pulmonary disease and smoking, whereas thyroid disease, hypertension and depression were more common in women (all p<0.05). Except for hypertension, all associations found in the univariate analysis were confirmed in the multivariate analysis after adjustment for age. Subgroup analysis of autopsy-confirmed cases confirmed these findings.

CONCLUSIONS: Our findings support the importance of considering sex-specific comorbidities in AD for precision medicine and emphasize the need for comprehensive assessment of comorbidities to improve clinical outcomes, treatment strategies and health equity.nt.},
}

@article {pmid40735367,
year = {2025},
author = {Xu, H and Yang, L and Hu, S and Xu, X and Yang, Y},
title = {An analysis of the global, regional, and national epidemiology and trends of Alzheimer's disease and other dementias linked to smoking from 1990 to 2021 and projections to 2050.},
journal = {Tobacco induced diseases},
volume = {23},
number = {},
pages = {},
pmid = {40735367},
issn = {1617-9625},
abstract = {INTRODUCTION: This research assesses the smoking-related impact on Alzheimer's disease and other dementias (ADOD), analyzing variables such as sex, age, sociodemographic index (SDI), region, and country from 1990 to 2021, with forecasts to 2050.

METHODS: Using data from the Global Burden of Disease Study 2021, we examined smoking-related ADOD trends from 1990 to 2021, focusing on deaths, disability-adjusted life years (DALYs), years of life lost (YLLs), and years lived with disability (YLDs) by age, sex, SDI, location, and country. We quantified trends with estimated annual percentage changes and used decomposition analysis to evaluate the effects of population growth, aging, and epidemiological shifts. A frontier analysis identified improvement areas and disparities among countries by development status. Time series prediction models were used to predict smoking-attributable ADOD trends from 2022 to 2050, considering population profiles.

RESULTS: Between 1990 and 2021, there was an observable upward trend in deaths, DALYs, YLLs, and YLDs. In 2021, the burden of smoking-attributable age-related diseases predominantly impacted males across all age groups. Females, however, experienced a more pronounced reduction in age-standardized rates (ASR) of deaths, DALYs, YLLs, and YLDs compared to their male counterparts. The data from 2021 reveal that ASR of deaths, DALYs, and YLLs increased with age, reaching a peak among individuals aged ≥95 years. These ASR trends were consistent across genders, although higher rates were observed in males than in females. In 2021, the high-middle SDI region recorded the highest ASR of deaths, DALYs, YLLs, and YLDs. All five SDI regions experienced declines in ASR of deaths, DALYs, YLLs, and YLDs, with the high-SDI region demonstrating the most significant reductions in the estimated annual percentage change (EAPC). Decomposition analyses suggested that population growth was the primary factor contributing to the increase in overall deaths.

CONCLUSIONS: From 1990 to 2021, there was an increase in deaths, DALYs, YLLs, and YLDs attributable to smoking-related ADOD, with projections indicating a continued rise globally until 2050. The burden of disease is mainly caused by males and middle-aged and elderly people, which should be given sufficient attention. Understanding epidemiological factors is crucial for designing effective, tailored interventions to mitigate the global burden.},
}

