@article {pmid41469705,
year = {2025},
author = {Li, T and Zhang, J and Song, H and Zhang, R and Fan, F and Huang, Z and Zeng, ML and Peng, BW and Zhang, J},
title = {Border-associated macrophages: an emerging perspective from physiological basis and multi-disease roles to the mechanism of vascular cognitive impairment and dementia.},
journal = {Journal of neuroinflammation},
volume = {22},
number = {1},
pages = {302},
pmid = {41469705},
issn = {1742-2094},
support = {82501747//the Natural Science Foundation of China/ ; 82571371//the Natural Science Foundation of China/ ; 2025AFC006//the Natural Science Foundation of Hubei Province/ ; PTXM2025032//Medical Sci-Tech Innovation Platform of Zhongnan Hospital, Wuhan University/ ; ZY2023Z018//Key projects of Traditional Chinese Medicine Scientific research in 2023-2024 by Hubei Provincial Administration of Traditional Chinese Medicine/ ; },
mesh = {Humans ; *Cognitive Dysfunction/pathology/immunology/metabolism ; *Dementia, Vascular/pathology/immunology/metabolism/physiopathology ; Animals ; *Macrophages/pathology/metabolism/immunology ; *Brain/pathology/immunology/metabolism ; },
abstract = {Brain border-associated macrophages (BAMs) are resident immune cells at the border of the central nervous system (CNS), and their physiological functions and roles in neurological diseases have been widely reported. However, the specific mechanisms by which BAMs contribute to vascular cognitive impairment and dementia (VCID) remain unclear. This article systematically reviews the subsets, origin and differentiation, molecular markers of BAMs, and their research progress in various brain diseases such as hypertension, Alzheimer's disease (AD), and stroke. On this basis, this article deeply analyzes the potential hypotheses of BAMs' involvement in the pathogenesis of VCID, including their regulation of neurovascular unit (NVU) homeostasis, their core role in neuroimmune inflammation, their impact on the lipid metabolism pathways in the CNS, and their involvement in the pathogenesis of vascular risk factor-related cognitive impairment (VRFCI). The mechanistic hypotheses proposed in this article aim to provide new perspectives for understanding the pathophysiology of VCID and may open up new directions for the development of early intervention and targeted treatment strategies.},
}

Humans
*Cognitive Dysfunction/pathology/immunology/metabolism
*Dementia, Vascular/pathology/immunology/metabolism/physiopathology
Animals
*Macrophages/pathology/metabolism/immunology
*Brain/pathology/immunology/metabolism

@article {pmid41469672,
year = {2025},
author = {Wang, Q and Sun, L and Ma, J and Qiu, A and Cong, G and An, X and Qu, Y and Zhang, M and Wang, X and Zeng, L and Yang, J and Wu, Y and Chen, H and Liu, J and Han, F and Wang, D and Wang, T and Ai, J},
title = {Tincr protects against cognitive decline by upregulating MYPT1 mediated phosphorylation of structural protein NM IIA in microglia.},
journal = {Journal of neuroinflammation},
volume = {22},
number = {1},
pages = {303},
pmid = {41469672},
issn = {1742-2094},
support = {JJYQ 2024-06//Haiyan Fund Project of Harbin Medical University Cancer Hospital/ ; 2022ZD0211804//STI2030-Major Projects/ ; },
abstract = {Microglial deformation and migration represent the final stages of inflammatory cytokines release, a key contributor to Alzheimer's disease (AD) pathology. However, the upstream regulators that initiate these morphological and functional changes in microglia remain unclear. In this study, we observed marked cytoskeletal reorganization in the hippocampal microglia of 2VO rats at 8 weeks, indicative of a shift from a homeostatic to a pro-inflammatory state. Notably, Tincr expression was significantly downregulated in both the microglia of 2VO rats and the hippocampi of AD patients. Tincr knockdown promoted microglial deformation and migration, accompanied by enhanced cytokines release and phagocytic capacity. These morphological changes correlated with redistribution of non-muscle myosin IIA (NM IIA) and reduced expression of MYPT1, both in vitro and in vivo, effects that were reversed by Tincr overexpression. Genetic rescue of Mypt1 restored MYPT1 levels and attenuated Tincr-deficiency-induced microglial deformation in the hippocampi of 5xFAD mice. Mechanistically, Tincr enhanced MYPT1 protein expression through dual: functioning as a competing endogenous RNA (ceRNA) that sponged miR-153-3p, and serving as a direct protein-binding scaffold for MYPT1, thereby suppressing NM IIA phosphorylation and stabilizing microglial structure. These findings identify the Tincr-MYPT1-NM IIA axis as a critical regulatory pathway underlying chronic cerebral hypoperfusion (CCH)-induced microglial deformation and dysfunction, offering a novel mechanistic insight into the pathogenesis of neuroinflammation in AD.},
}

@article {pmid41469552,
year = {2025},
author = {Han, X and Cen, X and Li, Z and Zhou, X and Ji, Z},
title = {DCPR: a deep learning framework for circadian phase reconstruction.},
journal = {BMC bioinformatics},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12859-025-06363-2},
pmid = {41469552},
issn = {1471-2105},
support = {CX (23) 3125//Agricultural Science and Technology Innovation Foundation of Jiangsu Province/ ; },
abstract = {BACKGROUND: The circadian clock is an evolutionarily conserved system that orchestrates 24-h physiological rhythms through transcriptional and translational feedback loops. Mounting evidence suggests a bidirectional relationship between circadian rhythm alteration and disease progression, positioning the circadian clock as a potential therapeutic target. Due to the scarcity of high-resolution temporal omics data, it remains very challenging to elucidate the underlying regulatory mechanisms of the circadian system. As a practical alternative, public untimed transcriptomic datasets offer the potential to infer gene expression oscillations retrospectively. However, existing computational approaches for circadian phase estimation often suffer from limited predictive accuracy, reducing their ability to reliably reconstruct rhythmic gene expression patterns.

RESULTS: To overcome these limitations, we develop DCPR, an unsupervised deep learning framework designed to accurately reconstruct the circadian phase from untimed transcriptomic data. Through comprehensive analyses of both simulated and real data, DCPR consistently overperforms existing methods in circadian phase estimation. Additional validations using knowledgebase mining and ex vivo experimental data further support DCPR's efficacy in reconstructing the oscillatory pattern of gene expression and detecting circadian variation.

CONCLUSIONS: Our study demonstrates that DCPR is a highly versatile tool for systematically identifying transcriptional rhythms from untimed expression data. This tool will facilitate therapeutics discovery for circadian-related behavioral and pathological disorders.},
}

@article {pmid41468956,
year = {2025},
author = {Kang, Z and Zhang, J and Zhu, C and Lau, EC and Zhu, Y and Li, P and Li, K and Tong, Q and Dai, SM},
title = {Plasma proteomics mediate the association between degenerative joint diseases and dementia risk.},
journal = {Journal of advanced research},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jare.2025.12.044},
pmid = {41468956},
issn = {2090-1224},
abstract = {OBJECTIVE: To assess the association between degenerative joint diseases (DJD) and dementia risk and to identify potential proteomic mediators.

METHODS: We conducted a prospective cohort study using data from 500,805 participants in the UK Biobank. Three DJD diagnoses (osteoarthritis [OA], intervertebral disc degeneration [IVDD], and degenerative spinal diseases [DSD]) were identified from the clinical records. Dementia outcomes (all-cause dementia [ACD], Alzheimer's disease [AD], and vascular dementia [VaD]) were tracked over 14.45 years. Multivariable Cox regression models were used to assess DJD-dementia associations, adjusted for demographics, lifestyle, and comorbidities. Propensity score matching (PSM) was employed for validation. Plasma proteomic profiling of 2,923 proteins was performed to identify potential mediators, followed by causal mediation analysis.

RESULTS: After a median follow-up of 14.45 years, 9,884 participants developed ACD, including 4,404 with AD and 2,224 with VaD. After adjusting for covariates, the DJD group exhibited a significantly elevated risk of ACD (HR: 1.271, 95 % CI: 1.173-1.376) and VaD (HR: 1.587, 95 % CI: 1.323-1.903), but not AD (HR: 1.107, 95 % CI: 0.982-1.248). Subgroup analyses revealed significant effect modifications according to age, activity levels, and surgical procedures. PSM analyses confirmed the robustness of these associations. Proteomic analysis identified plasma proteins associated with both DJDs and ACD risk. Mediation analysis revealed that 18 proteins, including HAVCR1 (mediation proportion 52.6 %, 95 % CI: 39.1 %-78 %), GDF15 (22 %, 95 % CI: 14.5 %-46.8 %), and COL6A3 (14.3 %, 95 % CI: 7.7 %-28.4 %), significantly mediated the association between DJDs and ACD.

CONCLUSION: DJDs are independently associated with an increased risk of developing dementia. This correlation is mediated by systemic proteomic alterations. Our findings highlight inflammation and vascular dysfunction as central mechanisms, offering insights into risk stratification and therapeutic targets for preventing dementia.},
}

@article {pmid41468943,
year = {2025},
author = {Flavell, J and Roberts, K and Morris, PLP and Mosley, PE and Ahern, EGM and Logan, B and Adam, RJ and McElligott, CAT and Shaw, TB and Nestor, PJ},
title = {A preliminary investigation of a Geriatric Depression Scale, Dementia version (GDS-D).},
journal = {Journal of affective disorders},
volume = {},
number = {},
pages = {121056},
doi = {10.1016/j.jad.2025.121056},
pmid = {41468943},
issn = {1573-2517},
abstract = {BACKGROUND: Depression is a frequent comorbidity in dementia; however, diagnosis is complicated by overlapping cognitive and behavioural symptoms. The Geriatric Depression Scale (GDS) is a widely used screening tool to probe for depression, comprising 30 items in its full version (GDS-30) but also existing as a range of shorter versions (GDS-15, GDS-10, GDS-8, GDS-4). All versions contain items that may be confounded in dementia patients such as probes for cognitive symptoms, apathy, and negative feelings about the future. This study aimed to develop and validate a 10-item version (GDSD) optimised for diagnosing depression in dementia by removing these confounds.

METHODS: Data were retrospectively analysed in participants with Alzheimer's disease (AD, n = 29), frontotemporal dementia (FTLD, n = 30), or a depressive disorder (n = 23) who had completed the GDS-30 and undergone psychiatric assessment and application of the Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5) criteria. Diagnostic accuracy of the GDS-D was compared to all previous GDS versions using sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV).

RESULTS: The GDS-D had an accuracy of 92-97 % in diagnosing depression in a memory clinic setting and in dementia (AD and FTLD), which was superior to the GDS-30 and all briefer versions.

CONCLUSION: The GDS-D enhances depression screening in a memory clinic setting by excluding the confounding items of other GDS versions. In addition, it performs better at diagnosing depression in a dementia cohort. Future studies should validate its utility in larger, diverse dementia populations.},
}

@article {pmid41468784,
year = {2025},
author = {Palanivel, V and Salkar, A and Shenoy, A and Eva, TA and Perera, R and Chitranshi, N and Gupta, V and You, Y and Mirzaei, M and Graham, SL and Gupta, V and Basavarajappa, D},
title = {Neuropeptide Y at the crossroads of neurodegeneration: Mechanistic insights and emerging therapeutic strategies.},
journal = {Neuropeptides},
volume = {115},
number = {},
pages = {102583},
doi = {10.1016/j.npep.2025.102583},
pmid = {41468784},
issn = {1532-2785},
abstract = {Neuropeptide Y (NPY), a widely distributed and highly conserved neuropeptide, plays a central role in the regulation of diverse physiological processes, including stress responses, energy homeostasis, vascular tone, and immune modulation, via activation of its receptor subtypes. Beyond its physiological roles, the dysregulation of NPY expression has been documented in several neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, Machado-Joseph disease, and retinal disorders such as diabetic retinopathy and glaucoma. These alterations in NPY levels and receptor activity highlight its potential not only as a biomarker for disease progression but also as a promising therapeutic target. Previous evidence revealed that NPY exerts neuroprotection by alleviating excitotoxicity, oxidative stress, mitochondrial dysfunction, and neuroinflammation while concurrently facilitating neurogenesis, synaptic plasticity, and cellular resilience. NPY activates receptor-mediated intracellular signaling cascades like PI3K/Akt, MAPK/ERK, and p38K, that control cellular survival, proteostasis, and inflammation and thereby influence disease trajectories. Understanding NPY operation with these mechanisms can unveil new avenues for targeted therapy. Current insights into the complex roles of NPY in neurodegeneration are discussed in this review, and their implications in diagnostic and treatment strategies are addressed.},
}

@article {pmid41468641,
year = {2025},
author = {Hu, S and Hu, C and Tong, M},
title = {Mitochondrial-derived microproteins in cancer and neurodegeneration: A new era of cross-disease mechanistic insights.},
journal = {Pathology, research and practice},
volume = {278},
number = {},
pages = {156344},
doi = {10.1016/j.prp.2025.156344},
pmid = {41468641},
issn = {1618-0631},
abstract = {Mitochondrial-derived microproteins (MDPs) translate mitochondrial stress into cellular decisions that shape aging, metabolism, cancer biology, and neurodegeneration. Humanin, MOTS-c, SHLPs, and the recently identified SHMOOSE act through distinct intracellular and receptor-mediated pathways to regulate apoptosis, nutrient sensing, redox balance, and mito-nuclear communication. These programs confer neuroprotection in post-mitotic tissues but can be co-opted by tumors for survival, invasion, and therapy resistance, helping explain the inverse comorbidity between cancer and Alzheimer's disease. This review synthesizes the divergent signaling architectures of major MDPs, including Humanin-FPR2/gp130, MOTS-c-AMPK/NRF2-LARS1/mTORC1, SHLP2-CXCR7, and SHMOOSE's genotype-dependent activity, and outlines how these mechanisms produce disease-specific outcomes. Recent advances in mitoribosome profiling, DIA-based proteogenomics, and mitochondrial base editing have accelerated the discovery and functional characterization of MDPs. Emerging translational opportunities include MDP-targeted agonists, antagonists, and engineered delivery systems designed for application in neurodegenerative disorders and cancer. Overall, MDPs represent a druggable signaling layer whose context-dependent effects can be selectively directed across diseases.},
}

@article {pmid41468543,
year = {2025},
author = {Wenzheng, H and Agyemang, EF and Srivastav, SK and Shaffer, JG and Kakraba, S},
title = {Artificial Intelligence-Enhanced Multi-Algorithm R Shiny Application for Predictive Modeling and Analytics: Case Study of Alzheimer Disease Diagnostics.},
journal = {JMIR aging},
volume = {8},
number = {},
pages = {e70272},
doi = {10.2196/70272},
pmid = {41468543},
issn = {2561-7605},
mesh = {Humans ; *Alzheimer Disease/diagnosis ; *Artificial Intelligence ; Aged ; Female ; Male ; *Algorithms ; Neural Networks, Computer ; *Handwriting ; Aged, 80 and over ; Case-Control Studies ; },
abstract = {BACKGROUND: Artificial intelligence (AI) has demonstrated superior diagnostic accuracy compared with medical practitioners, highlighting its growing importance in health care. SMART-Pred (Shiny Multi-Algorithm R Tool for Predictive Modeling) is an innovative AI-based application for Alzheimer disease (AD) prediction using handwriting analysis.

