@article {pmid40368227,
year = {2025},
author = {Mohan, M and Mannan, A and Singh, S and Singh, TG},
title = {Unlocking the cellular mystery: how proton pump inhibitors may alter the dementia landscape.},
journal = {Brain research},
volume = {},
number = {},
pages = {149702},
doi = {10.1016/j.brainres.2025.149702},
pmid = {40368227},
issn = {1872-6240},
abstract = {Proton pump inhibitors (PPIs) have become virtually the sole class of histamine-2 receptor antagonists due to their greater effectiveness and general availability. However, concern has been increasing about long-term use and some possible neurological adverse effects, including a link with dementia. Several studies indicate that long-term use of PPIs can raise the risk for both Alzheimer's disease (AD) and non-Alzheimer's dementia, though there is opposing evidence. Neurological side effects of PPIs are cognitive impairment, neuropathies, depression, anxiety, and hallucinations. The mechanisms are unknown but could be due to PPIs crossing the BBB and interfering with neuronal function or causing systemic deficiencies, e.g., vitamin B12 deficiency. Vitamin B12 is essential for cognitive function, and its deficiency has been linked to dementia. PPIs also cause B12 deficiency by inhibiting gastric acid secretion, which is required for B12 absorption. B12 deficiency causes hyperhomocysteinemia, which facilitates tau hyperphosphorylation and amyloid-β (Aβ) deposition, major pathological hallmarks of AD. PPIs have also been found to disrupt amyloid precursor protein processing, mitochondrial function, and neuroinflammation, further enhancing neurodegenerative processes. Experimental evidence indicates that PPIs affect brain homeostasis through inhibition of vacuolar ATPases, modulation of microglial Aβ phagocytosis, and induction of synaptic dysfunction. While the specific molecular mechanisms are unknown, findings suggest that long-term PPI exposure could contribute to neurodegeneration, especially in elderly patients. With increasing dementia prevalence, additional clinical research is needed to ascertain whether PPIs are a causative agent or a contributing factor to cognitive impairment.},
}

@article {pmid40368121,
year = {2025},
author = {Irfan, B and Wiseman, E and Boyd, JW and Reader, J and Rahman-Filipiak, A},
title = {Toward a person-centered return of research results of dementia risk: A pluralistic, constructive expansion.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251343319},
doi = {10.1177/13872877251343319},
pmid = {40368121},
issn = {1875-8908},
abstract = {Graham et al.'s article offers a thoughtful account of why disclosing modifiable dementia risk factors to cognitively unimpaired research participants may be ethically defensible. In this Ethics Response, we seek to engage constructively with their arguments, affirming value in a person-centered approach, while also expanding on how cultural, communal, and religious contexts can further illuminate the ethics of returning individual research results. Drawing on emerging ethical issues and examples from diverse settings, this response highlights how stigmatization, religious worldviews, family care traditions, and broader socioeconomic factors may influence the perceived meaning and impact of dementia risk communication.},
}

@article {pmid40368056,
year = {2025},
author = {Bonarota, S and Caruso, G and Domenico, CD and Sperati, S and Tamigi, FM and Giulietti, G and Giove, F and Caltagirone, C and Serra, L},
title = {Integration of Automatic MRI Segmentation Techniques with Neuropsychological Assessments for Early Diagnosis and Prognosis of Alzheimer's Disease. A systematic review.},
journal = {NeuroImage},
volume = {},
number = {},
pages = {121264},
doi = {10.1016/j.neuroimage.2025.121264},
pmid = {40368056},
issn = {1095-9572},
abstract = {BACKGROUND: This systematic review investigates the integration of automatic segmentation techniques of magnetic resonance imaging (MRI) with neuropsychological assessments for early diagnosis and prognosis of Alzheimer's Disease (AD).

OBJECTIVES: Focus on studies that utilise automated MRI segmentation and neuropsychological evaluations across the AD spectrum.

DATA SOURCES: A literature search was conducted on the PubMed database on 7 November 2024, using key terms related to MRI, segmentation, brain structures, AD, and cognitive decline.

STUDY ELIGIBILITY CRITERIA: Studies including individuals with AD, mild cognitive impairment (MCI), or subjective cognitive decline (SCD), utilising structural MRI, focusing on grey matter and automatic segmentation, and reporting cognitive assessments were included.

Data were extracted and synthesised focusing on associations between MRI measures and cognitive tests, and discriminative values for diagnosis or prognosis.

RESULTS: Seven studies were included, showing a significant association between structural changes in the medial temporal lobe and cognitive decline. The combination of MRI volumetric measures and neuropsychological scores enhanced diagnostic accuracy. Neuropsychological measures demonstrated superiority in the identification of patients with MCI and mild AD in comparison to MRI measures alone.

LIMITATIONS: Heterogeneity across studies, selection and measurement bias, and lack of non-response data were noted.

CONCLUSIONS AND IMPLICATIONS: This review emphasises the necessity of integrating automated MRI segmentation with neuropsychological assessments for the diagnosis and prognosis of AD. While MRI is valuable, neuropsychological testing remains essential for early detection. Future studies should focus on developing integrated predictive models and refining neuroimaging techniques.},
}

@article {pmid40368008,
year = {2025},
author = {Kaur, S and Darden, CJ and Adegbola, GM and Warrington, JP},
title = {History of hypertensive disorders of pregnancy and risk of Alzheimer's disease and vascular dementia.},
journal = {Frontiers in neuroendocrinology},
volume = {},
number = {},
pages = {101198},
doi = {10.1016/j.yfrne.2025.101198},
pmid = {40368008},
issn = {1095-6808},
abstract = {The incidence of dementia, and specifically, Alzheimer's disease, is higher in women than men, even in middle age, making it possible to rule out lifespan differences between men and women as a contributing factor. Thus, it is plausible that pregnancy experience, which is unique to women, may play a contributing role. In this review, we discuss the different hypertensive disorders of pregnancy (HDP), Alzheimer's and vascular dementia, clinical, epidemiological, and preclinical studies that link a history of HDP with dementia. We also present potential mechanisms linking HDP, Alzheimer's, and vascular dementia. Several key symptoms that are shared among the disorders are presented as potential underlying mechanisms that link the adverse pregnancy disorder with the long-term postpartum neurological changes. Further, we present limitations of the existing literature, gaps, and opportunities for further research.},
}

@article {pmid40367960,
year = {2025},
author = {Sun, Y and Feng, L and Xu, B and Jia, S and Duan, L and Ni, W and Jia, Z},
title = {Enhanced Alzheimer's detection with EEG source imaging and multi-branch joint attention.},
journal = {Journal of neural engineering},
volume = {},
number = {},
pages = {},
doi = {10.1088/1741-2552/add8bb},
pmid = {40367960},
issn = {1741-2552},
abstract = {OBJECTIVE: Alzheimer's disease (AD) is a neurodegenerative disorder detectable via electroencephalogram (EEG). Traditional EEG-based AD detection methods do not fully leverage spatial information about brain activity and the correlation between different frequency bands, leading to suboptimal cross-patient performance.

APPROACH: We propose a new Multi-Branch Joint Attention Network (MJANet) based on electrophysiological source imaging (ESI) to create comprehensive spatial power maps, improving the spatial resolution of EEG. The MJANet incorporates a multi-branch joint attention mechanism to capture interactions across different frequency bands. The MJANet employs a new multi-branch joint attention mechanism to capture interactions across frequency bands and a moving shifted window to capture global image features. It analyzes correlations between activities in various bands and brain regions to boost cross-patient detection capabilities.

MAIN RESULTS: The proposed approach is validated on a public dataset with a Leave-One-Subject-Out (LOSO) cross-validation strategy, achieving an 85.23% accuracy rate in differentiating AD from normal controls NC), representing an 8.03% improvement over the state-of-the-art. Moreover, it achieves 75.57% accuracy in distinguishing Frontotemporal Dementia (FTD) from NC, and 63.97% for the classification of AD, NC, and FTD. We utilize GradCAM to visualize the joint attention mechanism, providing insights into its decision-making process.

SIGNIFICANCE: This work explores a novel biomarker that has the potential to enhance clinical diagnostic methods and improve diagnostic accuracy.},
}

@article {pmid40367557,
year = {2025},
author = {Forloni, G},
title = {Doxycycline: An essential tool for Alzheimer's disease.},
journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie},
volume = {188},
number = {},
pages = {118159},
doi = {10.1016/j.biopha.2025.118159},
pmid = {40367557},
issn = {1950-6007},
abstract = {The identification of active interventions in neurodegenerative disorders is a major challenge in neurology; the use of repurposed drugs may represent a valuable strategy. Tetracyclines, a second generation of antibiotic molecules, offer various potential applications. Following an anecdotal observation of the potential anti-amyloidogenic activity of iododoxorubicin, the search for chemical analogs with a better safety profile led to tetracyclines. Their heterocyclic structures with a planar conformation interfere with b-sheet amyloid formation. Thus, doxycycline, a derivative with favorable blood-brain barrier penetration, emerged as a strong candidate to combat peripheral and central amyloidosis. In particular, we tested the anti-prion activity of doxycycline in vitro and in vivo experiments, confirming its capacity to disrupt or inhibit the formation of prion protein aggregates associated with pathological events. Treatment with doxycycline in human subjects with prion - related encephalopathies yielded contradictory results, suggesting that a preventive approach is a more favorable condition to verify efficacy; a clinical trial involving subjects at genetic risk of developing fatal familial insomnia, exposed to doxycycline for ten years, is currently ongoing. The anti-amyloidogenic capacity of doxycycline, combined with its safety profile in long-term treatment, has suggested its use in peripheral amyloidosis, which was tested with positive results. A specific interaction with β-amyloid or α-synuclein oligomers, as well as tau aggregation has also been demonstrated. More recently, the action of doxycycline has been extended to its anti-inflammatory and antioxidant capacities. In particular, the anti-inflammatory activity of doxycycline may explain the drug 's efficacy in numerous experimental models where protein misfolding has been associated with neuroinflammation, including Huntington's and Parkinson' s diseases. Thus, the pleiotropic action of doxycycline appears to be an interesting tool for addressing progressive neuronal dysfunction in multifactorial neurodegenerative diseases. The application of precision medicine principles to doxycycline treatment represents the best strategy to determine its efficacy. These aspects are illustrated here concerning another pleiotropic tetracycline, minocycline.},
}

@article {pmid40367504,
year = {2025},
author = {Shaik, MA and Anik, FI and Hasan, MM and Chakravarty, S and Ramos, MD and Rahman, MA and Ahamed, SI and Sakib, N},
title = {Advancing Remote Monitoring for Patients With Alzheimer Disease and Related Dementias: Systematic Review.},
journal = {JMIR aging},
volume = {8},
number = {},
pages = {e69175},
doi = {10.2196/69175},
pmid = {40367504},
issn = {2561-7605},
abstract = {BACKGROUND: Using remote monitoring technology in the context of Alzheimer disease (AD) care presents exciting new opportunities to lessen caregiver stress and improve patient care quality. The application of wearables, environmental sensors, and smart home systems designed specifically for patients with AD represents a promising interdisciplinary approach that integrates advanced technology with health care to enhance patient safety, monitor health parameters in real time, and provide comprehensive support to caregivers.

OBJECTIVE: The objectives of this study included evaluating the effectiveness of various remote sensing technologies in enhancing patient outcomes and identifying strategies to alleviate the burden on health care professionals and caregivers. Critical elements such as regulatory compliance, user-centered design, privacy and security considerations, and the overall efficacy of relevant technologies were comprehensively examined. Ultimately, this study aimed to propose a comprehensive remote monitoring framework tailored to the needs of patients with AD and related dementias.

METHODS: Guided by the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) framework, we conducted a systematic review on remote monitoring for patients with AD and related dementias. Our search spanned 4 major electronic databases-Google Scholar, PubMed, IEEE Xplore, and DBLP on February 20, 2024, with an updated search on May 18, 2024.

RESULTS: A total of 31 publications met the inclusion criteria, highlighting 4 key research areas: existing remote monitoring technologies, balancing practicality and empathy, security and privacy in monitoring, and technology design for AD care. The studies revealed a strong focus on various remote monitoring methods for capturing behavioral, physiological, and environmental data yet showed a gap in evaluating these methods for patient and caregiver needs, privacy, and usability. The findings also indicated that many studies lacked robust reference standards and did not consistently apply critical appraisal criteria, underlining the need for comprehensive frameworks that better integrate these essential considerations.

CONCLUSIONS: This comprehensive literature review of remote monitoring technologies for patients with AD provides an understanding of remote monitoring technologies, trends, and gaps in the current research and the significance of novel strategies for remote monitoring to enhance patient outcomes and reduce the burden among health professionals and caregivers. The proposed remote monitoring framework aims to inspire the development of new interdisciplinary research models that advance care for patients with AD.},
}

@article {pmid40367328,
year = {2025},
author = {Yang, N and Zhang, X and Liu, A and Wang, Y and Wei, W},
title = {A Sensitive SERS Sensor for Simultaneous Detection of Two Potential Biomarkers of Alzheimer's Disease: AChE and MAO-B.},
journal = {Analytical chemistry},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.analchem.5c01757},
pmid = {40367328},
issn = {1520-6882},
abstract = {Monoamine oxidase B (MAO-B) and acetylcholinesterase (AChE) are potential biomarkers for Alzheimer's disease (AD). However, few methods exist to detect both AChE and MAO-B simultaneously. In this study, we developed a SERS sensor for the simultaneous detection of AChE and MAO-B based on the one-pot reaction system, which provided more valuable information for early AD diagnosis. Au NPs modified with Raman reporter 4-aminothiophenol (Au[PATP] NPs) were attached to Cu-BTC via Schiff's base reaction (Au[PATP] NPs@Cu-BTC), resulting in great Raman intensity. Phenethylamine (PEA), a substrate of MAO-B, competed with Au[PATP] NPs for binding to Cu-BTC, reducing the intensity of the Raman signal. Additionally, two PATP molecules on free Au NPs coupled to DMAB due to the catalysis of Cu[2+] in Cu-BTC, transforming Au[PATP] NPs into Au[DMAB] NPs and generating three new Raman peaks. TCh, the catalytic product of AChE, was chelated with Cu[2+], so the coupling efficiency of PATP has been decreased, and the conversion of Au[PATP] NPs to Au[DMAB] NPs has been prevented. Based on the one-pot reaction system, both MAO-B and AChE can be detected by Raman signals from precipitated Au[PATP] NPs@Cu-BTC and supernatant Au[DMAB] NPs after centrifugation. The detection limits were 2.3 × 10[-3] μg mL[-1] for MAO-B and 1.6 × 10[-3] U L[-1] for AChE. We successfully detected MAO-B and AChE in serum with recoveries ranging from 100.0 to 113.7% for MAO-B and 93.6 to 120% for AChE. This manuscript presents a novel method for the simultaneous detection of MAO-B and AChE, showing great potential for early AD diagnosis.},
}

@article {pmid40367237,
year = {2025},
author = {Yin, T and Ramon, A and Greenig, M and Sormanni, P and D'Adamio, L},
title = {Development of potent humanized TNFα inhibitory nanobodies for therapeutic applications in TNFα-mediated diseases.},
journal = {mAbs},
volume = {17},
number = {1},
pages = {2498164},
doi = {10.1080/19420862.2025.2498164},
pmid = {40367237},
issn = {1942-0870},
mesh = {Humans ; *Single-Domain Antibodies/immunology/therapeutic use/pharmacology/chemistry ; *Tumor Necrosis Factor-alpha/antagonists & inhibitors/immunology ; Animals ; *Antibodies, Monoclonal, Humanized/immunology ; },
abstract = {Tumor necrosis factor-alpha (TNFα) is a key pro-inflammatory cytokine implicated in the pathogenesis of numerous inflammatory and autoimmune diseases, including rheumatoid arthritis, inflammatory bowel disease, and neurodegenerative disorders such as Alzheimer's disease. Effective inhibition of TNFα is essential for mitigating disease progression and improving patient outcomes. In this study, we present the development and comprehensive characterization of potent humanized TNFα inhibitory nanobodies (TNFI-Nbs) derived from camelid single-domain antibodies. In silico analysis of the original camelid nanobodies revealed low immunogenicity, which was further reduced through machine learning-guided humanization and developability optimization. The two humanized TNFI-Nb variants we developed demonstrated high anti-TNFα activity, achieving IC50 values in the picomolar range. Binding assays confirmed their high affinity for TNFα, underscoring robust neutralization capabilities. These TNFI-Nbs present valid alternatives to conventional monoclonal antibodies currently used in human therapy, offering potential advantages in potency, specificity, and reduced immunogenicity. Our findings establish a solid foundation for further preclinical development and clinical translation of TNFα-targeted nanobody therapies in TNFα-mediated diseases.},
}

Humans
*Single-Domain Antibodies/immunology/therapeutic use/pharmacology/chemistry
*Tumor Necrosis Factor-alpha/antagonists & inhibitors/immunology
Animals
*Antibodies, Monoclonal, Humanized/immunology

@article {pmid40367077,
year = {2025},
author = {Mikhailov, IG and Mikhailova, MS and Shuvaev, AN and Gorina, YV and Belozor, OS},
title = {RAGE-Mediated Effects of Formaldehyde in Alzheimer's Disease.},
journal = {Biochemistry. Biokhimiia},
volume = {90},
number = {3},
pages = {334-348},
doi = {10.1134/S0006297924604593},
pmid = {40367077},
issn = {1608-3040},
abstract = {Alzheimer's disease (AD) remains an incurable pathology with a huge socio-economic impact. One of the known mechanisms of AD pathogenesis is deposition of amyloid plaques as a result of beta-amyloid (Aβ) accumulation. The receptor for glycation end products (RAGE) plays an important role in the Aβ transport across the blood-brain barrier. Ligand interaction with RAGE regulates the expression of the amyloid precursor protein (APP), which plays a key role in the Aβ accumulation. In this review, we discuss the biochemical mechanisms underlying the toxic effects of exogenous formaldehyde in the hippocampus leading to the insulin resistance development, as well as molecular mechanisms of neuroinflammation contributing to the upregulation of RAGE expression. Accumulation of endogenous formaldehyde in the body can be a result of impaired metabolism. However, accumulation of exogenous formaldehyde has much more acute and dangerous consequences. Formaldehyde is one of the most important toxins; its maximum permissible concentration (MPC) is exceeded in many cities of Russia, as well as in the countries of East, South, and Southeast Asia, Central Africa, and North and South Americas. Formaldehyde plays an important role in the pathogenesis of neurodegenerative diseases, as its mechanism of action is closely linked to the increased Aβ accumulation. In people more susceptible to Aβ accumulation (due to age or genetic predisposition), exposure to exogenous formaldehyde may contribute to this process. The role of formaldehyde in neurodegenerative diseases has been already investigated. It was found that the level of air pollution correlates with the incidence of hyperglycemia, but the detailed mechanism of the following development of neurodegeneration remains unclear. This review highlights the importance of studying the relationship between environmental toxins and neurodegenerative diseases, which may lead to the development of therapeutic approaches for the protection of neurons from the effects of toxic substances in individuals susceptible to neurodegenerative diseases.},
}

@article {pmid40367036,
year = {2025},
author = {Gao, L and Hu, S and Lv, Y and Zheng, G and Lin, Z},
title = {Overexpression of LINC00672 promotes autophagy in Alzheimer's disease by upregulating GPNMB.},
journal = {PloS one},
volume = {20},
number = {5},
pages = {e0322708},
doi = {10.1371/journal.pone.0322708},
pmid = {40367036},
issn = {1932-6203},
abstract = {BACKGROUND: Alzheimer's disease (AD) is an irreversible neurodegenerative brain disorder, and autophagy crafts a new dawn on AD therapeutics. However, whether LINC00672 exerts its biological effects involvement in autophagy-mediated mechanisms in AD remain obscure.

METHODS: SH-SY5Y cells were treated with Amyloid Beta 1-42 (Aβ1-42, Aβ), while an AD mouse model was established using streptozotocin (STZ). The effects of LINC00672 overexpression on cell proliferation, apoptosis, and autophagy were evaluated in Aβ-stimulated SH-SY5Y cells. Besides, the impact of LINC00672 on cognitive function and pathological changes of the hippocampal tissues were validated in AD mice. Additionally, the interaction between LINC00672 overexpression and GPNMB silencing were determined in vitro.

RESULTS: Aβ stimulation diminished viability, augmented apoptosis, restricted the activation of autophagy in SH-SY5Y cells, while these alterations were partially abolished by LINC00672 overexpression. Furthermore, LINC00672 upregulation could improve cognitive impairment, and attenuate neuronal damage and even death in the STZ-treated AD mice. Additionally, GPNMB knockdown aggravated the improved neuronal injury and relatively restrained autophagy in Aβ-stimulated cells after LINC00672 overexpression.

CONCLUSIONS: LINC00672 exerted a protective effect in the AD progression by upregulating GPNMB to promote autophagy.},
}

@article {pmid40366903,
year = {2025},
author = {Awad, AS and El-Mokadem, BM and Sherif, MM and Bishr, A},
title = {Can Quercetin protect against the pre-disposing factors for Alzheimer's disease via inhibiting NLRP3 inflammasome pathway?.},
journal = {The Journal of pharmacy and pharmacology},
volume = {},
number = {},
pages = {},
doi = {10.1093/jpp/rgaf020},
pmid = {40366903},
issn = {2042-7158},
abstract = {OBJECTIVES: The brain and its cognitive functions are most liable to stress, where it is known to promote the pathological manifestation of Alzheimer's disease (AD). This study aimed to investigate the effect of a 2-week-period of restraint stress (RS), as well as the protective effect of Quercetin in a dose-dependent manner against the early start of AD via studying the NLRP3 inflammasome pathway.

METHODS: The rats were divided into four groups: control (Con), induction (Ind), where 6 h/day for 2 weeks of RS was induced, low and high doses of Q (Q1+Ind and Q2+Ind, respectively), which were administered before the induction of RS for the same period. Behavioral tests were performed to assess the cognitive functions.

KEY FINDINGS: The higher dose of Q has shown more inhibition of the NLRP3 inflammasome pathway, oxidative stress, as well as the phosphorylated-tau and amyloid-β (Aβ) protein, which were significantly fired up by the 2 weeks of RS. These results were backed with the improved cellular structure in the histopathological examination and enhanced cognitive functions, where the two doses of Q have shown their protective effect.

CONCLUSIONS: This proves that Q shielded the brain against the initial pathogenesis of AD, induced by 2 weeks of RS.},
}

@article {pmid40366727,
year = {2025},
author = {Wang, R and Li, J and Li, X and Guo, Y and Chen, P and Peng, T},
title = {Exercise-induced modulation of miRNAs and gut microbiome: a holistic approach to neuroprotection in Alzheimer's disease.},
journal = {Reviews in the neurosciences},
volume = {},
number = {},
pages = {},
pmid = {40366727},
issn = {2191-0200},
abstract = {Alzheimer's disease (AD), a progressive neurodegenerative disorder, is marked by cognitive decline, neuroinflammation, and neuronal loss. MicroRNAs (miRNAs) have emerged as critical regulators of gene expression, influencing key pathways involved in neuroinflammation and neurodegeneration in AD. This review delves into the multifaceted role of exercise in modulating miRNA expression and its interplay with the gut microbiome, proposing a comprehensive framework for neuroprotection in AD. By synthesizing current research, we elucidate how exercise-induced changes in miRNA profiles can mitigate inflammatory responses, promote neurogenesis, and reduce amyloid-beta and tau pathologies. Additionally, we explore the gut-brain axis, highlighting how exercise-driven alterations in gut microbiota composition can further influence miRNA expression, thereby enhancing cognitive function and reducing neuroinflammatory markers. This holistic approach underscores the potential of targeting exercise-regulated miRNAs and gut microbiome interactions as a novel, noninvasive therapeutic strategy to decelerate AD progression and improve quality of life for patients. This approach aims to decelerate disease progression and improve patient outcomes, offering a promising avenue for enhancing the effectiveness of AD management.},
}

@article {pmid40366557,
year = {2025},
author = {Chen, YH and Wang, ZB and Liu, XP and Mao, ZQ and , },
title = {Cerebrospinal Fluid CCL25 as a Biomarker for Alzheimer's Disease: Associations with Pathology, Neurodegeneration, and Cognitive Decline.},
journal = {Molecular neurobiology},
volume = {},
number = {},
pages = {},
pmid = {40366557},
issn = {1559-1182},
support = {2021ZD0200407//China Brain Project/ ; },
abstract = {Neuroinflammation plays a crucial role in Alzheimer's disease (AD) pathogenesis. We investigated the relationship between cerebrospinal fluid (CSF) C-C chemokine ligand 25 (CCL25), an inflammatory regulator, and AD pathology and progression. We analyzed data on CSF CCL25, AD biomarkers (CSF β-amyloid [Aβ]42, phosphorylated tau [pTau]181, amyloid positron emission tomography [PET]), postmortem neuropathology, magnetic resonance imaging-based neurodegeneration, and cognitive function from 703 participants in the Alzheimer's Disease Neuroimaging Initiative cohort. We found that elevated CSF CCL25 levels were associated with cognitive impairment, abnormal Aβ and tau pathology, greater brain atrophy, and worse cognitive performance (all P < 0.05). Notably, CSF CCL25 exhibited nonlinear relationships with Aβ and tau pathology, reaching a plateau as AD pathology increased. CSF CCL25 showed acceptable diagnostic accuracy in distinguishing amyloid-positive/negative (A ±) and tau-positive/negative (T ±) participants (area under the curve [AUC] = 0.71-0.77) and autopsy-confirmed AD cases (AUC = 0.77), with optimal performance in differentiating A + T + from A-T- participants (AUC = 0.82-0.85 with age and sex adjustment). Longitudinally, higher baseline CSF CCL25 predicted accelerated amyloid accumulation, hippocampal atrophy, and cognitive decline. Mediation analyses revealed that CCL25 partially mediated associations between Aβ pathology and tau pathology (mediating effect: 54.5%), neurodegeneration (18.2%), and cognitive decline (7.4%). Among 37 CSF CCL and CXCL chemokines examined, 28 were associated with at least one AD-related outcome, with CCL25 demonstrating the strongest associations overall. These findings suggest that CSF CCL25 is involved in early AD pathological progression and may serve as an inflammatory biomarker for diagnosis and monitoring of disease progression in AD.},
}

@article {pmid40366510,
year = {2025},
author = {Durak, B and Özol, D and Durak, İ and Saraç, S},
title = {Is β- amyloid a reliable marker for assessing neurocognitive functions in middle-aged OSAS patients??.},
journal = {Sleep & breathing = Schlaf & Atmung},
volume = {29},
number = {2},
pages = {185},
pmid = {40366510},
issn = {1522-1709},
mesh = {Humans ; *Sleep Apnea, Obstructive/blood/diagnosis/complications ; Female ; Male ; Middle Aged ; *Amyloid beta-Peptides/blood ; Cross-Sectional Studies ; Biomarkers/blood ; Polysomnography ; Prospective Studies ; *Cognitive Dysfunction/blood/diagnosis ; Neuropsychological Tests ; },
abstract = {BACKGROUND: Obstructive sleep apnea syndrome (OSAS) is a condition defined by recurrent episodes of airflow cessation or significant reduction during sleep, resulting in fragmented sleep patterns and intermittent hypoxemia. These physiological disturbances are known to contribute to cognitive deficits, including impairments in attention, memory, and overall cognitive function. In parallel, amyloid beta (β-Amyloid, Aβ) has gained prominence as a crucial biomarker in Alzheimer's disease pathogenesis, raising interest in its potential role in the early detection of neurocognitive dysfunction. This study aims to explore the association between plasma Aβ levels, neurocognitive performance, and polysomnographic parameters in middle-aged patients diagnosed with OSAS.

METHODS: This prospective, cross-sectional study was conducted over a four-month period in a sleep disorders clinic. Patients who diagnosed as OSA in polysomnographic evaluation with no pre-existing neurocognitive conditions and possessed at least a primary school education were included. The study participants were evaluated using Montreal Cognitive Assessment (MoCA) test and Epworth Sleepiness Scale (ESS). Morning fasting blood samples were collected to measure plasma total Aβ levels.

RESULTS: A total of 126 individuals (mean age: 54.7 ± 7.5 years; 53 females, 42%) participated in the study. Based on their apnea-hypopnea index (AHI), patients were categorized into two groups: Group 1 (AHI < 15, 23.8% mild OSA) and Group 2 (AHI ≥ 15, moderate-severe OSA, 76.2%). The mean MoCA scores were 25 ± 7 in Group 1 and 24 ± 6 in Group 2. Following multivariable adjustment, reduced sleep duration, lower mean nocturnal oxygen saturation, and prolonged time with SpO2 below 90% (T90%) were significantly correlated with lower MoCA scores. Serum Aβ concentrations were notably elevated in patients with severe OSAS, exhibiting a negative correlation with MoCA scores and slow wave sleep stage. Additionally, serum Aβ levels showed a direct correlation with both AHI and oxygen desaturation index (ODI), while an inverse correlation was found with minimum oxygen saturation.