@article {pmid40735265,
year = {2025},
author = {Abuwarda, H and Trainer, A and Horien, C and Shen, X and Moret, S and Ju, S and Constable, RT and Fredericks, C},
title = {Whole-brain functional connectivity predicts regional tau PET in preclinical Alzheimer's disease.},
journal = {Brain communications},
volume = {7},
number = {4},
pages = {fcaf274},
pmid = {40735265},
issn = {2632-1297},
abstract = {Preclinical Alzheimer's disease, characterized by the abnormal accumulation of amyloid-β prior to cognitive symptoms, presents a critical opportunity for early intervention. Past work has described functional connectivity (FC) changes in preclinical Alzheimer's disease, yet the predictive nature between the functional connectome and Alzheimer's disease pathology during this window remains unexplored. We applied connectome-based predictive modelling to investigate the ability of resting-state whole-brain FC to predict tau (18F-flortaucipir) and amyloid-β (18F-florbetapir) PET binding in preclinical Alzheimer's disease (A4, n = 342 amyloid-β-positive, age 65-85). Separate models were developed to predict amyloid PET signal in the posterior cingulate, precuneus, and cortical composite regions, and to predict tau PET signal in each of 14 cortical regions that demonstrated meaningful tau elevation as identified through a Gaussian mixture model approach. Model performance was assessed using a Spearman's correlation between predicted and observed PET binding standard uptake value ratios. We assessed the validity of significant models by applying them to an external dataset and visualized the underlying connectivity that was positively and negatively correlated to regional tau. We found that whole-brain FC predicts regional tau PET, outperforming FC-amyloid-β PET models. The best-performing tau models were for regions affected in Braak stage IV-V regions (posterior cingulate, precuneus, lateral occipital cortex, middle temporal, inferior temporal, and banks of the superior temporal sulcus), while models for regions of earlier tau pathology (entorhinal, parahippocampal, fusiform, and amygdala) performed poorly. Importantly, FC-based models predicted tau PET signal in the Alzheimer's Disease Neuroimaging Intitative-3 dataset (amyloid-β-positive, n = 211, age 55-90) in tau-elevated but not tau-negative individuals. For the posterior cingulate tau model, the most accurate model in A4, the predictive edges positively correlated with posterior cingulate tau predominantly came from nodes within temporal, limbic, and cerebellar regions. The most predictive edges negatively associated with tau were from nodes of heteromodal association areas, particularly within the prefrontal and parietal cortices. These findings reveal that whole-brain FC meaningfully predicts tau PET in preclinical Alzheimer's disease, particularly in regions affected in advanced disease, and are relevant across the Alzheimer's disease clinical spectrum in individuals with elevated tau PET burden. This suggests that functional connectivity, likely in conjunction with other factors, may play a key role in early processes that facilitate later-stage tau spread. These models highlight the potential of the functional connectome for the early detection and monitoring of Alzheimer's disease pathology, especially in later-stage target regions.},
}

@article {pmid40735247,
year = {2025},
author = {Blew, CO and Duggan, MR and Tsitsipatis, D and Gomez, GT and Hernandez, ZR and Pilling, LC and Chen, J and Jacobsen, E and Dark, HE and Lu, Y and Drouin, SM and Joynes, CM and Yao, M and Bilgel, M and Moghekar, A and Tian, Q and Candia, J and Kaileh, M and Gupta, A and Mazan-Mamczarz, K and Gorospe, M and Lyashkov, A and Lukyanenko, Y and Kivimaki, M and Frank, P and Jennings, LL and Gudmundsdottir, V and Gudnason, V and Launer, LJ and Kaneko, N and Kato, S and Furuichi, M and Shibayama, M and Katsuno, M and Hiraga, K and Nishita, Y and Otsuka, R and Pike, JR and Rooney, MR and Schlosser, P and Cui, Y and Erus, G and Davatzikos, C and Gottesman, RF and Waga, I and Palta, P and Ballantyne, C and Griswold, M and Liu, Z and Ferrucci, L and Herman, AB and Walker, KA},
title = {Plasma GDF15 affects long-term dementia risk and alters neuro-immune signaling.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.07.18.25331297},
pmid = {40735247},
abstract = {Growth/differentiation factor-15 (GDF15) is a secreted peptide hormone and cytokine that is strongly associated with dementia risk. However, the extent to which plasma GDF15 represents a biomarker and driver of dementia risk remains unclear. Across multiple cohorts, we demonstrated that plasma GDF15 is associated with greater dementia risk over 15-to 25-year follow-up periods when measured in midlife, with stronger associations observed for vascular dementia compared to Alzheimer's disease (AD). Two-sample Mendelian randomization supported plasma GDF15's mechanistic role in AD and related dementias, while cohort studies linked it to cerebral small vessel disease, diffuse neurodegeneration, phosphorylated tau, and a cerebrospinal fluid proteomic signature indicative of neuro-immune activation. Exposure of cultured myeloid cells to recombinant GDF15 altered biological pathways that we subsequently demonstrated are predictive of dementia risk, including interferon/antiviral responses, pyruvate metabolism, and scavenging of heme. These findings support circulating GDF15's role as an early biomarker - particularly for vascular dementia and neuroinflammation - and identify the mechanisms by which it may drive dementia risk.},
}