OBJECTIVE: This study aimed to develop and evaluate a noninvasive, cost-effective AI tool for early AD detection, addressing the need for accessible and accurate screening methods.

METHODS: The study used principal component analysis for dimensionality reduction of handwriting data, followed by training and evaluation of 10 diverse AI models, including logistic regression, naïve Bayes, random forest, adaptive boosting, support vector machine, and neural network. Model performance was assessed using accuracy, sensitivity, precision, specificity, F1-score, and area under the curve (AUC) metrics. The DARWIN (Diagnosis Alzheimer With Handwriting) dataset, comprising handwriting samples from 174 participants (89 patients with AD and 85 healthy controls), was used for validation and testing.

RESULTS: The neural network classifier achieved an accuracy of 91% (95% CI 0.79-0.97) and an AUC of 94% on the test set after identifying the most significant features for AD prediction. These performance results surpass those of current clinical diagnostic tools, which typically achieve around 81% accuracy. SMART-Pred's performance aligns with recent AI advancements in AD prediction, such as Cambridge scientists' AI tool achieving 82% accuracy in identifying AD progression within 3 years, using cognitive tests and magnetic resonance imaging scans. The variables "air_time" and "paper_time" consistently emerged as critical predictors for AD across all 10 AI models, highlighting their potential importance in early detection and risk assessment. To augment transparency and interpretability, we incorporated the principles of explainable AI, specifically using Shapley Additive Explanations, a state-of-the-art method to emphasize the features responsible for our model's efficacy.

CONCLUSIONS: SMART-Pred offers noninvasive, cost-effective, and efficient AD prediction, demonstrating the transformative potential of AI in health care. While clinical validation is necessary to confirm the practical applicability of the identified key variables, the findings of this study contribute to the growing body of research on AI-assisted AD diagnosis and may lead to improved patient outcomes through early detection and intervention.},
}

Humans
*Alzheimer Disease/diagnosis
*Artificial Intelligence
Aged
Female
Male
*Algorithms
Neural Networks, Computer
*Handwriting
Aged, 80 and over
Case-Control Studies

@article {pmid41468220,
year = {2025},
author = {Best, MN and Laurent, SE and Doyle, C and Torres, ER and Mahmoudi, E and Zahodne, LB},
title = {Racial composition in K-12 schooling and cognitive health of older Black adults.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251409190},
doi = {10.1177/13872877251409190},
pmid = {41468220},
issn = {1875-8908},
abstract = {BackgroundIn the U.S., historical legal and contemporary social segregation results in K-12 school differences based on racial composition. We hypothesize that racial composition of K-12 schools contributes to higher Alzheimer's disease (AD) and related dementia risk among non-Hispanic Black (NHB) older adults.ObjectiveTo better understand the social determinants of AD, this original research study adopts a life course perspective. Specifically, we investigate associations between K-12 schools' racial composition and later-life cognitive health among U.S.-born and educated NHB older adults.MethodsWe used the Health and Retirement Study's 2015, 2017, and 2019 Life History Mail Survey and categorized participants (N = 2105) by the majority racial composition of K-12 schools they attended: only majority non-Hispanic White (NHW) schools (n = 193), only majority NHB schools (n = 1387), or both school types (n = 525). We used adjusted regressions to assess associations between school racial composition and total cognition, episodic memory, and vocabulary. To examine mediation by educational attainment, we performed path analyses.ResultsAttending only majority NHW schools or attending both school types was associated with better total cognition (p < 0.01 and p < 0.001, respectively) and episodic memory (p < 0.05 and p < 0.01, respectively) compared to only attending majority NHB schools. Attending both school types was also associated with better vocabulary (p < 0.0001). Between 24 and 64% of these associations were mediated by participants' educational attainment.ConclusionsOur findings highlight the long-term cognitive benefits of attending majority NHW schools for this cohort. These findings also underscore the need for initiatives that promote educational equity in majority NHB schools.},
}

@article {pmid41468178,
year = {2025},
author = {Purushothaman, A and Krishnan, A},
title = {Unveiling Neurological Benefits: A Review of Hemp Leaf, Flower, Seed Oil Extract, and Their Phytochemical Properties in Neurological Disorders.},
journal = {Cannabis and cannabinoid research},
volume = {},
number = {},
pages = {},
doi = {10.1177/25785125251410822},
pmid = {41468178},
issn = {2378-8763},
abstract = {Neurological disorders such as epilepsy, Alzheimer's disease, Parkinson's disease, and multiple sclerosis present significant global health care challenges, with complex pathophysiology and limited therapeutic options that often carry substantial side effects. Hemp-derived compounds, particularly from Cannabis sativa seeds, leaves, and flowers, have gained attention for their potential neuroprotective properties. This review aims to synthesize the current evidence surrounding the therapeutic benefits of hemp-derived compounds, focusing on their bioactive phytochemical profiles, mechanisms of action, and therapeutic efficacy in treating neurological disorders. A comprehensive review of pre-clinical and clinical studies was conducted, analyzing the phytochemical composition of hemp extracts, including cannabinoids (such as cannabidiol, CBD), terpenes, flavonoids, and polyunsaturated fatty acids. We explored their mechanisms of action through interactions with the endocannabinoid system, neurotransmitter receptors, inflammatory pathways, and oxidative stress mechanisms. The review highlights the therapeutic potential of hemp-derived extracts in mitigating various neurological conditions. Pre-clinical and clinical studies have demonstrated their efficacy in reducing seizure frequency in epilepsy, protecting dopaminergic neurons in Parkinson's disease, alleviating neuroinflammation and oxidative stress in Alzheimer's disease, and promoting remyelination in multiple sclerosis. The entourage effect, where cannabinoids, terpenes, and flavonoids work synergistically, enhances these therapeutic effects. Innovations in extraction technologies have optimized yield and preserved bioactivity, further enhancing clinical relevance. Hemp-derived compounds exhibit significant neuroprotective and therapeutic potential for managing neurological disorders. However, challenges such as product standardization, safety profiles, and regulatory frameworks must be addressed for clinical translation. Further research is essential to optimize dosing, establish safety parameters, and develop standardized formulations, which will be crucial for fully harnessing the therapeutic potential of hemp-derived products in treating neurological conditions.},
}

@article {pmid41468036,
year = {2025},
author = {Hannonen, S and Andberg, S and Kärkkäinen, V and Lehtola, JM and Saari, T and Hänninen, T and Hokkanen, L and Rusanen, M and Hallikainen, M and Leinonen, V and Kaarniranta, K and Bednarik, R and Koivisto, AM},
title = {Eye-tracking saccade parameters reveal early cognitive decline in relation to Clinical Dementia Rating-Sum of Boxes scores.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251406625},
doi = {10.1177/13872877251406625},
pmid = {41468036},
issn = {1875-8908},
abstract = {BackgroundVarious functional impairments in eye movements have been observed in Alzheimer's disease (AD) and other neurodegenerative disorders. Detecting abnormal eye movements may help identify individuals at risk of memory diseases even when evident clinical symptoms are absent.ObjectiveTo investigate the earliest possible stage at which the risk of memory impairment can be detected using computer-based eye-tracking (ET) analysis of King-Devick (KD) test performance.MethodsWe recruited a total of 34 healthy controls and 33 participants with a Clinical Dementia Rating-Sum of Boxes (CDR-SOB) score of 0.5 or higher. They all underwent a neurological examination, the Consortium to Establish a Registry for Alzheimer's Disease neuropsychological test battery (CERAD-NB), and a CDR interview. The KD reading test was performed using computer-based ET. We analyzed fixation durations, saccade durations, and saccade amplitudes. For this study, test results were analyzed in relation to CDR-SOB.ResultsThe mean duration of saccades was significantly shorter in the CDR-SOB 0.5 group compared to healthy controls (p = 0.001), and this difference remained significant across groups with CDR-SOB >0.5. The mean amplitude of saccades was significantly lower in individuals with CDR-SOB scores ranging from 1 to 4, as well as those with scores exceeding 4.5, in comparison to healthy controls (p = 0.007).ConclusionsThese findings suggest that ET analysis of the KD test may help detect individuals with very early cognitive problems. Therefore, this method shows promise as a supportive or potentially indicative biomarker for future studies aimed at developing user-friendly tools to identify individuals at risk for AD or other memory diseases.},
}

@article {pmid41468026,
year = {2025},
author = {Marcolini, S and Mondragón, JD and van Roon, AM and Tegegne, BS and Riese, H and Vliegenthart, R and Dierckx, RAJO and Borra, RH and De Deyn, PP},
title = {Limited evidence for heart rate variability as a predictor of cognitive and pathophysiological brain markers.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251409343},
doi = {10.1177/13872877251409343},
pmid = {41468026},
issn = {1875-8908},
abstract = {BackgroundHeart rate variability (HRV) is related to cognitive functioning and may serve as an early Alzheimer's disease biomarker.ObjectiveWe examine whether HRV predicts cognitive and pathophysiological brain markers assessed eight and thirteen years later, independently of coronary calcification.Methods269 cognitively unimpaired adults were selected based on their coronary artery calcification score (absent, score=0; high, score≥300), obtained from cardiac computed tomography scans (T2, 2017-2022). HRV in the time domain (root mean square of successive RR interval differences), measured at T0 (2007-2013), T1 (2014-2017), and the change between T0 and T1, was the predictor. Outcomes included cognitive measures, serum Alzheimer's disease biomarkers, and brain imaging markers obtained at T3 (2022-2023). Linear regression models were run, stratified by coronary calcification groups and adjusted for demographics, lifestyle and cardiometabolic factors.ResultsParticipants with high T2 calcification showed lower HRV at T0 and a positive change compared to those with absent calcification. In participants with high T2 calcification, higher HRV at T0 was associated with lower Aβ42/Aβ40 at T3, while associations with all other markers were not significant. HRV at T1 and the change were not associated with any of the outcomes.ConclusionsHRV was not associated with cognitive and brain imaging outcomes. In participants with high calcification, higher HRV measured thirteen-year earlier, typically a marker of a healthier state, was associated with a lower Aβ42/Aβ40 ratio, typically linked to Alzheimer's disease. Findings underscore the need to consider coronary calcification in research of HRV as a marker of cognitive decline.},
}

@article {pmid41467972,
year = {2025},
author = {Chang, ST and Wu, HY and Chiu, YL and Chuang, YF},
title = {Anti-herpetic treatment reduces dementia risk: A systematic review and meta-analysis.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251409323},
doi = {10.1177/13872877251409323},
pmid = {41467972},
issn = {1875-8908},
abstract = {BackgroundHuman herpesvirus (HHV) infections, particularly for herpes simplex virus (HSV) and varicella-zoster virus (VZV), may increase dementia risk, yet the protective effects of anti-herpetic medications remained unclear.ObjectiveThis systematic review and meta-analysis of observational studies aimed to examine the association between anti-herpetic medications and dementia, focusing on HSV or VZV-related infections.MethodsThis study followed PRISMA guidelines (CRD42022368318). Cohort or nested case-control studies published from databases' inception to December 2024 were systematically searched in PubMed, MEDLINE, Embase, Cochrane Library, PsycINFO, and Web of Science. Eligible studies evaluated anti-herpetic medications (e.g., acyclovir, famciclovir, ganciclovir, valacyclovir, valganciclovir) and dementia risk in non-demented adults aged ≥50. Pooled adjusted hazard ratios (aHR) and 95% confidence intervals (CIs) were analyzed using random-effects models. Subgroup and meta-regression analyses were performed to explore potential sources of heterogeneity and effect modifiers.ResultsFourteen cohort studies involving more than 10 million older adults were included. To demonstrate the effects of anti-herpetic medications in various clinical scenarios, the meta-analysis compared: diagnosed and treated versus diagnosed but untreated (aHR=0.77, 95% CI: 0.67-0.89); treated versus untreated regardless of diagnosis (aHR=0.90, 95% CI: 0.87-0.94); and diagnosed and treated versus neither diagnosed nor treated (aHR=0.87, 95% CI: 0.78-0.97). Subgroup analysis and meta-regression identified infection severity as a significant modifier (p < 0.0001), explaining 89.01% of heterogeneity.ConclusionsThis systematic review and meta-analysis reveals notable protective effect of anti-herpetic medication usage on dementia, and the effect is especially pronounced in patients with severe alpha herpesvirus infections.},
}

@article {pmid41467925,
year = {2025},
author = {Rivière, C and Götze, K and Lacaille, S and Paquet, C and Dumurgier, J and Diard, C and Seux, ML and Tomeo, C and Lynch, A and Greffard, S and Raynaud Simon, A and Decaix, T and Lilamand, M},
title = {Driving knowledge assessment in cognitively impaired older adults: evidence from geriatric day hospitals.},
journal = {Aging clinical and experimental research},
volume = {},
number = {},
pages = {},
doi = {10.1007/s40520-025-03223-0},
pmid = {41467925},
issn = {1720-8319},
abstract = {BACKGROUND: Evidence and appropriate tools are often lacking to support the decision of driving discontinuation in cognitively impaired older adults by Alzheimer's disease and related disorders. Maintaining strong driving knowledge as individuals age is crucial for ensuring their fitness to drive. The objectives of this study were to describe the driving knowledge of older drivers > 65 referred for cognitive assessment compared to control subjects. We also analyzed the relationship between neuropsychological tests and driving knowledge assessment.