CONCLUSION: Neurocognitive impairment was common in OSAS patients. Elevated serum Aβ levels were found to be directly associated with OSA severity, and OSA-related hypoxemia was linked to diminished cognitive function.},
}

Humans
*Sleep Apnea, Obstructive/blood/diagnosis/complications
Female
Male
Middle Aged
*Amyloid beta-Peptides/blood
Cross-Sectional Studies
Biomarkers/blood
Polysomnography
Prospective Studies
*Cognitive Dysfunction/blood/diagnosis
Neuropsychological Tests

@article {pmid40366471,
year = {2025},
author = {Kaur, A and Goel, RK},
title = {Modelling Epilepsy Associated Alzheimer's Disease Through Mitochondrial Complex-I Inhibition: Neurochemical and Therapeutic Perspectives.},
journal = {Neurochemical research},
volume = {50},
number = {3},
pages = {163},
pmid = {40366471},
issn = {1573-6903},
mesh = {Animals ; *Alzheimer Disease/metabolism/drug therapy/complications ; *Epilepsy/metabolism/drug therapy/complications ; Mice ; *Disease Models, Animal ; *Electron Transport Complex I/antagonists & inhibitors/metabolism ; Male ; Kindling, Neurologic/drug effects ; Oxidative Stress/drug effects/physiology ; Rotenone ; Mitochondria/metabolism/drug effects ; },
abstract = {Alzheimer's disease (AD) is comorbid condition in epilepsy. Mitochondrial dysfunction serves as a common disease mechanism. This study aimed to develop a new mouse of epilepsy-associated AD by inhibiting mitochondrial complex-I and exploring neurochemistry to identify therapeutic targets. Swiss albino mice were divided into naïve, corneal kindled (CK), and rotenone corneal kindled (RCK) groups. CK underwent epileptogenesis by using 6 Hz corneal kindling model (15 mA, 20 V, 6-Hz, 3 s for 15 days), while RCK underwent both epileptogenesis and mitochondrial dysfunction via rotenone administration (2.5 mg/kg, i.p daily). RCK mice exhibited generalised tonic-clonic seizures, cognitive deficits, oxidative stress, and Aβ/tau deposition. Neurochemical analysis showed increased glutamate, kynurenine, and reduced GABA, taurine, monoamines, antioxidants, and acetylcholinesterase activity. The RCK model replicates construct and face validity of both epilepsy and AD, may serve as a new model to investigate shared disease mechanisms and associated altered neurotransmitter as therapeutic approach.},
}

Animals
*Alzheimer Disease/metabolism/drug therapy/complications
*Epilepsy/metabolism/drug therapy/complications
Mice
*Disease Models, Animal
*Electron Transport Complex I/antagonists & inhibitors/metabolism
Male
Kindling, Neurologic/drug effects
Oxidative Stress/drug effects/physiology
Rotenone
Mitochondria/metabolism/drug effects

@article {pmid40366450,
year = {2025},
author = {Li, Y and Qi, W and Chen, L and Chu, F and Jiang, W and Xu, Z and Luo, Y and Hu, X and Götz, J and Li, C},
title = {Fyn-dependent Tau microcluster formation seeds and boosts extensive Tau pathology.},
journal = {Acta neuropathologica},
volume = {149},
number = {1},
pages = {48},
pmid = {40366450},
issn = {1432-0533},
support = {GNT1176326//National Health and Medical Research Council of Australia/ ; 31900692//National Natural Science Foundation of China/ ; 2024AFB558//Hubei Natural Science Foundation project/ ; },
mesh = {*tau Proteins/metabolism ; *Proto-Oncogene Proteins c-fyn/metabolism/genetics ; Animals ; Mice ; *Tauopathies/pathology/metabolism ; Humans ; *Brain/pathology/metabolism ; Mice, Transgenic ; Phosphorylation ; Mice, Inbred C57BL ; Glycogen Synthase Kinase 3 beta/metabolism ; },
abstract = {Tau seeding and propagation are defining features of all tauopathies, including Alzheimer's disease, but the underlying molecular drivers remain incompletely understood. Here, we reveal that Fyn expression boosts massive Tau pathology in the mouse brain and enhances Tau seeding induced by pathological Tau seeds in biosensor cells. However, even in the absence of seeds, Fyn itself, via its palmitoylation, triggers the de novo formation of small, plasma membrane-anchored Tau microclusters, which initiate pronounced and diverse intra- and transcellular Tau seeding in vitro and in vivo. Mechanistically, membrane-associated Fyn phosphorylates Tau at its Tyr310 epitope and then recruits and activates GSK3β locally, which further phosphorylates Tau at Ser/Thr sites in the microclusters, eliciting their full seeding capacity. Our data suggest that Fyn not only serves as a master switch that initiates Tau pathogenesis on its own, but also augments a pre-existing Tau pathology, leading to a vicious cycle of Tau aggregation.},
}

*tau Proteins/metabolism
*Proto-Oncogene Proteins c-fyn/metabolism/genetics
Animals
Mice
*Tauopathies/pathology/metabolism
Humans
*Brain/pathology/metabolism
Mice, Transgenic
Phosphorylation
Mice, Inbred C57BL
Glycogen Synthase Kinase 3 beta/metabolism

@article {pmid40366448,
year = {2025},
author = {Khoshnam, SE and Sarkaki, A and Farbood, Y and Keshavarz Zarjani, A and Ghasemi Dehcheshmeh, M and Moradi Vastegani, S},
title = {Anethole Ameliorates Scopolamine-Induced Memory Deficits and Neuronal Damage Through Antioxidant, Anti-Inflammatory, and Anticholinesterase Activities in Rats.},
journal = {Neurochemical research},
volume = {50},
number = {3},
pages = {165},
pmid = {40366448},
issn = {1573-6903},
support = {APRC-0016//Ahvaz Jundishapur University of Medical Sciences/ ; },
mesh = {Animals ; *Scopolamine/toxicity ; *Memory Disorders/chemically induced/drug therapy/metabolism ; Allylbenzene Derivatives ; Male ; *Anisoles/therapeutic use/pharmacology ; *Antioxidants/pharmacology/therapeutic use ; Rats ; *Cholinesterase Inhibitors/pharmacology/therapeutic use ; *Anti-Inflammatory Agents/pharmacology/therapeutic use ; Hippocampus/drug effects/metabolism/pathology ; Oxidative Stress/drug effects ; Blood-Brain Barrier/drug effects/metabolism ; *Neurons/drug effects/pathology/metabolism ; Acetylcholinesterase/metabolism ; Rats, Sprague-Dawley ; Avoidance Learning/drug effects ; },
abstract = {Scopolamine-induced memory impairment is a well-established model for studying the therapeutic potential of novel compounds in the pathogenesis of Alzheimer's disease (AD). This study aimed to evaluate the protective effects and underlying mechanisms of anethole against scopolamine-induced memory and cognitive disorders. Rats were treated with scopolamine (0.7 mg/kg, i.p.) for 14 consecutive days. Anethole (125, 250, and 500 mg/kg, i.g.) was administered one hour prior to scopolamine injection. Memory and cognitive performance were assessed using the Passive Avoidance Test (PAT) and the Novel Object Recognition Test (NORT). In addition, blood-brain barrier (BBB) permeability, brain water content (BWC), and hippocampal levels of oxidative stress markers, inflammatory cytokines, acetylcholine (ACh), and acetylcholinesterase (AChE) were evaluated following the behavioral tests. Histological changes in the hippocampus were examined using hematoxylin and eosin (H&E) staining. Anethole treatment significantly improved scopolamine-induced memory deficits in both NORT and PAT. Furthermore, anethole reduced BBB permeability and BWC in the AD rat model. Hippocampal levels of oxidative stress and inflammation were also attenuated following anethole administration. Additionally, anethole exerted cholinergic effects by inhibiting AChE and increasing ACh levels in the scopolamine-induced AD model. The neuroprotective effects of anethole were further confirmed by H&E staining. Our findings demonstrate that anethole effectively reverses scopolamine-induced memory and cognitive impairments through antioxidant, anti-inflammatory, and anticholinesterase mechanisms in rats. Therefore, anethole may be considered a promising therapeutic candidate for alleviating symptoms of AD and warrants further investigation in future studies.},
}

Animals
*Scopolamine/toxicity
*Memory Disorders/chemically induced/drug therapy/metabolism
Allylbenzene Derivatives
Male
*Anisoles/therapeutic use/pharmacology
*Antioxidants/pharmacology/therapeutic use
Rats
*Cholinesterase Inhibitors/pharmacology/therapeutic use
*Anti-Inflammatory Agents/pharmacology/therapeutic use
Hippocampus/drug effects/metabolism/pathology
Oxidative Stress/drug effects
Blood-Brain Barrier/drug effects/metabolism
*Neurons/drug effects/pathology/metabolism
Acetylcholinesterase/metabolism
Rats, Sprague-Dawley
Avoidance Learning/drug effects

@article {pmid40366433,
year = {2025},
author = {Joshi, A and Lehene, S and Mishra, A},
title = {Non-transgenic rodent models of Alzheimer's disease for preclinical research: a review.},
journal = {Molecular biology reports},
volume = {52},
number = {1},
pages = {456},
pmid = {40366433},
issn = {1573-4978},
mesh = {*Alzheimer Disease/genetics/metabolism/pathology/physiopathology ; Animals ; *Disease Models, Animal ; Humans ; tau Proteins/metabolism/genetics ; Amyloid beta-Peptides/metabolism ; Rodentia ; Mice ; Brain/metabolism/pathology ; Plaque, Amyloid/pathology/metabolism ; },
abstract = {Alzheimer's disease (AD) is a prevalent neurodegenerative disorder characterized by progressive memory loss and cognitive decline. It involves the irreversible destruction of higher brain structures, leading to significant cognitive deficits, personality changes, and aberrant behavior. Key pathological features include the accumulation of amyloid-beta (Aβ) plaques and hyperphosphorylated tau protein neurofibrillary tangles, which disrupt cellular communication and neuron function. Chronic inflammation, vascular abnormalities, and genetic factors like the APOE (apolipoprotein E) ε4 allele also play crucial roles in AD progression. Epidemiological data indicate a substantial global impact, especially among older adults, with women disproportionately affected. Animal models, both transgenic and non-transgenic, are pivotal in researching AD pathophysiology and potential treatments. This review presents a full overview regarding a variety of non-transgenic rodent models of Alzheimer's disease utilized in the preclinical research for treatment approaches in Alzheimer's disease.},
}

*Alzheimer Disease/genetics/metabolism/pathology/physiopathology
Animals
*Disease Models, Animal
Humans
tau Proteins/metabolism/genetics
Amyloid beta-Peptides/metabolism
Rodentia
Mice
Brain/metabolism/pathology
Plaque, Amyloid/pathology/metabolism

@article {pmid40366190,
year = {2025},
author = {Samokhina, E and Mangat, A and Malladi, CS and Gyengesi, E and Morley, JW and Buskila, Y},
title = {Potassium homeostasis during disease progression of Alzheimer's disease.},
journal = {The Journal of physiology},
volume = {},
number = {},
pages = {},
doi = {10.1113/JP287903},
pmid = {40366190},
issn = {1469-7793},
support = {//Ainsworth Foundation/ ; 162435//Ainsworth Medical research Innovation fund/ ; },
abstract = {Alzheimer's disease (AD) is an age-dependent neurodegenerative disorder characterized by neuronal loss leading to dementia and ultimately death. Whilst the loss of neurons is central to this disease, it is becoming clear that glia, specifically astrocytes, contribute to the onset and progression of neurodegeneration. The role of astrocytes in maintaining ion homeostasis in the extracellular milieu is fundamental for multiple brain functions, including synaptic plasticity and neuronal excitability, which are compromised during AD and affect neuronal signalling. In this study, we measured the astrocytic K[+] clearance rate in the hippocampus and somatosensory cortex of a mouse model for AD during disease progression. Our results establish that astrocytic [K[+]]o (extracellular K[+] concentration) clearance in the hippocampus is reduced in symptomatic 5xFAD mice, and this decrease is region-specific, as no significant alterations were detected in the superficial layers of the somatosensory cortex. The decrease in the [K[+]]o clearance rate correlated with a significant reduction in the expression and conductivity of Kir4.1 channels and a decline in the number of primary connected astrocytes. Moreover, astrocytes in the hippocampus of symptomatic 5xFAD mice demonstrated increased reactivity which was accompanied by an increased excitability and altered spiking profile of nearby neurons. These findings indicate that the supportive function astrocytes typically provide to nearby neurons is diminished during disease progression, which affects the neuronal circuit signalling in this area and provides a potential explanation for the increased vulnerability of neurons in AD. KEY POINTS: Astrocytic potassium clearance from the extracellular milleu is fundamental for multiple brain functions. Alterations in the clearance rate can affect the excitability and overall viability of neurons. A symptomatic mouse model for Alzheimer's disease (5xFAD) exhibits a significant decline in astrocytic K[+] clearance at the hippocampus, but not the somatosensory cortex. The decrease in the clearance rate correlated with a reduction in the expression and conductivity of astrocytic Kir4.1 channels and a decrease in the number of primary connected astrocytes, specifically at the stratum lacunosum moleculare layer of the CA1 region. Astrocytes in the hippocampus of symptomatic 5xFAD mice displayed increased reactivity. The excitability profile and firing patterns of neurons at the hippocampus were affected by alterations in K[+] homeostasis, indicating that the supportive function astrocytes typically provide to nearby neurons is diminished during progression of Alzheimer's disease.},
}

@article {pmid40366088,
year = {2025},
author = {Grossberg, G and Willey, C and Houle, C and Schein, J and Bungay, R and Cloutier, M and Gauthier-Loiselle, M and Chan, D and Guerin, A and Ismail, Z and Aggarwal, J},
title = {Agitation in individuals with Alzheimer's disease: An assessment of behaviors using the cohen-mansfield agitation inventory in community-dwellers and impact on caregiver experience.},
journal = {Dementia (London, England)},
volume = {},
number = {},
pages = {14713012251340463},
doi = {10.1177/14713012251340463},
pmid = {40366088},
issn = {1741-2684},
abstract = {BackgroundAgitation is a common neuropsychiatric symptom of Alzheimer's disease; however, limited information exists on how measurable changes in agitated behaviors relate to overall caregiver experience. We sought to describe agitated behaviors measured by the Cohen-Mansfield Agitation Inventory (CMAI) score among individuals with Alzheimer's disease living in US community-based settings and experience of their caregivers.MethodsAn online survey was conducted (08/26/2021-09/24/2021) among adult caregivers who lived with and provided unpaid care for an individual with Alzheimer's disease. The 3-part survey involved (1) informed consent and screening; (2) CMAI assessment (total and sub-scores for four agitation factors); (3) characteristics and outcomes of caregivers and individuals with Alzheimer's disease. Descriptive statistics are reported. Association between the CMAI total score and caregiver burden (measured using the Zarit Burden Interview), mental health (measured using the Patient Health Questionnaire 4-item), and work/activity impairment (measured using the Work Productivity and Activity Impairment: Caregiver scale) was estimated using regression models.ResultsA total of 250 caregivers (mean age: 44.5 years; 55.2% male; 86.4% White) completed the survey. Based on the CMAI, 99.6% of individuals with Alzheimer's disease (mean age: 68.6 years; 55.2% male; 83.2% White) experienced ≥1 agitated behavior in the past 2 weeks. Caregivers reported providing an average of 39.1 hours of care per week for individuals with Alzheimer's disease (additional non-paid and paid care provided by other caregivers was 58.8% and 38.4%, respectively); 60.8% of caregivers had a high caregiving burden, 35.2% experienced moderate-to-severe distress, and 68.2/64.0% had impairment in work/daily activities. Agitation among individuals with Alzheimer's disease was associated with significantly poorer caregiver outcomes.ConclusionsIndividuals with Alzheimer's disease frequently experience several different agitated behaviors. Effective management of agitated behaviors is important and has the potential to improve the overall caregiver experience.},
}

@article {pmid40366085,
year = {2025},
author = {Wang, X and Chen, C and Tian, Y and Zhang, QW},
title = {Dual-Channel Phosphorescence Ratiometry and Phosphorescence Lifetime Imaging of Mitochondria-Specific Methionine Sulfoxide Reductase Activity.},
journal = {Journal of the American Chemical Society},
volume = {},
number = {},
pages = {},
doi = {10.1021/jacs.5c03235},
pmid = {40366085},
issn = {1520-5126},
abstract = {Methionine sulfoxide reductases (Msrs) are essential for preserving redox homeostasis in the nervous system, with dysregulation implicated in Alzheimer's disease (AD). Conventional fluorescence-based assays for Msrs activity sensing are hampered by background interference, limited sensitivity, and inadequate quantification. This work introduces a novel supramolecular probe exhibiting redox-responsive dual-channel room-temperature phosphorescence (RTP) in aqueous media on a microsecond time scale. Upon reduction by Msrs, the probe transitions from its oxidized to reduced state, manifested by a red-shifted phosphorescence emission and extended lifetime in the microsecond range, which enables precise quantification of mitochondria-targeted Msrs activity via phosphorescence ratiometry and phosphorescence lifetime imaging (PLIM). The probe's utility is demonstrated in visualizing neuronal Msrs activity and distribution within the mouse brain, which reveals a marked downregulation of Msrs activity in an AD model, highlighting the probe's potential in elucidating redox-related pathological mechanisms underlying neurodegenerative disorders.},
}

@article {pmid40365999,
year = {2025},
author = {Gao, Z and Qiu, R and Dave, DR and Chandravanshi, P and Soares, GP and Smith, CS and Ortega, JA and Palmer, LC and Álvarez, Z and Stupp, SI},
title = {Supramolecular Copolymerization of Glycopeptide Amphiphiles and Amyloid Peptides Improves Neuron Survival.},
journal = {Journal of the American Chemical Society},
volume = {},
number = {},
pages = {},
doi = {10.1021/jacs.5c00105},
pmid = {40365999},
issn = {1520-5126},
abstract = {Neurodegenerative diseases such as Alzheimer's disease and amyotrophic lateral sclerosis are characterized by progressive neuronal loss and the accumulation of misfolded proteins including amyloid proteins. Current therapeutic options include the use of antibodies for these proteins, but novel chemical strategies need to be developed. The disaccharide trehalose has been widely reported to prevent misfolding and aggregation of proteins, and we therefore investigated the conjugation of this moiety to biocompatible peptide amphiphiles (TPAs) known to undergo supramolecular polymerization. Using X-ray scattering, circular dichroism, and infrared spectroscopy, we found that trehalose conjugation destabilized the internal β-sheet structures within the TPA supramolecular polymers as evidenced by a lower thermal transition. Thioflavin T fluorescence showed that these metastable TPA nanofibers suppressed A42 aggregation. Interestingly, we found that the suppression involved supramolecular copolymerization of TPA polymers with Aβ42, which effectively trapped the peptides within the filamentous structures. In vitro assays with human induced pluripotent stem cell-derived neurons demonstrated that these TPAs significantly improved neuron survival compared to other conditions. Our study highlights the potential of properly tuned supramolecular polymerizations of monomers to safely remove amyloidogenic proteins in neurodegeneration.},
}

@article {pmid40365904,
year = {2025},
author = {Schmitt, FA and Abner, EL and Fardo, DW and Gold, BT and Jicha, GA and Kryscio, RJ and Lee, DC and Nelson, PT and Van Eldik, LJ},
title = {Celebrating 40 years of the University of Kentucky Alzheimer's Disease Research Center.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {5},
pages = {e70181},
doi = {10.1002/alz.70181},
pmid = {40365904},
issn = {1552-5279},
support = {//UK-ADRC/ ; P50 AG005144/AG/NIA NIH HHS/United States ; P30 AG028383/AG/NIA NIH HHS/United States ; P30 AG072946/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *Alzheimer Disease/therapy ; Kentucky ; *Biomedical Research/history ; National Institute on Aging (U.S.) ; Universities ; United States ; History, 20th Century ; History, 21st Century ; },
abstract = {Four decades of the National Institute on Aging's sponsored research into Alzheimer's disease (AD) have resulted in symptomatic and mechanistic therapies, lifestyle interventions, increased understanding of genetic factors and protein misfolding, and descriptions of non-AD neuropathological entities that mimic AD clinical symptoms. This is an overview of contributions from one of the original ten Alzheimer Disease Research Centers (ADRCs), the University of Kentucky ADRC. We celebrate 40 years of helping the field to define early pathogenetic mechanisms underlying transitions from normal cognitive aging to impairment in our elderly community-based cohort, increased appreciation of the heterogeneity and multiple pathologies that characterize late-life dementia, strategies for therapeutic intervention, and novel statistical approaches. We also highlight our educational efforts to train the workforce of the future and our long-standing community outreach and partnerships. HIGHLIGHTS: The University of Kentucky Alzheimer's Disease Research Center (UK-ADRC) is an experienced and collaborative center celebrating its 40th year of National Institute on Aging funding in 2025. Our long-standing community-based cohort of motivated older adult volunteers and strong neuropathology program support the rationale for our overarching theme: "Transitions from Normal to Late-Life Multi-Etiology Dementia." The UK-ADRC's focus on normal aging and early cognitive transitions has been central to elucidating pathogenic mechanisms underlying transitions from normal cognitive aging to impairment and defining the heterogeneity and multiple pathologies that characterize late-life dementia. UK-ADRC infrastructure and resources support and create new opportunities for innovative and inclusive research, clinical programs across the cognitive continuum, educational and training opportunities, and community and national partnerships.},
}

Humans
*Alzheimer Disease/therapy
Kentucky
*Biomedical Research/history
National Institute on Aging (U.S.)
Universities
United States
History, 20th Century
History, 21st Century

@article {pmid40365825,
year = {2025},
author = {Wisse, LEM and La Joie, R},
title = {Medial temporal lobe structural changes when Down syndrome and Alzheimer's disease collide.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awaf176},
pmid = {40365825},
issn = {1460-2156},
}

@article {pmid40365745,
year = {2025},
author = {Liu, Y and Han, C and Guo, L and Li, W and Wu, S and Sheng, J and Zhai, L and Shen, H},
title = {Deer Antler Uridine Regulates Glycolysis in Microglia via HSP90/HIF-1α to Improve Cognitive Impairment in Alzheimer's Disease Mice.},
journal = {CNS neuroscience & therapeutics},
volume = {31},
number = {5},
pages = {e70416},
doi = {10.1111/cns.70416},
pmid = {40365745},
issn = {1755-5949},
mesh = {Animals ; Mice ; *HSP90 Heat-Shock Proteins/metabolism ; *Microglia/drug effects/metabolism ; *Glycolysis/drug effects/physiology ; *Cognitive Dysfunction/drug therapy/metabolism ; *Alzheimer Disease/metabolism/drug therapy ; *Hypoxia-Inducible Factor 1, alpha Subunit/metabolism ; Mice, Transgenic ; Male ; Deer ; Mice, Inbred C57BL ; Disease Models, Animal ; Maze Learning/drug effects ; },
abstract = {AIM: To investigate the role and mechanism of uridine (URI), an active component in deer antler, in improving cognitive impairment in Alzheimer's disease (AD) mice.

METHOD: The APP/PS1 mouse model was used for AD. After URI gavage administration, cognitive behavioral changes in mice were detected using the Morris water maze, eight-arm maze, and novel object recognition tests. Levels of inflammatory cytokines and lactate, pyruvate in the cortex were measured. The proportions of IBA-1 and CD86 cells in tissues were detected, and the expression of key glycolysis proteins was examined. Network pharmacology was employed to analyze the targets of URI-AD-glycolysis. AAV-CMV-shHSP90 was injected to knock down brain HSP90 levels to further explore the anti-AD mechanism of URI. In vitro, primary microglia were used to detect the proportion of CD86+ M1 cells and glycolysis levels.

RESULT: URI can improve cognitive impairment in AD mice, with significant changes in cognitive ability and behavior. URI reduces glycolysis levels, the proportion of M1 cells (CD86+), and the activation degree of microglia, while inhibiting the activation of HSP90-HIF-1α. Network pharmacology analysis revealed that HSP90 is a major target of URI. When HSP90 is inhibited, the effect of URI is diminished. In vitro experiments showed that URI can inhibit the M1 polarization of microglia and reduce glycolysis levels.

CONCLUSION: URI can inhibit microglial glycolysis and M1 polarization via HSP90/HIF-1α, thereby improving cognitive behavioral deficits in AD mice due to neuroinflammation. Uridine in deer antler is a novel small molecule for anti-AD.},
}

Animals
Mice
*HSP90 Heat-Shock Proteins/metabolism
*Microglia/drug effects/metabolism
*Glycolysis/drug effects/physiology
*Cognitive Dysfunction/drug therapy/metabolism
*Alzheimer Disease/metabolism/drug therapy
*Hypoxia-Inducible Factor 1, alpha Subunit/metabolism
Mice, Transgenic
Male
Deer
Mice, Inbred C57BL
Disease Models, Animal
Maze Learning/drug effects

@article {pmid40365577,
year = {2025},
author = {Dardouri, S},
title = {An efficient method for early Alzheimer's disease detection based on MRI images using deep convolutional neural networks.},
journal = {Frontiers in artificial intelligence},
volume = {8},
number = {},
pages = {1563016},
pmid = {40365577},
issn = {2624-8212},
abstract = {Alzheimer's disease (AD) is a progressive, incurable neurological disorder that leads to a gradual decline in cognitive abilities. Early detection is vital for alleviating symptoms and improving patient quality of life. With a shortage of medical experts, automated diagnostic systems are increasingly crucial in healthcare, reducing the burden on providers and enhancing diagnostic accuracy. AD remains a global health challenge, requiring effective early detection strategies to prevent its progression and facilitate timely intervention. In this study, a deep convolutional neural network (CNN) architecture is proposed for AD classification. The model, consisting of 6,026,324 parameters, uses three distinct convolutional branches with varying lengths and kernel sizes to improve feature extraction. The OASIS dataset used includes 80,000 MRI images sourced from Kaggle, categorized into four classes: non-demented (67,200 images), very mild demented (13,700 images), mild demented (5,200 images), and moderate demented (488 images). To address the dataset imbalance, a data augmentation technique was applied. The proposed model achieved a remarkable 99.68% accuracy in distinguishing between the four stages of Alzheimer's: Non-Dementia, Very Mild Dementia, Mild Dementia, and Moderate Dementia. This high accuracy highlights the model's potential for real-time analysis and early diagnosis of AD, offering a promising tool for healthcare professionals.},
}

@article {pmid40365469,
year = {2025},
author = {Dünnwald, M and Krohn, F and Sciarra, A and Sarkar, M and Schneider, A and Fliessbach, K and Kimmich, O and Jessen, F and Rostamzadeh, A and Glanz, W and Incesoy, EI and Teipel, S and Kilimann, I and Goerss, D and Spottke, A and Brustkern, J and Heneka, MT and Brosseron, F and Lüsebrink, F and Hämmerer, D and Düzel, E and Tönnies, K and Oeltze-Jafra, S and Betts, MJ},
title = {Fully automated MRI-based analysis of the locus coeruleus in aging and Alzheimer's disease dementia using ELSI-Net.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {17},
number = {2},
pages = {e70118},
pmid = {40365469},
issn = {2352-8729},
abstract = {INTRODUCTION: The locus coeruleus (LC) is linked to the development and pathophysiology of neurodegenerative diseases such as Alzheimer's disease (AD). Magnetic resonance imaging-based LC features have shown potential to assess LC integrity in vivo.

METHODS: We present a deep learning-based LC segmentation and feature extraction method called Ensemble-based Locus Coeruleus Segmentation Network (ELSI-Net) and apply it to healthy aging and AD dementia datasets. Agreement to expert raters and previously published LC atlases were assessed. We aimed to reproduce previously reported differences in LC integrity in aging and AD dementia and correlate extracted features to cerebrospinal fluid (CSF) biomarkers of AD pathology.

RESULTS: ELSI-Net demonstrated high agreement to expert raters and published atlases. Previously reported group differences in LC integrity were detected and correlations to CSF biomarkers were found.

DISCUSSION: Although we found excellent performance, further evaluations on more diverse datasets from clinical cohorts are required for a conclusive assessment of ELSI-Net's general applicability.

HIGHLIGHTS: We provide a thorough evaluation of a fully automatic locus coeruleus (LC) segmentation method termed Ensemble-based Locus Coeruleus Segmentation Network (ELSI-Net) in aging and Alzheimer's disease (AD) dementia.ELSI-Net outperforms previous work and shows high agreement with manual ratings and previously published LC atlases.ELSI-Net replicates previously shown LC group differences in aging and AD.ELSI-Net's LC mask volume correlates with cerebrospinal fluid biomarkers of AD pathology.},
}

@article {pmid40365453,
year = {2025},
author = {Zhang, H and Yuan, S and Bao, H and Chen, W and Cai, B and Sun, J and Zhu, H and Lu, W},
title = {Mapping the intersection of HIV and Alzheimer's disease: a bibliometric analysis of emerging research trends.},
journal = {Frontiers in neurology},
volume = {16},
number = {},
pages = {1568022},
pmid = {40365453},
issn = {1664-2295},
abstract = {BACKGROUND: HIV and Alzheimer's disease (AD) are significant global health challenges with overlapping neuroinflammatory and protein aggregation mechanisms. Understanding their intersection is critical for advancing therapeutic strategies, particularly in aging populations.