@article {pmid40735190,
year = {2025},
author = {Arnsten, AFT and Perone, I and Wang, M and Yang, S and Uchendu, S and Bolat, D and Datta, D},
title = {Dysregulated calcium signaling in the aged primate association cortices: vulnerability to Alzheimer's disease neuropathology.},
journal = {Frontiers in aging neuroscience},
volume = {17},
number = {},
pages = {1610350},
pmid = {40735190},
issn = {1663-4365},
abstract = {The common, late onset form of Alzheimer's disease (AD) selectively impacts higher brain circuits, with tau pathology and neurodegeneration preferentially afflicting glutamatergic neurons in the limbic and association cortices. Understanding this selective vulnerability may help reveal the etiology of sporadic AD and therapeutic targets for prevention. The current review describes that these vulnerable circuits express magnified calcium signaling needed for higher cognition and memory, but that heightened calcium signaling becomes toxic when dysregulated by age and inflammation. Many of the earliest pathological events in AD are challenging to study in human brain, as proteins such as tau rapidly dephosphorylate postmortem. However, they can be studied in aging macaques, who are all APOE-ε4 homozygotes and naturally develop cognitive deficits, calcium dysregulation, synapse loss, tau and amyloid pathology and autophagic degeneration, including elevated plasma pT217Tau, a new blood biomarker of incipient AD. High resolution nanoscale imaging of aging macaque brains reveals the earliest stages of soluble tau pathology and its relationships with Aβ42 and calcium signaling. These data indicate that inflammation erodes regulation of calcium signaling leading to the activation of calpain-2, which drives tau hyperphosphorylation, APP cleavage to Aβ42 and autophagic degeneration. These in turn propel further calcium dysregulation to drive vicious cycles. Restoring calcium dysregulation, e.g., with calpain-2 inhibitors, thus may be a rational strategy for slowing or preventing AD pathology. Recent data show that an agent that reduces GCPII inflammation and restores mGluR3 regulation of calcium reduced tau pathology in aged macaques, encouraging this approach. Targeting inflammation and dysregulated calcium may be especially helpful for patients who are APOE-ε4 carriers and insufficiently aided by current anti-amyloid antibody treatments.},
}

@article {pmid40735128,
year = {2025},
author = {Ribeiro, EG and Oliveira, CMDS and Mourão, AM and Vicente, LCC and Motta, AR and Honório, HM and Berretin-Felix, G},
title = {Immediate Effect of Neuromuscular Electrical Stimulation on Swallowing in Elderly People with Alzheimer's Dementia.},
journal = {International archives of otorhinolaryngology},
volume = {29},
number = {3},
pages = {1-7},
pmid = {40735128},
issn = {1809-9777},
abstract = {INTRODUCTION: Dysphagia affects a significant number of patients with Alzheimer's dementia. Neuromuscular electrical stimulation may be a promising resource for dysphagia rehabilitation in this population.

OBJECTIVE: To investigate the immediate effects of neuromuscular electrical stimulation on hyoid bone displacement, pharyngeal transit time, and swallowing safety in elderly people with Alzheimer's dementia.

METHODS: We evaluated 30 elderly individuals with an average age of 82.79 years, regardless of the stage of dementia and with reduced hyolaryngeal elevation, using the Northwestern Dysphagia Patient Check Sheet. Neuromuscular electrical stimulation was performed at the sensory and motor levels in the submental region during videofluoroscopy, with food being offered in solid, pudding, and liquid consistencies, and in portions of 5 mL and 10 mL. We applied Analysis of variance and the Friedman test, adopting a significance level of < 5%.

RESULTS: The comparison between the sensory and motor levels of stimulation showed that there was a significant difference in hyoid bone displacement for the mushy consistency, with neuromuscular stimulation at the motor level. There was no difference in the application of stimuli for the other consistencies regarding hyoid bone displacement, pharyngeal transit time, and the penetration and aspiration scale.

CONCLUSION: In elderly people with Alzheimer's dementia, neuromuscular electrical stimulation at the motor level generated a reduction in hyoid bone displacement during swallowing of food with pudding consistency, with no effects on pharyngeal transit time or swallowing safety.},
}

@article {pmid40735110,
year = {2025},
author = {Sen, MK and Dunville, K and Miles, N and Newbery, M and Ng, NS and Ooi, L},
title = {Editorial: Recent advances in mitochondrial dysfunction and therapeutics for neurodegeneration and aging.},
journal = {Frontiers in cellular neuroscience},
volume = {19},
number = {},
pages = {1650938},
pmid = {40735110},
issn = {1662-5102},
}