METHODS: Cross-sectional, observational, multicenter study in geriatric day hospitals including older drivers with cognitive complaints who underwent a comprehensive neuropsychological assessment. Their performance on a driving theory test (knowledge of driving laws and road rules) and self-evaluation of driving abilities were assessed via a computer-based exam and compared to those of healthy younger drivers. Regression models were used to examine the relationship between driving knowledge and the neuropsychological examination scores with adjustment for age, gender and cognitive performance.

RESULTS: We included 144 patients (mean age 79.6 ± 4.9) and 249 controls (mean age 28.1 ± 6.6). Performance in the driving theory test was significantly lower in patients than in controls (p < 0.001). We showed a significative association between driving knowledge, the Montreal Cognitive Assessment (MoCA) and the Digit Symbol Substitution Test (DSST) independent from age, gender and cognitive performance.

CONCLUSION: Our study has raised concerns regarding the overall poor theoretical driving skills in older drivers and their low self-evaluation ability. The MoCA and the DSTT may be useful for guiding driving discontinuation in cognitively impaired older adults.},
}

@article {pmid41467766,
year = {2025},
author = {Wang, J and Li, J},
title = {The Role of Exercise in Regulating Brain Health and Aging through Glymphatic Function.},
journal = {The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry},
volume = {},
number = {},
pages = {10738584251404010},
doi = {10.1177/10738584251404010},
pmid = {41467766},
issn = {1089-4098},
abstract = {The glymphatic system is a recently discovered brain clearance pathway that removes metabolic waste, including toxic proteins, via cerebrospinal fluid flow along perivascular spaces. It helps maintain neural homeostasis, and its dysfunction is linked to neurodegenerative diseases like Alzheimer's. Emerging evidence suggests that physical exercise can enhance glymphatic function and promote cerebral clearance, offering a potential nonpharmacological approach to support brain health. In rodent studies, voluntary wheel running has been shown to increase glymphatic flux, likely through improvements in cerebrospinal fluid circulation, vascular pulsatility, and the exchange of interstitial fluid along perivascular routes. Exercise also upregulates the expression and polarization of aquaporin 4 on astrocytic endfeet, which is essential for directing fluid movement and facilitating efficient glymphatic transport, potentially reducing the accumulation of neurotoxic proteins such as β-amyloid and tau. Beyond these direct effects, exercise-induced enhancements in cerebral blood flow, arterial compliance, and sleep quality may indirectly optimize the physiological environment for glymphatic clearance. Together, these mechanisms suggest that regular physical activity is an established, noninvasive intervention to maintain cerebral homeostasis, accelerate metabolic waste removal, and support long-term cognitive function. This review summarizes evidence linking exercise to glymphatic function and its role in brain waste clearance and cognitive function.},
}

@article {pmid41467748,
year = {2025},
author = {Clarke, K and Deng, Z and Dickerson, AS},
title = {Associations Between Joint Air Pollution Exposure, Mental Health, and Physical Health and Dementia Incidence in an Aging U.S. Cohort.},
journal = {The journals of gerontology. Series B, Psychological sciences and social sciences},
volume = {},
number = {},
pages = {},
doi = {10.1093/geronb/gbaf275},
pmid = {41467748},
issn = {1758-5368},
abstract = {OBJECTIVE: Understanding the joint relationship between air pollution and other risk factors on the risk of Alzheimer's disease and related dementias (ADRD) is important for determining priorities for interventions. This study aimed to estimate the joint effects of air pollution, mental health symptoms, and overall physical health condition on ADRD risk in a U.S. sample of older adults and examine differences by sex.

METHODS: Analyses include 9,186 Medicare beneficiaries enrolled in the National Health and Aging Trends Study (2011-2018). We used quantile g-computation Cox proportional hazard models to examine the joint effects of air pollution, anxiety, depression, and overall health on ADRD incidence, stratified by sex.

RESULTS: We found significant associations between ADRD risk and particulate matter <2.5µm in diameter and nitrogen dioxide in women. Among men, we found a significant association between ADRD risk and ozone (aHR per IQR increment = 1.11; 95% CI: 1.01, 1.22). The association between ADRD risk and feelings of depression, anxiety, and general health condition was significant in both women and men. Jointly, these factors were associated with more than 2 times greater ADRD incidence among both men (aHR = 2.03; 95% CI: 1.13, 3.66) and men (aHR = 2.57; 95% CI: 1.27, 5.22).

DISCUSSION: The results suggest a synergistic relationship between air pollution and mental and physical health factors in ADRD risk. Results from this study support the need for establishing stronger measures to reduce air pollution and highlight the benefit of ADRD mitigation through improving mental and physical health.},
}

@article {pmid41467738,
year = {2025},
author = {Qi, X and Tian, Q and Luo, H and Resnick, SM and Ferrucci, L and Wu, B},
title = {Oral Health Conditions and Domain-Specific Cognitive Decline in Older Adults: Evidence from the Baltimore Longitudinal Study of Aging 2005-2024.},
journal = {The journals of gerontology. Series A, Biological sciences and medical sciences},
volume = {},
number = {},
pages = {},
doi = {10.1093/gerona/glaf294},
pmid = {41467738},
issn = {1758-535X},
abstract = {BACKGROUND: While associations between poor oral health and cognitive impairment are documented, research on how different oral health conditions relate to specific cognitive measures remains limited.

METHODS: Using data from 756 Baltimore Longitudinal Study of Aging 2005-2024 participants (mean age=72.0 years, 52.5% women, 24.2% Black), we investigated the association between the first oral health assessment and subsequent cognitive decline across domains in older adults aged 60+ who were free of cognitive impairment at baseline over an average of 7.7 follow-up. Cognitive function was assessed across language, executive function, attention, memory, and visuospatial ability domains, with domain-specific composite scores calculated using various cognitive tests. Oral health was evaluated for clinically-assessed tooth loss and dental plaque, alongside self-reported periodontal symptoms. Linear mixed-effect models were used to examine the longitudinal associations with cognitive decline, adjusted for socio-demographic and clinical characteristics.

RESULTS: After covariate adjustment, more tooth loss was associated with greater declines across all cognitive domains, including language (β=-0.0017; 95% CI=-0.0025, -0.0008), executive function (β=-0.0011; 95% CI=-0.0019, -0.0002), attention (β=-0.0011; 95% CI=-0.0021, -0.0001), memory (β=-0.0018; 95% CI=-0.0030, -0.0005), and visuospatial ability (β=-0.0017; 95% CI=-0.0029, -0.0006). Dental plaque was associated with executive function (β=-0.0165; 95% CI=-0.0276, -0.0054) and memory (β=-0.0279; 95% CI=-0.0444, -0.0115) declines. Presence of periodontal symptoms was only associated with executive function decline (β=-0.0004; 95% CI=-0.0007, -0.0001).

CONCLUSIONS: Tooth loss may indicate broader cognitive decline, while other oral health conditions, such as plaque and periodontal symptoms, particularly affect memory or executive function. Future studies are warranted to investigate underlying mechanisms.},
}

@article {pmid41467443,
year = {2025},
author = {Yang, Y and Chen, M and Ding, L and Liu, J and Luo, J and Yan, R and Ning, J and Xie, S and Li, X and Ren, Z and Zhou, R and Chen, Z},
title = {Mitochondria-associated endoplasmic reticulum membranes and calcium ion exchange: A novel direction for aging and neurodegenerative diseases.},
journal = {Neural regeneration research},
volume = {},
number = {},
pages = {},
doi = {10.4103/NRR.NRR-D-25-00857},
pmid = {41467443},
issn = {1673-5374},
abstract = {Mitochondria-associated endoplasmic reticulum membranes serve as crucial signaling hubs mediating communication between the endoplasmic reticulum and mitochondria, and play a central role in calcium ion exchange. This dynamic interface regulates key cellular processes including bioenergetic metabolism, apoptosis, autophagy, and stress responses. Dysregulation of calcium transport associated with mitochondria-associated endoplasmic reticulum membranes can disrupt intracellular homeostasis, leading to mitochondrial dysfunction, oxidative stress, and neuronal death, which are hallmarks of aging and neurodegenerative diseases. This review systematically examines the functions of protein complexes within mitochondria-associated endoplasmic reticulum membranes and the pathogenic mechanisms of calcium signaling regulated by these membranes in neurodegenerative disorders. It places particular emphasis on structural alterations in calcium ion transport machinery as a common mechanism underlying various neurodegenerative diseases. In Alzheimer's disease, mitochondria-associated endoplasmic reticulum membranes exhibit a hyperactive state, promoting the generation of amyloid-β and enhancing calcium ion flux from the endoplasmic reticulum to the mitochondria. In contrast, in Parkinson's disease and amyotrophic lateral sclerosis, the activity of mitochondria-associated endoplasmic reticulum membranes is reduced, leading to a decline in mitochondrial calcium ion buffering capacity and exacerbating excitotoxicity. Proteins residing in mitochondria-associated endoplasmic reticulum membranes are disrupted across various neurodegenerative diseases, resulting in abnormal communication between the endoplasmic reticulum and mitochondria. Recent studies indicate that mitochondria-associated endoplasmic reticulum membranes play a bidirectional role in disease progression, and compensatory mechanisms often exacerbate the pathological process. Therapeutic strategies aimed at preserving the integrity of mitochondria-associated endoplasmic reticulum membranes hold promise for alleviating neurodegenerative damage. Therefore, calcium ion exchange mediated by mitochondria-associated endoplasmic reticulum membranes plays a key role in aging and neurodegenerative diseases, making it a highly promising therapeutic target.},
}

@article {pmid41467440,
year = {2025},
author = {Akbergenov, R and Wolfer, DP and Gillingham, D and Shcherbakov, D},
title = {Error-prone translation as a driver of proteostasis collapse and neurodegeneration.},
journal = {Neural regeneration research},
volume = {},
number = {},
pages = {},
doi = {10.4103/NRR.NRR-D-25-00795},
pmid = {41467440},
issn = {1673-5374},
abstract = {Error-prone translation, resulting in inaccuracies in protein synthesis, is increasingly recognized as a critical contributor to proteostasis disruption and the pathogenesis of age-related neurological disorders. In recent years, numerous studies have elucidated that stochastic errors during mRNA translation may act as a molecular "tipping point" initiating pathogenic protein misfolding. A detailed analysis of how translation errors lead to protein misfolding, aggregation, and subsequent neurotoxicity will facilitate the identification of promising therapeutic targets for neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. This article explores the contribution of mistranslation to proteostasis decline, focusing on the unique vulnerabilities of neuronal cells. We review the sources of translation errors, effects of ribosomal ambiguity and error-restrictive mutations, role of proteostatic mechanisms (such as molecular chaperones, ubiquitin-proteasome system, and unfolded protein response), and provide a unified perspective that links age-related translational infidelity to neurodegeneration. By synthesizing the most recent data obtained with genetically modified cellular and animal model studies, we highlight how age-associated decline in translational fidelity exacerbates proteostasis failure and propose potential therapeutic interventions targeting translation accuracy to mitigate neurodegeneration.},
}

@article {pmid41467439,
year = {2025},
author = {Dong, T and Zhang, T and Wang, H and Zhang, J and Abdullah, R and Sun, B and Peng, G},
title = {Microbiota-gut-brain axis and bile acids-driven neuromodulation.},
journal = {Neural regeneration research},
volume = {},
number = {},
pages = {},
doi = {10.4103/NRR.NRR-D-25-00927},
pmid = {41467439},
issn = {1673-5374},
abstract = {Bile acids emerge as multifunctional signaling molecules with dual hepatic and microbial origins, acting through farnesoid X receptor and Takeda G protein coupled receptor 5 to influence inflammation and metabolism. Their dysregulation is consistently observed across various neurodegenerative diseases. The microbiota-gut-brain axis is a pivotal conduit for bile acids-driven neuromodulation, while sex-specific bile acid profiles and signaling pathways introduce critical biological heterogeneity. Emerging translational evidence indicates the promise of bile acids as biomarkers and therapeutic targets, yet highlights the critical hurdles that need to be addressed to realize precision interventions. Our core findings are: (1) Bile acids are far more than mere metabolic byproducts. They orchestrate core pathological processes such as neuroinflammation and energy metabolism. Their functions, whether neuroprotective or neurotoxic, are highly context-dependent, varying with cell type and disease-specific pathological backgrounds, thus exhibiting a potent "double-edged sword" effect. (2) The "microbiota-bile acids-brain axis" serves as a crucial bridge linking peripheral metabolic dysregulation to central nervous system pathology. (3) Sexual dimorphism emerges as a fundamental biological variable essential for understanding the heterogeneity in bile acid profiles and disease susceptibility. The primary contribution of this work is the proposal of an integrated "microbiota-bile acids-sex" framework that systematically describes the key scientific challenge of the context-dependent, dual roles of bile acids. Ultimately, this review champions a paradigm shift from a traditional brain-centric view to a systemic, metabolic perspective, establishing the bile acid system as a promising target for future precision therapeutic interventions.},
}

@article {pmid41467438,
year = {2025},
author = {Zhao, J and Wang, J and Guo, X},
title = {Organoids: Key advances, optimization, and technological iterations in their application to neurodegenerative diseases.},
journal = {Neural regeneration research},
volume = {},
number = {},
pages = {},
doi = {10.4103/NRR.NRR-D-25-00924},
pmid = {41467438},
issn = {1673-5374},
abstract = {Organoid technology, as an innovative approach, has shown great potential in disease modeling, target screening, and the development of treatment strategies. However, traditional organoids still have three major limitations in research: the absence of specific cell types, the lack of blood-brain barrier structure, and insufficient reproducibility of experimental results. In recent years, researchers have gradually overcome these limitations by introducing innovative techniques such as advanced culture methods, microfluidic systems, bioprinting, organoid transplantation, and assembloid construction. This progress has facilitated the widespread application of organoids in the study of neurodegenerative diseases. This paper aims to systematically review the technological innovations of organoids in the study of neurodegenerative diseases. By summarizing classical organoid construction strategies and their limitations, it emphasizes the value of organoids in comprehensive applications within neurodegenerative disease research. In this review, we focus on five specific neurodegenerative diseases: Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and frontotemporal dementia. Research in these diseases demonstrates that organoids improve experimental accessibility and reduce development cycles in disease modeling, target discovery, and therapeutic strategy formation. Using customized equipment and gene editing techniques, these organoids can be tailored to specific needs, providing pathophysiologically relevant disease models and enhancing our understanding of neurodegenerative diseases. Although organoid technology has demonstrated significant advantages in disease research, its potential for treating neurodegenerative diseases has not yet been fully explored, which may become an important direction for future research.},
}