OBJECTIVE: This study aims to provide a comprehensive bibliometric analysis of research trends at the intersection of HIV and AD, identify emerging themes, and highlight key contributors in this interdisciplinary field.

METHODS: Using the Web of Science Core Collection, we retrieved 4,856 articles and reviews published between 1994 and 2025. Bibliometric analysis was conducted with VOSviewer, CiteSpace, and R software to examine publication trends, international collaboration, institutional contributions, journal dynamics, author networks, and thematic evolution.

RESULTS: The analysis reveals a 14.18% annual growth rate in publications, with the U.S. leading in productivity, followed by China, Germany, and Japan. Key institutions include the NIH and the University of California System, while journals such as Journal of Biological Chemistry and PLOS ONE show significant growth. Prominent authors include Masliah, Eliezer, and Heaton, RK. Research highlights the overlap between HIV-associated neurocognitive disorders (HAND) and AD, emphasizing shared mechanisms like neuroinflammation, protein aggregation, and blood-brain barrier disruption. Recent advances focus on cerebrospinal fluid biomarkers, oxidative stress, and the impact of antiretroviral therapy (ART) on neurological outcomes. Studies increasingly explore the role of advanced methodologies, including machine learning, in elucidating shared mechanisms such as neuroinflammation, endoplasmic reticulum stress, and protein misfolding.

CONCLUSION: This bibliometric analysis underscores the dynamic and rapidly evolving research landscape at the intersection of HIV and AD, driven by collaborative efforts and technological advancements. Future research should prioritize longitudinal studies, mechanistic insights, and translational applications to address unanswered questions in this critical field.},
}

@article {pmid40365420,
year = {2025},
author = {d'Orchymont, F and Tong, J and Vasdev, N},
title = {Synthesis, Radiosynthesis, in Vitro and in Vivo Evaluation of the GABAA-Benzodiazepine Receptor Agonist [[11]C]RO6899880.},
journal = {ACS medicinal chemistry letters},
volume = {16},
number = {5},
pages = {844-850},
pmid = {40365420},
issn = {1948-5875},
abstract = {The aim of this study is to synthesize and evaluate the GABAA-benzodiazepine receptor agonist radiotracer (S)-10-chloro-1-(3-(methoxy-[11]C)pyrrolidine-1-carbonyl)-3-phenyl-6,7-dihydro-4H-pyrido[2,1-a]isoquinolin-4-one ([[11]C]RO6899880) using in vitro and in vivo experiments to determine its suitability for human positron emission tomography (PET) neuroimaging studies. RO6899880 and its desmethyl precursor were synthesized over multiple steps in 3% and 2% yields, respectively. Reaction of the precursor with [[11]C]CH3I in DMF with NaOH at 23 °C for 5 min followed by HPLC purification and formulation produced [[11]C]RO6899880 with a radiochemical yield of 4.1 ± 1.6% (nondecay corrected), radiochemical purity >95% and molar activities of 6.40 ± 0.63 GBq/μmol (n = 3). Preliminary autoradiography with [[3]H]RO6899880 was carried out in brain tissues from rat, healthy human, patients with Alzheimer's disease and chronic traumatic encephalopathy, and aligned with the GABAA antagonist radiotracer [[3]H]flumazenil. PET imaging in rats revealed modest brain permeability, moderate clearance, and distribution across brain regions with higher uptake in cortical areas. However, polar radiometabolites were found in both plasma and brain homogenates. PET imaging of [[11]C]RO6899880 in higher species including radiometabolism studies are needed prior to human translation.},
}

@article {pmid40365352,
year = {2025},
author = {Bathla, S and Datta, D and Bolat, D and Woo, E and Duque, A and Arellano, JI and Arnsten, AFT and Nairn, AC},
title = {Dysregulated calcium signaling in the aged macaque entorhinal cortex associated with tau hyperphosphorylation.},
journal = {Frontiers in aging neuroscience},
volume = {17},
number = {},
pages = {1549770},
pmid = {40365352},
issn = {1663-4365},
abstract = {INTRODUCTION: Tau pathology in sporadic Alzheimer's disease (AD) follows a distinct pattern, beginning in the entorhinal cortex (ERC) and spreading to interconnected brain regions. Early-stage tau pathology, characterized by soluble phosphorylated tau, is difficult to study in human brains post-mortem due to rapid dephosphorylation.

METHODS: Rhesus macaques, which naturally develop age-related tau pathology resembling human AD, provide an ideal model for investigating early tau etiology. This study examines the molecular processes underlying tau pathology in the macaque ERC, focusing on calcium and inflammatory signaling pathways using biochemical and immunohistochemistry.

RESULTS: Our findings reveal an age-related decrease in PDE4 phosphodiesterase that hydrolyzes cAMP and increases in calpain-2 and glutamate carboxypeptidase II that occur in parallel with early-stage tau hyperphosphorylation at multiple epitopes (pS214-tau, pT181-tau, pT217-tau).

DISCUSSION: These findings suggest that dysregulated calcium signaling in ERC, beginning in middle-age, may prime tau for hyperphosphorylation, potentially driving the early stages of AD, advancing our understanding of how ERC vulnerabilities contribute to neurodegeneration in AD.},
}

@article {pmid40364858,
year = {2025},
author = {Doroszkiewicz, J and Winkel, I and Mroczko, B},
title = {Comparative analysis of neuroinflammatory pathways in Alzheimer's disease, Parkinson's disease, and multiple sclerosis: insights into similarities and distinctions.},
journal = {Frontiers in neuroscience},
volume = {19},
number = {},
pages = {1579511},
pmid = {40364858},
issn = {1662-4548},
abstract = {Neurodegenerative diseases, contributing to the significant socioeconomic burden due to aging society, are gaining increasing interest. Despite each disease having different etiologies, neuroinflammation is believed to play a crucial role in Alzheimer's disease (AD), Parkinson's disease (PD), and multiple sclerosis (MS). In addition to the pathogenic function of inflammation in the brain there is growing evidence that immune responses are essential for neuroregeneration. This review compares and contrasts the neuroinflammatory pathways that selected neurodegenerative diseases share and have in common. In AD, tau tangles and beta-amyloid plaques cause microglia and astrocytes to become activated in an inflammatory response. Alpha-synuclein aggregation stimulate neuroinflammation in Parkinson's disease, especially in the substantia nigra. In Multiple Sclerosis an autoimmune attack on myelin is connected to inflammation via invading immune cells. Commonalities include the release of pro-inflammatory mediators like cytokines and activation of signaling pathways such as NF-κB and MAPK. Comprehending these common routes is essential for discovering early diagnostic possibilities for the diseases and possible tailored treatments. Our work underscores the potential for insights into disease mechanisms. Identifying common targets offers promise for advancing our understanding and potential future treatment approaches across these debilitating disorders.},
}

@article {pmid40364847,
year = {2025},
author = {Nie, W and Yue, Y and Hu, J},
title = {The role of monocytes and macrophages in the progression of Alzheimer's disease.},
journal = {Frontiers in immunology},
volume = {16},
number = {},
pages = {1590909},
pmid = {40364847},
issn = {1664-3224},
mesh = {*Alzheimer Disease/metabolism/immunology/pathology/etiology ; Humans ; *Monocytes/immunology/metabolism ; *Macrophages/immunology/metabolism ; Disease Progression ; Animals ; Amyloid beta-Peptides/metabolism ; tau Proteins/metabolism ; Biomarkers ; Microglia/immunology ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by β-amyloid (Aβ) plaques, neurofibrillary tangles (NFTs), and neuroinflammation. Monocytes and macrophages, particularly microglia, play a dual role in AD pathogenesis. In the early stages, they delay disease progression by phagocytosing Aβ, but chronic activation leads to Aβ accumulation and exacerbated neuroinflammation. Monocyte chemoattractant protein 1 (MCP-1) is a key regulator in neuroinflammation, Aβ deposition, and tau pathology, making it a potential therapeutic target. Moreover, recent breakthroughs in fluid and imaging biomarkers and targeted immunomodulatory agents underscore the growing importance of early diagnostic and therapeutic interventions. This review explores the complex interplay between monocytes, macrophages, and AD pathology, highlighting their roles in neuroinflammation, Aβ metabolism, and tau phosphorylation. Understanding these mechanisms offers new insights into developing effective diagnostic biomarkers and therapeutic strategies for AD.},
}

*Alzheimer Disease/metabolism/immunology/pathology/etiology
Humans
*Monocytes/immunology/metabolism
*Macrophages/immunology/metabolism
Disease Progression
Animals
Amyloid beta-Peptides/metabolism
tau Proteins/metabolism
Biomarkers
Microglia/immunology

@article {pmid40364662,
year = {2025},
author = {You, Z and Liu, Y and Li, Z and Liu, J and Li, J},
title = {Application of Upper Limb Multimodal Tasks Combined With fNIRS Technology in the Assessment of Mild Cognitive Impairment.},
journal = {Journal of biophotonics},
volume = {},
number = {},
pages = {e202500020},
doi = {10.1002/jbio.202500020},
pmid = {40364662},
issn = {1864-0648},
support = {//Fundamental Research Funds for Central Public Welfare Research Institutes (118009001000160001)/ ; 2023SYLTD04//The interdisciplinary Team of Intelligent Elderly Care and Rehabilitation in the "Double first-class" Construction of Beijing University of Posts and Telecommunications in 2023/ ; 2022YFC3601200//National Key Research and Development Program of China/ ; 32271370//National Natural Science Foundation of China/ ; },
abstract = {Mild cognitive impairment (MCI) is primarily characterized by a gradual decline in cognitive function, where early detection and intervention are crucial to preventing Alzheimer's disease progression. This study integrates upper limb multimodal tasks (ULMTs) with functional near-infrared spectroscopy (fNIRS) to assess cognitive and motor functions in MCI patients. Thirty-seven elderly participants were categorized into healthy control (HC) and MCI groups. The experiment consisted of resting state, numerical cognitive task (NCT), motor task (MT), and ULMT phases. fNIRS measured hemodynamic responses in the prefrontal and motor cortices, while an upper limb trainer recorded motor data. Results showed weaker cortical responses in the MCI group during rest and reduced motor cortex activation during NCT. Both groups displayed increased cortical activity during ULMT compared to NCT but reduced motor performance compared to MT. These findings demonstrate the potential of ULMTs combined with fNIRS for early MCI assessment and intervention.},
}

@article {pmid40364625,
year = {2025},
author = {Leite-Aguiar, R and Paiva-Pereira, E and Coutinho-Silva, R and Figueiredo, CP and Savio, LEB},
title = {Extracellular nucleotides mediate viral central nervous system infections: key alarmins of neuroinflammation and neurodegeneration.},
journal = {Neural regeneration research},
volume = {},
number = {},
pages = {},
doi = {10.4103/NRR.NRR-D-24-01464},
pmid = {40364625},
issn = {1673-5374},
abstract = {Recent increases in infectious diseases affecting the central nervous system have raised concerns about their role in neuroinflammation and neurodegeneration. Viral pathogens or their products can invade the central nervous system and cause damage, leading to meningitis, encephalitis, meningoencephalitis, myelitis, or post-infectious demyelinating diseases. Although neuroinflammation initially has a protective function, chronic inflammation can contribute to the development of neurodegenerative diseases. Mechanisms such as protein aggregation and cellular disturbances are implicated with specific viruses such as herpes simplex virus type 1 and Epstein-Barr virus being associated with Alzheimer's disease and multiple sclerosis, respectively. Extracellular nucleotides, particularly adenosine triphosphate and its metabolites are released from activated, infected, and dying cells, acting as alarmins mediating neuroinflammation and neurodegeneration. When viruses infect central nervous system cells, adenosine triphosphate is released as an alarmin, triggering inflammatory responses. This process is mediated by purinergic receptors, divided into two families: P1, which responds to adenosine, and P2, activated by adenosine triphosphate and other nucleotides. This review highlights how specific viruses, such as human immunodeficiency virus type 1, Theiler's murine encephalomyelitis virus, herpes simplex virus type 1, Epstein-Barr virus, dengue virus, Zika virus, and severe acute respiratory syndrome coronavirus 2, can initiate inflammatory responses through the release of extracellular nucleotides, particularly adenosine triphosphate, which act as critical mediators in the progression of neuroinflammation and neurodegenerative disorders. A better understanding of purinergic signaling pathways in these diseases may suggest new potential therapeutic strategies for targeting neuroinflammation to mitigate the long-term consequences of viral infections in the central nervous system.},
}

@article {pmid40364547,
year = {2025},
author = {Ho, EH and Karpouzian-Rogers, T and Ayturk, E and Bedjeti, K and Weintraub, S and Gershon, R},
title = {NIH Toolbox Cognition Performance in Older Adults with Normal Cognition, Mild Cognitive Impairment, and Mild Dementia of the Alzheimer's Type: Results from the ARMADA Study.},
journal = {Archives of clinical neuropsychology : the official journal of the National Academy of Neuropsychologists},
volume = {},
number = {},
pages = {},
doi = {10.1093/arclin/acaf035},
pmid = {40364547},
issn = {1873-5843},
support = {//Advancing Reliable Measurement in Alzheimer's Disease and Cognitive Aging/ ; AG057441//National Institute on Aging, Northwestern University/ ; //Mayo Clinic Florida/ ; AG016574/AG/NIA NIH HHS/United States ; 1P30AG066511/AG/NIA NIH HHS/United States ; P30AG062429/AG/NIA NIH HHS/United States ; P30 AG072977/AG/NIA NIH HHS/United States ; AG058724/AG/NIA NIH HHS/United States ; PO1AG07232/AG/NIA NIH HHS/United States ; R01AG037212/AG/NIA NIH HHS/United States ; RF1AG054023/AG/NIA NIH HHS/United States ; //Emory University: Goizueta Alzheimer's Disease Research Center at Emory University/ ; //University of California, San Diego: UCSD Alzheimer's Disease Research Center/ ; R01AG045571//National Institute on Aging Cognitive SuperAging studies/ ; R56AG045571//National Institute on Aging Cognitive SuperAging studies/ ; R01AG067781//National Institute on Aging Cognitive SuperAging studies/ ; AG005133//University of Pittsburgh: Alzheimer's Disease Research Center, National Institute on Aging/ ; AG025204//University of Pittsburgh National Institute on Aging/ ; //University of Pittsburgh Imaging Pathophysiology in Aging and Neurodegeneration/ ; AG052446//Young-Old National Institute on Aging/ ; P30AG062421//Massachusetts General Hospital: Massachusetts Alzheimer's Disease Research Center, National Institute on Aging/ ; P01AG036694//Massachusetts ADRC; National Center for Biotechnology Information- Harvard Aging Brain Study/ ; AG053760//University of Michigan: National Institute on Aging/ ; AG054484//Michigan Alzheimer's Disease Research Center National Institute on Aging/ ; //Treating Mild Cognitive Impairment with High Definition Transcranial Direct Current Stimulation/ ; AG047866/NH/NIH HHS/United States ; //Columbia University: Washington Heights-Inwood Columbia Aging Project/ ; UL1TR001873//National Center for Advancing Translational Sciences, National Institutes of Health/ ; AG033514//University of Wisconsin: Wisconsin Alzheimer's Disease Research Center, National Institute on Aging/ ; AG062715//University of Wisconsin: Wisconsin Alzheimer's Disease Research Center, National Institute on Aging/ ; AG066518//Oregon Health & Science University: Layton Aging and Alzheimer's Disease Center, National Institute on Aging/ ; },
abstract = {OBJECTIVE: Efficient and early detection of cognitive impairment may be facilitated using the NIH Toolbox (NIHTB), a computerized suite of assessments measuring multiple aspects of neurological functioning.

METHODS: The Advancing Reliable Measurement in Alzheimer's Disease and cognitive Aging study validated the NIHTB across a geographically diverse cognitive aging sample. Participants aged >64 with normal cognition (NC), mild cognitive impairment (MCI), and dementia of the Alzheimer type (DAT) across nine research sites completed the NIHTB. One-way ANOVAs captured differences in performance on the Cognition Battery and effect sizes were calculated.

RESULTS: Groups differed substantially across all cognition measures, with large differences in Total and Fluid Cognition, after demographic adjustment. The largest differentiators were in fluid measures, particularly for working and episodic memory.

CONCLUSIONS: NIHTB-CB differentiates NC, MCI, and DAT groups. Future studies will examine longitudinal differences and performance in enriched samples (African American participants, Spanish NIHTB, 85+ years old).},
}

@article {pmid40364523,
year = {2025},
author = {Andreo-Lopez, J and Nuñez-Diaz, C and Do Huynh, K and Nguyen, MMT and Da Cunha, C and Cantero-Molina, FJ and Campos-Moreno, C and Zimbone, S and Bellia, F and Giuffrida, ML and Trujillo-Estrada, L and Garcia-Leon, JA and Bettinetti-Luque, M and Gamez, N and Valdes, C and Morales, R and Forner, S and Martini, AC and Gutierrez, A and LaFerla, FM and Baglietto-Vargas, D},
title = {Human and Mouse Alzheimer's Seeds Differentially Affect Amyloid Deposition and Microglia-Dependent Plaque Response in Aged Mice.},
journal = {Aging cell},
volume = {},
number = {},
pages = {e70094},
doi = {10.1111/acel.70094},
pmid = {40364523},
issn = {1474-9726},
support = {R01AI132695/NH/NIH HHS/United States ; U54-AG054349/NH/NIH HHS/United States ; U42OD11158//National Disease Research Interchange/ ; BEAGAL18/00052//Beatriz Galindo program/ ; PI21/00915//Institute of Health Carlos III/ ; PI24/00274//Institute of Health Carlos III/ ; PID2019-108911RA-100//The Minister of Science and Innovation/ ; AARG-22-928219/ALZ/Alzheimer's Association/United States ; AARGD-22-972125/ALZ/Alzheimer's Association/United States ; },
abstract = {Alzheimer's disease (AD) is a complex neurodegenerative proteinopathy in which Aβ and tau misfold and aggregate into entities that structurally unsettle native proteins, mimicking a prion-like or "seeding" process. These Aβ and tau "seeds" can arrange in different conformations or strains that might display distinct pathogenic properties. Furthermore, recent evidence suggests that microglia play a key role in the amyloidogenic event and can modulate the propagation and aggregation processes. Here, we employed histological and molecular approaches to determine whether seeds from human AD brains compared to those from transgenic mice (3xTg-AD) are more prone to induce Aβ and tau aggregates in vivo, as well as potential differences in the microglial response to the plaque pathology. Brain homogenates were injected into the hippocampus of 3xTg-AD mice and hAβ-KI mice and examined at 18-20 months of age. The seeds from the human AD brain induced more aggressive amyloid pathology compared to seeds from aged 3xTg-AD mice. However, the AD seeds from aged transgenic mice triggered more tau pathology. Interestingly, such mice seeds impaired microglial clustering around plaques, leading to more severe neuritic pathology. Furthermore, the human AD seeds injected into the hippocampus of hAβ-KI mice were not able to induce plaque formation. These results suggest that multiple variables such as the AD seed, recipient model, and time are critical factors that can modulate the amyloid pathology onset and progression. Thus, more profound understanding of these factors will provide key insight into how amyloid and tau pathology progresses in AD.},
}

@article {pmid40364449,
year = {2025},
author = {Chen, TL and Zhang, TL and Lu, HJ and Yue, AX and Wang, YE and Zhou, YJ and Hou, J},
title = {Comment on "Oral Microbiome and Serological Analyses on Association of Alzheimer's Disease and Periodontitis".},
journal = {Oral diseases},
volume = {},
number = {},
pages = {},
doi = {10.1111/odi.15379},
pmid = {40364449},
issn = {1601-0825},
support = {2023SHZDZX02-030702//Shanghai Science and Technology Major Special Project "International Human Phenome Project"/ ; //2023 Basic Medical Research Special Project of the First Affiliated Hospital of Naval Medical University (2023PY09)/ ; //234 Discipline Peak Climbing Project of the First Affiliated Hospital of Naval Medical University (2020YXK028)/ ; },
}

@article {pmid40364443,
year = {2025},
author = {Widera, E},
title = {Falsification periods seen with an immediate reduction in Alzheimer's disease with semaglutide.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {5},
pages = {e70150},
doi = {10.1002/alz.70150},
pmid = {40364443},
issn = {1552-5279},
}

@article {pmid40363884,
year = {2025},
author = {Bagán, A and López-Ruiz, A and Abás, S and Molins, E and Pérez, B and Muneta-Arrate, I and Callado, LF and Escolano, C},
title = {Synthesis of Diversely Substituted Diethyl (Pyrrolidin-2-Yl)Phosphonates.},
journal = {Molecules (Basel, Switzerland)},
volume = {30},
number = {9},
pages = {},
doi = {10.3390/molecules30092078},
pmid = {40363884},
issn = {1420-3049},
support = {Spain, PID2022-1380790B-I00 MICIU/AEI /10.13039/501100011033 and FEDER, UE and PDC2022-133441-I00 MICIU/AEI /10.13039/501100011033 Europea Next Genera-tionEU/ PRTR//Ministerio de Ciencia, Innovación y Universidades, Agencia Estatal de Investigación/ ; IT1512/22//the Basque Government/ ; 2021 SGR 00357//Generalitat de Catalunya/ ; },
mesh = {*Organophosphonates/chemical synthesis/chemistry/pharmacology ; *Pyrrolidines/chemistry/chemical synthesis ; Crystallography, X-Ray ; Molecular Structure ; Humans ; Animals ; Models, Molecular ; Structure-Activity Relationship ; Mice ; },
abstract = {Imidazoline I2 receptors (I2-IR) are untapped therapeutic targets lacking a structural description. Although the levels of I2-IR are dysregulated in a plethora of illnesses, the arsenal of ligands that can modulate I2-IR is limited. In this framework, we have reported several new structural families embodying the iminophosphonate functional group that have an excellent affinity and selectivity for I2-IR, and selected members have demonstrated relevant pharmacological properties in murine models of neurodegeneration and Alzheimer's disease. Starting with these iminophosphonates, we continued to exploit their high degree of functionalization through a short and efficient synthesis to access unprecedented 2,3-di, 2,2,3-tri, 2,3,4-tri, and 2,2,3,4-tetrasubstituted diethyl (pyrrolidine-2-yl) phosphonates. The stereochemistry of the new compounds was unequivocally characterized by X-ray crystallographic analyses. Two selected compounds with structural features shared with the starting products were pharmacologically evaluated, allowing us to deduce the required key structural motifs for biologically active aminophosphonate derivatives.},
}

*Organophosphonates/chemical synthesis/chemistry/pharmacology
*Pyrrolidines/chemistry/chemical synthesis
Crystallography, X-Ray
Molecular Structure
Humans
Animals
Models, Molecular
Structure-Activity Relationship
Mice

@article {pmid40363876,
year = {2025},
author = {Baravkar, SB and Lu, Y and Zhao, Q and Peng, H and Zhou, W and Hong, S},
title = {Rationally Designed Pentapeptide Analogs of Aβ19-23 Fragment as Potent Inhibitors of Aβ42 Aggregation.},
journal = {Molecules (Basel, Switzerland)},
volume = {30},
number = {9},
pages = {},
doi = {10.3390/molecules30092071},
pmid = {40363876},
issn = {1420-3049},
support = {R21AG060430, R21AG066119, R21AG068756 and R01GM136874/GF/NIH HHS/United States ; },
mesh = {*Amyloid beta-Peptides/chemistry/antagonists & inhibitors/metabolism ; *Peptide Fragments/chemistry ; *Protein Aggregates/drug effects ; Humans ; *Oligopeptides/chemistry/pharmacology/chemical synthesis ; Drug Design ; Circular Dichroism ; },
abstract = {Amyloid beta (Aβ42 and Aβ40) aggregation, along with neurofibrillary tangles, is one of the major neurotoxic events responsible for the onset of Alzheimer's disease. Many potent peptide-based inhibitors mainly focusing on central hydrophobic core Aβ16-20 (KLVFF) have been reported in recent years. Herein, we report pentapeptides 1-4, based on the β-turn-inducing fragment Aβ19-23 (FFAED). The synthesis of peptides 1-4 was carried out using Fmoc/tBu-based solid-phase peptide synthesis technique, and it was found that pentapeptide 3 potently inhibit the aggregation propensity of Aβ42, when incubated with it at 37 °C for 48 h. The aggregation inhibition study was conducted using thioflavin T-based fluorescence assay and circular dichroism spectroscopy, and supported by transmission electron microscope imaging. The conformational change on the aggregation of Aβ42 and aggregation inhibition by peptides 1-4 was further evaluated using [1]H-[15]N HSQC NMR spectroscopy. The results demonstrated that the most potent analog, peptide 3, effectively disrupts the aggregation process. This study is the first to demonstrate that an Aβ19-23 fragment mimic can disrupt the aggregation propensity of Aβ42.},
}

*Amyloid beta-Peptides/chemistry/antagonists & inhibitors/metabolism
*Peptide Fragments/chemistry
*Protein Aggregates/drug effects
Humans
*Oligopeptides/chemistry/pharmacology/chemical synthesis
Drug Design
Circular Dichroism

@article {pmid40363853,
year = {2025},
author = {Simakov, A and Chhor, S and Ismaili, L and Martin, H},
title = {Nrf2 Activation and Antioxidant Properties of Chromone-Containing MTDLs for Alzheimer's Disease Treatment.},
journal = {Molecules (Basel, Switzerland)},
volume = {30},
number = {9},
pages = {},
doi = {10.3390/molecules30092048},
pmid = {40363853},
issn = {1420-3049},
mesh = {*NF-E2-Related Factor 2/metabolism/genetics ; *Alzheimer Disease/drug therapy/metabolism ; *Antioxidants/pharmacology/chemistry ; Humans ; *Chromones/pharmacology/chemistry ; Oxidative Stress/drug effects ; Signal Transduction/drug effects ; Ligands ; NAD(P)H Dehydrogenase (Quinone)/genetics/metabolism ; Antioxidant Response Elements ; },
abstract = {Alzheimer's disease (AD) is a devastating neurodegenerative disorder affecting millions worldwide and imposing a significant social and economic burden. Despite extensive research, there is still no effective cure for this disease. AD is multifactorial and involves multiple etiopathogenic mechanisms, one of which is oxidative stress. Consequently, the Nrf2/ARE pathway, which regulates the expression of cellular defense genes, including those for antioxidant enzymes, is considered to be a prospective therapeutic target for AD. Meanwhile, multitarget-directed ligands (MTDLs) are a promising approach for developing effective AD medications. In this regard, we evaluated the antioxidant potential of eight chromone-containing MTDLs in vitro, including Nrf2 transcriptional activation potencies, Nrf2/ARE downstream genes activation, and antioxidant effects in vitro. All tested compounds effectively activated the Nrf2/ARE pathway. Notably, compounds 4b, 4c, 4f, and 4h demonstrated the highest Nrf2 activation potencies, while compounds 4b, 4c, 4d, and 4g significantly induced the expression of Nrf2-target antioxidant genes, specifically NQO1 and HO1. Additionally, compound 4d exhibited a significant antioxidant effect in vitro. These findings encourage further investigation of the studied compounds, with particular emphasis on compound 4d as the most promising candidate.},
}

*NF-E2-Related Factor 2/metabolism/genetics
*Alzheimer Disease/drug therapy/metabolism
*Antioxidants/pharmacology/chemistry
Humans
*Chromones/pharmacology/chemistry
Oxidative Stress/drug effects
Signal Transduction/drug effects
Ligands
NAD(P)H Dehydrogenase (Quinone)/genetics/metabolism
Antioxidant Response Elements