@article {pmid40735049,
year = {2025},
author = {Kang, MJY and Eratne, D and Loi, SM and Dang, C and Santillo, AF and Zetterberg, H and Blennow, K and Mitchell, PB and Hopwood, M and Malpas, CB and Velakoulis, D},
title = {Apathy and affective symptoms associated with elevated plasma neurofilament light but not p-tau181 in Alzheimer's disease.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {17},
number = {3},
pages = {e70151},
pmid = {40735049},
issn = {2352-8729},
abstract = {INTRODUCTION: Apathy and affective neuropsychiatric symptoms (NPS) are prevalent in Alzheimer's disease (AD), yet their neurobiological cause is still unclear. We examined associations between plasma neurofilament light chain (NfL) and tau pathology (p-tau181) with apathy and affective symptoms in mild cognitive impairment (MCI) and AD dementia.

METHODS: This longitudinal study analyzed data from 781 participants with MCI and AD dementia enrolled in ADNI, with annual blood samples collected over 4 years. NPS were assessed via the Neuropsychiatric Interview (NPI), and biomarker trajectories were analyzed using mixed-effects models.

RESULTS: Elevated plasma NfL levels were associated with apathy, anxiety and depression in MCI and AD dementia, with apathy linked to a significantly higher rate of NfL increase, indicating accelerated neurodegeneration.

DISCUSSION: Apathy and affective symptoms may indicate greater neurodegenerative burden in AD independent of tau-related pathology. Apathy was associated with a steeper rise in plasma NfL, suggesting a more aggressive disease progression.

HIGHLIGHTS: Apathy and affective neuropsychiatric symptoms (NPS) are highly prevalent in clinical Alzheimer's disease (AD).The presence of apathy, depression or anxiety was associated with higher plasma levels of neurofilament light chain (NfL).Apathy was associated with an accelerated increase in plasma NfL levels over time.Apathy and affective NPS were not associated with p-tau181 levels in plasma.},
}

@article {pmid40735048,
year = {2025},
author = {Xia, Y and Bourgeat, P and Doré, V and Fripp, J and Lim, YY and Laws, SM and Fowler, C and Rowe, CC and Masters, CL and Coulson, EJ and Maruff, P and , },
title = {Amyloid accumulation, brain atrophy, and cognitive decline in emergent Alzheimer's disease.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {17},
number = {3},
pages = {e70155},
pmid = {40735048},
issn = {2352-8729},
abstract = {INTRODUCTION: Emergent Alzheimer's disease (AD) represents a transitional stage where cognitively unimpaired (CU) individuals exhibit subthreshold but increasing amyloid-β (Aβ) levels. The impact of Aβ accumulation on brain volume loss and cognition during this early stage remains unclear.

METHODS: This retrospective cohort study analyzed data from 408 CU participants who were initially Aβ- (< 15 Centiloids) and followed for up to 15 years. Changes in basal forebrain and hippocampal volume, along with domain-specific cognitive performance, were compared between those who progressed to Aβ+ (≥20 Centiloids) and those who remained Aβ-.

RESULTS: Sixty-five CU participants progressed to Aβ+, indicating emergent AD, and showed faster Aβ accumulation and subtle memory decline. However, no significant differences in rate of BF and hippocampal atrophy were observed between groups.

DISCUSSION: The results suggest that during this emergent phase of AD, Aβ accumulation is associated with episodic memory loss, in the absence of detectable accelerated brain atrophy.

HIGHLIGHTS: Identified cognitively unimpaired individuals in the emergent stage of Alzheimer's disease (AD).Emergent AD exhibits a greater rate of amyloid-β (Aβ) accumulation.No accelerated volume loss detected in the basal forebrain or hippocampus.Emergent AD is also associated with a subtle decline in memory.Early Aβ accumulation may impair cognitive function before structural atrophy.},
}

@article {pmid40734994,
year = {2025},
author = {Swirska, M and Laurell, AAS and Sidhom, E and Pizzol, D and Smith, L and Underwood, BR},
title = {Communicating the risk of dementia: a scoping review.},
journal = {BMJ neurology open},
volume = {7},
number = {2},
pages = {e001138},
pmid = {40734994},
issn = {2632-6140},
abstract = {BACKGROUND: Dementia is a syndrome characterised by progressive cognitive and functional decline arising from a neurodegenerative disease. Genetic testing, imaging and fluid biomarkers mean that levels of risk of dementia diagnosis are becoming frequent and complex. How risk is communicated in this context is an increasingly important topic.