@article {pmid41467436,
year = {2025},
author = {Qi, A and He, Y and Zhang, F and Liu, S and Xiang, Q and Dong, Y and Wang, B and Zhao, Y},
title = {Circadian transcriptomic disruptions in the hippocampus precede cognitive deficits in a mouse model of Alzheimer's disease.},
journal = {Neural regeneration research},
volume = {},
number = {},
pages = {},
doi = {10.4103/NRR.NRR-D-25-00851},
pmid = {41467436},
issn = {1673-5374},
abstract = {Mounting evidence suggests that circadian rhythm disruption may be linked to the onset and progression of Alzheimer's disease. However, whether this disruption occurs before the appearance of cognitive symptoms and whether it drives disease development remain unclear. Understanding the temporal relationship between circadian rhythm dysregulation and early Alzheimer's disease pathological changes may open up new avenues for disease prevention and intervention. To determine if circadian rhythm disruption precedes cognitive decline, we conducted high-resolution transcriptome analyses of the hippocampus in a 5-month-old mouse model of Alzheimer's disease and age-matched wild-type control mice at multiple time points over a 24-hour period. While the mouse model of Alzheimer's disease did not exhibit obvious cognitive symptoms at this stage, the expression of circadian-related genes in the hippocampus exhibited extensive abnormalities. In the control group, 2109 genes exhibited rhythmic expression characteristics. In the mouse model of Alzheimer's disease, a marked proportion of these genes lost their rhythmicity, some genes newly developed rhythmicity, and some maintained rhythmicity but with altered expression patterns. Genes related to neuronal function, including those involved in protein homeostasis regulation, neuroinflammation, and ion homeostasis, showed significant changes in circadian rhythm amplitude and phase, and some completely lost their rhythmicity. These findings point to the following critical early events in Alzheimer's disease: hippocampal circadian gene disruption occurs before cognitive symptoms emerge, genes related to neuronal function are uniquely susceptible to this early dysregulation, and circadian dysfunction may even precede the pathological changes of Alzheimer's disease and influence disease onset. This work advances Alzheimer's disease research by clarifying that circadian disruption is an early pre-symptomatic event, reinforcing the potential of circadian rhythm regulation as a strategy for early intervention of Alzheimer's disease, and identifying neuronal pathways that may serve as intervention targets.},
}

@article {pmid41467429,
year = {2025},
author = {Liang, X and Qin, R and Qin, Q and Xu, W and Xu, H and Lai, X and Shao, L and Li, C and Xie, M and Xiong, X and Tang, Q and Chen, L},
title = {Therapeutic potential of astrocyte transdifferentiated neurons.},
journal = {Neural regeneration research},
volume = {},
number = {},
pages = {},
doi = {10.4103/NRR.NRR-D-25-00554},
pmid = {41467429},
issn = {1673-5374},
abstract = {The permanent functional deficits resulting from the inability of adult mammalian central nervous system neurons to regenerate after injury present a significant clinical challenge. While traditional stem cell transplantation strategies continue to encounter ethical concerns and the risk of immune rejection, this impasse has shifted regenerative medicine research toward targeting endogenous astrocytes. Due to their intrinsic plasticity, widespread distribution throughout the central nervous system, and affinity for neurodevelopmental lineage, astrocytes are a unique target for in situ neuronal regeneration. This review systematically elucidates the core regulatory network governing astrocyte transdifferentiation, identifying 10 key signaling pathways, such as Wnt signaling pathway, that form a cascade regulatory system. Directed overexpression of transcription factors such as NeuroD1, Ascl1, or Neurog2 can directly initiate neuronal phenotypic conversion. Meanwhile, small molecule compounds such as valproic acid combined with CHIR99021 activate endogenous neurogenic programs by inhibiting the bone morphogenetic protein signaling axis. Notably, polypyrimidine tract binding protein 1 (PTB) gene silencing significantly enhances transdifferentiation efficiency by suppressing the microRNA 124/re1 silencing transcription factor (miR-124/REST) feedback loop. From a translational perspective, a multidimensional evaluation system based on morphological, molecular marker, and electrophysiological properties has demonstrated considerable therapeutic potential. In stroke models, NeuroD1-mediated transdifferentiation replenished approximately 30% of lost cortical neurons and improved motor coordination, evidenced by enhanced performance in food pellet retrieval, grid walking, and cylinder tests compared with controls. In spinal cord injury studies, SOX2-induced glutamatergic neurons moderately reduced glial scar density by about 25%, permitting regenerating axons to pass through while preserving the supportive structure of scar. In neurodegenerative contexts, PTB inhibition yielded functionally mature dopaminergic neurons and reconstructed nigrostriatal pathways in Parkinson's disease models. In Alzheimer's disease models, adeno-associated virus-delivered NeuroD1 induced whole-brain neural circuit remodeling, generating 500,000 new neurons widely distributed across the cortex and hippocampus, accompanied by improved cognitive performance. Current technical limitations include off-target effects of adeno-associated virus vectors, which cause nonspecific gene expression and require rigorous validation via Cre-loxP lineage tracing. Transdifferentiation efficiency is also highly influenced by regional microenvironments: gray matter astrocytes show higher conversion rates than those in white matter, and oxidative stress increases apoptosis among newly generated neurons. Clinical translation is further constrained by the safety of delivery systems and the aging tissue microenvironment, where transforming growth factor beta 1 is often elevated. Ferroptosis inhibitors have been shown to nearly double the survival rate of transdifferentiated cells, offering a novel strategy to mitigate oxidative damage. Based on current evidence, astrocyte transdifferentiation enables neural functional recovery across multiple disease models through endogenous repair mechanisms. Future advances should focus on optogenetically inducible vectors for spatiotemporal precision, non-viral delivery systems to mitigate vector-related risks, and integration of long-term safety validation in non-human primates with single-cell multi-omics technologies to facilitate the clinical translation of personalized regenerative therapies.},
}

@article {pmid41467426,
year = {2025},
author = {Bruqi, K and Strappazzon, F},
title = {Autophagy and selective autophagy receptors: Key players against Alzheimer's disease.},
journal = {Neural regeneration research},
volume = {},
number = {},
pages = {},
doi = {10.4103/NRR.NRR-D-25-00976},
pmid = {41467426},
issn = {1673-5374},
abstract = {The devastating neurodegenerative disorder of Alzheimer's disease hallmarks the presence of protein aggregates known as amyloid-β plaques and neurofibrillary tangles, composed of amyloid-β peptides and aberrantly phosphorylated Tau protein, respectively. The accumulation of these inclusions leads to significant alterations in neuronal homeostasis and overall brain function, resulting in a progressive and rapid cognitive decline. Autophagy, the molecular mechanism of cellular waste removal through the lysosomal pathway, accounts for the degradation of both amyloid-β plaques and neurofibrillary tangles in the brain, conferring therefore protection against the pathology. In addition to general autophagy, several lines of evidence have reported the implication of selective autophagy receptors, including sequestosome1/p62, the neighbor of BRCA1 gene, the nuclear-dot protein 52, and optineurin, in mediating the autophagic clearance of amyloid-β, phosphorylated Tau, or both. Herein, we have highlighted autophagy and selective autophagy as pivotal mechanisms in Alzheimer's disease, underlining selective autophagy receptors as a potential target for treatments in the future.},
}

@article {pmid41467422,
year = {2025},
author = {Izrael, M and Frenkel, OM},
title = {Targeting innovative therapeutic approaches to the hallmarks of aging to combat Alzheimer's disease.},
journal = {Neural regeneration research},
volume = {},
number = {},
pages = {},
doi = {10.4103/NRR.NRR-D-25-00966},
pmid = {41467422},
issn = {1673-5374},
abstract = {Aging is the leading risk factor for neurodegenerative diseases, including Alzheimer's disease. Mounting evidence implicates twelve interconnected hallmarks of aging, such as genomic instability, mitochondrial dysfunction, cellular senescence, and altered intercellular communication, as core contributors to cognitive decline. In this review, we will first delineate the hallmarks of aging and their mechanistic roles according to their functions in the aging brain and Alzheimer's disease. These hallmarks can be grouped into four major functional clusters: (i) Genomic and epigenomic instability, (ii) proteostasis and organelle dysfunction, (iii) cellular fate and regenerative decline, and (iv) cellular senescence. Then, we provide an overview of innovative therapeutic approaches aimed at modifying these hallmarks, focusing on the emerging paradigm of supplementation of rejuvenation factors that are derived from young plasma, stem cell secretomes, or their derivatives (e.g., extracellular vesicles). Finally, we discuss key aging-related biological factors that can influence Alzheimer's disease progression and evaluate their potential as therapeutic targets.},
}

@article {pmid41467421,
year = {2025},
author = {Huerta, TJ and Urbina-Muñoz, V and Urra-Alvarez, V and Villablanca, C and Gomez-Perez, LS and Saavedra, B and Contreras, T and Vidal, RL},
title = {Cell-based immunotherapy for neurodegenerative disease: A promising avenue.},
journal = {Neural regeneration research},
volume = {},
number = {},
pages = {},
doi = {10.4103/NRR.NRR-D-25-00816},
pmid = {41467421},
issn = {1673-5374},
abstract = {Neurodegenerative diseases such as amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, and Huntington's disease are characterized by progressive neuronal loss and chronic neuroinflammation, with current treatments remaining largely symptomatic. This review explores the potential of cell-based immunotherapy as a disease-modifying strategy. Advances in stem cell biology and immune engineering have facilitated the development of therapies using mesenchymal stem cells, chimeric antigen receptor T cells, macrophages, regulatory T cells, modified macrophages, and monoclonal antibodies. These approaches aim to regulate immune mechanisms implicated in neurodegeneration, such as microglial activation, systemic inflammation, and immune checkpoint dysregulation. Notably, macrophage-mediated delivery systems, such as genetically modified cells expressing neurotrophic factors or antioxidant enzymes, have demonstrated neuroprotective effects. Likewise, emerging data support T-cell modulation and monoclonal antibody development as therapeutic targets in amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, and Huntington's disease. We highlight current preclinical findings, underlying mechanisms, and translational challenges, emphasizing that immunomodulatory cell therapies represent a promising avenue for precision medicine in neurodegenerative diseases.},
}

@article {pmid41467414,
year = {2025},
author = {Li, J and Wu, N and Xiao, Y and Xia, Y},
title = {High mobility group box 1 and its post-translational modifications: Molecular mechanisms underlying neurodegenerative disease pathogenesis.},
journal = {Neural regeneration research},
volume = {},
number = {},
pages = {},
doi = {10.4103/NRR.NRR-D-25-01091},
pmid = {41467414},
issn = {1673-5374},
abstract = {High mobility group box 1 is a dynamic nuclear protein that acts as a damage-associated molecular pattern when released from cells and plays key roles in neurodegenerative diseases. This review comprehensively analyzes the related post-translational modifications that affect the dual functions of high mobility group box 1 in neuroinflammation and neuronal survival, including acetylation, phosphorylation, oxidation, S-nitrosylation, lactylation, and ubiquitination. Post-translational modifications play critical regulatory roles in high mobility group box 1 subcellular localization, release processes and the specificity of receptor binding. In Alzheimer's disease, high mobility group box 1 exacerbates the disease through the Toll-like receptor 4/nuclear factor kappa B signaling pathway. Inhibition of high mobility group box 1 acetylation can alleviate neuroinflammation. Parkinson's disease models indicate that the S-nitrosylation of Cys106 is essential for the secretion of high mobility group box 1, which contributes to dopaminergic degeneration through the activation of microglia. In multiple sclerosis, high mobility group box 1 obstructs remyelination by inhibiting the maturation of oligodendrocytes and activating pro-inflammatory pathways. In contrast, high mobility group box 1 can maintain autophagy and DNA repair functions, suggesting its protective role. Therapeutic strategies targeting high mobility group box 1 show potential benefits. Glycyrrhizic acid inhibits disulfide-linked high mobility group box 1, SIRT activators suppress acetylation, and anti-high mobility group box 1 antibodies neutralize extracellular isoforms, thereby improving the results of preclinical studies. However, the diverse functions of high mobility group box 1 and the lack of post-translational modification-specific biomarkers present challenges for clinical translation. Future research should aim to create selective inhibitors that can cross the blood-brain barrier to target harmful forms of high mobility group box 1, and establish post-translational modification-based biomarkers for early detection. This review emphasizes that accurately targeting of high mobility group box 1 post-translational modifications in neurodegenerative diseases could be a new approach that can interrupt neuroinflammatory cascades while maintaining neuroprotective functions.},
}

@article {pmid41467412,
year = {2025},
author = {Zhang, W and Zhou, Y and Chen, J and Perez, M and Claure, X and Leblanc, RM},
title = {Prospect in Alzheimer's disease integrative therapy targeting both amyloid-beta and tau.},
journal = {Neural regeneration research},
volume = {},
number = {},
pages = {},
doi = {10.4103/NRR.NRR-D-24-00916},
pmid = {41467412},
issn = {1673-5374},
abstract = {Alzheimer's disease is well characterized by the buildup of amyloid-β plaques and tau protein tangles, leading to neurodegeneration and cognitive impairments. Recent prosperous Alzheimer's disease therapeutic development targeting amyloid-β validates the amyloid hypothesis. Nonetheless, the limited efficacy of single-target therapies plus as-observed synergy between amyloid-β and tau calls for a thorough understanding of Alzheimer's disease pathogenesis. Thus, this review introduces Alzheimer's disease pathogenesis, specifically focusing on the amyloid-β and tau pathologies, highlights their interconnected nature, presents personal perspectives on therapeutic and diagnostic challenges, and underscores the necessity of combined therapeutic approaches to effectively address Alzheimer's disease.},
}

@article {pmid41467404,
year = {2025},
author = {Kancheva, AK and Lyall, DM and Tsvetanov, KA and Kancheva, IK and Mavromati, K and Koychev, I and Tari, B and Garcia, DJ and Hughes, L and Wardlaw, JM and Quinn, TJ},
title = {Cardiovascular Risk as a Moderator of the Relationship Between Plasma Alzheimer Disease Biomarkers and Cognitive Status.},
journal = {Journal of the American Heart Association},
volume = {},
number = {},
pages = {e044438},
doi = {10.1161/JAHA.125.044438},
pmid = {41467404},
issn = {2047-9980},
abstract = {BACKGROUND: Plasma biomarkers may aid Alzheimer disease (AD) diagnosis and prognosis. Cardiovascular risk contributes to cognitive decline in AD, but whether it modifies the relationship between plasma biomarkers and cognitive status has not been assessed in a large multisite cohort. We aimed to explore if cardiovascular risk moderates plasma AD biomarkers' relationship with cognitive status.