@article {pmid40363838,
year = {2025},
author = {Quintero-Espinosa, DA and Velez-Pardo, C and Jimenez-Del-Rio, M},
title = {PF-06447475 Molecule Attenuates the Neuropathology of Familial Alzheimer's and Coexistent Parkinson's Disease Markers in PSEN1 I416T Dopaminergic-like Neurons.},
journal = {Molecules (Basel, Switzerland)},
volume = {30},
number = {9},
pages = {},
doi = {10.3390/molecules30092034},
pmid = {40363838},
issn = {1420-3049},
support = {1RF1AG062479-01/AG/NIA NIH HHS/United States ; },
mesh = {*Presenilin-1/genetics/metabolism ; *Alzheimer Disease/metabolism/pathology/drug therapy/genetics ; Humans ; *Parkinson Disease/metabolism/pathology/drug therapy/genetics ; *Dopaminergic Neurons/metabolism/drug effects/pathology ; Biomarkers/metabolism ; tau Proteins/metabolism ; Amyloid beta-Peptides/metabolism ; alpha-Synuclein/metabolism ; Mutation ; Phosphorylation ; },
abstract = {Familial Alzheimer's disease (FAD) is a complex multifactorial disorder clinically characterized by cognitive impairment and memory loss. Pathologically, FAD is characterized by intracellular accumulation of the protein fragment Aβ42 (iAβ), hyperphosphorylated microtubule-associated protein TAU (p-TAU), and extensive degeneration of basal forebrain cholinergic neurons of the nucleus basalis of Meynert (NbM) and the medial septal nucleus (MSN), mainly caused by mutations in the amyloid precursor protein (APP), presenilin 1 (PSEN1), and PSEN2 gene. Since the dopaminergic system may contribute to FAD symptoms, alterations in the nigro-hippocampal pathway may be associated with cognitive impairment in FAD. Interestingly, p-α-synuclein (p-α-Syn), Aβ, and p-TAU have been found to coexist in vulnerable regions of postmortem AD brains. However, the mechanism by which Aβ, p-TAU, and α-Syn coexist in DAergic neurons in AD brains has not been determined. We generated PSEN1 I416T dopaminergic-like neurons (DALNs) from I416T menstrual stromal cells (MenSCs) in NeuroForsk 2.0 medium for 7 days and then cultured them in minimal culture medium (MCm) for another 4 days. On day 11, DALNs were analyzed for molecular and pathological markers by flow cytometry and fluorescence microscopy. We found that mutant DALNs showed increased accumulation of iAβ as well as increased phosphorylation of TAU at S202/T205 compared to WT DALNs. Thus, mutant DALNs exhibited typical pathological hallmarks of Alzheimer's disease. Furthermore, PSEN1 I416T DALNs showed concomitant signs of OS as evidenced by the appearance of oxidized sensor protein DJ-1 (i.e., DJ-1C106-SO3) and apoptotic markers TP53, pS63-c-JUN, PUMA, and cleavage caspase 3 (CC3). Notably, these DALNs exhibited PD-associated proteins such as intracellular accumulation of α-Syn (detected as aggregates of pS129-α-Syn) and phosphorylation of LRRK2 kinase at residue S935. In addition, mutant DALNs showed a 17.16- and 6.17-fold decrease in DA-induced Ca[2+] flux, compared to WT DALNs. These observations suggest that iAβ and p-TAU, together with p-α-Syn, and p-LRRK2 kinase, may damage DAergic neurons and thereby contribute to the exacerbation of neuropathologic processes in FAD. Remarkably, the LRRK2 inhibitor PF-06447475 (PF-475) significantly reversed PSEN1 I416T-induced neuropathological markers in DAergic neurons. PF-465 inhibitor reduced iAβ, oxDJ-1C106-SO3, and p-TAU. In addition, this inhibitor reduced pS935-LRRK2, pS129-αSYN, pS63-c-JUN, and CC3. We conclude that the observed neuroprotective effects of PF-475 are due to direct inhibition of LRRK2 activity and that the LRRK2 protein is upstream of the molecular cascade of apoptosis and proteinopathy. Our results suggest that PF-475 is an effective neuroprotective agent against endogenous PSEN1 I416T-induced neurotoxicity in DALNs coexisting with Parkinson's disease markers. Therefore, PF-475 may be of great therapeutic value in FAD.},
}

*Presenilin-1/genetics/metabolism
*Alzheimer Disease/metabolism/pathology/drug therapy/genetics
Humans
*Parkinson Disease/metabolism/pathology/drug therapy/genetics
*Dopaminergic Neurons/metabolism/drug effects/pathology
Biomarkers/metabolism
tau Proteins/metabolism
Amyloid beta-Peptides/metabolism
alpha-Synuclein/metabolism
Mutation
Phosphorylation

@article {pmid40363835,
year = {2025},
author = {Kim, TK and Hong, JM and Cho, Y and Jeon, Y and Cho, H and Lee, J and Kim, J and Kim, KH and Kim, IC and Han, SJ and Oh, H and Jo, DG and Yim, JH},
title = {Synthesis and Biological Evaluation of Novel Ramalin Derivatives as Multi-Target Agents for Alzheimer's Disease.},
journal = {Molecules (Basel, Switzerland)},
volume = {30},
number = {9},
pages = {},
doi = {10.3390/molecules30092030},
pmid = {40363835},
issn = {1420-3049},
support = {KOPRI PE25160//Korea Polar Research Institute/ ; RS-2021-KS211513//Ministry of Oceans and Fisheries/ ; },
mesh = {*Alzheimer Disease/drug therapy/metabolism ; Humans ; Amyloid beta-Peptides/metabolism ; *Neuroprotective Agents/pharmacology/chemical synthesis/chemistry ; Antioxidants/pharmacology/chemical synthesis/chemistry ; tau Proteins/metabolism ; Animals ; Anti-Inflammatory Agents/pharmacology/chemical synthesis/chemistry ; Amyloid Precursor Protein Secretases/antagonists & inhibitors/metabolism ; Oxidative Stress/drug effects ; Mice ; Aspartic Acid Endopeptidases/antagonists & inhibitors/metabolism ; },
abstract = {Alzheimer's disease (AD) is a complex neurodegenerative disorder characterized by cognitive decline, oxidative stress, neuroinflammation, amyloid-beta (Aβ) accumulation, and tau protein hyperphosphorylation. In this study, we synthesized novel Ramalin derivatives and evaluated their therapeutic potential against AD, focusing on antioxidant, anti-inflammatory, and neuroprotective activities. RA-2OMe, RA-4OMe, RA-2CF3, and RA-4OCF3 showed strong antioxidant effects, while RA-2OMe exhibited potent NO and NLRP3 inhibition (~20%). RA-NAP, RA-PYD, and RA-2Q showed moderate anti-inflammatory activity. BACE-1 inhibition was significant in RA-3CF3, RA-NAP, and RA-PYD, with IC50 values lower than that of positive control, indicating greater inhibitory potency. RA-NAP and RA-PYD effectively inhibited both Aβ and tau aggregation, highlighting their multi-target potential for AD therapy. These findings indicate that Ramalin derivatives exhibit potential for multi-target activity in AD treatment. However, further studies on their pharmacokinetics, in vivo efficacy, and long-term safety are required to confirm their therapeutic applicability.},
}

*Alzheimer Disease/drug therapy/metabolism
Humans
Amyloid beta-Peptides/metabolism
*Neuroprotective Agents/pharmacology/chemical synthesis/chemistry
Antioxidants/pharmacology/chemical synthesis/chemistry
tau Proteins/metabolism
Animals
Anti-Inflammatory Agents/pharmacology/chemical synthesis/chemistry
Amyloid Precursor Protein Secretases/antagonists & inhibitors/metabolism
Oxidative Stress/drug effects
Mice
Aspartic Acid Endopeptidases/antagonists & inhibitors/metabolism

@article {pmid40363789,
year = {2025},
author = {Küpeli Akkol, E and Karatoprak, GŞ and Dumlupınar, B and Bahadır Acıkara, Ö and Arıcı, R and Yücel, Ç and Aynal, LC and Sobarzo Sánchez, E},
title = {Stilbenes Against Alzheimer's Disease: A Comprehensive Review of Preclinical Studies of Natural and Synthetic Compounds Combined with the Contributions of Developed Nanodrug Delivery Systems.},
journal = {Molecules (Basel, Switzerland)},
volume = {30},
number = {9},
pages = {},
doi = {10.3390/molecules30091982},
pmid = {40363789},
issn = {1420-3049},
mesh = {*Alzheimer Disease/drug therapy/metabolism ; Humans ; *Stilbenes/chemistry/therapeutic use/pharmacology/chemical synthesis ; Animals ; *Neuroprotective Agents/chemistry/pharmacology/therapeutic use ; *Drug Delivery Systems ; Amyloid beta-Peptides/metabolism ; },
abstract = {This review covers preclinical studies of stilbene derivative compounds (both natural and synthetic) with potential preventive and therapeutic effects against Alzheimer's disease (AD). AD is a worldwide neurodegenerative disease characterized by the destruction of nerve cells in the brain and the loss of cognitive function due to aging. Stilbenes are a unique class of natural phenolic compounds distinguished by a C6-C2-C6 (1,2-diphenylethylene) structure and two aromatic rings connected by an ethylene bridge. Stilbenes' distinct features make them an intriguing subject for pharmacological research and development. Several preclinical studies have suggested that stilbenes may have neuroprotective effects by reducing Aβ generation and oligomerization, enhancing Aβ clearance, and regulating tau neuropathology through the prevention of aberrant tau phosphorylation and aggregation, as well as scavenging reactive oxygen species. Synthetic stilbene derivatives also target multiple pathways involved in neuroprotection and have demonstrated promising biological activity in vitro. However, some properties of stilbenes, such as sensitivity to physiological conditions, low solubility, poor permeability, instability, and low bioavailability, limit their usefulness in clinical applications. To address this issue, current investigations have developed new drug delivery systems based on stilbene derivative molecules. This review aims to shed light on the development of next-generation treatment strategies by examining in detail the role of stilbenes in Alzheimer's pathophysiology and their therapeutic potential.},
}

*Alzheimer Disease/drug therapy/metabolism
Humans
*Stilbenes/chemistry/therapeutic use/pharmacology/chemical synthesis
Animals
*Neuroprotective Agents/chemistry/pharmacology/therapeutic use
*Drug Delivery Systems
Amyloid beta-Peptides/metabolism

@article {pmid40363702,
year = {2025},
author = {Vela Navarro, N and De Nadai Mundim, G and Cudic, M},
title = {Implications of Mucin-Type O-Glycosylation in Alzheimer's Disease.},
journal = {Molecules (Basel, Switzerland)},
volume = {30},
number = {9},
pages = {},
doi = {10.3390/molecules30091895},
pmid = {40363702},
issn = {1420-3049},
support = {24A02//Florida Department of Health, Ed and Ethel Moore Alzheimer's Disease Research Program/ ; },
mesh = {Humans ; *Alzheimer Disease/metabolism/pathology ; Glycosylation ; *Mucins/metabolism ; Animals ; Amyloid beta-Peptides/metabolism ; Polysaccharides/metabolism ; },
abstract = {Alzheimer's disease (AD) is one of the most common neurodegenerative disorders linked to aging. Major hallmarks of AD pathogenesis include amyloid-β peptide (Aβ) plaques, which are extracellular deposits originating from the processing of the amyloid precursor protein (APP), and neurofibrillary tangles (NFTs), which are intracellular aggregates of tau protein. Recent evidence indicates that disruptions in metal homeostasis and impaired immune recognition of these aggregates trigger neuroinflammation, ultimately driving disease progression. Therefore, a more comprehensive approach is needed to understand the underlying causes of the disease. Patients with AD present abnormal glycan profiles, and most known AD-related molecules are either modified with glycans or involved in glycan regulation. A deeper understanding of how O-glycosylation influences the balance between amyloid-beta peptide production and clearance, as well as microglia's pro- and anti-inflammatory responses, is crucial for deciphering the early pathogenic events of AD. This review aims to provide a comprehensive summary of the extensive research conducted on the role of mucin-type O-glycosylation in the pathogenesis of AD, discussing its role in disease onset and immune recognition.},
}

Humans
*Alzheimer Disease/metabolism/pathology
Glycosylation
*Mucins/metabolism
Animals
Amyloid beta-Peptides/metabolism
Polysaccharides/metabolism

@article {pmid40363322,
year = {2025},
author = {Huh, YJ and Park, JH and Kim, YJ and Kim, KG},
title = {Ensemble Learning-Based Alzheimer's Disease Classification Using Electroencephalogram Signals and Clock Drawing Test Images.},
journal = {Sensors (Basel, Switzerland)},
volume = {25},
number = {9},
pages = {},
doi = {10.3390/s25092881},
pmid = {40363322},
issn = {1424-8220},
support = {GRRC-Gachon2023(B01)//GRRC program of Gyeonggi province/ ; K_G012001185601//Industrial Strategic Technology Development Program/ ; },
mesh = {*Alzheimer Disease/diagnosis/classification/physiopathology ; Humans ; *Electroencephalography/methods ; *Machine Learning ; Algorithms ; Male ; Female ; Aged ; Ensemble Learning ; },
abstract = {Ensemble learning (EL), a machine learning technique that combines the results of multiple learning algorithms to obtain predicted values, aims to achieve better predictive performance than a single learning algorithm alone. Machine learning techniques, including EL, have been applied in the field of medicine to assist in the clinical interpretation of specific diseases. Although neurodegenerative diseases, especially Alzheimer's disease (AD), are of interest to clinicians and researchers due to their rapid increase in clinical cases, the application of EL in AD diagnosis has been relatively less attempted. In this research, we demonstrate that three machine learning algorithms, trained on an ensemble of electroencephalogram (EEG) and clock drawing test (CDT) feature data for an AD classification task, show improved AD detection accuracy compared to when either the EEG or CDT dataset is used independently. We also explore which feature contributes most to decision-making in AD and healthy control (HC) classification. In conclusion, the current study suggests that EL can be a novel clinical application of machine learning (ML) in the automated AD screening process.},
}

*Alzheimer Disease/diagnosis/classification/physiopathology
Humans
*Electroencephalography/methods
*Machine Learning
Algorithms
Male
Female
Aged
Ensemble Learning

@article {pmid40363158,
year = {2025},
author = {Cardinali, L and Mariano, V and Rodriguez-Duarte, DO and Tobón Vasquez, JA and Scapaticci, R and Crocco, L and Vipiana, F},
title = {Early Detection of Alzheimer's Disease via Machine Learning-Based Microwave Sensing: An Experimental Validation.},
journal = {Sensors (Basel, Switzerland)},
volume = {25},
number = {9},
pages = {},
doi = {10.3390/s25092718},
pmid = {40363158},
issn = {1424-8220},
support = {THERAD - Microwave Theranostics for Alzheimer's Disease//Compagnia di San Paolo/ ; Piano Nazionale di Ripresa e Resilienza (PNRR) - MISSIONE 4 COMPONENTE 2, INVESTIMENTO 1.4 - D.D. 1032 17/06/2022, CN00000022//European Union Next-Generation EU/ ; Microwave Imaging and Detection powered by Artificial Intelligence for Medical and Industrial Applications (DM 1062/21)//Ministero dell'università e della ricerca/ ; },
mesh = {*Alzheimer Disease/diagnosis/cerebrospinal fluid ; Humans ; *Microwaves ; *Machine Learning ; Early Diagnosis ; Algorithms ; *Biosensing Techniques/methods ; Biomarkers/cerebrospinal fluid ; },
abstract = {The early diagnosis of Alzheimer's disease remains an unmet medical need due to the cost and invasiveness of current methods. Early detection would ensure a higher quality of life for patients, enabling timely and suitable treatment. We investigate microwave sensing for low-cost, non-intrusive early detection and assessment of Alzheimer's disease. This study is based on the emerging evidence that the electromagnetic properties of cerebrospinal fluid are affected by abnormal concentrations of proteins recognized as early-stage biomarkers. We design a conformal six-element antenna array placed on the upper portion of the head, operating in the 500 MHz to 6.5 GHz band. It measures scattering response due to changes in the dielectric properties of intracranial cerebrospinal fluid. A multi-layer perceptron network extracts the diagnostic information. Data classification consists of two steps: binary classification to identify the disease presence and multi-class classification to evaluate its stage. The algorithm is trained and validated through controlled experiments mimicking various pathological severities with an anthropomorphic multi-tissue head phantom. Results support the feasibility of the proposed method using only amplitude data and lay the foundation for more extensive studies on microwave sensing for early Alzheimer's detection.},
}

*Alzheimer Disease/diagnosis/cerebrospinal fluid
Humans
*Microwaves
*Machine Learning
Early Diagnosis
Algorithms
*Biosensing Techniques/methods
Biomarkers/cerebrospinal fluid

@article {pmid40362907,
year = {2025},
author = {Christopher, CJ and Morgan, KH and Tolleson, CM and Trudell, R and Fernandez-Romero, R and Rice, L and Abiodun, BA and Vickery, Z and Jones, KA and Woodall, BM and Nagy, C and Mieczkowski, PA and Bowen, G and Campagna, SR and Ellis, JC},
title = {Specific Bacterial Taxa and Their Metabolite, DHPS, May Be Linked to Gut Dyshomeostasis in Patients with Alzheimer's Disease, Parkinson's Disease, and Amyotrophic Lateral Sclerosis.},
journal = {Nutrients},
volume = {17},
number = {9},
pages = {},
doi = {10.3390/nu17091597},
pmid = {40362907},
issn = {2072-6643},
support = {N/A//The Cole Family who support Parkinson's care and research at the Cole Center for Parkinson's Disease and Movement Disorders/ ; N/A//University of Tennessee at Knoxville's Human Health & Wellness Program/ ; N/A//Laboratory Directed Research and Development Program at Oak Ridge National Laboratory, managed by UT-Battelle, LLC, for the U.S. Department of Energy/ ; N/A//A philanthropic donor to ALS research at the University of Tennessee Medical Center/ ; },
mesh = {Humans ; *Gastrointestinal Microbiome/physiology ; *Parkinson Disease/microbiology/metabolism ; *Alzheimer Disease/microbiology/metabolism ; *Dysbiosis/microbiology ; Male ; Female ; *Amyotrophic Lateral Sclerosis/microbiology/metabolism ; Aged ; Middle Aged ; Feces/microbiology ; *Bacteria/metabolism/classification ; Homeostasis ; Metabolomics ; Case-Control Studies ; },
abstract = {Background: Neurodegenerative diseases (NDDs) are multifactorial disorders frequently associated with gut dysbiosis, oxidative stress, and inflammation; however, the pathophysiological mechanisms remain poorly understood. Methods: Using untargeted mass spectrometry-based metabolomics and 16S sequencing of human stool, we investigated bacterial and metabolic dyshomeostasis in the gut microbiome associated with early disease stages across three NDDs-amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), Parkinson's disease (PD)-and healthy controls (HC). Results: We discovered a previously unrecognized link between a microbial-derived metabolite with an unknown role in human physiology, 2,3-dihydroxypropane-1-sulfonate (DHPS), and gut dysbiosis in NDDs. DHPS was downregulated in AD, ALS, and PD, while bacteria involved in DHPS metabolism, Eubacterium and Desulfovibrio, were increased in all disease cohorts. Additionally, select taxa within the Clostridia class had strong negative correlations to DHPS, suggesting a potential role in DHPS metabolism. A catabolic product of DHPS is hydrogen sulfide, and when in excess, it is known to promote inflammation, oxidative stress, mitochondrial damage, and gut dysbiosis, known hallmarks of NDDs. Conclusions: These findings suggest that cryptic sulfur metabolism via DHPS is a potential missing link in our current understanding of gut dysbiosis associated with NDD onset and progression. As this was a hypothesis generating study, more work is needed to elucidate the role of DHPS in gut dysbiosis and neurodegenerative diseases.},
}

Humans
*Gastrointestinal Microbiome/physiology
*Parkinson Disease/microbiology/metabolism
*Alzheimer Disease/microbiology/metabolism
*Dysbiosis/microbiology
Male
Female
*Amyotrophic Lateral Sclerosis/microbiology/metabolism
Aged
Middle Aged
Feces/microbiology
*Bacteria/metabolism/classification
Homeostasis
Metabolomics
Case-Control Studies

@article {pmid40362855,
year = {2025},
author = {Kim, SH and Hong, SM and Ko, EJ and Park, MJ and Kim, JY and Kim, SY},
title = {Neuroprotective Effects of a Combination of Dietary Trans-Resveratrol and Hesperidin Against Methylglyoxal-Induced Neurotoxicity in a Depressive Amnesia Mouse Model.},
journal = {Nutrients},
volume = {17},
number = {9},
pages = {},
doi = {10.3390/nu17091548},
pmid = {40362855},
issn = {2072-6643},
support = {RS-2022-NR075834//This research was supported by a grant from the Basic Science Research Program through the National Research Foundation of Korea (NRF), funded by the Ministry of Education/ ; RS-2023-007607//This research was supported by a grant from the Basic Science Research Program through the National Research Foundation of Korea (NRF), funded by the Ministry of Education/ ; GCU-09020001//This study was supported by Gachon University Research Fund 2022/ ; },
mesh = {Animals ; *Pyruvaldehyde/toxicity ; *Neuroprotective Agents/pharmacology/administration & dosage ; Mice ; *Hesperidin/pharmacology/administration & dosage ; Disease Models, Animal ; *Resveratrol/pharmacology/administration & dosage ; Male ; Reactive Oxygen Species/metabolism ; Apoptosis/drug effects ; Cell Line, Tumor ; *Neurotoxicity Syndromes/drug therapy/etiology ; Cell Survival/drug effects ; Behavior, Animal/drug effects ; *Depression/drug therapy/chemically induced ; },
abstract = {BACKGROUND: Methylglyoxal (MGO), a reactive dicarbonyl compound, has been implicated in the formation of advanced glycation end-products (AGEs) and neuronal dysfunction. This study investigated the neuroprotective effects of the combination of trans-resveratrol and hesperidin (tRES-HESP) against MGO-induced neurotoxicity, focusing on memory dysfunction and depression-like behavior.

METHODS: Neuroblastoma 2a (N2a) cells were treated with MGO to induce neurotoxicity. The effects of tRES-HESP on cell viability, reactive oxygen species (ROS) production, apoptotic markers (BAX/Bcl 2 ratio, caspase 3 activity, and poly [ADP ribose] polymerase cleavage), and components of the glyoxalase system (glyoxalase-1, glyoxalase- 2, and receptors for AGEs) were assessed. The activation of the Kelch-like ECH-associated protein 1/Nuclear factor erythroid-2-related factor 2/Heme oxygenase-1 (Keap1/Nrf2/HO-1) pathway was also evaluated. In vivo, mice with MGO-induced depressive amnesia were treated with tRES-HESP (200 mg/kg) for eight weeks, and behavioral, biochemical, and histological assessments were performed.

RESULTS: tRES-HESP significantly reduced MGO-induced cytotoxicity, ROS production, and apoptosis in N2a cells. In addition, it restored the glyoxalase system and activated the Keap1/Nrf2/HO-1 pathway. In an in vivo model, tRES-HESP improved memory and depression-like behaviors, reduced cortisol and interleukin (IL)-6 levels, increased IL-10 levels, and lowered the expression of amyloid precursor protein and amyloid beta. Furthermore, tRES-HESP protected CA2/3 hippocampal subregions from MGO-induced damage. tRES-HESP exhibited neuroprotective effects through antioxidant, anti-apoptotic, and anti-inflammatory mechanisms.

CONCLUSIONS: Our results suggest that tRES-HESP is a potential dietary supplement for preventing cognitive decline and depression, particularly in neurodegenerative conditions such as Alzheimer's disease. Further studies are required to assess its clinical relevance and efficacy in the human population.},
}

Animals
*Pyruvaldehyde/toxicity
*Neuroprotective Agents/pharmacology/administration & dosage
Mice
*Hesperidin/pharmacology/administration & dosage
Disease Models, Animal
*Resveratrol/pharmacology/administration & dosage
Male
Reactive Oxygen Species/metabolism
Apoptosis/drug effects
Cell Line, Tumor
*Neurotoxicity Syndromes/drug therapy/etiology
Cell Survival/drug effects
Behavior, Animal/drug effects
*Depression/drug therapy/chemically induced

@article {pmid40362738,
year = {2025},
author = {Cerullo, M and Armeli, F and Mengoni, B and Menin, M and Crudeli, ML and Businaro, R},
title = {Curcumin Modulation of the Gut-Brain Axis for Neuroinflammation and Metabolic Disorders Prevention and Treatment.},
journal = {Nutrients},
volume = {17},
number = {9},
pages = {},
doi = {10.3390/nu17091430},
pmid = {40362738},
issn = {2072-6643},
mesh = {*Curcumin/pharmacology/therapeutic use ; Humans ; *Metabolic Diseases/prevention & control/drug therapy ; Gastrointestinal Microbiome/drug effects ; Animals ; *Neuroinflammatory Diseases/prevention & control/drug therapy ; *Brain/drug effects ; Oxidative Stress/drug effects ; Anti-Inflammatory Agents/pharmacology ; *Brain-Gut Axis/drug effects ; Inflammation/prevention & control ; },
abstract = {Curcumin, a polyphenolic compound derived from Curcuma longa, has gained significant attention for its potential therapeutic benefits, particularly counteracting inflammation, oxidative stress, and metabolic disorders. Its chemical structure, featuring conjugated double bonds between two aromatic rings, allows it to act as an electron donor, thereby mitigating free radical formation. Despite its poor solubility in water, curcumin is stable in acidic environments and undergoes significant metabolism in both the liver and the gut. Intestinal microbiota, particularly at the colon level, further metabolizes curcumin into several derivatives, including dihydrocurcumin and tetrahydrocurcumin, which exhibit antioxidant and anti-inflammatory properties. Studies suggest that curcumin can reduce body mass index (BMI) and improve other body composition parameters, especially when used in combination with lifestyle changes, though its bioavailability is low due to its rapid metabolism and the resulting low blood concentration. In obesity, dysfunctional adipose tissue remodeling and chronic inflammation play critical roles in the development of metabolic complications. Curcumin's anti-inflammatory properties are related to the inhibition of the NF-κB pathway, leading to the reduction in inflammatory markers in adipocytes and macrophages. Additionally, curcumin modulates oxidative stress by activating the NRF2 pathway, enhancing cellular antioxidant defenses. Emerging evidence also supports curcumin's potential in improving gut health by modulating microbiota composition, enhancing intestinal barrier function, and reducing systemic inflammation. This interaction with the gut-brain axis highlights the broader implications of curcumin in neuroprotection, as it positively affects cognitive function and mitigates neuroinflammation in neurodegenerative diseases like Alzheimer's. disease. Thus, curcumin holds promise as a multifaceted agent in the management of obesity and associated diseases.},
}

*Curcumin/pharmacology/therapeutic use
Humans
*Metabolic Diseases/prevention & control/drug therapy
Gastrointestinal Microbiome/drug effects
Animals
*Neuroinflammatory Diseases/prevention & control/drug therapy
*Brain/drug effects
Oxidative Stress/drug effects
Anti-Inflammatory Agents/pharmacology
*Brain-Gut Axis/drug effects
Inflammation/prevention & control

@article {pmid40362609,
year = {2025},
author = {Qin, C and Li, D and Zhang, J and Yin, Z and Li, F},
title = {Scorpion Venom Heat-Resistant Synthetic Peptide Alleviates Neuronal Necroptosis in Alzheimer's Disease Model by Regulating Lnc Gm6410 Under PM2.5 Exposure.},
journal = {International journal of molecular sciences},
volume = {26},
number = {9},
pages = {},
doi = {10.3390/ijms26094372},
pmid = {40362609},
issn = {1422-0067},
support = {No. LJKZ0844//Liaoning Provincial Department of Education Research Foundation of China/ ; },
mesh = {Animals ; *Particulate Matter/adverse effects/toxicity ; *Alzheimer Disease/drug therapy/metabolism/pathology/genetics/etiology ; Mice ; *Neurons/drug effects/metabolism/pathology ; *Necroptosis/drug effects ; *RNA, Long Noncoding/genetics/metabolism ; Disease Models, Animal ; *Scorpion Venoms/pharmacology/chemistry ; *Peptides/pharmacology ; Humans ; Male ; Mice, Inbred C57BL ; Neuroprotective Agents/pharmacology ; },
abstract = {Recent epidemiological studies have indicated that exposure to particulate matter with an aerodynamic diameter of 2.5 μm or less in the ambient air (PM2.5) is significantly associated with an elevated risk of developing Alzheimer's disease (AD) and its progression. Scorpion venom heat-resistant synthetic peptide (SVHRSP) exhibits anti-inflammatory and neuroprotective properties. However, the exact ways in which SVHRSP mitigates the progression of AD induced by PM2.5 are still unknown. Long non-coding RNA (lncRNA) plays a crucial role in various biological processes. Necroptosis, a form of programmed cell death, has garnered considerable attention in recent years. This study aims to investigate whether Lnc Gm16410 and neuronal necroptosis are involved in PM2.5-exacerbated AD progression and the mechanisms of SVHRSP in alleviating this process. Through the establishment of a PM2.5 exposure model in AD mice and an in vitro model, it was found that PM2.5 exposure could promote necroptosis and the down-regulation of Lnc Gm16410, thereby promoting the progression of AD. Behavioral tests showed that SVHRSP alleviated cognitive impairment in PM2.5-induced AD mice. WB, qRT-PCR, and other molecular biological assays indicate that Lnc Gm16410 regulates neuronal necroptosis under PM2.5 exposure via the p38 MAPK pathway. SVHRSP is a potential regulator of AD progression by regulating Lnc Gm16410 to alleviate PM2.5 exposure-induced necroptosis. These findings offer new insights into the mechanism through which PM2.5 exposure accelerates the progression of AD, examined from the perspective of LncRNA. Furthermore, we offer new targets for the treatment and prevention of AD following PM2.5 exposure by investigating the mechanism of action of SVHRSP in alleviating AD.},
}

Animals
*Particulate Matter/adverse effects/toxicity
*Alzheimer Disease/drug therapy/metabolism/pathology/genetics/etiology
Mice
*Neurons/drug effects/metabolism/pathology
*Necroptosis/drug effects
*RNA, Long Noncoding/genetics/metabolism
Disease Models, Animal
*Scorpion Venoms/pharmacology/chemistry
*Peptides/pharmacology
Humans
Male
Mice, Inbred C57BL
Neuroprotective Agents/pharmacology