AIMS: The aim of this scoping review is to map the existing literature regarding the components of risk communication, the factors influencing its outcomes and the guidelines developed to support clinicians in this process.

METHODS: This is a systematic scoping review addressing the communication of risk to individuals living with or at risk of dementia, as well as perspectives of family, carers and healthcare professionals.

RESULTS: 115 articles were identified, including genetic (n=41), amyloid (n=45) and other biomarkers (n=9). Patients expressed a desire to be informed about their risk of developing dementia, listing future planning and participation in clinical research as benefits of disclosure. While risk disclosure did not significantly impact anxiety or depression, it was associated with increased event distress among participants identified as elevated risk. Individuals at high risk frequently overestimated their likelihood of developing dementia. Tools and guidelines that have supported clinicians in risk disclosure emphasised the use of educational materials, clear communication about risk and prognosis, and regular follow-up appointments. Gaps in literature include blood biomarkers, non-Alzheimer's disease dementias and communication to people with cognitive impairment.

CONCLUSIONS: Risk communication is a crucial topic for healthcare professionals, especially since the emergence of novel techniques to predict dementia.},
}

@article {pmid40734951,
year = {2025},
author = {Yang, JC and Kuo, PJ and Chang, C and Wang, YM and Ou, YC and Cheng, YC and Wu, SC and Chien, PC and Hsieh, CH and Lin, WC},
title = {Linking Lymphedema, Chronic Inflammation, Oxidative Stress, Alzheimer Disease, and Potential Role of Lymphaticovenous Anastomosis.},
journal = {Plastic and reconstructive surgery. Global open},
volume = {13},
number = {7},
pages = {e6955},
pmid = {40734951},
issn = {2169-7574},
abstract = {BACKGROUND: Lymphedema and Alzheimer disease (AD) share common mechanisms involving oxidative stress and chronic inflammation. However, the link between these 2 conditions and the impact of lymphaticovenous anastomosis (LVA) has not been fully explored. This study aimed to evaluate their association by examining changes in AD biomarkers, inflammatory cytokines, and oxidative stress markers before and after LVA.

METHODS: Twenty-four patients with unilateral lower limb lymphedema who underwent LVA as primary treatment and 18 healthy controls were recruited. Exclusion criteria included previous LVA, liposuction, or excisional surgery. Venous blood samples were obtained before and 1 month after LVA.

RESULTS: After matching, 15 patients remained in each group. The lymphedema group had significantly elevated levels of t-tau (p < 0.001), amyloid beta (Aβ)1-40 (P = 0.033), Aβ1-42 (P = 0.033), Aβ1-42 × t-tau (P < 0.001), and Aβ1-42/Aβ1-40 ratio (P = 0.021) compared with controls. One month post-LVA, there were significant reductions in t-tau (P = 0.007) and Aβ1-42 × t-tau (P = 0.002), and a notable increase in brain-derived neurotrophic factor (P = 0.006). Post-LVA samples also showed significant improvements in antioxidative enzymes, antioxidant capacity, and reductions in lipid peroxidation. Inflammatory cytokine levels were also significantly reduced, indicating decreased oxidative stress and inflammation. The median follow-up period was 6.3 months.

CONCLUSIONS: Findings suggest a possible association between lymphedema and increased AD risk possibly linked to elevated oxidative stress and inflammation. LVA may modulate this risk by reducing AD biomarkers and systemic inflammation/oxidative stress, supporting further investigation into its neuroprotective potential.},
}

@article {pmid40734823,
year = {2025},
author = {Yoshida, N and Kageyama, H and Akai, H and Kasai, S and Sasaki, K and Sakurai, N and Kodama, N},
title = {Reducing the acquisition time for magnetic resonance imaging using super-resolution image generation and evaluating the accuracy of hippocampal volumes for diagnosing Alzheimer's disease.},
journal = {Frontiers in neurology},
volume = {16},
number = {},
pages = {1507722},
pmid = {40734823},
issn = {1664-2295},
abstract = {INTRODUCTION: Brain magnetic resonance imaging (MRI) is important for diagnosing Alzheimer's disease (AD), and MRI acquisition time should be reduced. The current study aimed to identify which Pix2Pix-based super-resolution images can reduce errors associated with brain anatomical analysis with diffeomorphic deformation examination and MRI acquisition time.