METHODS: We included cognitively normal (n=301) participants and participants with mild cognitive impairment or probable AD (n=444) from the Bio-Hermes-001 study. Cardiovascular risk was quantified using the Atherosclerotic Cardiovascular Disease risk calculator. Logistic regression analyzed associations of cardiovascular risk and plasma biomarkers (amyloid beta 42/amyloid beta 40, phosphorylated tau [p-tau]181, p-tau217, apoE4 [apolipoprotein E]) with cognitive status. Moderation by cardiovascular risk was tested in each model.

RESULTS: We included 745 participants (mean age=72.3 years; 423 [56.8%] female). Plasma biomarkers and cardiovascular risk were independently associated with cognitive status across models; the strongest association was with p-tau217 (odds ratio [OR], 2.33 [95% CI, 1.89-2.9]; P<0.001). Cardiovascular risk moderated only the relationships of p-tau181 and p-tau217 with cognitive status (P<0.05).

CONCLUSIONS: Plasma AD biomarkers and cardiovascular risk were independently associated with cognitive status, with cardiovascular risk moderating the p-tau181 and p-tau217 cognitive status relationships. If certain plasma biomarkers and cardiovascular risk independently contribute to dementia risk, cardiovascular risk assessment should complement other biomarker evaluations in cognitive screening. Results should be interpreted with caution as associations might be primarily driven by age and sex. Future research including education and genetic risk is needed to clarify the studied relationships.},
}

@article {pmid41467396,
year = {2025},
author = {Tan, ESJ and Sim, MA and Li, L and Toh, A and Chong, E and Chan, SP and Gonzales, P and Lim, MJH and Hilal, S and Chong, J and Lai, MKP and Venketasubramanian, N and Tan, BY and Richards, AM and Ling, LH and Chen, C},
title = {Association of Atrial Electrophysiological Abnormalities With Cognitive Decline and Cerebrovascular Disease.},
journal = {Journal of the American Heart Association},
volume = {},
number = {},
pages = {e045054},
doi = {10.1161/JAHA.125.045054},
pmid = {41467396},
issn = {2047-9980},
abstract = {BACKGROUND: Atrial electrophysiological abnormalities (AEA) are associated with cognitive dysfunction. We evaluated the associations of AEA with longitudinal cognitive decline and incident dementia and investigated underlying mechanisms.

METHODS: In subjects without atrial fibrillation followed prospectively for 5 years, 12-lead ECGs were evaluated for AEA, defined as the presence of sinus node dysfunction (SND), frequent premature atrial complexes, advanced interatrial block (a-IAB), or P-terminal force in V1 (>40 mm*ms). Rate of decline in global cognition (Z-score averaged from 6 cognitive domains), Clinical Dementia Rating-Sum of Boxes score, and associations with cerebrovascular disease on neuroimaging and circulating biomarkers of neurodegenerative disease were determined.

RESULTS: Among 358 subjects (age 73.3±7.6 years, 55% female, 47% dementia), 188 (53%) had AEA (94 SND, 6 frequent premature atrial complexes, 52 a-IAB, 92 P-terminal force in V1 >40 mm*ms). Compared with non-AEA, AEA was associated with accelerated decline in both global cognition and Clinical Dementia Rating-Sum of Boxes score (Pinteraction<0.05), 2 times increased risk of dementia in competing risk analyses, and increased burden of cortical infarcts, lacunes, and cerebral microinfarcts (P<0.05). Among AEA subtypes, SND (versus non-SND) and a-IAB (versus non-a-IAB) both associated with accelerated decline in global cognition and Clinical Dementia Rating-Sum of Boxes score (Pinteraction<0.05). a-IAB was associated with 3 times increased risk of incident ischemic stroke and P-terminal force in V1 with increased burden of lacunes. SND was associated with increased burden of cerebral microinfarcts and cerebral microbleeds, incident cerebral microbleeds, higher circulating pTau-181 levels, and increased odds of Alzheimer disease among subjects with preexisting dementia (P<0.05).

CONCLUSIONS: AEA is associated with worse cognitive trajectories and increased cerebrovascular disease burden. These associations may be underpinned by AEA-subtype-specific mechanisms.},
}

@article {pmid41467389,
year = {2025},
author = {Stahlke, S and Theiss, C},
title = {Sex hormones, the gut microbiome, and neurodegenerative diseases: Lifespan perspective.},
journal = {Neural regeneration research},
volume = {},
number = {},
pages = {},
doi = {10.4103/NRR.NRR-D-25-00932},
pmid = {41467389},
issn = {1673-5374},
abstract = {The gut-brain axis represents a highly integrated communication network, connecting the gastrointestinal tract and the central nervous system via neural, immune, endocrine, and metabolic pathways. Steroid hormones, such as estrogens, androgens, and glucocorticoids, play a pivotal role in modulating these interactions across the lifespan. These hormones influence the composition of microbiota, intestinal permeability, and neuroimmune responses, thereby shaping brain function and behavior. Emerging evidence suggests a correlation between disruptions in the gut-brain axis and the onset and progression of neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease, and multiple sclerosis. The diseases exhibit distinct sex-specific patterns in terms of prevalence, symptomatology, and progression. These patterns are often the consequence of differences in steroid hormone levels, receptor distribution, and immune responses. Despite these differences, the role of sex as a biological variable remains underrepresented in experimental and clinical research. This review synthesizes current evidence on how steroid hormones modulate gut-brain axis interactions and how these mechanisms contribute to neurodegeneration in a sex-specific manner. We highlight recent findings on hormonal regulation of the gut microbiome and its impact on neuroinflammation and neuronal vulnerability. This overview focuses not only on Parkinson's disease, in which genetic variations in the gene for brain-derived neurotrophic factor have been observed among others as triggers for dopaminergic neurodegeneration. In addition, Alzheimer's disease and multiple sclerosis are also considered, in which the prevalence of intestinal dysbiosis and impaired intestinal barrier function have been identified as significant influencing factors. This review provides a comprehensive framework for understanding the gender-specific neurobiology of gut-brain axis by integrating perspectives from the fields of endocrinology, neuroimmunology, and microbiome research. It is argued that a targeted investigation of the interactions between hormones and gut-brain axis is essential for the development of sex-specific therapeutic strategies for neurodegenerative diseases.},
}

@article {pmid41467385,
year = {2025},
author = {Zhou, Z and Zhao, Y and Fan, X and Zhang, J and Niu, R and Ma, Y and Xie, F and Tang, P and Mei, X and Zhang, L and Deng, J},
title = {CD11c+ microglia: From basic research to clinical application.},
journal = {Neural regeneration research},
volume = {},
number = {},
pages = {},
doi = {10.4103/NRR.NRR-D-25-00868},
pmid = {41467385},
issn = {1673-5374},
abstract = {CD11c+ microglia are a functionally specialized subpopulation of microglia that play a crucial role in the pathophysiological processes of various central nervous system diseases. This review synthesizes compelling evidence that CD11c+ microglia exhibit unique transcriptomic and phagocytic characteristics. These characteristics distinguish them from homeostatic microglia and support their specialized functions. During development, CD11c+ microglia are crucial for the maturation of oligodendrocytes and the integrity of white matter, particularly in regions such as the corpus callosum and cerebellum. In preclinical models of neurodegenerative diseases (such as Alzheimer's disease and amyotrophic lateral sclerosis) and central nervous system injuries (such as stroke and spinal cord injury), they are consistently associated with neuroprotective phenotypes. CD11c+ microglia exhibit enhanced phagocytic capacity near amyloid plaques and damaged neurons, helping to clear pathological protein aggregates and cell debris, thereby reducing neurotoxicity and promoting a repair environment. The current consensus is that specific microenvironmental cues, particularly hazard signaling molecules (DAMPs) and cytokines (such as interferon-γ), are the main drivers of the differentiation and activation of CD11c+ microglia. Among these, the TREM2-APOE signaling axis is a key and widely accepted regulatory pathway for their survival, proliferation, and functional status. The plasticity of CD11c+ microglia is regulated by multiple signaling pathways, including CSF1R, SIRPα-CD47, IFN-γ, and the complement cascade. Emerging therapeutic strategies aim to regulate their activities through gene targeting, metabolic intervention, and immune regulation using TREM2 agonists, CSF1R inhibitors, or nanopharmacological methods. However, challenges remain in defining specific CD11c+ biomarkers, understanding environment-dependent functions, and achieving targeted delivery. Future prospects depend on clearly addressing individual developmental issues, deciphering the molecular switches that control phenotypic plasticity, and developing highly specific therapeutic strategies to leverage their beneficial functions, thereby paving the way for new intervention methods for neurological diseases.},
}

@article {pmid41467384,
year = {2025},
author = {De Paolis, ML and Zaccone, C and D'Amelio, M},
title = {Neurovascular therapeutic potential of neuromodulation in Alzheimer's disease.},
journal = {Neural regeneration research},
volume = {},
number = {},
pages = {},
doi = {10.4103/NRR.NRR-D-25-00958},
pmid = {41467384},
issn = {1673-5374},
}

@article {pmid41467376,
year = {2025},
author = {Alexandrova, EG and Abakumova, TR and Ziganshina, LE},
title = {Use of nootropics in Alzheimer's disease: An analysis of regulatory positions and drug policies in the countries of the Commonwealth of Independent States.},
journal = {The International journal of risk & safety in medicine},
volume = {},
number = {},
pages = {9246479251410817},
doi = {10.1177/09246479251410817},
pmid = {41467376},
issn = {1878-6847},
abstract = {ObjectiveTo analyse regulatory positions and drug policies of the Commonwealth of Independent States (CIS), compared to those of the EU, UK, USA i of the nootropics, used in Russia for Alzheimer's disease.MethodsWe searched E-library to reveal the list of nootropics used and studied in Russia for Alzheimer's disease. We assessed official pharmaceutical registries of nine countries for registration status of identified nootropics, 7 National Essential Medicines Lists (EML), and four clinical practice guidelines (CPG) on Alzheimer's disease. We compared the results of Russia with other countries regulatory and policy positions.ResultsE-Library searches identified 11 nootropicspiracetam, citicoline, idebenone, vinpocetine, choline alfoscerate, Cerebrolysin®, Kortexin®, ethylmethylhydroxypyridine succinate, glycine, nicergoline, nimodipine. Eight nootropic have registration for use in all CIS countries (excluding idebenone, nimodipine), four (piracetam, nimodipine, nicergoline, idebenone) - in UK, nimodipine - in the USA, and idebenone - in EU. National EMLs included: nine nootropics (Russia), 8 - Belarus and Kazakhstan, 4 - Uzbekistan, 2 - Armenia. The studied nootropic agents are not included on the WHO Model EML and on the National EML of the Kyrgyz Republic. They are not listed in the CPG for Treatment of dementia and Alzheimer's disease in the USA, the EU, and the UK. Russian CPGs for Alzheimer's disease recommend Cerebrolysin® and choline alfoscerate.ConclusionsThe studied nootropics are registered for use and listed on National EMLs of Russia, Armenia, Belarus, Kazakhstan, Uzbekistan. None is included on the WHO Model EML and the National EML of Kyrgyzstan, Only CPG of the RF recommend using two nootropics as adjuvant therapy of Alzheimer's disease, Cerebrolysin® and choline alfoscerate. CPG of the European Union, the United Kingdom, and the USA do not mention nootropics as potential treatment options for Alzheimer's disease.},
}

@article {pmid41466826,
year = {2025},
author = {Akhtar, M and Farooqi, HA and Nabi, R and Iqbal, J and Ain Munir Abbasi, SU and Rashid, M and Mushtaq Gardezi, SK and Ripley, DP and Ahmed, R},
title = {Corrigendum to 'Trends in mortality due to ischemic heart diseases among patients with Alzheimer's disease in the United States from 1999 to 2020' [Int J Cardiol Cardiovasc Risk Prev. 2025 Mar 7;25:200390].},
journal = {International journal of cardiology. Cardiovascular risk and prevention},
volume = {27},
number = {},
pages = {200498},
doi = {10.1016/j.ijcrp.2025.200498},
pmid = {41466826},
issn = {2772-4875},
abstract = {[This corrects the article DOI: 10.1016/j.ijcrp.2025.200390.].},
}

@article {pmid41466825,
year = {2025},
author = {Satapathy, P and Mehta, R and Sah, R},
title = {Comment on "Trends in mortality due to ischemic heart diseases among patients with Alzheimer's disease in the United States from 1999 to 2020".},
journal = {International journal of cardiology. Cardiovascular risk and prevention},
volume = {27},
number = {},
pages = {200491},
doi = {10.1016/j.ijcrp.2025.200491},
pmid = {41466825},
issn = {2772-4875},
}

@article {pmid41466681,
year = {2025},
author = {Gupta, PS and Padmakumar, VM and Usmani, OI},
title = {Cross-sectional analysis of gut microbiome diversity with progression of Alzheimer's disease.},
journal = {Bioinformation},
volume = {21},
number = {9},
pages = {3329-3332},
doi = {10.6026/973206300213329},
pmid = {41466681},
issn = {0973-2063},
abstract = {The relationship between gut microbiome diversity and stages of Alzheimer's disease (AD) progression is of interest. Hence, a total of 124 participants, including cognitively normal controls and patients with mild, moderate, and severe AD, were assessed for microbiome composition using 16S rRNA sequencing. Results revealed significantly reduced microbial diversity and altered bacterial profiles, notably lower levels of Bifidobacterium and Faecalibacterium and increased Proteobacteria, in advanced AD stages. Correlations were observed between cognitive declines and reduced alpha diversity. Thus, we show gut dysbiosis may play a contributory role in Alzheimer's pathology.},
}