@article {pmid40362589,
year = {2025},
author = {Ontawong, A and Nehra, G and Maloney, BJ and Vaddhanaphuti, CS and Bauer, B and Hartz, AMS},
title = {N-Acetylcysteine Attenuates Aβ-Mediated Oxidative Stress, Blood-Brain Barrier Leakage, and Renal Dysfunction in 5xFAD Mice.},
journal = {International journal of molecular sciences},
volume = {26},
number = {9},
pages = {},
doi = {10.3390/ijms26094352},
pmid = {40362589},
issn = {1422-0067},
support = {1R01NS133250-24A1/NH/NIH HHS/United States ; },
mesh = {Animals ; *Oxidative Stress/drug effects ; *Blood-Brain Barrier/drug effects/metabolism ; *Acetylcysteine/pharmacology ; *Amyloid beta-Peptides/metabolism ; Mice ; *Alzheimer Disease/metabolism/drug therapy ; Mice, Transgenic ; Disease Models, Animal ; Aldehydes/metabolism ; Male ; Antioxidants/pharmacology ; Brain/metabolism/drug effects ; Kidney/drug effects/metabolism ; S100 Calcium Binding Protein beta Subunit/blood ; },
abstract = {Alzheimer's disease (AD) is characterized by amyloid-beta (Aβ) pathology and is closely linked to oxidative stress, which contributes to blood-brain barrier leakage, renal dysfunction, and cognitive decline. We investigated the effects of N-acetyl cysteine (NAC), an FDA-approved antioxidant, on oxidative stress, brain Aβ levels, barrier leakage, renal function, and cognition in 5xFAD mice. Eight-week-old 5xFAD mice were fed a rodent diet supplemented with 600 mg/kgDiet NAC for 4 weeks; wild-type (WT) mice and control 5xFAD mice were fed a regular rodent diet. We detected elevated brain and renal 4-hydroxynonenal(4-HNE) levels, reduced creatinine clearance, and increased plasma S100β levels in untreated 5xFAD mice compared to WT controls. Untreated 5xFAD mice also had higher capillary leakage, reduced P-gp activity, and impaired cognition compared to WT. NAC treatment of 5xFAD mice reduced brain Aβ40 levels, normalized 4-HNE levels to control levels, improved creatinine clearance, decreased capillary leakage, and lowered S100β plasma levels. NAC improved cognitive performance in 5xFAD mice, as shown by Y-maze. Our findings indicate that Aβ-induced oxidative stress contributes to barrier dysfunction, renal impairment, and cognitive deficits in 5xFAD mice. Notably, NAC treatment mitigates these effects, suggesting its potential as an adjunct therapy for AD and other Aβ-related pathologies by reducing oxidative stress.},
}

Animals
*Oxidative Stress/drug effects
*Blood-Brain Barrier/drug effects/metabolism
*Acetylcysteine/pharmacology
*Amyloid beta-Peptides/metabolism
Mice
*Alzheimer Disease/metabolism/drug therapy
Mice, Transgenic
Disease Models, Animal
Aldehydes/metabolism
Male
Antioxidants/pharmacology
Brain/metabolism/drug effects
Kidney/drug effects/metabolism
S100 Calcium Binding Protein beta Subunit/blood

@article {pmid40362548,
year = {2025},
author = {De Rino, F and Rispoli, F and Zuffi, M and Matteucci, E and Gavazzi, A and Salvatici, M and Sansico, DF and Pollaroli, G and Drago, L},
title = {Assessment of Plasma and Cerebrospinal Fluid Biomarkers in Patients with Alzheimer's Disease and Other Dementias: A Center-Based Study.},
journal = {International journal of molecular sciences},
volume = {26},
number = {9},
pages = {},
doi = {10.3390/ijms26094308},
pmid = {40362548},
issn = {1422-0067},
mesh = {Humans ; *Alzheimer Disease/blood/cerebrospinal fluid/diagnosis ; *Biomarkers/blood/cerebrospinal fluid ; Male ; Female ; *Amyloid beta-Peptides/blood/cerebrospinal fluid ; tau Proteins/blood/cerebrospinal fluid ; Aged ; Middle Aged ; *Dementia/blood/cerebrospinal fluid/diagnosis ; Peptide Fragments/cerebrospinal fluid/blood ; Cognitive Dysfunction/blood/cerebrospinal fluid ; Aged, 80 and over ; },
abstract = {Neuropsychological interviews and neuroimaging techniques are traditional diagnostic methods for Alzheimer's disease (AD). However, the development of blood-based biomarkers, such as Amyloid beta (Aβ), phosphorylated Tau (pTau), and their ratios, offers promising non-invasive alternatives for early AD detection. This study aimed to analyze the correlation between CSF and plasma biomarkers (Aβ40, Aβ42, Aβ42/Aβ40, pTau181) and evaluate their diagnostic performance in 51 patients with cognitive impairments. Biomarkers were analyzed in both plasma and CSF using an automated chemiluminescence enzyme immunoassay, Lumipulse (Fujirebio). The results showed significant positive correlations between CSF and plasma levels of Aβ42, the Aβ42/Aβ40 ratio, and pTau181, but not for Aβ40. Plasma Aβ42, pTau181, Aβ42/Aβ40 ratio, and pTau181/Aβ42 ratio demonstrated significant differences between patients A+ vs. A- classified based on CSF Amyloid status, as well as between those classified as A+T+ and A-T- according to both CSF Amyloid and Tau levels. Plasma pTau181, Aβ42/Aβ40, and pTau181/Aβ42 ratio showed high diagnostic accuracy in distinguishing A+ from A- (AUC = 0.93-0.95) and A+T+ from A-T- patients (AUC = 0.93-0.97). These findings suggest that plasma biomarkers can effectively differentiate between AD and other forms of dementia, and serve as a reliable, non-invasive tool for early detection and monitoring of Alzheimer's disease.},
}

Humans
*Alzheimer Disease/blood/cerebrospinal fluid/diagnosis
*Biomarkers/blood/cerebrospinal fluid
Male
Female
*Amyloid beta-Peptides/blood/cerebrospinal fluid
tau Proteins/blood/cerebrospinal fluid
Aged
Middle Aged
*Dementia/blood/cerebrospinal fluid/diagnosis
Peptide Fragments/cerebrospinal fluid/blood
Cognitive Dysfunction/blood/cerebrospinal fluid
Aged, 80 and over

@article {pmid40362507,
year = {2025},
author = {Toader, C and Serban, M and Munteanu, O and Covache-Busuioc, RA and Enyedi, M and Ciurea, AV and Tataru, CP},
title = {From Synaptic Plasticity to Neurodegeneration: BDNF as a Transformative Target in Medicine.},
journal = {International journal of molecular sciences},
volume = {26},
number = {9},
pages = {},
doi = {10.3390/ijms26094271},
pmid = {40362507},
issn = {1422-0067},
mesh = {Humans ; *Brain-Derived Neurotrophic Factor/metabolism/genetics ; *Neuronal Plasticity ; Animals ; *Neurodegenerative Diseases/metabolism/therapy ; Biomarkers/metabolism ; },
abstract = {The brain-derived neurotrophic factor (BDNF) has become one of the cornerstones of neuropathology, influencing synaptic plasticity, cognitive resilience, and neuronal survival. Apart from its molecular biology, BDNF is a powerful target for transformative benefit in precision medicine, leading to innovative therapeutic approaches for neurodegenerative and psychiatric diseases like Alzheimer's disease (AD), Parkinson's disease (PD), major depressive disorder (MDD), and post-traumatic stress disorder (PTSD). Nevertheless, clinical applicability is obstructed by hurdles in delivery, patient-specific diversity, and pleiotropic signaling. Here, we summarize findings in BDNF research, including its regulatory pathways and diagnostic/prognostic biomarkers and integrative therapeutic approaches. We describe innovative delivery systems, such as lipid nanoparticle-based mRNA therapies and CRISPR-dCas9-based epigenetic editing that bypass obstacles such as BBB (blood-brain barrier) and enzymatic degradation. The recent implementation of multiplex panels combining BDNF biodynamic indicators with tau and amyloid-β signaling markers showcases novel levels of specificity for both early detection and potential therapeutic monitoring. Humanized preclinical models like iPSC-derived neurons and organoids point to the key role of BDNF in neurodeveloping and neurodegenerative processes, paralleling advances in bridging preclinical observation and clinical environments. Moreover, novel therapeutic tools delivering TrkB activators or the implementation of AI-based dynamic care platforms enable tailored and scalable treatments. This review also aims to extend a framework used in the understanding of BDNF's relevance to traditional neurodegenerative models by situating more recent work detailing BDNF's actions in ischemic tissues and the gut-brain axis in the context of systemic health. Finally, we outline a roadmap for the incorporation of BDNF-centered therapies into worldwide healthcare, highlighting ethical issues, equity, and interdisciplinary decomposition. The therapeutic potential of BDNF heralds a new era in neuroscience and medicine, revolutionizing brain health and paving the way for the advancement of precision medicine.},
}

Humans
*Brain-Derived Neurotrophic Factor/metabolism/genetics
*Neuronal Plasticity
Animals
*Neurodegenerative Diseases/metabolism/therapy
Biomarkers/metabolism

@article {pmid40362488,
year = {2025},
author = {Volloch, V and Rits-Volloch, S},
title = {Alzheimer's Is a Multiform Disease of Sustained Neuronal Integrated Stress Response Driven by the C99 Fragment Generated Independently of AβPP; Proteolytic Production of Aβ Is Suppressed in AD-Affected Neurons: Evolution of a Theory.},
journal = {International journal of molecular sciences},
volume = {26},
number = {9},
pages = {},
doi = {10.3390/ijms26094252},
pmid = {40362488},
issn = {1422-0067},
support = {NIH R21 GM056179; NIH RO1 AR036819/GF/NIH HHS/United States ; },
mesh = {*Alzheimer Disease/metabolism/pathology/etiology ; Humans ; *Neurons/metabolism/pathology ; *Amyloid beta-Peptides/metabolism ; Animals ; *Amyloid beta-Protein Precursor/metabolism ; Proteolysis ; *Peptide Fragments/metabolism ; },
abstract = {The present Perspective analyzes the remarkable evolution of the Amyloid Cascade Hypothesis 2.0 (ACH2.0) theory of Alzheimer's disease (AD) since its inception a few years ago, as reflected in the diminishing role of amyloid-beta (Aβ) in the disease. In the initial iteration of the ACH2.0, Aβ-protein-precursor (AβPP)-derived intraneuronal Aβ (iAβ), accumulated to neuronal integrated stress response (ISR)-eliciting levels, triggers AD. The neuronal ISR, in turn, activates the AβPP-independent production of its C99 fragment that is processed into iAβ, which drives the disease. The second iteration of the ACH2.0 stemmed from the realization that AD is, in fact, a disease of the sustained neuronal ISR. It introduced two categories of AD-conventional and unconventional-differing mainly in the manner of their causation. The former is caused by the neuronal ISR triggered by AβPP-derived iAβ, whereas in the latter, the neuronal ISR is elicited by stressors distinct from AβPP-derived iAβ and arising from brain trauma, viral and bacterial infections, and various types of inflammation. Moreover, conventional AD always contains an unconventional component, and in both forms, the disease is driven by iAβ generated independently of AβPP. In its third, the current, iteration, the ACH2.0 posits that proteolytic production of Aβ is suppressed in AD-affected neurons and that the disease is driven by C99 generated independently of AβPP. Suppression of Aβ production in AD seems an oxymoron: Aβ is equated with AD, and the later is inconceivable without the former in an ingrained Amyloid Cascade Hypothesis (ACH)-based notion. But suppression of Aβ production in AD-affected neurons is where the logic leads, and to follow it we only need to overcome the inertia of the preexisting assumptions. Moreover, not only is the generation of Aβ suppressed, so is the production of all components of the AβPP proteolytic pathway. This assertion is not a quantum leap (unless overcoming the inertia counts as such): the global cellular protein synthesis is severely suppressed under the neuronal ISR conditions, and there is no reason for constituents of the AβPP proteolytic pathway to be exempted, and they, apparently, are not, as indicated by the empirical data. In contrast, tau protein translation persists in AD-affected neurons under ISR conditions because the human tau mRNA contains an internal ribosomal entry site in its 5'UTR. In current mouse models, iAβ derived from AβPP expressed exogenously from human transgenes elicits the neuronal ISR and thus suppresses its own production. Its levels cannot principally reach AD pathology-causing levels regardless of the number of transgenes or the types of FAD mutations that they (or additional transgenes) carry. Since the AβPP-independent C99 production pathway is inoperative in mice, the current transgenic models have no potential for developing the full spectrum of AD pathology. What they display are only effects of the AβPP-derived iAβ-elicited neuronal ISR. The paper describes strategies to construct adequate transgenic AD models. It also details the utilization of human neuronal cells as the only adequate model system currently available for conventional and unconventional AD. The final alteration of the ACH2.0, introduced in the present Perspective, is that AβPP, which supports neuronal functionality and viability, is, after all, potentially produced in AD-affected neurons, albeit not conventionally but in an ISR-driven and -compatible process. Thus, the present narrative begins with the "omnipotent" Aβ capable of both triggering and driving the disease and ends up with this peptide largely dislodged from its pedestal and retaining its central role in triggering the disease in only one, although prevalent (conventional), category of AD (and driving it in none). Among interesting inferences of the present Perspective is the determination that "sporadic AD" is not sporadic at all ("non-familial" would be a much better designation). The term has fatalistic connotations, implying that the disease can strike at random. This is patently not the case: The conventional disease affects a distinct subpopulation, and the basis for unconventional AD is well understood. Another conclusion is that, unless prevented, the occurrence of conventional AD is inevitable given a sufficiently long lifespan. This Perspective also defines therapeutic directions not to be taken as well as auspicious ways forward. The former category includes ACH-based drugs (those interfering with the proteolytic production of Aβ and/or depleting extracellular Aβ). They are legitimate (albeit inefficient) preventive agents for conventional AD. There is, however, a proverbial snowball's chance in hell of them being effective in symptomatic AD, lecanemab, donanemab, and any other "…mab" or "…stat" notwithstanding. They comprise Aβ-specific antibodies, inhibitors of beta- and gamma-secretase, and modulators of the latter. In the latter category, among ways to go are the following: (1) Depletion of iAβ, which, if sufficiently "deep", opens up a tantalizing possibility of once-in-a-lifetime preventive transient treatment for conventional AD and aging-associated cognitive decline, AACD. (2) Composite therapy comprising the degradation of C99/iAβ and concurrent inhibition of the neuronal ISR. A single transient treatment could be sufficient to arrest the progression of conventional AD and prevent its recurrence for life. Multiple recurrent treatments would achieve the same outcome in unconventional AD. Alternatively, the sustained reduction/removal of unconventional neuronal ISR-eliciting stressors through the elimination of their source would convert unconventional AD into conventional one, preventable/treatable by a single transient administration of the composite C99/iAβ depletion/ISR suppression therapy. Efficient and suitable ISR inhibitors are available, and it is explicitly clear where to look for C99/iAβ-specific targeted degradation agents-activators of BACE1 and, especially, BACE2. Directly acting C99/iAβ-specific degradation agents such as proteolysis-targeting chimeras (PROTACs) and molecular-glue degraders (MGDs) are also viable options. (3) A circumscribed shift (either upstream or downstream) of the position of transcription start site (TSS) of the human AβPP gene, or, alternatively, a gene editing-mediated excision or replacement of a small, defined segment of its portion encoding 5'-untranslated region of AβPP mRNA; targeting AβPP RNA with anti-antisense oligonucleotides is another possibility. If properly executed, these RNA-based strategies would not interfere with the protein-coding potential of AβPP mRNA, and each would be capable of both preventing and stopping the AβPP-independent generation of C99 and thus of either preventing AD or arresting the progression of the disease in its conventional and unconventional forms. The paper is interspersed with "validation" sections: every conceptually significant notion is either validated by the existing data or an experimental procedure validating it is proposed.},
}

*Alzheimer Disease/metabolism/pathology/etiology
Humans
*Neurons/metabolism/pathology
*Amyloid beta-Peptides/metabolism
Animals
*Amyloid beta-Protein Precursor/metabolism
Proteolysis
*Peptide Fragments/metabolism

@article {pmid40362451,
year = {2025},
author = {Park, CK and Choi, SJ and Kim, CR and Shin, HR and Shin, EC and Kim, YJ and Cho, TJ and Shin, DH and Kim, JK},
title = {Ethanolic Extract of Rosa rugosa Roots and Its Bioactive Compound, Oleamide, Prevented Amyloid β-Induced Oxidative Stress and Improved Behavioral Tests in Mice.},
journal = {International journal of molecular sciences},
volume = {26},
number = {9},
pages = {},
doi = {10.3390/ijms26094214},
pmid = {40362451},
issn = {1422-0067},
support = {RS-2024-00332492//the Ministry of Food and Drug Safety of South Korea/ ; NRF-2022R1A4A3033775//the National Research Foundation of Korea (NRF) grants funded by the Korean government (Ministry of Science and ICT, MSIT)/ ; RS-2024-00393604//the National Research Foundation of Korea (NRF)/ ; },
mesh = {Animals ; *Rosa/chemistry ; *Oxidative Stress/drug effects ; *Amyloid beta-Peptides/toxicity/metabolism ; Mice ; *Plant Extracts/pharmacology/chemistry ; Male ; Rats ; *Plant Roots/chemistry ; *Oleic Acids/pharmacology/chemistry ; PC12 Cells ; *Neuroprotective Agents/pharmacology/chemistry ; Ethanol/chemistry ; Behavior, Animal/drug effects ; Alzheimer Disease/drug therapy/metabolism ; Antioxidants/pharmacology ; Brain/metabolism/drug effects ; },
abstract = {Researchers have long focused on the accumulation of amyloid beta (Aβ) peptides in the brain as a primary pathological hallmark driving cognitive decline. This study investigated the neuroprotective effects of Rosa rugosa (RR) root extract and its key bioactive constituent, oleamide, against amyloid beta (Aβ)-induced neurotoxicity. Initially, an ethanolic extract of RR root was screened via in vitro assays to assess antioxidant and cytoprotective potential in rat pheochromocytoma cells. Subsequent fractionation, open-column chromatography, and preparatory thin-layer chromatography led to the isolation of oleamide, confirmed by gas chromatography-mass spectrometry and [1]H/[13]C nuclear magnetic resonance analyses. In vivo experiments using intracerebroventricularly injected Aβ in male mice demonstrated that both RR root extract and oleamide significantly improved cognitive performance in the Y-maze and passive avoidance tests. Additionally, oleamide restored acetylcholine levels and reduced malondialdehyde concentrations in brain tissue, indicating mitigation of oxidative stress and support of cholinergic function. No significant toxicity was observed, as evidenced by stable serum transaminase levels and unaltered body or brain weights. These findings highlight oleamide's potential to protect against Aβ-driven pathology through multiple mechanisms, including reduced lipid peroxidation and improved neurotransmission. Further investigations into oleamide's molecular targets and synergy with existing therapies may advance its development as a novel candidate for Alzheimer's disease prevention or adjunct treatment.},
}

Animals
*Rosa/chemistry
*Oxidative Stress/drug effects
*Amyloid beta-Peptides/toxicity/metabolism
Mice
*Plant Extracts/pharmacology/chemistry
Male
Rats
*Plant Roots/chemistry
*Oleic Acids/pharmacology/chemistry
PC12 Cells
*Neuroprotective Agents/pharmacology/chemistry
Ethanol/chemistry
Behavior, Animal/drug effects
Alzheimer Disease/drug therapy/metabolism
Antioxidants/pharmacology
Brain/metabolism/drug effects

@article {pmid40362446,
year = {2025},
author = {Ponce-Lopez, T},
title = {Peripheral Inflammation and Insulin Resistance: Their Impact on Blood-Brain Barrier Integrity and Glia Activation in Alzheimer's Disease.},
journal = {International journal of molecular sciences},
volume = {26},
number = {9},
pages = {},
doi = {10.3390/ijms26094209},
pmid = {40362446},
issn = {1422-0067},
mesh = {Humans ; *Alzheimer Disease/metabolism/pathology ; *Blood-Brain Barrier/metabolism/pathology ; *Insulin Resistance ; *Neuroglia/metabolism/pathology ; *Inflammation/metabolism/pathology ; Animals ; Diabetes Mellitus, Type 2/metabolism ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, memory impairment, and synaptic dysfunction. The accumulation of amyloid beta (Aβ) plaques and hyperphosphorylated tau protein leads to neuronal dysfunction, neuroinflammation, and glial cell activation. Emerging evidence suggests that peripheral insulin resistance and chronic inflammation, often associated with type 2 diabetes (T2D) and obesity, promote increased proinflammatory cytokines, oxidative stress, and immune cell infiltration. These conditions further damage the blood-brain barrier (BBB) integrity and promote neurotoxicity and chronic glial cell activation. This induces neuroinflammation and impaired neuronal insulin signaling, reducing glucose metabolism and exacerbating Aβ accumulation and tau hyperphosphorylation. Indeed, epidemiological studies have linked T2D and obesity with an increased risk of developing AD, reinforcing the connection between metabolic disorders and neurodegeneration. This review explores the relationships between peripheral insulin resistance, inflammation, and BBB dysfunction, highlighting their role in glial activation and the exacerbation of AD pathology.},
}

Humans
*Alzheimer Disease/metabolism/pathology
*Blood-Brain Barrier/metabolism/pathology
*Insulin Resistance
*Neuroglia/metabolism/pathology
*Inflammation/metabolism/pathology
Animals
Diabetes Mellitus, Type 2/metabolism

@article {pmid40362435,
year = {2025},
author = {Pagano, L and Lagrotteria, D and Facconi, A and Saraceno, C and Longobardi, A and Bellini, S and Ingannato, A and Bagnoli, S and Ducci, T and Mingrino, A and Laganà, V and Paparazzo, E and Borroni, B and Maletta, R and Nacmias, B and Montesanto, A and Ghidoni, R},
title = {Evaluation of Illumina and Oxford Nanopore Sequencing for the Study of DNA Methylation in Alzheimer's Disease and Frontotemporal Dementia.},
journal = {International journal of molecular sciences},
volume = {26},
number = {9},
pages = {},
doi = {10.3390/ijms26094198},
pmid = {40362435},
issn = {1422-0067},
support = {PNRR-MR1- 2022-12375654//European Union/ ; },
mesh = {*DNA Methylation ; Humans ; *Alzheimer Disease/genetics ; *Frontotemporal Dementia/genetics ; *Nanopore Sequencing/methods ; *Sequence Analysis, DNA/methods ; *High-Throughput Nucleotide Sequencing/methods ; CpG Islands ; Epigenesis, Genetic ; },
abstract = {DNA methylation is a critical epigenetic mechanism involved in numerous physiological processes. Alterations in DNA methylation patterns are associated with various brain disorders, including dementias such as Alzheimer's disease (AD) and frontotemporal dementia (FTD). Investigating these alterations is essential for understanding the pathogenesis and progression of these disorders. Among the various methods for detecting DNA methylation, DNA sequencing is one of the most widely employed. Specifically, two main sequencing approaches are commonly used for DNA methylation analysis: bisulfite sequencing and single-molecule long-read sequencing. In this review, we compared the performances of CpG methylation detection obtained using two popular sequencing platforms, Illumina for bisulfite sequencing and Oxford Nanopore (ON) for long-read sequencing. Our comparison considers several factors, including accuracy, efficiency, genomic regions, costs, wet-lab protocols, and bioinformatics pipelines. We provide insights into the strengths and limitations of both methods with a particular focus on their application in research on AD and FTD.},
}

*DNA Methylation
Humans
*Alzheimer Disease/genetics
*Frontotemporal Dementia/genetics
*Nanopore Sequencing/methods
*Sequence Analysis, DNA/methods
*High-Throughput Nucleotide Sequencing/methods
CpG Islands
Epigenesis, Genetic

@article {pmid40362426,
year = {2025},
author = {de la Monte, SM and Yang, Y and Prabhu, A and Tong, M},
title = {Comparative Brain and Serum Exosome Expression of Biomarkers in an Experimental Model of Alzheimer-Type Neurodegeneration: Potential Relevance to Liquid Biopsy Diagnostics.},
journal = {International journal of molecular sciences},
volume = {26},
number = {9},
pages = {},
doi = {10.3390/ijms26094190},
pmid = {40362426},
issn = {1422-0067},
support = {R01-AA011431//National Institutes of/ ; R01-AA-028408/AA/NIAAA NIH HHS/United States ; R21-AA032106/AA/NIAAA NIH HHS/United States ; },
mesh = {Animals ; *Alzheimer Disease/metabolism/blood/pathology/diagnosis ; *Biomarkers/blood/metabolism ; Rats ; *Exosomes/metabolism ; Disease Models, Animal ; Liquid Biopsy/methods ; *Brain/metabolism/pathology ; Male ; Rats, Long-Evans ; Streptozocin ; },
abstract = {The development of more effective disease-modifying treatments for Alzheimer's disease (AD) is compromised by the lack of streamlined measures to detect and monitor the full spectrum of neurodegeneration, including white matter pathology, which begins early. This study utilized an established intracerebral streptozotocin (STZ) model of AD to examine the potential utility of a non-invasive serum extracellular vesicle (SEV)-based liquid biopsy approach for detecting a broad range of molecular pathologies related to neurodegeneration. The design enabled comparative analysis of immunoreactivity in frontal lobe tissue (FLTX), frontal lobe-derived EVs (FLEVs), and SEVs. Long Evans rats were administered i.c. STZ or saline (control) on postnatal day 3 (P3). Morris Water Maze testing was performed from P24 to P27. On P31-32, the rats were sacrificed to harvest FLTX and serum for EV characterization. STZ caused brain atrophy, with deficits in spatial learning and memory. STZ significantly impacted FLEV and SEV nanoparticle abundance and size distributions and concordantly increased AD (Tau, pTau, and Aβ) and oxidative stress (ubiquitin, 4-HNE) biomarkers, as well as immunoreactivity to immature oligodendrocyte (PLP), non-myelinating glial (PDGFRA, GALC) proteins, MAG, nestin, and GFAP in FLTX and FLEV. The SEVs also exhibited concordant STZ-related effects, but they were limited to increased levels of 4-HNE, PLP, PDGFRA, GALC, MAG, and GFAP. The findings suggest that non-invasive EV-based liquid biopsy approaches could potentially be used to detect and monitor some aspects of AD-type neurodegeneration. Targeting brain-specific EVs in serum will likely increase the sensitivity of this promising non-invasive approach for diagnostic and clinical management.},
}

Animals
*Alzheimer Disease/metabolism/blood/pathology/diagnosis
*Biomarkers/blood/metabolism
Rats
*Exosomes/metabolism
Disease Models, Animal
Liquid Biopsy/methods
*Brain/metabolism/pathology
Male
Rats, Long-Evans
Streptozocin

@article {pmid40362405,
year = {2025},
author = {Riemann, K and von Ahsen, J and Böhm, T and Schlegel, M and Kreuzer, M and Fenzl, T and Russ, H and Parsons, CG and Rammes, G},
title = {GAL-201 as a Promising Amyloid-β-Targeting Small-Molecule Approach for Alzheimer's Disease Treatment: Consistent Effects on Synaptic Plasticity, Behavior and Neuroinflammation.},
journal = {International journal of molecular sciences},
volume = {26},
number = {9},
pages = {},
doi = {10.3390/ijms26094167},
pmid = {40362405},
issn = {1422-0067},
mesh = {Animals ; *Alzheimer Disease/drug therapy/metabolism/pathology ; *Amyloid beta-Peptides/metabolism ; *Neuronal Plasticity/drug effects ; Mice ; Disease Models, Animal ; *Neuroinflammatory Diseases/drug therapy/metabolism ; Microglia/drug effects/metabolism ; Humans ; *Neuroprotective Agents/pharmacology/therapeutic use ; Mice, Transgenic ; Hippocampus/drug effects/metabolism ; Male ; Astrocytes/drug effects/metabolism ; Peptide Fragments/metabolism ; },
abstract = {Soluble oligomeric forms of Amyloid-β (Aβ) are considered the major toxic species leading to the neurodegeneration underlying Alzheimer's disease (AD). Therefore, drugs that prevent oligomer formation might be promising. The atypical dipeptide GAL-201 is orally bioavailable and interferes as a modulator of Aβ aggregation. It binds to aggregation-prone, misfolded Aβ monomers with high selectivity and affinity, thereby preventing the formation of toxic oligomers. Here, we demonstrate that the previously observed protective effect of GAL-201 on synaptic plasticity occurs irrespective of shortages and post-translational modifications (tested isoforms: Aβ1-42, Aβ(p3-42), Aβ1-40 and 3NTyr(10)-Aβ). Interestingly, the neuroprotective activity of a single dose of GAL-201 was still present after one week and correlated with a prevention of Aβ-induced spine loss. Furthermore, we could observe beneficial effects on spine morphology as well as the significantly reduced activation of proinflammatory microglia and astrocytes in the presence of an Aβ1-42-derived toxicity. In line with these in vitro data, GAL-201 additionally improved hippocampus-dependent spatial learning in the "tgArcSwe" AD mouse model after a single subcutaneous administration. By this means, we observed changes in the deposition pattern: through the clustering of misfolded monomers as off-pathway non-toxic Aβ agglomerates, toxic oligomers are removed. Our results are in line with previously collected preclinical data and warrant the initiation of Investigational New Drug (IND)-enabling studies for GAL-201. By demonstrating the highly efficient detoxification of β-sheet monomers, leading to the neutralization of Aβ oligomer toxicity, GAL-201 represents a promising drug candidate against Aβ-derived pathophysiology present in AD.},
}