METHODS: Fifty patients with dementia who uderwent scanning using a 3-T MRI scanner in the OASIS-3 database were used to construct a super-resolution network. Network training was performed using a scaled image (64 × 64) down-sampled from the original image as the input image and paired with the original high-resolution (256 × 256) supervised image. The hippocampal volume was measured using brain anatomical analysis with diffeomorphic deformation software, which employs machine learning algorithms and performs voxel-based morphometry. Peak signal-to-noise ratio (PSNR) and Multiscale structural similarity (MS-SSIM) score were used to objectively evaluate the generated images.

RESULTS: At λ = e[3], the PSNR and MS-SSIM score of the generated images were 27.91 ± 1.78 dB and 0.96 ± 0.0045, respectively. This finding indicated that the generated images had the highest objective evaluation. Using the images generated at λ = e[4], the left and right hippocampal volumes did not significantly differ between the original and generated super-resolution images (p = 0.76, p = 0.19, respectively).

DISCUSSION: With super-resolution using the Pix2Pix network, the hippocampal volume can be accurately measured, and the MRI acquisition time can be reduced. The proposed method does not require special hardware and can be applied to previous images.},
}

@article {pmid40734820,
year = {2025},
author = {Zhang, X and Fu, P and Cai, Y},
title = {Association of plasma BMP6 levels with the rates of brain atrophy in older people without dementia.},
journal = {Frontiers in neurology},
volume = {16},
number = {},
pages = {1559219},
pmid = {40734820},
issn = {1664-2295},
abstract = {BACKGROUND: Bone morphogenetic protein 6 (BMP6) has been implicated in the pathogenesis of Alzheimer's disease (AD), and its levels have been reported to be associated with cognitive performance. However, few studies have examined the association between plasma BMP6 levels and brain atrophy in older adults.

METHODS: A total of 340 older adults without dementia were included in the current study. Study participants had baseline plasma BMP6 data available and at least two structural MRI scans. Volumes of six brain regions were measured, including the hippocampus, entorhinal cortex, middle temporal gyrus, fusiform gyrus, ventricles, and whole brain. A series of linear mixed-effects models were built to examine the associations of plasma BMP6 levels with brain atrophy over time.

RESULTS: Our study revealed that higher plasma BMP6 levels were associated with a reduced rate of volume loss in the hippocampus, entorhinal cortex, middle temporal gyrus, and whole brain. However, there was no significant link between plasma BMP6 levels and changes in the volume of the fusiform gyrus or ventricles.

CONCLUSION: Our results may provide novel insights into the mechanisms of neurodegeneration in AD, contributing to new avenues for timely intervention and potentially slowing disease progression.},
}