@article {pmid41466523,
year = {2025},
author = {Watabe, K},
title = {Praja1 E3 ubiquitin ligase and the role it plays in neurodegeneration.},
journal = {The FEBS journal},
volume = {},
number = {},
pages = {},
doi = {10.1111/febs.70383},
pmid = {41466523},
issn = {1742-4658},
abstract = {Protein aggregation and transmission are hallmarks of neurodegenerative diseases. Praja1 E3 ubiquitin ligase has been shown to suppress the aggregation of causative proteins in amyotrophic lateral sclerosis, frontotemporal lobar degeneration, Parkinson's disease, Huntington's disease, and spinocerebellar degeneration, which include transactivation response DNA-binding protein of 43 kDa, fused in sarcoma, superoxide dismutase 1, α-synuclein, huntingtin, and ataxin-3. Aoki et al. demonstrated that Praja1 ubiquitinates and degrades tau, a key molecule in tauopathies such as Alzheimer's disease, Pick's disease, progressive supranuclear palsy, and corticobasal syndrome, furthering our understanding of the role of Praja1 in neurodegenerative diseases and potential therapeutic approaches.},
}

@article {pmid41466345,
year = {2025},
author = {Lindauer, A and Brandis, L and Dhar, N and Wohner, M and Barnes, C and McCormack, JL and Dickinson, C and Morgan, E},
title = {Dementia diagnosis in primary care: testing an educational program in Oregon.},
journal = {Gerontology & geriatrics education},
volume = {},
number = {},
pages = {1-14},
doi = {10.1080/02701960.2025.2608977},
pmid = {41466345},
issn = {1545-3847},
abstract = {The Dementia Diagnosis in Primary Care (DDPC) program was designed to support primary care clinicians and their teams in identifying and diagnosing Alzheimer's disease and other types of dementia. Here we describe the development, delivery, and evaluation of the DDPC in Oregon, a largely rural state. Primary care clinics across Oregon participated. Of the 28 clinics that enrolled in the program, 14 (50%) were in rural and frontier communities. The program consisted of two cohorts of 8-session, 1-hour webinars for clinic staff members from the enrolled clinics. There was strong attendance at each webinar, averaging 38 attendees per session, and 132 participants attended at least one webinar. Each enrolled clinic was offered coaching with non-clinicians, clinician subject matter experts, and an electronic medical record management specialist. Pre- and post- program assessments, chart audits, per-session webinar surveys, and a clinic exit interview were utilized to determine the overall key outcomes of the program. Quantitative and qualitative data indicate that the program was helpful in building clinic team confidence in identifying and treating dementia. Findings indicate that the DDPC clinical teams will be better prepared to address the increasing prevalence of dementia across this rural state.},
}

@article {pmid41466307,
year = {2025},
author = {Zhong, X and Jia, G and Yin, Z and Chen, R and Cheng, K and Rzhetsky, A and Li, B and Cox, NJ},
title = {Longitudinal analysis of electronic health records reveals medical conditions associated with subsequent Alzheimer's disease development.},
journal = {Alzheimer's research & therapy},
volume = {17},
number = {1},
pages = {263},
pmid = {41466307},
issn = {1758-9193},
support = {R01AG069900//National Institute of Aging/ ; R01AG069900//National Institute of Aging/ ; R01AG069900//National Institute of Aging/ ; U54HG012510/HG/NHGRI NIH HHS/United States ; R01MH137646/MH/NIMH NIH HHS/United States ; C2021013133//J & J contract/ ; },
mesh = {Humans ; *Alzheimer Disease/epidemiology/genetics ; *Electronic Health Records/statistics & numerical data ; Male ; Female ; Longitudinal Studies ; Retrospective Studies ; Aged ; Middle Aged ; Aged, 80 and over ; Cohort Studies ; Risk Factors ; Databases, Factual ; },
abstract = {BACKGROUND: Several health conditions are known to increase the risk of Alzheimer's disease (AD). We aim to systematically identify medical conditions that are associated with subsequent development of AD by leveraging the growing resources of electronic health records (EHRs).

METHODS: This retrospective cohort study used de-identified EHRs from two independent databases (MarketScan and VUMC) with 153 million individuals to identify AD cases and age- and gender-matched controls. By tracking their EHRs over a 10-year window before AD diagnosis and comparing the EHRs between AD cases and controls, we identified medical conditions that occur more likely in those who later develop AD. We further assessed the genetic underpinnings of these conditions in relation to AD genetics using data from two large-scale biobanks (BioVU and UK Biobank, total N = 450,000).

RESULTS: We identified 43,508 AD cases and 419,455 matched controls in MarketScan, and 1,320 AD cases and 12,720 matched controls in VUMC. We detected 406 and 102 medical phenotypes that are significantly enriched among the future AD cases in MarketScan and VUMC databases, respectively. In both EHR databases, mental disorders and neurological disorders emerged as the top two most enriched clinical categories. More than 70 medical phenotypes are replicated in both EHR databases, which are dominated by mental disorders (e.g., depression), neurological disorders (e.g., sleep orders), circulatory system disorders (e.g. cerebral atherosclerosis) and endocrine/metabolic disorders (e.g., type 2 diabetes). We identified 19 phenotypes that are either associated with individual risk variants of AD or a polygenic risk score of AD.

CONCLUSIONS: In this study, analysis of longitudinal EHRs from independent large-scale databases enables robust identification of health conditions associated with subsequent development of AD, highlighting potential opportunities of therapeutics and interventions to reduce AD risk.},
}

Humans
*Alzheimer Disease/epidemiology/genetics
*Electronic Health Records/statistics & numerical data
Male
Female
Longitudinal Studies
Retrospective Studies
Aged
Middle Aged
Aged, 80 and over
Cohort Studies
Risk Factors
Databases, Factual

@article {pmid41465832,
year = {2025},
author = {Pilśniak, J and Węgrzynek-Gallina, J and Bednarczyk, B and Buczek, A and Pilśniak, A and Chmiela, T and Jarosińska, A and Siuda, J and Holecki, M},
title = {The Role of Glucagon-like Peptide-1 Receptor Agonists in Alzheimer's and Parkinson's Disease: A Literature Review of Clinical Trials.},
journal = {Life (Basel, Switzerland)},
volume = {15},
number = {12},
pages = {},
doi = {10.3390/life15121893},
pmid = {41465832},
issn = {2075-1729},
abstract = {Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are widely used in the treatment of type 2 diabetes and obesity due to their metabolic effects. Emerging evidence suggests they may also have neuroprotective effects, indicating their potential as disease-modifying therapies in neurodegenerative disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD). Preclinical studies in animal models have demonstrated that GLP-1RAs can reduce neuroinflammation, oxidative stress, neuronal apoptosis, and pathological protein aggregation, while enhancing glucose metabolism and mitochondrial function. This narrative review analyzed results from human clinical trials evaluating GLP-1RAs in AD and PD, based on a search of four databases (Web of Science, Medline, Embase, and Clinical Trials). The analysis included eleven studies. In AD, clinical trials suggest that GLP-1RAs such as liraglutide and semaglutide may enhance brain glucose metabolism, facilitate glucose transport across the blood-brain barrier, and benefit neuronal networks. However, most studies did not demonstrate improvements in cognitive functions or radiological markers. Short-term clinical trials of GLP-1RAs, including exenatide and lixisenatide, demonstrated promising effects on motor and selected non-motor symptoms in patients with PD, but their disease-modifying effects remain unproven. GLP-1RAs showed a favorable safety profile. Despite promising findings, small study populations, heterogeneous protocols, and short observation periods limit definitive conclusions. Further larger, long-term studies are needed, particularly to clarify the risk-benefit balance, weight control, and long-term outcomes.},
}

@article {pmid41465790,
year = {2025},
author = {Suswidiantoro, V and Puteri, MU and Kato, M and Ariestanti, DM and James, RJ and Saputri, FC},
title = {The Roles of PCSK9 in Alzheimer's Disease: A Systematic Review of Clinical, Genetic, and Preclinical Evidence.},
journal = {Life (Basel, Switzerland)},
volume = {15},
number = {12},
pages = {},
doi = {10.3390/life15121851},
pmid = {41465790},
issn = {2075-1729},
support = {NKB-175/UN2.RST/HKP.05.00/2024//Directorate of Research and Development, Universitas Indonesia under Hibah PUTI 2024/ ; },
abstract = {Alzheimer's disease (AD) is increasingly associated with alterations in cholesterol metabolism. Proprotein convertase subtilisin/kexin type 9 (PCSK9), an enzyme regulating low-density lipoprotein receptor (LDLR) degradation, has been implicated in AD through mechanisms involving amyloid-β (Aβ) processing, tau phosphorylation, and synaptic dysfunction. This review aimed to evaluate clinical, genetic, and experimental evidence regarding the role of PCSK9 in AD and its potential as a biomarker or therapeutic target. A systematic search was conducted in PubMed, Scopus, ScienceDirect, and Google Scholar (2020-2025) using predefined terms related to PCSK9 and Alzheimer's disease. Eligible studies included clinical, in vivo, and in vitro investigations reporting PCSK9 expression, regulation, or inhibition in relation to AD pathology. Due to methodological heterogeneity, a narrative synthesis was performed. Forty-two studies met inclusion criteria. Preclinical findings consistently showed that elevated PCSK9 may indirectly promote Aβ accumulation, tau hyperphosphorylation, neuroinflammation, and cognitive decline, while genetic deletion or pharmacological inhibition of PCSK9 mitigates these effects. Clinical evidence was variable: several studies identified increased PCSK9 levels in cerebrospinal fluid or brain tissue of AD patients, often correlating with tau markers, but large-scale genetic and Mendelian randomization studies did not confirm a causal association. PCSK9 inhibitors, widely used in cardiovascular therapy, demonstrated potent LDL-C reduction without cognitive adverse effects. Experimental data suggest that PCSK9 contributes to AD-related pathology, whereas human evidence indicates a modulatory or biomarker role rather than a causative one. Despite strong preclinical data, human genetics lacks causal evidence for PCSK9 in Alzheimer's. It may be a disease modifier or biomarker; its clinical relevance requires confirmation through longitudinal studies and CNS-penetrant therapies.},
}

@article {pmid41465568,
year = {2025},
author = {Dermawan, D and Alotaiq, N},
title = {Rescuing Verubecestat: An Integrative Molecular Modeling and Simulation Approach for Designing Next-Generation BACE1 Inhibitors.},
journal = {International journal of molecular sciences},
volume = {26},
number = {24},
pages = {},
doi = {10.3390/ijms262412143},
pmid = {41465568},
issn = {1422-0067},
support = {IMSIU-DDRSP2501//Deanship of Scientific Research at Imam Mohammad Ibn Saud Islamic University (IMSIU)/ ; },
mesh = {*Amyloid Precursor Protein Secretases/antagonists & inhibitors/chemistry/metabolism ; *Aspartic Acid Endopeptidases/antagonists & inhibitors/chemistry/metabolism ; Molecular Dynamics Simulation ; Molecular Docking Simulation ; Humans ; Drug Design ; Alzheimer Disease/drug therapy ; Protein Binding ; Cyclic S-Oxides ; Thiadiazines ; },
abstract = {β-site amyloid precursor protein cleaving enzyme 1 (BACE1) is a central therapeutic target in Alzheimer's disease, as it catalyzes the rate-limiting step in amyloid-β production. Verubecestat (VER), a clinical BACE1 inhibitor, failed in late-stage trials due to limited efficacy and safety concerns. This study employed an integrative computational approach to design VER derivatives with improved binding affinity, stability, and pharmacokinetic profiles. Structural similarity analysis, Molecular docking, frontier molecular orbital (FMO) analysis, pharmacophore modeling, 200 ns molecular dynamics (MD) simulations, MM/PBSA free energy calculations, and per-residue decomposition were performed. In silico ADMET profiling assessed drug-likeness, absorption, and safety parameters. Docking and pharmacophore analyses identified derivatives with stronger complementarity in the BACE1 catalytic pocket. MD simulations revealed that VERMOD-33 and VERMOD-57 maintained low root mean square deviations (RMSDs) and stable binding orientations and induced characteristic flexibility in the flap and catalytic loops surrounding the catalytic dyad (Asp93 and Asp289), consistent with inhibitory activity. MM/PBSA confirmed the superior binding free energies of VERMOD-33 (-51.12 kcal/mol) and VERMOD-57 (-43.85 kcal/mol), both outperforming native VER (-35.33 kcal/mol). Per-residue decomposition highlighted Asp93, Asp289, and adjacent flap residues as major energetic contributors. ADMET predictions indicated improved oral absorption, BBB penetration, and no mutagenicity or toxicity alerts. Rationally designed VER derivatives, particularly VERMOD-33 and VERMOD-57, displayed enhanced binding energetics, stable inhibitory dynamics, and favorable pharmacokinetic properties compared with native VER. These findings provide a computational framework for rescuing VER and support further synthesis and experimental validation of next-generation BACE1 inhibitors for Alzheimer's disease.},
}

*Amyloid Precursor Protein Secretases/antagonists & inhibitors/chemistry/metabolism
*Aspartic Acid Endopeptidases/antagonists & inhibitors/chemistry/metabolism
Molecular Dynamics Simulation
Molecular Docking Simulation
Humans
Drug Design
Alzheimer Disease/drug therapy
Protein Binding
Cyclic S-Oxides
Thiadiazines