Animals
*Alzheimer Disease/drug therapy/metabolism/pathology
*Amyloid beta-Peptides/metabolism
*Neuronal Plasticity/drug effects
Mice
Disease Models, Animal
*Neuroinflammatory Diseases/drug therapy/metabolism
Microglia/drug effects/metabolism
Humans
*Neuroprotective Agents/pharmacology/therapeutic use
Mice, Transgenic
Hippocampus/drug effects/metabolism
Male
Astrocytes/drug effects/metabolism
Peptide Fragments/metabolism

@article {pmid40362380,
year = {2025},
author = {Joseph, D},
title = {The Unified Theory of Neurodegeneration Pathogenesis Based on Axon Deamidation.},
journal = {International journal of molecular sciences},
volume = {26},
number = {9},
pages = {},
doi = {10.3390/ijms26094143},
pmid = {40362380},
issn = {1422-0067},
support = {FL/03-09-2024/1250//Flogen Technologies Inc./ ; },
mesh = {Humans ; *Axons/metabolism/pathology ; *Neurodegenerative Diseases/metabolism/pathology/etiology ; Animals ; Oxidative Stress ; Protein Biosynthesis ; Amides/metabolism ; },
abstract = {Until now, neurodegenerative diseases like Alzheimer's and Parkinson's have been studied separately in biochemistry and therapeutic drug development, and no causal link has ever been established between them. This study has developed a Unified Theory, which establishes that the regulation of axon and dendrite-specific 4E-BP2 deamidation rates controls the occurrence and progression of neurodegenerative diseases. This is based on identifying axon-specific 4E-BP2 deamidation as a universal denominator for the biochemical processes of deamidation, translational control, oxidative stress, and neurodegeneration. This was achieved by conducting a thorough and critical review of 224 scientific publications regarding (a) deamidation, (b) translational control in protein synthesis initiation, (c) neurodegeneration and (d) oxidative stress, and by applying my discovery of the fundamental neurobiological mechanism behind neuron-specific 4E-BP2 deamidation to practical applications in medicine. Based on this newly developed Unified Theory and my critical review of the scientific literature, I also designed three biochemical flowsheets of (1) in-vivo deamidation, (2) protein synthesis initiation and translational control, and (3) 4E-BP2 deamidation as a control system of the four biochemical processes. The Unified Theory of Neurodegeneration Pathogenesis based on axon deamidation, developed in this work, paves the way to controlling the occurrence and progression of neurodegenerative diseases such as Alzheimer's and Parkinson's through a unique, neuron-specific regulatory system that is 4E-BP2 deamidation, caused by the proteasome-poor environment in neuronal projections, consisting mainly of axons.},
}

Humans
*Axons/metabolism/pathology
*Neurodegenerative Diseases/metabolism/pathology/etiology
Animals
Oxidative Stress
Protein Biosynthesis
Amides/metabolism

@article {pmid40362335,
year = {2025},
author = {Litus, EA and Shevelyova, MP and Vologzhannikova, AA and Deryusheva, EI and Chaplygina, AV and Rastrygina, VA and Machulin, AV and Alikova, VD and Nazipova, AA and Permyakova, ME and Dotsenko, VV and Permyakov, SE and Nemashkalova, EL},
title = {Interaction Between Glucagon-like Peptide 1 and Its Analogs with Amyloid-β Peptide Affects Its Fibrillation and Cytotoxicity.},
journal = {International journal of molecular sciences},
volume = {26},
number = {9},
pages = {},
doi = {10.3390/ijms26094095},
pmid = {40362335},
issn = {1422-0067},
support = {20-74-10072//Russian Science Foundation/ ; },
mesh = {*Amyloid beta-Peptides/metabolism/chemistry ; *Glucagon-Like Peptide 1/metabolism/analogs & derivatives/chemistry/pharmacology ; Humans ; *Peptide Fragments/metabolism/chemistry ; Protein Binding ; Liraglutide/pharmacology/chemistry/metabolism ; Surface Plasmon Resonance ; Exenatide/pharmacology/chemistry ; Cell Survival/drug effects ; },
abstract = {Clinical data as well as animal and cell studies indicate that certain antidiabetic drugs, including glucagon-like peptide 1 receptor agonists (GLP-1RAs), exert therapeutic effects in Alzheimer's disease (AD) by modulating amyloid-β peptide (Aβ) metabolism. Meanwhile, the direct interactions between GLP-1RAs and Aβ and their functional consequences remain unexplored. In this study, the interactions between monomeric Aβ40/Aβ42 of GLP-1(7-37) and its several analogs (semaglutide (Sema), liraglutide (Lira), exenatide (Exen)) were studied using biolayer interferometry and surface plasmon resonance spectroscopy. The quaternary structure of GLP-1RAs was investigated using dynamic light scattering. The effects of GLP-1RAs on Aβ fibrillation were assessed using the thioflavin T assay and electron microscopy. The impact of GLP-1RAs on Aβ cytotoxicity was evaluated via the MTT assay. Monomeric Aβ40 and Aβ42 directly bind to GLP-1(7-37), Sema, Lira, and Exen, with the highest affinity for Lira (the lowest estimates of equilibrium dissociation constants were 42-60 nM). GLP-1RAs are prone to oligomerization, which may affect their binding to Aβ. GLP-1(7-37) and Exen inhibit Aβ40 fibrillation, whereas Sema promotes it. GLP-1 analogs decrease Aβ cytotoxicity toward SH-SY5Y cells, while GLP-1(7-37) enhances Aβ40 cytotoxicity without affecting the cytotoxic effect of Aβ42. Overall, GLP-1RAs interact with Aβ and differentially modulate its fibrillation and cytotoxicity, suggesting the need for further studies of our observed effects in vivo.},
}

*Amyloid beta-Peptides/metabolism/chemistry
*Glucagon-Like Peptide 1/metabolism/analogs & derivatives/chemistry/pharmacology
Humans
*Peptide Fragments/metabolism/chemistry
Protein Binding
Liraglutide/pharmacology/chemistry/metabolism
Surface Plasmon Resonance
Exenatide/pharmacology/chemistry
Cell Survival/drug effects

@article {pmid40362276,
year = {2025},
author = {Hudák, A and Letoha, T},
title = {Endocytic Pathways Unveil the Role of Syndecans in the Seeding and Spreading of Pathological Protein Aggregates: Insights into Neurodegenerative Disorders.},
journal = {International journal of molecular sciences},
volume = {26},
number = {9},
pages = {},
doi = {10.3390/ijms26094037},
pmid = {40362276},
issn = {1422-0067},
support = {2020-1.1.2-PIACI-KFI-2021-00233//National Research Development and Innovation Office, Hungary/ ; 2024-1.2.2-ERA_NET-2024-00013//National Research Development and Innovation Office, Hungary/ ; },
mesh = {Humans ; *Neurodegenerative Diseases/metabolism/pathology ; *Protein Aggregation, Pathological/metabolism/pathology ; Animals ; *Endocytosis ; *Syndecans/metabolism ; Amyloid beta-Peptides/metabolism ; Alzheimer Disease/metabolism/pathology ; tau Proteins/metabolism ; alpha-Synuclein/metabolism ; *Protein Aggregates ; },
abstract = {Alzheimer's disease and other neurodegenerative disorders are characterized by the accumulation of misfolded proteins, such as amyloid-beta, tau, and α-synuclein, which disrupt neuronal function and contribute to cognitive decline. Heparan sulfate proteoglycans, particularly syndecans, play a pivotal role in the seeding, aggregation, and spreading of toxic protein aggregates through endocytic pathways. Among these, syndecan-3 is particularly critical in regulating the internalization of misfolded proteins, facilitating their propagation in a prion-like manner. This review examines the mechanisms by which syndecans, especially SDC3, contribute to the seeding and spreading of pathological protein aggregates in neurodegenerative diseases. Understanding these endocytic pathways provides valuable insights into the potential of syndecans as biomarkers and therapeutic targets for early intervention in Alzheimer's disease and other related neurodegenerative disorders.},
}

Humans
*Neurodegenerative Diseases/metabolism/pathology
*Protein Aggregation, Pathological/metabolism/pathology
Animals
*Endocytosis
*Syndecans/metabolism
Amyloid beta-Peptides/metabolism
Alzheimer Disease/metabolism/pathology
tau Proteins/metabolism
alpha-Synuclein/metabolism
*Protein Aggregates

@article {pmid40362265,
year = {2025},
author = {Zhdanova, DY and Bobkova, NV and Chaplygina, AV and Svirshchevskaya, EV and Poltavtseva, RA and Vodennikova, AA and Chernyshev, VS and Sukhikh, GT},
title = {Effect of Small Extracellular Vesicles Produced by Mesenchymal Stem Cells on 5xFAD Mice Hippocampal Cultures.},
journal = {International journal of molecular sciences},
volume = {26},
number = {9},
pages = {},
doi = {10.3390/ijms26094026},
pmid = {40362265},
issn = {1422-0067},
support = {23-13-00035//Russian Science Foundation/ ; },
mesh = {Animals ; *Hippocampus/metabolism/cytology/pathology ; *Mesenchymal Stem Cells/metabolism/cytology ; *Extracellular Vesicles/metabolism ; Mice ; Mice, Transgenic ; *Alzheimer Disease/metabolism/pathology/therapy/genetics ; Humans ; Amyloid beta-Peptides/metabolism ; Neurons/metabolism ; Disease Models, Animal ; Cells, Cultured ; Astrocytes/metabolism ; },
abstract = {Alzheimer's disease (AD) is one of the most common progressive neurodegenerative diseases leading to impairments in memory, orientation, and behavior. However, significant work is still needed to fully understand the progression of such disease and develop novel therapeutic agents for AD prevention and treatment. Small extracellular vesicles (sEVs) have received attention in recent years due to their potential therapeutic effects on AD. The aim of this study was to determine the potential effect of sEVs in an in vitro model of AD. sEVs were isolated from human Wharton's jelly mesenchymal stem cells (MSCs) by asymmetric depth filtration, a method developed recently by us. AD was modeled in vitro using cells obtained from the hippocampi of newborn 5xFAD transgenic mice carrying mutations involved in familial AD. After isolation, sEVs underwent detailed characterization that included scanning electron microscopy, nanoparticle tracking analysis, confocal microscopy, Western blotting, and Luminex assay. When added to 5xFAD hippocampal cells, sEVs were nontoxic, colocalized with neurons and astrocytes, decreased the level of Aβ peptide, and increased the synaptic density. These results support the possibility that sEVs can improve brain cell function during aging, decrease the risk of AD, and potentially be used for AD therapeutics.},
}

Animals
*Hippocampus/metabolism/cytology/pathology
*Mesenchymal Stem Cells/metabolism/cytology
*Extracellular Vesicles/metabolism
Mice
Mice, Transgenic
*Alzheimer Disease/metabolism/pathology/therapy/genetics
Humans
Amyloid beta-Peptides/metabolism
Neurons/metabolism
Disease Models, Animal
Cells, Cultured
Astrocytes/metabolism

@article {pmid40361900,
year = {2025},
author = {Chatzikostopoulos, A and Moraitou, D and Papaliagkas, V and Tsolaki, M},
title = {Mapping the Neuropsychiatric Symptoms in Alzheimer's Disease Using Biomarkers, Cognitive Abilities, and Personality Traits: A Systematic Review.},
journal = {Diagnostics (Basel, Switzerland)},
volume = {15},
number = {9},
pages = {},
doi = {10.3390/diagnostics15091082},
pmid = {40361900},
issn = {2075-4418},
abstract = {Background/Objectives: Symptoms (NPS) in Alzheimer's disease (AD) have multiple effects in daily living, not only for the patients but for their caregivers too. The present systematic review was performed in order to identify if biomarkers, cognitive functions, and personality traits can be considered as important factors for the development and maintenance of these symptoms. Methods: To achieve that, the existing literature spanning the period from 2018 to 2024 was critically analyzed. To be included in the review, a study had to investigate any of the factors mentioned above. In total, 182 articles were assessed for eligibility, and 50 met the inclusion criteria. Results: Most of the studies were focused on the role of biomarkers and found that amyloid β, tau and phospho-tau protein are closely related to the incidence and the severity of NPS. In fewer studies, cognitive function and personality traits were also associated with NPS. Conclusions: In conclusion, biomarkers, cognitive function and personality traits are associated with NPS, but the underlying mechanisms, still, mostly remain unknown.},
}

@article {pmid40361641,
year = {2025},
author = {Mafe, AN and Büsselberg, D},
title = {Could a Mediterranean Diet Modulate Alzheimer's Disease Progression? The Role of Gut Microbiota and Metabolite Signatures in Neurodegeneration.},
journal = {Foods (Basel, Switzerland)},
volume = {14},
number = {9},
pages = {},
doi = {10.3390/foods14091559},
pmid = {40361641},
issn = {2304-8158},
support = {NPRP 14S0311-210033//Qatar National Research Fund/ ; },
abstract = {Neurodegenerative disorders such as Alzheimer's disease (AD), the most common form of dementia, represent a growing global health crisis, yet current treatment strategies remain primarily palliative. Recent studies have shown that neurodegeneration through complex interactions within the gut-brain axis largely depends on the gut microbiota and its metabolites. This review explores the intricate molecular mechanisms linking gut microbiota dysbiosis to cognitive decline, emphasizing the impact of microbial metabolites, including short-chain fatty acids (SCFAs), bile acids, and tryptophan metabolites, on neuroinflammation, blood-brain barrier (BBB) integrity, and amyloid-β and tau pathology. The paper highlights major microbiome signatures associated with Alzheimer's disease, detailing their metabolic pathways and inflammatory crosstalk. Dietary interventions have shown promise in modulating gut microbiota composition, potentially mitigating neurodegenerative processes. This review critically examines the influence of dietary patterns, such as the Mediterranean and Western diets, on microbiota-mediated neuroprotection. Bioactive compounds like prebiotics, omega-3 fatty acids, and polyphenols exhibit neuroprotective effects by modulating gut microbiota and reducing neuroinflammation. Furthermore, it discusses emerging microbiome-based therapeutic strategies, including probiotics, prebiotics, postbiotics, and fecal microbiota transplantation (FMT), as potential interventions for slowing Alzheimer's progression. Despite these advances, several knowledge gaps remain, including interindividual variability in microbiome responses to dietary interventions and the need for large-scale, longitudinal studies. The study proposes an integrative, precision medicine approach, incorporating microbiome science into Alzheimer's treatment paradigms. Ultimately, cognizance of the gut-brain axis at a mechanistic level could unlock novel therapeutic avenues, offering a non-invasive, diet-based strategy for managing neurodegeneration and improving cognitive health.},
}

@article {pmid40361614,
year = {2025},
author = {Dong, Y and Wu, X and Zhang, Y and Hu, A and Zhou, Q and Yue, X and Liu, Z and Li, M},
title = {The Role of Probiotics in Modulating the Gut Microbiome in Alzheimer's Disease: A Review.},
journal = {Foods (Basel, Switzerland)},
volume = {14},
number = {9},
pages = {},
doi = {10.3390/foods14091531},
pmid = {40361614},
issn = {2304-8158},
abstract = {Alzheimer's disease (AD) has emerged as a global public health priority characterized by escalating prevalence and the limited efficacy of current therapeutic approaches. Although the pathological complexity of AD is well-recognized, its underlying etiology remains incompletely elucidated. Current research highlights a bidirectional gut-brain axis (GBA) interaction, wherein gut microbiome perturbations may impair intestinal barrier stability, influence immune responses, and blood-brain barrier permeability through microbial metabolite-mediated pathways, thereby contributing to AD pathophysiology. Notably, probiotics demonstrate therapeutic potential by restoring gut microbiome homeostasis, reinforcing intestinal barrier integrity, and mitigating neuroinflammatory responses via GBA. This review focuses on investigating the gut microbiome alterations in AD pathogenesis, the interaction of probiotics with GBA, and its significance in AD pathogenesis. By synthesizing current clinical evidence, this review aims to establish a scientific foundation for probiotic-based interventions as a novel therapeutic strategy in AD management.},
}

@article {pmid40361539,
year = {2025},
author = {Hontman, N and Gonçalves, J and Câmara, JS and Perestrelo, R},
title = {Multifaceted Biological Activities of Culinary Herb and Spice Extracts: In Vitro and In Silico Simulation Insights into Inflammation-Related Targets.},
journal = {Foods (Basel, Switzerland)},
volume = {14},
number = {9},
pages = {},
doi = {10.3390/foods14091456},
pmid = {40361539},
issn = {2304-8158},
support = {UIDB/00674/2020 (DOI: 10.54499/UIDB/00674/2020)//Fundação para a Ciência e Tecnologia/ ; UIDP/00674/2020 (DOI 10.54499/UIDP/00674/2020)//Fundação para a Ciência e Tecnologia/ ; M1420-01-0145-FEDER-000005//Agencia Regional para o Desenvolvimento da Investigacao Tecnologia e Inovacao/ ; },
abstract = {Culinary herbs and spices are valued worldwide for their flavor, aroma, and medicinal benefits. They encompass diverse bioactive metabolites, such as polyphenols and terpenoids, which contribute to plant defense and offer anticarcinogenic, anti-inflammatory, antioxidant, and cognitive-enhancing effects. This study aimed to establish the volatile fingerprint of culinary herbs (lemon verbena, chives, basil, sage, coriander, and parsley) and spices (curcuma, nutmeg, cumin, black pepper, Jamaica pepper, and juniper berry) using headspace solid-phase microextraction combined with gas chromatography-mass spectrometry (HS-SPME/GC-MS). The predominant volatile organic metabolites (VOMs) identified were subjected to in silico molecular docking simulations of anti-Alzheimer's (e.g., acetylcholinesterase (AChE), butyrylcholinesterase (BChE)), antioxidants (e.g., monoamine oxidase B (MAO-B), inducible nitric oxide synthase (iNOS)), and anti-inflammatory receptors (e.g., 5-lipoxygenase (5-LOX), cyclooxygenase-2 (COX-2)). The culinary herb and spice extracts were also subjected to in vitro assays to evaluate their potential as antioxidant (DPPH, ABTS, and ORAC) and anti-inflammatory (% protein denaturation) agents. A total of 121 VOMs were identified in the culinary herbs and spices, with the predominant chemical families being monoterpenoids (48.3%), sesquiterpenoids (14.0%), esters (11.9%), and carbonyl compounds (8.8%). In silico molecular docking simulations revealed that cuminaldehyde, β-caryophyllene, γ-curcumene, germacrene D, and τ-cadinol exhibited the strongest inhibitory activities against the selected receptors. Among the extracts, Jamaica pepper showed the highest antioxidant and anti-inflammatory activities, while lemon verbena exhibited the lowest ones. These findings highlight the promising potential of the studied culinary herbs and spices in the modulation of inflammatory processes related to Alzheimer's disease. However, further investigations, particularly clinical studies, are recommended to validate these results and explore their therapeutic applications.},
}

@article {pmid40361247,
year = {2025},
author = {Pikus, P and Turner, RS and Rebeck, GW},
title = {Mouse models of Anti-Aβ immunotherapies.},
journal = {Molecular neurodegeneration},
volume = {20},
number = {1},
pages = {57},
pmid = {40361247},
issn = {1750-1326},
support = {T32AG071745/AG/NIA NIH HHS/United States ; },
mesh = {Animals ; *Alzheimer Disease/therapy/immunology ; *Amyloid beta-Peptides/immunology/metabolism ; *Immunotherapy/methods ; *Disease Models, Animal ; Mice ; Humans ; Mice, Transgenic ; },
abstract = {BACKGROUND: The development of anti-amyloid-beta (Aβ) immunotherapies as the first disease modifying therapy for Alzheimer's Disease (AD) is a breakthrough of basic research and translational science.

MAIN TEXT: Genetically modified mouse models developed to study AD neuropathology and physiology were used for the discovery of Aβ immunotherapies and helped ultimately propel therapies to FDA approval. Nonetheless, the combination of modest efficacy and significant rates of an adverse side effect (amyloid related imaging abnormalities, ARIA), has prompted reverse translational research in these same mouse models to better understand the mechanism of the therapies.

CONCLUSION: This review considers the use of these mouse models in understanding the mechanisms of Aβ clearance, cerebral amyloid angiopathy (CAA), blood brain barrier breakdown, neuroinflammation, and neuronal dysfunction in response to Aβ immunotherapy.},
}

Animals
*Alzheimer Disease/therapy/immunology
*Amyloid beta-Peptides/immunology/metabolism
*Immunotherapy/methods
*Disease Models, Animal
Mice
Humans
Mice, Transgenic

@article {pmid40361002,
year = {2025},
author = {Ding, H and Kang, T and Gao, W and Wang, Q and Liu, S and Zhang, X and Yu, J},
title = {Exploring the association between hemoglobin glycation index and cognitive function in older adults with hypertension: a cross-sectional study.},
journal = {BMC geriatrics},
volume = {25},
number = {1},
pages = {331},
pmid = {40361002},
issn = {1471-2318},
support = {CY2022-QN-A17//CuiYing Scientific and Technological Innovation Program of Lanzhou University Second Hospital/ ; CYXZ2024-20//Cuiying Scientific Training Program for Undergraduates of The Second Hospital & Clinical Medical School, Lanzhou University/ ; 20240050067//Lanzhou University Student Innovation and Entrepreneurship Action Plan Project/ ; 82460084//National Natural Science Foundation of China/ ; 82160089//National Natural Science Foundation of China/ ; Gan Group Tongzi [2024] No. 4//Provincial Talent Project in 2024/ ; YJS-BD-24//Special Fund Project for Doctoral Training of the Lanzhou University Second Hospital/ ; },
mesh = {Humans ; Cross-Sectional Studies ; *Hypertension/blood/psychology/diagnosis/epidemiology ; Male ; Female ; Aged ; *Cognition/physiology ; *Glycated Hemoglobin/metabolism/analysis ; Middle Aged ; Nutrition Surveys/methods ; Blood Glucose/metabolism ; Aged, 80 and over ; Biomarkers/blood ; },
abstract = {BACKGROUND: The Hemoglobin Glycation Index (HGI) quantifies the difference between the actual and expected values of glycosylated hemoglobin (HbA1c), a marker that has been closely linked to various adverse health outcomes. Nonetheless, a significant gap exists in the current literature concerning the association between HGI and cognitive function. This study aims at testing such association in older adults with hypertension, a topic that has not yet been extensively investigated.

METHODS: A linear regression model between glycated hemoglobin A1c (HbA1c) levels and fasting plasma glucose (FPG) was constructed for the calculation of the HGI. The cross-sectional study focused on evaluating the cognitive function of hypertensive individuals (≥ 60 years old), based on the data from the 2011-2014 National Health and Nutrition Examination Survey (NHANES), by using a series of standardized tests, including the Word List Learning (CERAD-WL) and Delayed Recall (CERAD-DR) tests from the Consortium to Establish a Registry for Alzheimer's Disease (CERAD), the Animal Fluency Test (AFT), and the Digit Symbol Substitution Test (DSST). Weighted logistic and linear regression models served for evaluating the effect of HGI on hypertensive patients' cognitive function. Restricted cubic spline (RCS) curves assisted in detecting the underlying nonlinear associations between HGI and cognitive outcomes. Furthermore, subgroup analyses and interaction tests were performed to gain deeper insights into these associations.

RESULTS: The study included 1023 participants ≥ 60 years old from 2011 to 2014 NHANES. Higher HGI was accompanied by lower DSST score (P = 0.009). In the fully adjusted model, participants in the highest quartile (Q4) of HGI possessed a lower DSST score (β = -4.50, 95% CI -8.10- -0.88) versus the lowest quartile (Q1), and were more likely to exhibit low cognitive function as evaluated by the DSST (OR = 2.21, 95% CI 0.98-5.03). According to the results from RCS analysis, HGI presented a linear relevance to cognitive function scores in older adults with hypertension. There is no interaction between HGI and the stratifying variables (sex, age, BMI, alcohol consumption, and smoking status).

CONCLUSION: High HGI was an important risk factor leading to reduced cognitive performance in hypertensive patients, ensuring HGI to be used for effectively predicting patients' cognitive decline.},
}

Humans
Cross-Sectional Studies
*Hypertension/blood/psychology/diagnosis/epidemiology
Male
Female
Aged
*Cognition/physiology
*Glycated Hemoglobin/metabolism/analysis
Middle Aged
Nutrition Surveys/methods
Blood Glucose/metabolism
Aged, 80 and over
Biomarkers/blood

@article {pmid40360788,
year = {2025},
author = {Mashhour, MA and Youssef, I and Wahed, MA and Mabrouk, MS},
title = {The Intersection of Genetics and Neuroimaging: A Systematic Review of Imaging Genetics in Neurological Disease for Personalized Treatment.},
journal = {Journal of molecular neuroscience : MN},
volume = {75},
number = {2},
pages = {66},
pmid = {40360788},
issn = {1559-1166},
mesh = {Humans ; *Precision Medicine ; *Neuroimaging/methods ; *Nervous System Diseases/genetics/diagnostic imaging/therapy ; Catechol O-Methyltransferase/genetics ; tau Proteins/genetics ; C9orf72 Protein/genetics ; },
abstract = {Imaging genetics is one of the important keys to precision medicine that leads to personalized treatment based on a patient's genetics, phenotype, or psychosocial characteristics. It deepens the understanding of the mechanisms through which genetic variations contribute to neurological and psychiatric disorders. This systematic review overviews the methods and applications of imaging genetics in the context of neurological diseases, mentioning its potential role in personalized medicine. Following PRISMA guidelines, this review systematically analyzes 28 studies integrating genetic and neuroimaging data to explore disease mechanisms and their implications for precision medicine. Selected research included multiple neurological disorders, including frontotemporal dementia, Alzheimer's disease, bipolar disorder, schizophrenia, Parkinson's disease, and others. Voxel-based morphometry was the most common imaging technique, while frequently examined genetic variants included APOE, C9orf72, MAPT, GRN, COMT, and BDNF. Associations between these variants and regional gray matter loss (e.g., frontal, temporal, or subcortical regions) suggest that genetic risk factors play a key role in disease pathophysiology. Integrating genetic and neuroimaging analyses enhances our understanding of disease mechanisms and supports advancements in precision medicine.},
}

Humans
*Precision Medicine
*Neuroimaging/methods
*Nervous System Diseases/genetics/diagnostic imaging/therapy
Catechol O-Methyltransferase/genetics
tau Proteins/genetics
C9orf72 Protein/genetics

@article {pmid40360763,
year = {2025},
author = {Dai, J and Wei, W and Yan, C and Ji, DK and Liu, C and Huang, J and Liang, C and Liu, J and Guo, Z and Zhu, WH},
title = {Multiplex imaging of amyloid-β plaques dynamics in living brains with quinoline-malononitrile-based probes.},
journal = {Nature biomedical engineering},
volume = {},
number = {},
pages = {},
pmid = {40360763},
issn = {2157-846X},
abstract = {The dynamic behaviour of amyloid-β (Aβ) plaques in Alzheimer's disease remains poorly understood, and accumulation and distribution of Aβ plaques must be inferred from in vitro pathological changes in brain tissue. In situ detection of Aβ plaques in live imaging is challenging because of the lack of adequate probes. Here we report the design of unimolecular quinoline-malononitrile-based Aβ probes, termed QMFluor integrative framework, that binds in vivo to Aβ plaques, making them detectable via near-infrared fluorescence imaging, magnetic resonance imaging, positron emission tomography and computed tomography. QMFluor probes are permeable to the blood-brain barrier, and, upon systematic injection, enable real-time magnetic resonance imaging and positron emission tomography-computed tomography imaging of the Aβ biodistribution in the hippocampus and cerebral cortex, and accurately differentiate the brains of living Alzheimer's disease mouse models from wild-type controls. We further demonstrate the ability of QMFluor probes to reach the brain after intravenous injection in a large animal model. This strategy expands the toolbox of probes for in vivo visualization of amyloids in Alzheimer's disease pathological analysis, drug screening and clinical applications.},
}