@article {pmid40734544,
year = {2025},
author = {Sadeghpour, N and Lim, SA and Wuestefeld, A and Denning, AE and Ittyerah, R and Trotman, W and Chung, E and Sadaghiani, S and Prabhakaran, K and Bedard, ML and Ohm, DT and Artacho-Pérula, E and de Onzoño Martin, MMI and Muñoz, M and Romero, FJM and González, JCD and Del Arroyo Jiménez, M and Del Marcos Rabal, M and Insausti Serrano, AM and González, NV and Sánchez, SC and de la Rosa Prieto, C and Insausti, R and McMillan, C and Lee, EB and Detre, JA and Das, SR and Xie, L and Tisdall, MD and Irwin, DJ and Wolk, DA and Yushkevich, PA and Wisse, LEM},
title = {Developing an Anatomically Valid Segmentation Protocol for Anterior Regions of the Medial Temporal Lobe for Neurodegenerative Diseases.},
journal = {Hippocampus},
volume = {35},
number = {5},
pages = {e70027},
doi = {10.1002/hipo.70027},
pmid = {40734544},
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 ; P01-AG066597/NH/NIH HHS/United States ; U19-AG062418/NH/NIH HHS/United States ; R01-AG066152/NH/NIH HHS/United States ; R01-NS109260/NH/NIH HHS/United States ; R01-AG080734/NH/NIH HHS/United States ; 20230790//Crafoordska Stiftelsen/ ; AF-980872//Swedish Alzheimer Foundation/ ; //MultiPark/ ; 2022-GRIN-34392//UCLM Intramural Grant/ ; },
mesh = {Humans ; Aged ; Female ; Male ; Magnetic Resonance Imaging/methods ; *Temporal Lobe/diagnostic imaging/pathology ; Middle Aged ; Aged, 80 and over ; *Neurodegenerative Diseases/diagnostic imaging/pathology ; Image Processing, Computer-Assisted/methods ; Alzheimer Disease/pathology/diagnostic imaging ; },
abstract = {The anterior portion of the medial temporal lobe (MTL) is one of the first regions targeted by pathology in sporadic Alzheimer's disease (AD) and limbic-predominant age-related TDP-43 encephalopathy (LATE) indicating a potential for metrics from this region to serve as imaging biomarkers. Leveraging a unique post-mortem dataset of histology and magnetic resonance imaging (MRI) scans, we aimed to (1) develop an anatomically valid segmentation protocol for anterior entorhinal cortex (ERC), Brodmann area (BA) 35, and BA36 for in vivo 3 T MRI and (2) incorporate this protocol in an automated approach. We included 20 cases (61-97 years old, 50% females) with and without neurodegenerative diseases (11 vs. 9 cases) to ensure generalizability of the developed protocol. Digitized MTL Nissl-stained coronal histology sections from these cases were annotated and registered to same-subject post-mortem MRI. The protocol was developed by determining the location of histological borders of the MTL cortices in relation to anatomical landmarks. Subsequently, the protocol was applied to 15 cases twice, with a 2-week interval, to assess intra-rater reliability with the Dice Similarity Index (DSI). Thereafter, it was implemented in our in-house Automatic Segmentation of Hippocampal Subfields (ASHS)-T1 approach and evaluated with DSIs. The anterior histological border distances of ERC, BA35 and BA36 were evaluated with respect to various anatomical landmarks, and the distance relative to the beginning of the hippocampus was chosen. To formulate segmentation rules, we examined the histological sections for the location of borders in relationship to anatomical landmarks in the coronal sections. The DSI for the anterior MTL cortices for the intra-rater reliability was 0.85-0.88, and for the ASHS-T1 against the manual segmentation, it was 0.62-0.65. We developed a reliable segmentation protocol and incorporated it in an automated approach. Given the vulnerability of the anterior MTL cortices to tau deposition in AD and LATE, the updated approach is expected to improve imaging biomarkers for these diseases.},
}

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

@article {pmid40734473,
year = {2025},
author = {Prajapat, M and Sarma, P and Kaur, G and Choudhary, G and Jain, S and Kamal, R and Bains, O and Sangwan, N and Prakash, A and Medhi, B},
title = {Therapeutic potential of 6BIO and DKK1-LRP6 inhibitor in Wnt/β-catenin pathway modulation for amyloid-β-induced Alzheimer's disease model.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251362787},
doi = {10.1177/13872877251362787},
pmid = {40734473},
issn = {1875-8908},
abstract = {BackgroundThe Wnt/β-catenin signaling pathway plays a crucial role in central nervous system development, with emerging evidence linking its dysregulation to the progression of Alzheimer's disease (AD).ObjectiveThis study investigates the activation of Wnt signaling by targeting GSK3β and the DKK1/LRP6 interaction using a combination of 6BIO (6Bromoindirubin-3-oxime) and a novel gallocyanine derivative (8e) modulator.MethodsWe identified the interaction energy scores of both modulators with target proteins through an in-silico approach. Furthermore, the effects of 6BIO (10 µM) and 8e (20 µM) were assessed in SH-SY5Y cells treated with Aβ1-42 (20 µM). The efficacy of these modulators was also evaluated in male Wistar rats through dose-ranging studies. An Alzheimer's disease model was established via intracerebroventricular injection of Aβ1-42, followed by treatment with 6BIO (23.8 µg/kg/day, i.p.) and 8e (4.2 mg/kg/day, i.p.).ResultsBoth modulators demonstrated favorable binding energy scores and dynamic simulation results against the targeted proteins. In Aβ1-42-treated SHSY5Y cells, the combination of 6BIO and 8e significantly reduced reactive oxygen species production and apoptotic activity while modulating protein expression. In vivo study, rats treated with combination of 6BIO and 8e modulators exhibited improved neurobehavioral activity compared to AD model rats, along with altered expression of DKK1, β-catenin, p-tau, and pGSK3β. Additionally, decreased oxidative stress and apoptosis markers.ConclusionsThese findings suggest that the combined targeting of GSK3β and LRP6 represents a promising therapeutic strategy for AD. The combination of 6BIO and 8e shows potential as a novel modulator and warrants further investigation in clinical trials to assess its therapeutic efficacy.},
}