@article {pmid41465553,
year = {2025},
author = {Chowdhury, R and Das, AC and van Deventer, R and Shlyakhtenko, LS and Lyubchenko, YL},
title = {Catalytic Effect of Amyloid-β on Native Tau Aggregation at Physiologically Relevant Concentrations.},
journal = {International journal of molecular sciences},
volume = {26},
number = {24},
pages = {},
doi = {10.3390/ijms262412128},
pmid = {41465553},
issn = {1422-0067},
support = {GM148537/GF/NIH HHS/United States ; },
mesh = {*tau Proteins/metabolism/chemistry ; *Amyloid beta-Peptides/metabolism/chemistry ; Humans ; Microscopy, Atomic Force ; Alzheimer Disease/metabolism/pathology ; *Protein Aggregates ; *Peptide Fragments/metabolism/chemistry ; *Protein Aggregation, Pathological/metabolism ; Phosphorylation ; },
abstract = {Alzheimer's disease (AD) is characterized by the accumulation and aggregation of tau and amyloid-β (Aβ). The pathophysiology and progression of AD are facilitated by the neurotoxic effects of these aggregated proteins, resulting in neurodegeneration and memory loss. In this context, the interaction between tau and Aβ42 is considered, but the mechanism underlying their pathogenic interplay remains unclear. Here, we addressed this question by studying the aggregation of full-length, unmodified tau and Aβ42 at physiologically low concentrations using atomic force microscopy (AFM). AFM imaging and data analyses demonstrate an increase in tau aggregation in the presence of Aβ42, characterized by increased sizes and number of aggregates. Importantly, tau aggregation occurs without the need for phosphorylation or any other post-translational changes. The analysis of the data demonstrates that tau and Aβ42 form co-aggregates, with no visible accumulation of Aβ42 aggregates alone. Given that the catalysis of tau aggregation by Aβ42 is observed at physiological low nanomolar concentrations of Aβ42, the finding suggests that such aggregation catalysis of tau by Aβ42 can be a molecular mechanism underlying the pathological tau aggregation process associated with the onset and development of Alzheimer's disease.},
}

*tau Proteins/metabolism/chemistry
*Amyloid beta-Peptides/metabolism/chemistry
Humans
Microscopy, Atomic Force
Alzheimer Disease/metabolism/pathology
*Protein Aggregates
*Peptide Fragments/metabolism/chemistry
*Protein Aggregation, Pathological/metabolism
Phosphorylation

@article {pmid41465514,
year = {2025},
author = {Riku, Y and Brion, JP and Ando, K and Uchihara, T and Iwasaki, Y},
title = {The Determinant of Tau Spreading in Alzheimer's Disease: Dependent on Senile Plaque, Neural Circuits, or Spatial Proximity?.},
journal = {International journal of molecular sciences},
volume = {26},
number = {24},
pages = {},
doi = {10.3390/ijms262412088},
pmid = {41465514},
issn = {1422-0067},
support = {JPMH23FC1008//MHLW Research on rare and intractable diseases Program/ ; 23K06935, 25K22597, and 25K10781//JSPS-KAKENHI/ ; },
abstract = {Alzheimer's disease (AD) is neuropathologically characterized by tau-immunopositive neurofibrillary tangles (NFTs) and amyloid-β (Aβ)-immunopositive senile plaques. According to the widely accepted amyloid cascade hypothesis, Aβ pathology represents the upstream event in AD pathophysiology and induces tau aggregation. However, numerous studies have suggested that tau aggregates correlate more closely with neuronal loss and regional brain atrophy than with Aβ depositions. Tau aggregation in AD demonstrates a hierarchical spreading pattern beginning in the transentorhinal cortex, but the mechanisms underlying this spreading manner of lesions remain to be elucidated. This review aims to address current controversies regarding tau pathology in AD from the perspectives of both the 'amyloid cascade' and 'tauopathy' hypotheses. From the 'amyloid cascade' viewpoint, Aβ deposition prominently involves distal axon and axon terminals, and in some regions, there are anatomical correspondences between axonal Aβ pathology and cytoplasmic tau aggregations (e.g., a close relationship between senile plaques in the molecular layer of the hippocampal dentate gyrus and NFTs in the transentorhinal cortex). Nevertheless, this model cannot explain the whole body of hierarchical spreading of tau aggregation because notable spaciotemporal discrepancies also exist in many regions. From the 'tauopathy' perspective, the distribution of tau aggregates in AD involves key nodes within the memory circuits. Also, experimental studies have suggested that patient-derived tau exhibits seeding and neuron-to-neuron propagation properties. Interestingly, tau aggregation in AD appears to spread laterally in a proximity-dependent, cortico-cortical fashion rather than along long-range memory circuits. This contrasts with the system-selective, poly-nodal degenerations seen in four-repeat tauopathies, amyotrophic lateral sclerosis, or spinocerebellar degenerations. Moreover, the proportions of three-repeat and four-repeat isoforms shift during the maturation of NFTs in AD. Overall, spreading patterns of tau-pathology in AD cannot be fully explained by Aβ pathology and also differ from the system degeneration seen in other tauopathies.},
}

@article {pmid41465496,
year = {2025},
author = {López-Royo, T and Gascón, E and Moreno-Martínez, L and Macías-Redondo, S and Zaragoza, P and Manzano, R and Osta, R},
title = {Region-Specific Expression Patterns of lncRNAs in the Central Nervous System: Cross-Species Comparison and Functional Insights.},
journal = {International journal of molecular sciences},
volume = {26},
number = {24},
pages = {},
doi = {10.3390/ijms262412069},
pmid = {41465496},
issn = {1422-0067},
support = {PI21/00372//Instituto de Salud Carlos III and Fondo Europeo de Desarrollo Regional (FEDER) "Una manera de hacer Europa" from the European Union/ ; CB18/05/0037//CIBERNED/ ; A19_23R//Consolidated Groups from Gobierno de Aragón/ ; PRTR-C17.I1//The Spanish Ministry of Science and Innovation with funds from the European Union NextGenerationEU, from the Recovery, Transformation and Resilience Plan/ ; FPU19/05625//Ministerio de Universidades from Gobierno de España/ ; PT20/00109//Instituto de Salud Carlos III/ ; },
mesh = {*RNA, Long Noncoding/genetics/metabolism ; Animals ; Humans ; Male ; Female ; Mice ; *Central Nervous System/metabolism ; Spinal Cord/metabolism ; Species Specificity ; Brain/metabolism ; Gene Expression Profiling ; Organ Specificity ; },
abstract = {Increasing evidence demonstrates that long noncoding RNAs (lncRNAs) are crucial for brain evolution and proper development and function of the central nervous system (CNS), exhibiting specific time-, spatial-, and sex-biassed expression patterns. This study investigated whether region-specific spatial expression patterns of brain-relevant lncRNAs are conserved between the mouse and human CNS. Demonstrating such cross-species conservation informs the translational value of mouse models for lncRNA biology. To test this, the expression of 14 lncRNAs was studied in the adult CNS of mice and humans across three different regions (spinal cord, brainstem, and frontal cortex), and age effects were assessed in mice. The results demonstrated conserved expression patterns between the two species, with region-specific changes. The frontal cortex exhibited high expression of Meg3, Miat, and Pvt1 lncRNAs, while the spinal cord showed high levels of Hotair and Gas5. Additionally, Malat1 displayed lower levels in females compared to males in the spinal cord compared to other regions. Finally, through GO functional enrichment analysis and literature review, this study emphasizes the role of lncRNAs in CNS physiology and disease, suggesting their involvement in neurological processes and conditions such as cortical development, neuronal synapsis, schizophrenia, Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis. Overall, this research highlights the importance of further investigating the role of lncRNAs in brain function and their potential as key players in neurological disorders, opening the door to explaining the high region- and sex-specific effects of these disorders.},
}

*RNA, Long Noncoding/genetics/metabolism
Animals
Humans
Male
Female
Mice
*Central Nervous System/metabolism
Spinal Cord/metabolism
Species Specificity
Brain/metabolism
Gene Expression Profiling
Organ Specificity

@article {pmid41465483,
year = {2025},
author = {Kijak-Boćkowska, M and Czerwińska, J and Owczarczyk-Saczonek, A},
title = {Peptidylarginine Deiminases: An Overview of Recent Advances in Citrullination Research.},
journal = {International journal of molecular sciences},
volume = {26},
number = {24},
pages = {},
doi = {10.3390/ijms262412060},
pmid = {41465483},
issn = {1422-0067},
mesh = {Humans ; *Citrullination ; *Protein-Arginine Deiminases/metabolism/chemistry ; Animals ; Extracellular Traps/metabolism ; *Citrulline/metabolism ; Protein Processing, Post-Translational ; Histones/metabolism ; },
abstract = {The peptidylarginine deiminase (PAD) family includes five isozymes (PAD1-4 and PAD6) with unique tissue distributions and substrate specificities. These enzymes facilitate citrullination, a post-translational modification where positively charged arginine residues are converted into neutral citrulline residues in the presence of calcium ions. This process significantly changes protein properties, affecting molecular interactions, structural stability, and biological functions. Over the past six years (2019-2025), there has been significant progress in understanding PAD activity mechanisms and their therapeutic potential. Recent discoveries include the regulated nuclear translocation of PAD2, PAD4's specific role in forming cancer extracellular chromatin networks (CECNs), and the development of next-generation inhibitors with greatly improved pharmacological profiles. PAD4 is crucial in forming neutrophil extracellular traps (NETs). Citrullination of histones H3 and H4 by PAD4 destabilizes chromatin, helping release DNA-protein networks as an antibacterial defense. However, excessive NET formation can contribute to autoimmune diseases and thrombosis. Similarly, the bacterial peptidylarginine deiminase from Porphyromonas gingivalis (PPAD)-the only known prokaryotic citrullinating enzyme-plays a key role. Working with R-gingipains, PPAD triggers pathological citrullination of host proteins, leading to immune tolerance breakdown and linking periodontal disease with systemic autoimmune disorders such as rheumatoid arthritis, atherosclerosis, and Alzheimer's disease. Once thought to be a rare post-translational modification, citrullination is now understood as a vital regulatory mechanism in both normal physiology and disease, involving both internal processes of homeostasis and external mechanisms of bacterial pathogenesis.},
}

Humans
*Citrullination
*Protein-Arginine Deiminases/metabolism/chemistry
Animals
Extracellular Traps/metabolism
*Citrulline/metabolism
Protein Processing, Post-Translational
Histones/metabolism

@article {pmid41465466,
year = {2025},
author = {Xu, C and Owen, JE and Gislason, T and Benediktsdottir, B and Ye, J and Robinson, SR},
title = {Limited Microvascular Remodelling Occurs in the Aged Human Hippocampus in Obstructive Sleep Apnoea.},
journal = {International journal of molecular sciences},
volume = {26},
number = {24},
pages = {},
doi = {10.3390/ijms262412040},
pmid = {41465466},
issn = {1422-0067},
support = {Not applicable//RMIT University/ ; },
mesh = {Humans ; *Sleep Apnea, Obstructive/pathology/physiopathology/therapy ; Male ; Middle Aged ; Female ; Aged ; *Hippocampus/blood supply/pathology ; *Microvessels/pathology/physiopathology ; Adult ; *Aging/pathology ; *Vascular Remodeling ; Continuous Positive Airway Pressure ; },
abstract = {In mice, intermittent hypoxia is associated with an increase in microvessels in the hippocampus, whereas in humans with obstructive sleep apnoea (OSA), microvessels are lost from the heart and retina. The present study investigated microvascular changes in the hippocampus of patients with OSA, and whether patient age or use of continuous positive airway pressure (CPAP) influence microvascularisation. Using autopsy samples from 31 people with confirmed OSA, microvessels were immunolabelled and quantitatively analysed. Compared to the Low OSA group, the High OSA group had larger mean microvessel diameters in the fimbria and CA4, and greater mean microvessel length in the fimbria, which are indicative of microvascular remodelling. An absence of angiogenesis was indicated by similar mean vessel counts in both OSA severity groups. Increased age was associated with microvascular remodelling in the fimbria only. Treatment with CPAP was not associated with changed patterns of microvascularisation. We conclude that: (i) no evidence was found for angiogenesis in the human hippocampus in OSA or ageing; (ii) increased OSA severity is associated with microvascular remodelling in the fimbria and CA4; (iii) microvascular remodelling does not appear to be influenced by CPAP use; (iv) limited adaptability of the microvasculature may underpin the vulnerability of the hippocampus to hypoxic injury, particularly in severe OSA.},
}

Humans
*Sleep Apnea, Obstructive/pathology/physiopathology/therapy
Male
Middle Aged
Female
Aged
*Hippocampus/blood supply/pathology
*Microvessels/pathology/physiopathology
Adult
*Aging/pathology
*Vascular Remodeling
Continuous Positive Airway Pressure

@article {pmid41465422,
year = {2025},
author = {Ahremenko, E and Andreev, A and Apushkin, D and Korkotian, E},
title = {Glial Cells in the Early Stages of Neurodegeneration: Pathogenesis and Therapeutic Targets.},
journal = {International journal of molecular sciences},
volume = {26},
number = {24},
pages = {},
doi = {10.3390/ijms262411995},
pmid = {41465422},
issn = {1422-0067},
mesh = {Humans ; *Neurodegenerative Diseases/pathology/metabolism/therapy/etiology ; Animals ; *Neuroglia/metabolism/pathology ; Inflammasomes/metabolism ; Microglia/metabolism/pathology ; Signal Transduction ; Astrocytes/metabolism/pathology ; NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; },
abstract = {Astrocytes and microglia constitute nearly half of all central nervous system cells and are indispensable for its proper function. Both exhibit striking morphological and functional heterogeneity, adopting either neuroprotective (A2, M2) or proinflammatory (A1, M1) phenotypes in response to cytokines, pathogen-associated molecular patterns (PAMPs)/damage-associated molecular patterns (DAMPs), toll-like receptor 4 (TLR4) activation, and NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome signaling. Crucially, many of these phenotypic transitions arise during the earliest stages of neurodegeneration, when glial dysfunction precedes overt neuronal loss and may act as a primary driver of disease onset. This review critically examines glial-centered hypotheses of neurodegeneration, with emphasis on their roles in early disease phases: (i) microglial polarization from an M2 neuroprotective state to an M1 proinflammatory state; (ii) NLRP3 inflammasome assembly via P2X purinergic receptor 7 (P2X7R)-mediated K[+] efflux; (iii) a self-amplifying astrocyte-microglia-neuron inflammatory feedback loop; (iv) impaired microglial phagocytosis and extracellular-vesicle-mediated propagation of β-amyloid (Aβ) and tau; (v) astrocytic scar formation driven by aquaporin-4 (AQP4), matrix metalloproteinase-9 (MMP-9), glial fibrillary acidic protein (GFAP)/vimentin, connexins, and janus kinase/signal transducer and activator of transcription 3 (JAK/STAT3) signaling; (vi) cellular reprogramming of astrocytes and NG2 glia into functional neurons; and (vii) mitochondrial dysfunction in glia, including Dynamin-related protein 1/Mitochondrial fission protein 1 (Drp1/Fis1) fission imbalance and dysregulation of the sirtuin 1/peroxisome proliferator-activated receptor gamma coactivator 1-alpha (Sirt1/PGC-1α) axis. Promising therapeutic strategies target pattern-recognition receptors (TLR4, NLRP3/caspase-1), cytokine modulators (interleukin-4 (IL-4), interleukin-10 (IL-10)), signaling cascades (JAK2-STAT, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), phosphoinositide 3-kinase-protein kinase B (PI3K-AKT), adenosine monophosphate-activated protein kinase (AMPK)), microglial receptors (triggering receptor expressed on myeloid cells 2 (TREM2)/spleen tyrosine kinase (SYK)/ DNAX-activating protein 10 (DAP10), siglec-3 (CD33), chemokine C-X3-C motif ligand 1/ CX3C motif chemokine receptor 1 (CX3CL1/CX3CR1), Cluster of Differentiation 200/ Cluster of Differentiation 200 receptor 1 (CD200/CD200R), P2X7R), and mitochondrial biogenesis pathways, with a focus on normalizing glial phenotypes rather than simply suppressing pathology. Interventions that restore neuroglial homeostasis at the earliest stages of disease may hold the greatest potential to delay or prevent progression. Given the complexity of glial phenotypes and molecular isoform diversity, a comprehensive, multitargeted approach is essential for mitigating Alzheimer's disease and related neurodegenerative disorders. This review not only synthesizes pathogenesis but also highlights therapeutic opportunities, offering what we believe to be the first concise overview of the principal hypotheses implicating glial cells in neurodegeneration. Rather than focusing on isolated mechanisms, our goal is a holistic perspective-integrating diverse glial processes to enable comparison across interconnected pathological conditions.},
}