@article {pmid40360637,
year = {2025},
author = {Jia, J and Sheng, Z and Zhang, Y and Guo, L and Chen, Z and Zhu, D and Zeng, X and Liu, H},
title = {Thioredoxin-1 inhibits NLRP3-mediated pyroptosis by regulating TXNIP in models of Alzheimer's disease.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {16551},
pmid = {40360637},
issn = {2045-2322},
mesh = {*NLR Family, Pyrin Domain-Containing 3 Protein/metabolism/genetics ; *Thioredoxins/metabolism/genetics ; *Alzheimer Disease/metabolism/pathology/genetics ; *Pyroptosis ; Animals ; Mice ; *Carrier Proteins/metabolism/genetics ; Disease Models, Animal ; Cell Line ; Humans ; Hippocampus/metabolism/pathology ; Neurons/metabolism ; Mice, Transgenic ; Male ; Inflammasomes/metabolism ; },
abstract = {Alzheimer's disease (AD) is the most common neurodegenerative disease characterized by memory loss. Our recent study has demonstrated that thioredoxin-1 (Trx-1) could protect neurons via repressing NLRP1‑mediated neuronal pyroptosis in AD models. However, whether Trx-1 could inhibit NLRP3 activation is largely unknown. Here, we found that AAV-mediated Trx-1 overexpression significantly inhibited NLRP3-mediated pyroptosis in the hippocampus of APP/PS1 mice. A mouse hippocampal neuron HT22 cell line overexpressing Trx-1 was successfully obtained through lentivirus transfection. Further study showed that Trx-1 overexpression protected HT22 cells against the neurocytotoxicity of Aβ25-35. Consistently with the results of in vivo experiments, overexpression of Trx-1 remarkedly inhibited the activation of NLRP3. In the contrary, knockdown of Trx-1 by siRNA transfection further aggravated the activation of NLRP3. Mechanistically, Trx-1 overexpression significantly inhibited the increase of thioredoxin-interacting protein (TXNIP) in in vivo and in vitro and weakened the interaction between TXNIP and NLRP3. Taken together, Trx-1 inhibits NLRP3-mediated pyroptosis by regulating TXNIP expression and its interaction with NLRP3 in AD models.},
}

*NLR Family, Pyrin Domain-Containing 3 Protein/metabolism/genetics
*Thioredoxins/metabolism/genetics
*Alzheimer Disease/metabolism/pathology/genetics
*Pyroptosis
Animals
Mice
*Carrier Proteins/metabolism/genetics
Disease Models, Animal
Cell Line
Humans
Hippocampus/metabolism/pathology
Neurons/metabolism
Mice, Transgenic
Male
Inflammasomes/metabolism

@article {pmid40360566,
year = {2025},
author = {Hulse, JP and Maphis, NM and Peabody, J and Bondu, V and Chackerian, B and Bhaskar, K},
title = {pS396/pS404 (PHF1) tau vaccine outperforms pS199/pS202 (AT8) in rTg4510 tauopathy model.},
journal = {NPJ vaccines},
volume = {10},
number = {1},
pages = {94},
pmid = {40360566},
issn = {2059-0105},
support = {RF1NS083704//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; R01NS083704//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; P20GM109089//U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS)/ ; K12GM088021-10//U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS)/ ; P30AG086404//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; T32 AI007538/AI/NIAID NIH HHS/United States ; L70AA030440//U.S. Department of Health & Human Services | NIH | National Institute on Alcohol Abuse and Alcoholism (NIAAA)/ ; },
abstract = {Tauopathies, including Alzheimer's disease (AD) and Frontotemporal Dementia (FTD), are histopathologically defined by the aggregation of hyperphosphorylated pathological tau (pTau) as neurofibrillary tangles in the brain. Site-specific phosphorylation of tau occurs early in the disease process and correlates with progressive cognitive decline, thus serving as targetable pathological epitopes for immunotherapy development. Previously, we developed a vaccine (Qβ-pT181) displaying phosphorylated Thr181 tau peptides on the surface of a Qβ bacteriophage virus-like particle (VLP) that induced robust antibody responses, cleared pathological tau, and rescued memory deficits in a transgenic mouse model of tauopathy. Here we report the characterization and comparison of two additional Qβ VLP-based vaccines targeting the dual phosphorylation sites Ser199/Ser202 (Qβ-AT8) and Ser396/Ser404 (Qβ-PHF1). Both Qβ-AT8 and Qβ-PHF1 vaccines elicited high-titer antibody responses against their pTau epitopes. However, only Qβ-PHF1 rescued cognitive deficits, reduced soluble and insoluble pathological tau, and inflammatory microgliosis in a 4.5-month rTg4510 model of FTD. Both sera from Qβ-AT8 and Qβ-PHF1 vaccinated mice were specifically reactive to tau pathology in human AD post-mortem brain sections. These studies further support the use of VLP-based immunotherapies to target pTau in AD and related tauopathies and provide potential insight into the clinical efficacy of various pTau epitopes in the development of immunotherapies.},
}

@article {pmid40360341,
year = {2025},
author = {Lin, W and Huang, C and Tan, Z and Xu, H and Wei, W and Wang, L},
title = {Cu[II]-bis(thioureido) Complex: A Potential Radiotracer for Detecting Oxidative Stress and Neuroinflammation in Neurodegenerative Diseases.},
journal = {Seminars in nuclear medicine},
volume = {},
number = {},
pages = {},
doi = {10.1053/j.semnuclmed.2025.03.008},
pmid = {40360341},
issn = {1558-4623},
abstract = {Neurodegenerative diseases, characterized by progressive neuronal degeneration and associated with neuroinflammation and oxidative stress, present significant challenges in diagnosis and treatment. This review explores the potential of copper(II)-bis(thiosemicarbazone) complexes, particularly Cu-ATSM, as a dual-purpose radiopharmaceutical for imaging and therapeutic interventions. Cu-ATSM exhibits unique redox-dependent retention in pathological microenvironments, driven by mitochondrial dysfunction and hyper-reductive states, which enables the noninvasive detection of oxidative stress via positron emission tomography (PET). Preclinical studies demonstrate its efficacy in mitigating neuroinflammation by suppressing glial activation, reducing the secretion of pro-inflammatory cytokines (e.g., TNF-α, MCP-1), and increasing the expression of neuroprotective metallothionein-1 (MT1). Some Clinical research reveals elevated [64]Cu-ATSM uptake in Parkinson's disease (PD), Alzheimer's disease (AD), and amyotrophic lateral sclerosis (ALS) patients, correlating with disease severity and regional oxidative stress markers. Furthermore, Cu-ATSM derivatives show promise in modulating blood-brain barrier (BBB) permeability, enhancing amyloid-β clearance, and restoring copper homeostasis in ALS models. Despite these advances, limitations such as small cohort sizes and heterogeneity in clinical studies underscore the need for larger-scale validation. Multimodal imaging integrating PET and MRI, alongside novel structural analogs targeting Aβ plaques and redox imbalances, emerges as a strategic direction for future research. Collectively, Cu-ATSM represents a transformative tool for elucidating neuropathological mechanisms and advancing therapeutic strategies in neurodegenerative disorders.},
}

@article {pmid40360281,
year = {2025},
author = {Drumond-Bock, AL and Blankenship, HE and Pham, KD and Carter, KA and Freeman, WM and Beckstead, MJ},
title = {Parallel gene expression changes in ventral midbrain dopamine and GABA neurons during normal aging.},
journal = {eNeuro},
volume = {},
number = {},
pages = {},
doi = {10.1523/ENEURO.0107-25.2025},
pmid = {40360281},
issn = {2373-2822},
abstract = {The consequences of aging can vary dramatically between different brain regions and cell types. In the ventral midbrain, dopaminergic neurons develop physiological deficits with normal aging that likely convey susceptibility to neurodegeneration. While nearby GABAergic neurons are thought to be more resilient, decreased GABA signaling in other areas nonetheless correlates with age-related cognitive decline and the development of degenerative diseases. Here, we used two novel cell type-specific Translating Ribosome Affinity Purification models to elucidate the impact of healthy brain aging on the molecular profiles of dopamine and GABA neurons in the ventral midbrain. By analyzing differential gene expression from young adult (7-10 month) and old (21-24 month) mice, we detected commonalities in the aging process in both neuronal types, including increased inflammatory responses and upregulation of pro-survival pathways. Both cell types also showed downregulation of genes involved in synaptic connectivity and plasticity. Intriguingly, genes involved in serotonergic synthesis were upregulated with age in GABA neurons and not dopamine-releasing cells. In contrast, dopaminergic neurons showed alterations in genes connected with mitochondrial function and calcium signaling, which were markedly downregulated in male mice. Sex differences were detected in both neuron types, but in general were more prominent in dopamine neurons. Multiple sex effects correlated with the differential prevalence for neurodegenerative diseases such as Parkinson's and Alzheimer's seen in humans. In summary, these results provide insight into the connection between non-pathological aging and susceptibility to neurodegenerative diseases involving the ventral midbrain, and identify molecular phenotypes that could underlie homeostatic maintenance during normal aging.Significance statement This work describes altered gene expression profiles in ventral midbrain dopamine and GABA neurons with aging. Experiments used two novel cell type-specific reporter models to enable translatome analysis. Common age-driven alterations included increased inflammatory and pro-survival cell signaling, and downregulation of synaptic transmission and plasticity genes. In individual cell types, we observed upregulation of serotonergic synthesis in GABA neurons and downregulation of mitochondrial function genes in dopamine neurons. Sex differences were detected in both neuronal types, but were more prominent in dopamine neurons. These results reinforce aging as a risk factor for neurodegeneration in these neuronal populations while providing insight into potential mechanisms of homeostatic regulation during healthy aging and into genetic adaptations that are sex or neuron type specific.},
}

@article {pmid40360168,
year = {2025},
author = {Neumann, EK},
title = {Spatial Multiomics Toward Understanding Neurological Systems.},
journal = {Journal of mass spectrometry : JMS},
volume = {60},
number = {6},
pages = {e5143},
doi = {10.1002/jms.5143},
pmid = {40360168},
issn = {1096-9888},
support = {//UC Davis/ ; 1R21AG083965-01A1//NIH NIA/ ; },
mesh = {Humans ; *Proteomics/methods ; *Metabolomics/methods ; *Brain/metabolism/diagnostic imaging ; Animals ; Transcriptome ; Alzheimer Disease/metabolism ; Mass Spectrometry/methods ; Multiomics ; },
abstract = {Dynamic biological processes in the brain involve complex interactions between various cell types, and these interactions span multiple biological scales. Each of these domains are crucial in maintaining brain health. Traditional methods, such as transcriptomics and protein labeling, provide valuable insights but fail to capture the full molecular landscape of neurological function. Multimodal imaging, combining multiple imaging techniques, offers a more comprehensive approach to studying biological systems by integrating different omics technologies. Spatial metabolomics involves using techniques like mass spectrometry imaging to enable detection of metabolites within their native tissue context and reveals functional roles that are crucial for understanding disease. Spatial transcriptomics and proteomics contribute information on gene expression and protein function but face challenges in resolution and integration with other omics approaches. Combining metabolomics, transcriptomics, and proteomics will enhance our understanding of cellular interactions, but challenges remain in optimizing sample preparation, maintaining molecular integrity, and integrating data across omics layers. Future advancements in spatial multiomics, incorporating epigenetics and extending to whole-body or nanoscale imaging, will significantly advance our understanding of neuroscience and complex diseases like Alzheimer's disease or autism spectrum disorder.},
}

Humans
*Proteomics/methods
*Metabolomics/methods
*Brain/metabolism/diagnostic imaging
Animals
Transcriptome
Alzheimer Disease/metabolism
Mass Spectrometry/methods
Multiomics

@article {pmid40360016,
year = {2025},
author = {Zou, Y and Ma, X and Mao, C and Chu, S and Wang, T and Jin, W and Wang, Y and Yu, S and Gao, J and Qiu, L},
title = {Method comparison and re-calibration of three top-used immunoassays and one LC-MS/MS assay for four core cerebrospinal fluid biomarkers of Alzheimer's disease: an explorative study for harmonization.},
journal = {Clinica chimica acta; international journal of clinical chemistry},
volume = {},
number = {},
pages = {120352},
doi = {10.1016/j.cca.2025.120352},
pmid = {40360016},
issn = {1873-3492},
abstract = {BACKGROUND: We aimed to compare the analytical performance of four assays, for measuring β-amyloid 1-42 (Aβ1-42), β-amyloid 1-40 (Aβ1-40), total tau, and p-tau181 in cerebrospinal fluid (CSF) and evaluate the clinical performance for Alzheimer's disease (AD) diagnosis.

METHODS: The measured concentrations and analytical performance, including precision, linearity, and accuracy of four assays were compared. The discriminative accuracy for amyloid positron emission tomography (PET) status based on different assays was evaluated.

RESULTS: The measurements of the biomarkers based on the four assays demonstrated favorable agreement, while still significantly different. For the discriminative of PET status, the ratio of Aβ1-42/p-tau181 showed better diagnostic performance than other biomarkers, with liquid chromatography tandem-mass spectrometry (LC-MS/MS) and Lumipulse G assays performing better combined all biomarkers for each assay.

CONCLUSIONS: It is crucial to utilize the harmonization and standardization of pre-analytical and measurement procedures to achieve consistent and comparable results in different assays and laboratories.},
}

@article {pmid40359847,
year = {2025},
author = {Liu, S and Ao, C and Li, Z and Chio, LH and Gu, Y and Zhan, H and Li, H and Li, H and Li, Z and Wang, Q},
title = {Development and validation of a polysomnography-based nomogram for predicting amnestic mild cognitive impairment in middle-aged and elderly people.},
journal = {Sleep medicine},
volume = {132},
number = {},
pages = {106564},
doi = {10.1016/j.sleep.2025.106564},
pmid = {40359847},
issn = {1878-5506},
abstract = {BACKGROUND: Amnestic mild cognitive impairment (aMCI) is a subtype of mild cognitive impairment (MCI) that is considered an early stage of Alzheimer's disease (AD). Although early identification of aMCI is crucial for mitigating disease progression, objective and economic evaluation tools designed for aMCI prediction are lacking. Hence, we aimed to develop and validate a novel nomogram based on sleep characteristics to predict the risk of aMCI in middle-aged and elderly adults.

METHODS: This study included 817 eligible participants who underwent polysomnography (PSG), comprising 339 individuals diagnosed with aMCI. The participants were divided into a training cohort and a validation cohort using a 7:3 random split. Least absolute shrinkage and selection operator (LASSO) regression was employed to identify key predictive factors, followed by multivariable logistic regression to refine the predictors, which were subsequently used to construct a nomogram. The predictive performance of the nomogram was evaluated through receiver operating characteristic (ROC) curves, calibration curves, and decision curve analysis (DCA).

RESULTS: Among the 30 potential predictors, 9 independent sleep-related predictors were incorporated into the final nomogram: total sleep time (TST), sleep efficiency (SE), the proportions of nonrapid eye movement stage 1 (N1), nonrapid eye movement stage 3 (N3), and rapid eye movement (REM) sleep, the density and amplitude of fast spindles and the density and amplitude of K-complexes (KCs). The nomogram demonstrated excellent discriminative ability, with an area under the curve (AUC) of 0.968 in the training cohort and 0.953 in the validation cohort. Calibration curves indicated strong agreement between the predicted and observed outcomes, and DCA confirmed the clinical usefulness of the nomogram by showing consistent net benefits across a wide range of threshold probabilities.

CONCLUSION: In this study, we developed and validated an innovative nomogram based on objective sleep characteristics to predict aMCI risk. By reducing the reliance on subjective or costly diagnostic tools, the nomogram offers a reliable, accessible, and practical method for the early identification of aMCI.},
}

@article {pmid40359691,
year = {2025},
author = {Özdemir, AY and Çetin, EA and Novotný, J and Rudajev, V},
title = {Daidzein effectively mitigates amyloid-β-induced damage in SH-SY5Y neuroblastoma cells and C6 glioma cells.},
journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie},
volume = {187},
number = {},
pages = {118157},
doi = {10.1016/j.biopha.2025.118157},
pmid = {40359691},
issn = {1950-6007},
abstract = {Alzheimer's disease (AD) is the most debilitating form of dementia, characterized by amyloid-β (Aβ)-related toxic mechanisms such as oxidative stress, neuroinflammation, and mitochondrial dysfunction. The development of AD is influenced by environmental factors linked to lifestyle, including physical and mental inactivity, diet, and smoking, all of which have been associated with the severity of the disease and Aβ-related pathology. In this study, we used differentiated SH-SY5Y neuroblastoma and C6 glioma cells to investigate the neuroprotective and anti-inflammatory effects of daidzein, a naturally occurring isoflavone, in the context of Aβ oligomer-related toxicity. We observed that pre-treatment with daidzein prevented Aβ-induced cell viability loss, increased oxidative stress, and mitochondrial membrane potential decline in both SH-SY5Y and C6 cells. Furthermore, daidzein application reduced elevated levels of MAPK pathway proteins, pro-inflammatory molecules (cyclooxygenase-2 and IL-1β), and pyroptosis markers, including caspase-1 and gasdermin D, all of which were increased by Aβ exposure. These findings strongly suggest that daidzein alleviates inflammation and toxicity caused by Aβ oligomers. Our results indicate that daidzein could be a potential therapeutic agent for AD and other Aβ-related neurodegenerative diseases.},
}

@article {pmid40359673,
year = {2025},
author = {Lee, AL and Hwang, E and Hwang, J},
title = {Exploring the diagnostic potential of EEG theta power and interhemispheric correlation of temporal lobe activities in Alzheimer's Disease through random forest analysis.},
journal = {Computers in biology and medicine},
volume = {192},
number = {Pt B},
pages = {110248},
doi = {10.1016/j.compbiomed.2025.110248},
pmid = {40359673},
issn = {1879-0534},
abstract = {BACKGROUND: Considering the prevalence of Alzheimer's Disease (AD) among the aging population and the limited means of treatment, early detection emerges as a crucial focus area whereas electroencephalography (EEG) provides a promising diagnostic tool. To date, several studies indicated EEG dataset-based models sporting high diagnostic power in distinguishing patients with AD from healthy controls (HC). However, exploration into which features play a crucial role in the diagnosis remains limited.

METHODS: This study investigates the diagnostic capabilities of EEG for distinguishing patients with AD from HCs through random forest classification on EEG features. Band power and cross-correlation from the resting state EEG dataset of 22 HCs and 160 patients with AD were calculated using Welch's periodogram and Pearson's correlation, respectively. Welch's t-test was applied to identify features demonstrating significant differences between patients with AD and HCs. Band power and cross-correlation were analyzed using a random forest classifier (RFC) and feature-importance analysis. The importance of feature categories, defined as subsets of features grouped by frequency bands (for band power features) or brain regions (for cross-correlation features), was quantified by calculating their average occurrence across all hyperparameter configurations.

RESULT: Distinct patterns between the eyes-closed and eyes-open conditions in alpha power were not observed for patients with AD (vs. HC), whereas theta power (4-8 Hz) in all regions was higher in patients with AD (vs. HC)(p<0.05). Interhemispheric cross-correlation in the temporal lobes exhibited the most distinguishable distribution for the cross-correlation dataset. An RFC, exploring 512 models with varied hyperparameters followed by feature-importance analysis based on the mean decrease in impurity, highlighted "theta relative power" and "interhemispheric cross-correlation of channel pairs including temporal channels" as the most important features for distinguishing patients with AD from HCs. RFC on theta-band filtered cross-correlation dataset informed by important features demonstrated the robustness of important features across models with different hyperparameter settings.

DISCUSSION: The models achieved over 97% accuracy and 100% recall in test sets, although the interpretation of this extraordinarily high accuracy warrants caution due to the small dataset size with high data imbalance and the absence of external validation. This methodology demonstrates the efficacy of EEG-based metrics and machine learning in improving our understanding of EEG characteristics in patients with AD, emphasizing the potential of integrating machine learning techniques into clinical practices.},
}

@article {pmid40359457,
year = {2025},
author = {Mendes, AJ and Ribaldi, F and Pievani, M and Boccalini, C and Garibotto, V and Frisoni, GB and , },
title = {Validating the Amyloid Cascade Through the Revised Criteria of Alzheimer's Association Workgroup 2024 for Alzheimer Disease.},
journal = {Neurology},
volume = {104},
number = {11},
pages = {e213675},
doi = {10.1212/WNL.0000000000213675},
pmid = {40359457},
issn = {1526-632X},
mesh = {Humans ; *Alzheimer Disease/diagnostic imaging/metabolism/pathology ; Aged ; Female ; Male ; Cross-Sectional Studies ; Positron-Emission Tomography ; Aged, 80 and over ; tau Proteins/metabolism ; Disease Progression ; *Amyloid beta-Peptides/metabolism ; Cognitive Dysfunction/diagnostic imaging/metabolism ; Cohort Studies ; },
abstract = {BACKGROUND AND OBJECTIVES: The amyloid cascade hypothesis posits that Alzheimer disease (AD) progresses from amyloid deposition to tau deposition, neurodegeneration, and eventually cognitive impairment and is the foundation of the revised criteria of Alzheimer's Association Workgroup 2024 (AA-2024). To account for copathologies and cognitive resilience that affect the penetrance of the AD cascade, AA-2024 introduced a 2-dimensional biological-clinical staging framework. We aimed to estimate the proportion of persons along the AD continuum whose biological and clinical trajectories align with the amyloid cascade.

METHODS: Cross-sectional data of the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort were tested in the 4 × 4 biological/clinical staging matrix adapted from the AA-2024 criteria. Biological stages were defined by amyloid and tau-PET burden: stage A (amyloid positivity, A+), stage B (medial temporal tau, A+/T2MTL+), stage C (moderate neocortical tau, A+/T2MOD+), and stage D (high neocortical tau, A+/T2HIGH+). Clinical stages were cognitively unimpaired (stage 1), subtle cognitive impairment (stage 2), mild cognitive impairment (stage 3), and dementia (stages 4-6). Tau-PET cutoffs were defined through the implementation of 5 distinct methods. Participants were categorized into (1) compliant with the amyloid cascade (matrix diagonal), (2) resilient (advanced biological stage-early clinical stage), and (3) copathologic (early biological stage-advanced clinical stage). Observed distributions were compared with hypothetical scenarios with zero and high amyloid cascade penetrance using the χ[2] test, and differences among the 5 methods were tested using the Cochran Q test.

RESULTS: Two-hundred and fifty-six amyloid-positive individuals (mean age: 72.7 years; 51% female) from the ADNI cohort were considered. The proportion of participants compliant with the amyloid cascade was between 31% (95% CI 25%-37%) and 36% (95% CI 30%-42%) depending on the tau-PET cutoff method. The observed number of individuals compliant with the amyloid cascade was higher than in the zero-penetrance scenario but lower than in the high-penetrance distribution (p < 0.01). The proportion of copathologic (17%-63%) and resilient (6%-52%) individuals varied widely by tau-PET cutoff (p < 0.001).

DISCUSSION: Only approximately one-third of persons with an AA-2024 diagnosis of AD complied with the predictions of the amyloid cascade hypothesis. These results suggest the heterogeneity in how clinical symptoms and pathology are coupled along the AD continuum, which has significant implications for interpreting completed antiamyloid clinical trials and designing future studies.},
}

Humans
*Alzheimer Disease/diagnostic imaging/metabolism/pathology
Aged
Female
Male
Cross-Sectional Studies
Positron-Emission Tomography
Aged, 80 and over
tau Proteins/metabolism
Disease Progression
*Amyloid beta-Peptides/metabolism
Cognitive Dysfunction/diagnostic imaging/metabolism
Cohort Studies

@article {pmid40359351,
year = {2025},
author = {Lower, MJ and DeCataldo, MK and Kraynak, TE and Gianaros, PJ},
title = {Circulating Antioxidant Nutrients and Brain Age in Midlife Adults.},
journal = {Biopsychosocial science and medicine},
volume = {},
number = {},
pages = {},
doi = {10.1097/PSY.0000000000001399},
pmid = {40359351},
issn = {2998-8756},
abstract = {OBJECTIVE: Due to population aging, the increasing prevalence of Alzheimer's Disease (AD) and related dementias are major public health concerns. Dietary consumption of antioxidant nutrients, in particular the carotenoid β-carotene, has been associated with lower age-related neurocognitive decline. What is unclear, however, is the extent to which antioxidant nutrients may exert neuroprotective effects via their influence on established indicators of age-related changes in brain tissue. This study thus tested associations of circulating β-carotene and other nutrients with a structural neuroimaging indicator of brain age derived from cross-validated machine learning models trained to predict chronological age from brain tissue morphology in independent cohorts.

METHODS: Midlife adults (N=132, aged 30.4 to 50.8 years, 59 female at birth) underwent a structural magnetic resonance imaging (MRI) protocol and fasting phlebotomy to assess plasma concentrations of β-carotene, retinol, γ-tocopherol, ⍺-tocopherol, and β-cryptoxanthin.

RESULTS: In regression analyses adjusting for chronological age, sex at birth, smoking status, MRI image quality, season of testing, annual income, and education, greater circulating levels of β-carotene were associated with a lower (i.e., younger) predicted brain age (β=-0.23, 95% CI=-0.40 to -0.07, P=0.006). Other nutrients were not statistically associated with brain age, and results persisted after additional covariate control for body mass index, cortical volume, and cortical thickness.

CONCLUSIONS: These cross-sectional findings are consistent with the possibility that dietary intake of β-carotene may be associated with slower biological aging at the level of the brain, as reflected by a neuroimaging indicator of brain age.},
}

@article {pmid40359316,
year = {2024},
author = {Stern, A and H Frishman, W},
title = {Connections Between Hypertension, Atherosclerosis, Acute Myocardial Infarction, and Risk of Dementia.},
journal = {Cardiology in review},
volume = {},
number = {},
pages = {},
doi = {10.1097/CRD.0000000000000739},
pmid = {40359316},
issn = {1538-4683},
abstract = {As the percentage of geriatric patients continues to increase in both the United States and globally, the prevalence of both cardiovascular disease and dementia continues to climb. Both dementia and cardiovascular disease are devastating diseases that impose a significant burden economically, socially, and medically on both a local and systemic level. The most common fatal manifestation of cardiovascular disease is acute myocardial infarction, responsible for death in more than 80% of patients with cardiovascular disease. Prominent risk factors for acute myocardial infarction including hypertension and atherosclerosis have been independently associated with an increased risk for cognitive decline and all-cause dementia and Alzheimer disease, separate from vascular dementia. Acute myocardial infarction itself has also been independently associated with an increased incidence of all-cause dementia and Alzheimer disease. It is based on the connection between acute myocardial infarction, its major risk factors, and the incidence of dementia that it is of importance to define and explore the potential role that therapies for these conditions, as well as acute myocardial infarction itself, may play in mitigating the risk of dementia onset and severity. In this review, we assess current therapeutics that exist for atherosclerosis, hypertension and acute myocardial infarction that have been demonstrated to reduce later risk of dementia, and explore the mechanism that underlies the association between the incidence of acute myocardial infarction and the risk of dementia.},
}

@article {pmid40359180,
year = {2025},
author = {Scalzo, P and Clevenger, C and Cotter, V},
title = {Knowledge, confidence, and behavioral changes after an Alzheimer's disease continuing education program for nurse practitioners.},
journal = {Journal of the American Association of Nurse Practitioners},
volume = {},
number = {},
pages = {},
pmid = {40359180},
issn = {2327-6924},
abstract = {Alzheimer's disease (AD) is a progressive, neurodegenerative disorder that currently affects an estimated 6.9 million people in the United States. Despite the growing prevalence of AD, management of this common condition remains suboptimal. To address knowledge and practice gaps related to cognitive evaluation and Alzheimer's diagnosis and treatment, the American Association of Nurse Practitioners (NPs) developed a 1.5-contact hour NP-focused continuing education (CE) program on AD. Changes in learner knowledge, competence, and confidence were assessed with preactivity and postactivity surveys; qualitative follow-up interviews were conducted to evaluate retention of CE material and behavior changes. In total, 4,793 learners (NPs, 93.6%) who completed the activity and self-reported providing patient care were included in the outcomes analysis. In the pre-activity assessment, notable knowledge and competence deficiencies were identified related to the diagnosis, classification, and pharmacotherapeutic management of AD. The CE activity was associated with significant improvements in knowledge and competence, with a 20-percentage point increase in correct response rate from the pre-activity to post-activity survey (p < .001). Learner confidence in their ability to perform key clinical tasks related to Alzheimer's management also improved. Twelve NPs participated in follow-up interviews; most reported that the CE activity reinforced their current practices. Despite improvements in knowledge and competence, certain knowledge gaps persisted, and learners identified several ongoing barriers to optimal management, including lack of access to specialists. Given the changing Alzheimer's landscape, ongoing educational interventions targeted to the NP workforce are needed to serve the growing population of adults at risk for AD.},
}

@article {pmid40359034,
year = {2025},
author = {Chandra, S and Popovic, J and Singhal, NK and Watkins, EA and Dodiya, HB and Weigle, IQ and Salvo, MA and Ramakrishnan, A and Chen, Z and Watson, JT and Shetti, A and Piehl, N and Zhang, X and Cuddy, LK and Sadleir, KR and Schwulst, SJ and Prakriya, M and Gate, D and Sisodia, SS and Vassar, R},
title = {The gut microbiome controls reactive astrocytosis during Aβ amyloidosis via propionate-mediated regulation of IL-17.},
journal = {The Journal of clinical investigation},
volume = {},
number = {},
pages = {},
doi = {10.1172/JCI180826},
pmid = {40359034},
issn = {1558-8238},
abstract = {Accumulating evidence implicates the gut microbiome (GMB) in the pathogenesis and progression of Alzheimer's disease (AD). We recently showed that the GMB regulates reactive astrocytosis and Aβ plaque accumulation in male APPPS1-21 AD model mice. Yet, the mechanism(s) by which GMB perturbation alters reactive astrocytosis in a manner that reduces Aβ deposition remain unknown. Here, we performed metabolomics on plasma from mice treated with antibiotics (abx) and identified a significant increase in plasma propionate, a gut-derived short chain fatty acid, only in male mice. Administration of sodium propionate reduced reactive astrocytosis and Aβ plaques in APPPS1-21 mice, phenocopying the abx-induced phenotype. Astrocyte-specific RNA sequencing on abx and propionate treated mice showed reduced expression of pro-inflammatory and increased expression of neurotrophic genes. Next, we performed flow cytometry experiments where we found abx and propionate decreased peripheral RAR-related orphan receptor-γ (Rorγt)+ CD4+ (Th17) cells and IL-17 secretion, which positively correlated with reactive astrocytosis. Lastly, using an IL-17 monoclonal antibody to deplete IL-17, we found that propionate reduces reactive astrocytosis and Aβ plaques in an IL-17-dependent manner. Together, these results suggest that gut-derived propionate regulates reactive astrocytosis and Aβ amyloidosis by decreasing peripheral Th17 cells and IL-17 release. Thus, propionate treatment or strategies boosting propionate production may represent novel therapeutic strategies for AD.},
}

@article {pmid40359013,
year = {2025},
author = {Singhal, T and Cicero, S and Gale, SA and Horan, N and Dubey, S and Marshall, GA and Weiner, HL},
title = {Dampening of Microglial Activation With Nasal Foralumab Administration in Moderate Alzheimer's Disease Dementia.},
journal = {Clinical nuclear medicine},
volume = {},
number = {},
pages = {},
doi = {10.1097/RLU.0000000000005955},
pmid = {40359013},
issn = {1536-0229},
abstract = {A 78-year-old man with moderate Alzheimer disease (AD) dementia was treated with nasal-foralumab, a fully human anti-CD3 monoclonal antibody, as part of a Food and Drug Administration expanded-access-program, based on previously demonstrated efficacy of anti-CD3 antibody in animal models. 18F-PBR06-PET, utilizing a second-generation 18-kDa-translocator-protein ligand targeting microglia, showed diffuse reduction of radiotracer uptake throughout the brain, following 3 months of nasal-foralumab compared with baseline. In particular, precuneus, posterior cingulate and anterior cingulate gyri, regions that had high levels of amyloid deposition on a baseline 18F-Florbetapir-PET scan, showed reduction in microglial activation after nasal-foralumab treatment for 3 months.},
}

@article {pmid40359012,
year = {2025},
author = {Taha, AY and Shen, Q and Otoki, Y and Liang, N and Patten, KT and Valenzuela, AE and Wallis, CD and Rowland, DJ and Chaudhari, AJ and Bein, KJ and Wexler, AS and Jin, LW and Dugger, BN and Harvey, DJ and Lein, PJ},
title = {Air pollution and Alzheimer disease phenotype deplete esterified pro-resolving lipid mediator reserves in the brain.},
journal = {JCI insight},
volume = {},
number = {},
pages = {},
doi = {10.1172/jci.insight.175917},
pmid = {40359012},
issn = {2379-3708},
abstract = {BACKGROUND: Traffic-related air pollution (TRAP) is a risk factor for Alzheimer disease (AD), where unresolved brain inflammation has been linked to deficits in the levels of free lipid mediators that enable the resolution of inflammation. It is unknown whether these deficits are due to reductions in esterified lipid pools, the main source of free bioactive pro-resolving lipids in the brain, and whether they are related AD pathophysiology.

METHODS: This unknown was tested by measuring brain esterified lipid mediators and pathogenic markers of AD in TgF344-AD and wildtype (WT) male and female rats exposed to filtered air or TRAP for 14 months, and in human postmortem pre-frontal cortex of individuals with or without AD.

RESULTS: Significant reductions in pro-resolving lipid mediators esterified to neutral lipids and/or phospholipids were seen in AD and TRAP-exposed female rats, where levels were associated with inflammation, synaptic loss and impaired glucose metabolism. Lower esterified pro-resolving lipid mediator concentrations were associated with older age in pre-frontal cortex of humans with AD.

CONCLUSION: Impaired resolution in AD is due to depletion of esterified pro-resolving lipid pools that supply the brain with free bioactive mediators involved in inflammation resolution. TRAP exposure alters the same esterified resolution pathways, reflecting convergent mechanisms underlying AD.},
}

@article {pmid40358687,
year = {2025},
author = {Galankin, TL and Swartz, J and Moebius, HJ and Bespalov, AY},
title = {A Descriptive Statistical Analysis of Neuropsychiatric Symptom Pair Prevalence.},
journal = {Journal of geriatric psychiatry and neurology},
volume = {},
number = {},
pages = {8919887251341574},
doi = {10.1177/08919887251341574},
pmid = {40358687},
issn = {0891-9887},
abstract = {Neuropsychiatric symptoms (NPS) are very common and associated with high levels of distress, both in dementia patients and their caregivers. Especially at more advanced dementia disease stages, NPS rarely occur in isolation and the presence of two or more NPS may affect disease severity as well as the response to therapy. There is limited quantitative information on prevalence of specific symptom combinations in the general population, as well as in the populations recruited for symptom-specific investigations. We performed cross-sectional analyses of data from two longitudinal studies (Aging, Demographics, and Memory Study (ADAMS) and the National Alzheimer's Coordinating Center data (NACC)). In both studies and all Mini Mental State Examination (MMSE) strata, we observed every possible pair combination, from commonly recognized and discussed associations (e.g., hallucinations and delusions) to what might be seen as rather counter-intuitive patterns (e.g., apathy and agitation). In conclusion, prevalence of symptom pairs cannot be readily predicted based on prevalence of individual symptoms. Further, the presence of cognitive deficit and degree of cognitive impairment is associated with increased prevalence of all symptoms and symptom pairs, albeit to different degrees. The present study illustrates that, while there is the possibility of any combination of neuropsychiatric symptoms presenting during the course of dementia, their co-occurrence cannot be readily predicted based on the prevalence of individual symptoms. Thus, our study results serve as a source of reference information to inform the design and recruitment strategies for future clinical studies and epidemiological research on neuropsychiatric symptoms in people with dementia.},
}

@article {pmid40358251,
year = {2025},
author = {Koay, H and Haskali, MB and Van Zuylekom, J and Cullinane, C and McLean, CA and White, JM and Roselt, PD and Donnelly, PS},
title = {A gallium fluoride-18 complex containing a pentadentate macrocyclic ligand with a dimethylaminostilbene functional group designed for diagnostic imaging of Alzheimer's disease.},
journal = {Dalton transactions (Cambridge, England : 2003)},
volume = {},
number = {},
pages = {},
doi = {10.1039/d5dt00621j},
pmid = {40358251},
issn = {1477-9234},
abstract = {The molecular pathology of Alzheimer's disease is associated with the presence of aggregates of amyloid-β, a 39-43 amino acid peptide, that form amyloid plaques in the brain. Appropriately substituted stilbene derivatives, radiolabelled with positron-emitting radionuclides, that bind selectively to amyloid-β plaques can be used to assess plaque burden by Positron Emission Tomography (PET) imaging and assist in the diagnosis of Alzheimer's disease. In this work, a substituted pentadentate ligand based on a triazacyclononane backbone (H2L[1]) with one pendent stilbene functional group and two pendent carboxylate groups was synthesised. The new ligand binds to amyloid-β plaques present in human brain tissue. Non-conventional radiolabelling with fluorine-18 was achieved by the formation of a Ga[III]-[[18]F]F[-] coordinate bond to give a complex, [[18]F][GaL[1]F]. This ligand can also be radiolabelled with gallium-68 to give [[68]Ga][GaL[1]F], or copper-64 to give [[64]Cu][CuL[1]]. The in vivo biodistribution of [[18]F][GaL[1]F] and [[64]Cu][CuL[1]] was evaluated in mice, revealing that the initial uptake of [[18]F][GaL[1]F] and [[64]Cu][CuL[1]] in the brain was 0.85 ± 0.13% IA g[-1] and 0.71 ± 0.03% IA g[-1] respectively. An increase in radioactivity in bone at later time points suggested that [[18]F][GaL[1]F] is unstable in vivo.},
}

@article {pmid40358171,
year = {2025},
author = {Brustovetsky, T and Khanna, R and Brustovetsky, N},
title = {Collapsin Response Mediator Protein 2 (CRMP2) Modulates Mitochondrial Oxidative Metabolism in Knock-In AD Mouse Model.},
journal = {Cells},
volume = {14},
number = {9},
pages = {},
pmid = {40358171},
issn = {2073-4409},
support = {R01 NS098772/GF/NIH HHS/United States ; none//Faculty Research Support Program - External Resubmission grant from Indiana University/ ; none//Biomedical Research Grant from Indiana University School of Medicine/ ; },
mesh = {Animals ; *Mitochondria/metabolism ; *Alzheimer Disease/metabolism/genetics/pathology ; Phosphorylation ; *Nerve Tissue Proteins/metabolism/genetics ; Mice ; Disease Models, Animal ; *Intercellular Signaling Peptides and Proteins/metabolism/genetics ; Neurons/metabolism ; Gene Knock-In Techniques ; Mitochondrial ADP, ATP Translocases/metabolism ; Mice, Transgenic ; Oxidation-Reduction ; Cyclin-Dependent Kinase 5/metabolism ; },
abstract = {We explored how the phosphorylation state of collapsin response mediator protein 2 (CRMP2) influences mitochondrial functions in cultured cortical neurons and cortical synaptic mitochondria isolated from APP-SAA KI mice, a knock-in APP mouse model of Alzheimer's disease (AD). CRMP2 phosphorylation was increased at Thr 509/514 and Ser 522 in brain cortical lysates and cultured neurons from AD mice. The basal and maximal respiration of AD neurons were decreased. Mitochondria were hyperpolarized and superoxide anion production was increased in neurons from AD mice. In isolated synaptic AD mitochondria, ADP-stimulated and DNP-stimulated respiration were decreased, whereas ADP-induced mitochondrial depolarization was reduced and prolonged. We found that CRMP2 binds to the adenine nucleotide translocase (ANT) in a phosphorylation-dependent manner. The increased CRMP2 phosphorylation in AD mice correlated with CRMP2 dissociation from the ANT and decreased ANT activity in AD mitochondria. On the other hand, recombinant CRMP2 (rCRMP2), added to the ANT-reconstituted proteoliposomes, increased ANT activity. A small molecule (S)-lacosamide ((S)-LCM), which binds to CRMP2 and suppresses CRMP2 phosphorylation by Cdk5 and GSK-3β, prevented CRMP2 hyperphosphorylation, rescued CRMP2 binding to the ANT, improved ANT activity, and restored the mitochondrial membrane potential and respiratory responses to ADP and 2,4-dinitrophenol. Thus, our study highlights an important role for CRMP2 in regulating the mitochondrial oxidative metabolism in AD by modulating the ANT activity in a phosphorylation-dependent manner.},
}

Animals
*Mitochondria/metabolism
*Alzheimer Disease/metabolism/genetics/pathology
Phosphorylation
*Nerve Tissue Proteins/metabolism/genetics
Mice
Disease Models, Animal
*Intercellular Signaling Peptides and Proteins/metabolism/genetics
Neurons/metabolism
Gene Knock-In Techniques
Mitochondrial ADP, ATP Translocases/metabolism
Mice, Transgenic
Oxidation-Reduction
Cyclin-Dependent Kinase 5/metabolism

@article {pmid40358086,
year = {2025},
author = {Malek-Ahmadi, M and Schack, K and Duff, K and Koppelmans, V and King, JB and Su, Y and Schaefer, SY},
title = {Cortical Thickness Predictors of Performance-Based Functional Task Variability in the Alzheimer Disease Spectrum.},
journal = {Alzheimer disease and associated disorders},
volume = {},
number = {},
pages = {},
doi = {10.1097/WAD.0000000000000672},
pmid = {40358086},
issn = {1546-4156},
abstract = {PURPOSE: Determine whether regional measures of cortical thickness are associated with functional task performance.

PATIENTS: One hundred six older adults who were classified as either cognitively unimpaired (CU), mild cognitive impairment (MCI), or Alzheimer disease (AD) completed a performance-based functional task.

METHODS: The SD of completion times of 6 consecutive trials within a session of the functional task was used as the primary measure for each participant, reflecting intraindividual variability. Regression tree analysis identified cortical gray matter thickness measures that best predicted intraindividual variability on the functional task.

RESULTS: Cortical thickness measures from temporal, parietal, frontal, and occipital regions best predicted intraindividual variability on the task, which are cortical regions associated with learning, executive function, and visuospatial function. Specifically, the fusiform gyrus was featured prominently in these and prior regression tree results, suggesting its possible involvement in this behavioral task.

CONCLUSION: These analyses suggest a mechanistic focus of variability on this functional task, which could serve as an outcome in clinical trials.},
}

@article {pmid40358052,
year = {2025},
author = {Leal-Bernal, C and Noriega-Ramírez, S and Álvarez-Martínez, JV and Cifuentes-González, C and Rojas-Carabali, W and Manrique-Samer, A and Flórez-Esparza, V and Monsalve-García, I and Amézquita-Villanueva, JS and Mejía-Salgado, G and Nava-Mesa, MO and de-la-Torre, A},
title = {Retinal and Vascular Findings in Optical Coherence Tomography in Healthy Cognitive Patients With Alzheimer Disease Biomarkers: A Systematic Review and Meta-Analysis.},
journal = {Alzheimer disease and associated disorders},
volume = {},
number = {},
pages = {},
doi = {10.1097/WAD.0000000000000669},
pmid = {40358052},
issn = {1546-4156},
abstract = {PURPOSE: This systematic review and meta-analysis aimed to explore differences in optical coherence tomography (OCT) findings between cognitively healthy individuals with Alzheimer disease (AD) biomarkers and healthy controls.

METHODS: A thorough literature review was conducted on February 6, 2023, in PubMed, Embase, Cochrane Library, LILACS, and DANS EASY Archive. Studies that involved cognitively healthy individuals with AD biomarkers undergoing OCT or OCT angiography were included. The risk of bias was assessed using validated tools. A narrative synthesis and meta-analysis were performed with standardized mean differences and I2 heterogeneity assessments.

RESULTS: Seventeen studies comprising 601 participants with positive AD biomarkers and 881 controls were included. The reviewed studies varied in design, with notable findings indicating a reduction in retinal nerve fiber layer (RNFL) and ganglion cell layer (GCL) thickness, alongside an increase in inner plexiform layer (IPL) thickness. In addition, OCT angiography revealed reduced vascular density and an enlarged foveal avascular zone-however, variations and inconsistencies in results led to inconclusive outcomes for RNFL and GCL-IPL meta-analyses.

CONCLUSION: In summary, cognitively healthy individuals with positive AD biomarkers demonstrated RNFL, GCL thinning, and IPL thickening trends. Future longitudinal studies using standardized methods are critical to validate these OCT changes as potential early indicators for AD.},
}

@article {pmid40357923,
year = {2025},
author = {Friligkou, E and Pathak, GA and Tylee, DS and De Lillo, A and Koller, D and Cabrera-Mendoza, B and Polimanti, R},
title = {Characterizing pleiotropy among bipolar disorder, schizophrenia, and major depression: a genome-wide cross-disorder meta-analysis.},
journal = {Psychological medicine},
volume = {55},
number = {},
pages = {e145},
doi = {10.1017/S0033291725001217},
pmid = {40357923},
issn = {1469-8978},
support = {//One Mind/ ; },
mesh = {Humans ; *Bipolar Disorder/genetics ; Genome-Wide Association Study ; *Depressive Disorder, Major/genetics ; *Genetic Pleiotropy/genetics ; *Schizophrenia/genetics ; Transcriptome ; },
abstract = {BACKGROUND: To understand the pathogenetic mechanisms shared among schizophrenia (SCZ), bipolar disorder (BP), and major depression (MDD), we investigated the pleiotropic mechanisms using large-scale genome-wide and brain transcriptomic data.

METHODS: We analyzed SCZ, BP, and MDD genome-wide association datasets available from the Psychiatric Genomics Consortium using the PLEIO framework and characterized the pleiotropic loci identified using pathway and tissue enrichment analyses. Pleiotropic and disorder-specific loci were also assessed.

RESULTS: Our pleiotropy-informed genome-wide analysis identified 553 variants that included 192 loci not reaching genome-wide significance in input datasets. These were enriched for five molecular pathways: cadherin signaling (p = 2.18 × 10[-8]), Alzheimer's disease-amyloid secretase (p = 4 × 10[-4]), oxytocin receptor-mediated signaling (p = 1.47 × 10[-3]), metabotropic glutamate receptor group III (p = 5.82 × 10[-4]) and Wnt signaling (p = 1.61 × 10[-11]). Pleiotropic loci demonstrated the strongest enrichment in the brain cortex (p = 5.8 × 10[-28]), frontal cortex (p = 3 × 10[-31]), and cerebellar hemisphere (p = 9.8 × 10[-28]). SCZ-BP-MDD pleiotropic variants were also enriched for neurodevelopmental brain transcriptomic profiles related to the second-trimester post-conception (week 21, p = 7.35 × 10[-5]; week 17, p = 6.36 × 10[-4]) and first year of life (p = 3.25 × 10[-5]).

CONCLUSIONS: Genetic mechanisms shared among SCZ, BP, and MDD appear to be related to early neuronal development. Because the genetic architecture of psychopathology transcends diagnostic boundaries, pleiotropy-focused analyses can lead to increased gene discovery and novel insights into relevant pathogenic mechanisms.},
}

Humans
*Bipolar Disorder/genetics
Genome-Wide Association Study
*Depressive Disorder, Major/genetics
*Genetic Pleiotropy/genetics
*Schizophrenia/genetics
Transcriptome

@article {pmid40357887,
year = {2025},
author = {Gogniat, MA and Khan, OA and Li, J and Park, C and Hudson Robb, W and Zhang, P and Sun, Y and Moore, EE and Houston, ML and Pechman, KR and Shashikumar, N and Taylor Davis, L and Liu, D and Landman, BA and Cole, KR and Bolton, CJ and Gifford, KA and Hohman, TJ and Full, K and Jefferson, AL},
title = {Increased sedentary behavior is associated with neurodegeneration and worse cognition in older adults over a 7-year period despite high levels of physical activity.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {5},
pages = {e70157},
pmid = {40357887},
issn = {1552-5279},
support = {IIRG-08-88733/ALZ/Alzheimer's Association/United States ; //Richard Eugene Hickman Alzheimer's Disease Research Endowment/ ; S10-OD023680//Vanderbilt University High-Performance Computer Cluster for Biomedical Research/ ; UL1-TR000445//Vanderbilt Institute for Clinical and Translational Research/ ; UL1-TR002243//Vanderbilt Institute for Clinical and Translational Research/ ; T32-AG0585/AG/NIA NIH HHS/United States ; R01-AG034962/AG/NIA NIH HHS/United States ; K24-AG046373/AG/NIA NIH HHS/United States ; K01-AG083223/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *Sedentary Behavior ; Male ; Female ; Aged ; Cross-Sectional Studies ; Magnetic Resonance Imaging ; Longitudinal Studies ; Neuropsychological Tests ; Apolipoprotein E4/genetics ; *Brain/diagnostic imaging/pathology ; Aged, 80 and over ; Aging ; *Exercise ; Alzheimer Disease ; Middle Aged ; Cognition ; Actigraphy ; },
abstract = {INTRODUCTION: Sedentary behavior may be a modifiable risk factor for Alzheimer's disease (AD). We examined how sedentary behavior relates to longitudinal brain structure and cognitive changes in older adults.

METHODS: Vanderbilt Memory and Aging Project participants (n = 404) completed actigraphy (7 days), neuropsychological assessment, and 3T brain MRI over a 7-year period. Cross-sectional and longitudinal linear regressions examined sedentary time in relation to brain structure and cognition. Models were repeated testing for effect modification by apolipoprotein E (APOE) ε4 status.

RESULTS: In cross-sectional models, greater sedentary time related to a smaller AD-neuroimaging signature (β = -0.0001, p = 0.01) and worse episodic memory (β = -0.001, p = 0.003). Associations differed by APOE-ε4 status. In longitudinal models, greater sedentary time related to faster hippocampal volume reductions (β = -0.1, p = 0.008) and declines in naming (β = -0.001, p = 0.03) and processing speed (β = -0.003, p = 0.02; β = 0.01, p = 0.01).

DISCUSSION: Results support the importance of reducing sedentary time, particularly among aging adults at genetic risk for AD.

HIGHLIGHTS: Greater sedentary behavior is related to neurodegeneration and worse cognition. Associations differed by APOE-ε4 carrier status in cross-sectional models. Sedentary behavior is an independent risk factor for Alzheimer's disease.},
}

Humans
*Sedentary Behavior
Male
Female
Aged
Cross-Sectional Studies
Magnetic Resonance Imaging
Longitudinal Studies
Neuropsychological Tests
Apolipoprotein E4/genetics
*Brain/diagnostic imaging/pathology
Aged, 80 and over
Aging
*Exercise
Alzheimer Disease
Middle Aged
Cognition
Actigraphy

@article {pmid40357876,
year = {2025},
author = {Yang, Z and Liu, T and Kong, X and Wei, J},
title = {Neuroprotective Effect of Abscisic Acid on MPTP-Induced Parkinson's Disease in Mice.},
journal = {Molecular nutrition & food research},
volume = {},
number = {},
pages = {e70111},
doi = {10.1002/mnfr.70111},
pmid = {40357876},
issn = {1613-4133},
support = {32161143021 81271410//National Natural Science Foundation of China/ ; 182300410313//Henan Natural Science Foundation of China/ ; CJ1205A0240018//Bio-Med Interdisciplinary Innovative Program of Henan University/ ; },
abstract = {Parkinson's disease (PD) is the second largest neurodegenerative disease after Alzheimer's disease (AD), and neuroinflammation is one of its important causes. So far, there is no clear evidence that drugs can improve the onset of PD, so it is crucial to find and develop effective drugs for PD treatment. Abscisic acid (ABA) is a phytohormone with structural and medicinal functions similar to the PPAR-γ agonist thiazolidinedione drugs (TZDs). It has played therapeutic effects in a variety of inflammatory diseases, but the role and mechanism of PD have not been defined. The present study aimed to gain insight into the neuroprotection effects and mechanism of ABA in MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-induced PD models. In this study, we observed that in addition to significant behavioral abnormalities in MPTP-induced mice, Inflammatory parameters such as ion calcium-binding adaptor molecule 1 (IBA-1), glial fibrillary acid protein (GFAP), tumor necrosis factor (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6) were also significantly increased in substantia nigra pars compacta (SNpc). ABA treatment restored behavioral abnormalities and significantly reduced these inflammatory parameters in MPTP-induced mice. Interestingly, these effects were not related to the activation of the lanthionine synthetase C-like protein 2 (LANCL2) but were related to the regulation of the peroxisome proliferator-activated receptor gamma (PPAR-γ). Intraperitoneal injection of ABA ameliorated the MPTP-induced increase in PPAR-γ and peroxisome proliferator-activated receptor co-activator-1α (PGC-1α) expression. Our findings suggest that intraperitoneal injection of ABA is neuroprotective against neurodegeneration induced by MPTP, and this effect is associated with the downregulation of neuroinflammation and modulation of the expression of PPAR-γ and PGC-1α. These results suggest that ABA is expected to develop as a therapeutic candidate for PD.},
}

@article {pmid40357771,
year = {2025},
author = {Deng, Y and Chen, C and Li, H and Wang, T and Zhang, X and Wang, X and Pan, G},
title = {Traditional Chinese Medicines for Alzheimer's Disease: Current Knowledge, Clinical Applications, and Future Directions.},
journal = {Current topics in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115680266347052250407110353},
pmid = {40357771},
issn = {1873-4294},
abstract = {Alzheimer's disease (AD) is a prevalent neurodegenerative disorder that poses a significant challenge to the health of the global aging population. Despite extensive research, the complex mechanisms underlying AD pathogenesis remain largely elusive. In recent years, a growing number of clinical studies have demonstrated the preventive and therapeutic potential of Traditional Chinese Medicine (TCM) against AD through multiple pathways, targets, and compounds. In this study, we conducted a review of the literature published over the past 20 years through international and domestic databases, including PubMed, Medline, Cochrane Library, CNKI, SinoMed, Wanfang, and VIP Journal Integration Platform. This review systematically evaluates current research advancements regarding single-herb preparations, bioactive constituents, and compound formulations in Traditional Chinese Medicine (TCM), with focused analysis on three therapeutic categories: tonifying herbs, blood-activating and stasis-eliminating agents, as well as orifice-opening, phlegm-resolving, and mind-stabilizing medicinal substances. Furthermore, this review discusses the potential mechanisms underpinning the anti-AD effects of TCMs. By integrating these insights, this review aims to establish a theoretical foundation for the application of TCMs in AD treatment and provide a reference for future pharmacological studies and the development of health-related products.},
}

@article {pmid40357390,
year = {2025},
author = {Chang, Y and Xu, L and Gao, C and Khairi, NM and Gore, JC and Landman, BA and Gao, Y},
title = {Bundle-wise functional connectivity density and fractional amplitude of low-frequency fluctuations decrease in white matter in preclinical Alzheimer's disease and are associated with Aβ levels and cognition.},
journal = {Proceedings of SPIE--the International Society for Optical Engineering},
volume = {13410},
number = {},
pages = {},
doi = {10.1117/12.3046835},
pmid = {40357390},
issn = {0277-786X},
abstract = {Neurophysiological changes associated with Alzheimer's disease (AD) begin decades before clinical symptoms emerge, during preclinical AD. Functional abnormalities in white matter (WM) at this preclinical stage remain largely unexplored. We obtained resting-state functional magnetic resonance imaging (rs-fMRI) data of 295 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and evaluated bundle-wise functional connectivity density (FCD) and fractional amplitude of low-frequency fluctuations (fALFF) across 46 bundles, which reflects the strength of synchronizations of BOLD dynamics between each WM bundle and whole-brain 200 GM parcels, and spontaneous neural activity of each WM bundle, respectively. To mitigate site/scanner effects on the metrics, ComBat harmonization was applied to the data. We then performed permutation tests (n=5,000) on each harmonized metric for each bundle to determine differences in FCD and fALFF in preclinical AD relative to controls, adjusting for sex, age, and education using multiple linear regression. Linear correlations of the metrics with the pathological biomarker beta-amyloid (Aβ) and cognitive scores (mPACC and ADAS11) were assessed using general linear models. Multiple comparisons were corrected via a false discovery rate (FDR). We found that preclinical AD patients had reduced FCD and fALFF in specific WM bundles, such as cingulate and hippocampal cingulum, compared to controls (FDR corrected p < 0.05), some of which were associated with poorer cognitive performance and greater Aβ accumulation (FDR corrected p < 0.05). This study, to the best of our knowledge, is the first to examine bundle-wise FCD and fALFF of WM in preclinical AD using a large-scale, multi-site, cross-sectional dataset, suggesting potential applications of these metrics for assessing preclinical AD with rs-fMRI.},
}

@article {pmid40357359,
year = {2025},
author = {Zhu, B and Li, Y and Kuang, S and Wang, H and Yu, A and Zhang, J and Yang, J and Wang, J and Shen, S and Zhai, X and Xie, J and Ran, C},
title = {Creating Chemiluminescence Signature Arrays Coupled with Machine Learning for Alzheimer's Disease Serum Diagnosis.},
journal = {Research (Washington, D.C.)},
volume = {8},
number = {},
pages = {0653},
doi = {10.34133/research.0653},
pmid = {40357359},
issn = {2639-5274},
abstract = {Although omics and multi-omics approaches are the most used methods to create signature arrays for liquid biopsy, the high cost of omics technologies still largely limits their wide applications for point-of-care. Inspired by the bat echolocation mechanism, we propose an "echoes" approach for creating chemiluminescence signatures via screening of a compound library, and serum samples of Alzheimer's disease (AD) were used for our proof-of-concept study. We first demonstrated the discrepancy in physicochemical properties between AD and healthy control serums. On this basis, we developed a simple, cost-effective, and versatile platform termed UNICODE (UNiversal Interaction of Chemiluminescence echOes for Disease Evaluation). The UNICODE platform consists of a "bat" probe, which generates different chemiluminescence intensities upon interacting with various substrates, and a panel/array of "flag" molecules that are selected from library screening. The UNICODE array could enable the reflecting/"echoing" of the signatures of various serum components and intact physicochemical interactions between serum substrates. In this study, we screened a library of over 1,000 small molecules and identified 12 "flag" molecules (top 12) that optimally depict the differences between AD and healthy control serums. Finally, we employed the top 12 array to conduct tests on serum samples and utilized machine learning methods to optimize detection performance. We successfully distinguished AD serums, achieving the highest area under the curve of 90.24% with the random forest method. Our strategy could provide new insights into biofluid abnormality and prototype tools for developing liquid biopsy diagnoses for AD and other diseases.},
}