Humans
*Neurodegenerative Diseases/pathology/metabolism/therapy/etiology
Animals
*Neuroglia/metabolism/pathology
Inflammasomes/metabolism
Microglia/metabolism/pathology
Signal Transduction
Astrocytes/metabolism/pathology
NLR Family, Pyrin Domain-Containing 3 Protein/metabolism

@article {pmid41465389,
year = {2025},
author = {Wu, S and Rajiah, T and Ali, AB},
title = {Therapeutic Potential for Cannabidiol on Alzheimer's Disease-Related Neuroinflammation: A Systematic Review and Meta-Analysis.},
journal = {International journal of molecular sciences},
volume = {26},
number = {24},
pages = {},
doi = {10.3390/ijms262411963},
pmid = {41465389},
issn = {1422-0067},
mesh = {*Cannabidiol/therapeutic use/pharmacology ; *Alzheimer Disease/drug therapy/metabolism/pathology ; Humans ; Animals ; *Neuroinflammatory Diseases/drug therapy/metabolism ; *Anti-Inflammatory Agents/therapeutic use/pharmacology ; *Neuroprotective Agents/therapeutic use/pharmacology ; Biomarkers ; Inflammation/drug therapy ; },
abstract = {Alzheimer's disease (AD) is a pervasive neurodegenerative disorder characterized by chronic neuroinflammation; current interventions primarily offer symptomatic relief. Cannabidiol (CBD), a non-psychoactive phytocannabinoid, exhibits multi-target therapeutic potential due to its established anti-inflammatory and neuroprotective properties. While growing interest exists, the evidence regarding CBD's effects on AD-related neuroinflammation has not been robustly consolidated in a quantitative meta-analysis. Therefore, this article reviews the current literature around CBD related to its potential in alleviating neuroinflammation, followed by a meta-analysis of preclinical and clinical studies using random-effects modeling to assess CBD efficacy on neuroinflammation and clinical outcomes in AD. In preclinical AD models, the meta-analysis demonstrated that CBD significantly and consistently reduced key markers of neuroinflammation and reactive gliosis, specifically glial fibrillary acidic protein (GFAP) (p < 0.0001), Interleukin-6 (IL-6), and inducible nitric oxide synthase (iNOS). Effects on other markers, such as tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1β), were non-significant and heterogeneous. Clinical evidence, though limited by small sample size and heterogeneity, showed a borderline significant benefit favoring CBD for overall behavioral symptoms (p = 0.05), agitation, and caregiver distress. Adverse events were typically mild. We conclude that CBD demonstrates biologically consistent anti-inflammatory efficacy in preclinical AD models. While current clinical data remains insufficient to substantiate efficacy, they suggest promising signals for behavioral control. Determining CBD's full therapeutic potential in AD necessitates future rigorous, mechanism-driven trials with standardized preparations and biomarker-anchored endpoints.},
}

*Cannabidiol/therapeutic use/pharmacology
*Alzheimer Disease/drug therapy/metabolism/pathology
Humans
Animals
*Neuroinflammatory Diseases/drug therapy/metabolism
*Anti-Inflammatory Agents/therapeutic use/pharmacology
*Neuroprotective Agents/therapeutic use/pharmacology
Biomarkers
Inflammation/drug therapy

@article {pmid41465301,
year = {2025},
author = {Abramchuk, DS and Krasnovskaya, OO and Voskresenskaya, AS and Vaneev, AN and Kuanaeva, RM and Mamed-Nabizade, VV and Kolmogorov, VS and Kechko, OI and Mitkevich, VA and Makarov, AA and Nastenko, AA and Abakumov, MA and Gorelkin, PV and Salikhov, SV and Beloglazkina, EK and Erofeev, AS},
title = {Bifunctional BODIPY-Clioquinol Copper Chelator with Multiple Anti-AD Properties.},
journal = {International journal of molecular sciences},
volume = {26},
number = {24},
pages = {},
doi = {10.3390/ijms262411876},
pmid = {41465301},
issn = {1422-0067},
support = {19-74-30007//Russian Science Foundation/ ; },
mesh = {*Clioquinol/chemistry/pharmacology ; *Boron Compounds/chemistry/pharmacology ; *Copper/chemistry/metabolism ; *Chelating Agents/chemistry/pharmacology ; Amyloid beta-Peptides/metabolism/chemistry ; *Alzheimer Disease/drug therapy/metabolism ; Humans ; Fluorescent Dyes/chemistry/pharmacology ; Animals ; Antioxidants/pharmacology/chemistry ; },
abstract = {Alzheimer's disease (AD) is a worldwide problem due to the lack of effective therapy and accurate methods for timely diagnosis. The complexity of AD's pathophysiology complicates the development of effective therapeutic agents, as most drugs act on only one therapeutic target, bypassing others. The design and development of multifunctional agents capable of altering metal ion-induced abnormalities, oxidative stress, and toxic beta amyloid (Aβ) aggregates is of interest. Herein, we report the first boron dipyrromethene (BODIPY) based bifunctional copper chelator with clioquinol, BDP-CLQ, capable of both optical detection of Aβ fibrils and copper chelation, with multiple anti-AD properties. Foremost, BDP-CLQ demonstrated a 3-fold and 5-fold fluorescence increase at 650 nm and 565 nm in the presence of Aβ and effective copper chelation (pKd = 16.6 ± 0.3). In addition, BDP-CLQ demonstrated a potent inhibition of Aβ aggregation, reduction in Aβ-induced stiffness of neuronal cells, and antioxidant activity. BDP-CLQ is the first BODIPY-based fluorescent probe with multiple anti-AD activities, as well as the first clioquinol-based probe capable of Aβ optical visualization. This study demonstrates the prospects of the development of clioquinol-based theranostic probes since this allows combining several promising anti-AD actions in a single molecule and developing multi-targeted drugs.},
}

*Clioquinol/chemistry/pharmacology
*Boron Compounds/chemistry/pharmacology
*Copper/chemistry/metabolism
*Chelating Agents/chemistry/pharmacology
Amyloid beta-Peptides/metabolism/chemistry
*Alzheimer Disease/drug therapy/metabolism
Humans
Fluorescent Dyes/chemistry/pharmacology
Animals
Antioxidants/pharmacology/chemistry

@article {pmid41465278,
year = {2025},
author = {Marzetti, E and Di Lorenzo, R and Calvani, R and Coelho-Júnior, HJ and Landi, F and Pesce, V and Picca, A},
title = {Linking Cell Architecture to Mitochondrial Signaling in Neurodegeneration: The Role of Intermediate Filaments.},
journal = {International journal of molecular sciences},
volume = {26},
number = {24},
pages = {},
doi = {10.3390/ijms262411852},
pmid = {41465278},
issn = {1422-0067},
support = {D1.2024//Università Cattolica del Sacro Cuore/ ; D1.2025//Università Cattolica del Sacro Cuore/ ; Ricerca Corrente 2025//Italian Ministry of Health/ ; DM 1557 11.10.2022//European Commission/ ; 2022YNENP3//Italian Ministry of University and Research/ ; },
mesh = {Humans ; *Mitochondria/metabolism/pathology ; Animals ; *Neurodegenerative Diseases/metabolism/pathology ; *Intermediate Filaments/metabolism/pathology ; *Signal Transduction ; Neurons/metabolism/pathology ; },
abstract = {Mitochondrial dysfunction is a pivotal contributor to neurodegeneration. Neurons heavily rely on mitochondrial oxidative metabolism and therefore need highly efficient quality control mechanisms, including proteostasis, mitochondrial biogenesis, fusion-fission dynamics, and mitophagy, to sustain bioenergetics and synaptic function. With aging, deterioration of mitochondrial quality control pathways leads to impaired oxidative phosphorylation, excessive reactive oxygen species generation, calcium imbalance, and defective clearance of damaged organelles, ultimately compromising neuronal viability. Pathological protein aggregates, such as α-synuclein in Parkinson's disease, β-amyloid and tau in Alzheimer's disease, and misfolded superoxide dismutase 1 and transactive response DNA-binding protein 43 in amyotrophic lateral sclerosis, further aggravate mitochondrial stress, establishing self-perpetuating cycles of neurotoxicity. Such mitochondrial defects underscore mitochondria as a convergent pathogenic hub and a promising therapeutic target for neuroprotection. Intermediate filaments (IFs), traditionally viewed as passive structural elements, have recently gained attention for their roles in cytoplasmic organization, mitochondrial positioning, and energy regulation. Emerging evidence indicates that IF-mitochondria interactions critically influence organelle morphology and function in neurons. This review highlights the multifaceted involvement of mitochondrial dysfunction and IF dynamics in neurodegeneration, emphasizing their potential as targets for novel therapeutic strategies.},
}

Humans
*Mitochondria/metabolism/pathology
Animals
*Neurodegenerative Diseases/metabolism/pathology
*Intermediate Filaments/metabolism/pathology
*Signal Transduction
Neurons/metabolism/pathology

@article {pmid41465242,
year = {2025},
author = {Neupane, S and Hortobágyi, T},
title = {Molecular Crossroads: Shared and Divergent Molecular Signatures in Alzheimer's Disease and Dementia with Lewy Bodies.},
journal = {International journal of molecular sciences},
volume = {26},
number = {24},
pages = {},
doi = {10.3390/ijms262411811},
pmid = {41465242},
issn = {1422-0067},
mesh = {Humans ; *Alzheimer Disease/metabolism/genetics/pathology ; *Lewy Body Disease/metabolism/genetics/pathology ; Biomarkers/metabolism ; alpha-Synuclein/metabolism/genetics ; Amyloid beta-Peptides/metabolism ; tau Proteins/metabolism/genetics ; Animals ; Oxidative Stress ; },
abstract = {Alzheimer's disease (AD) and dementia with Lewy bodies (DLB) are the two most common forms of dementia due to neurodegeneration. AD is characterized by extracellular amyloid-β (Aβ) plaques and intracellular tau neurofibrillary tangles, whereas DLB is defined by α-synuclein (α-Syn)-containing Lewy bodies. Although AD and DLB exhibit divergent core features, the disorders frequently co-occur and converge on shared endpoints. Co-pathology is common and linked to more severe cognitive decline, faster progression, and clinicopathological heterogeneity. Here, we discuss the current understanding of shared and unique clinical and neuropathological features of AD and DLB. We compare genetic risk and pathological drivers (Aβ and tau in AD; α-Syn in DLB) and their overlapping co-pathology, and review downstream mechanisms-mitochondrial dysfunction, oxidative stress, neuroinflammation, and cerebrovascular contributions, including cerebral amyloid angiopathy. We highlight recent findings from state-of-the-art multi-omics (transcriptomic, proteomic, metabolomic, and single-cell/spatial studies) that reveal convergent and disease-specific molecular signatures of AD and DLB. We outline a framework for emerging next-generation biomarkers-from blood-based and cerebrospinal fluid assays to imaging and digital measures-for diagnosis and stratification, and discuss potential translational implications. Together, these advances help to disentangle shared from disease-specific mechanisms, which is essential for improved diagnosis and the development of precise, disease-modifying therapies.},
}

Humans
*Alzheimer Disease/metabolism/genetics/pathology
*Lewy Body Disease/metabolism/genetics/pathology
Biomarkers/metabolism
alpha-Synuclein/metabolism/genetics
Amyloid beta-Peptides/metabolism
tau Proteins/metabolism/genetics
Animals
Oxidative Stress

@article {pmid41465235,
year = {2025},
author = {Kim, H and Kim, H and Lee, Y and Park, C and Cho, B and Son, S and Kim, H and Kim, G and Park, J and Park, H},
title = {Lactobacillus delbrueckii subsp. lactis CKDB001 Ameliorates Scopolamine-Induced Cognitive Impairment Through Metabolic Modulation.},
journal = {International journal of molecular sciences},
volume = {26},
number = {24},
pages = {},
doi = {10.3390/ijms262411804},
pmid = {41465235},
issn = {1422-0067},
support = {HU22C0150//The Korea Dementia Research Project through the Korea Dementia Research Center (KDRC), funded by the Ministry of Health & Welfare and Ministry of Science and ICT/ ; },
mesh = {Animals ; *Cognitive Dysfunction/chemically induced/metabolism/therapy/microbiology ; Mice ; Gastrointestinal Microbiome/drug effects ; *Scopolamine/adverse effects ; Male ; *Lactobacillus delbrueckii/physiology ; Mice, Inbred ICR ; Donepezil/pharmacology ; Hippocampus/metabolism/drug effects ; *Probiotics/pharmacology ; },
abstract = {Microbiome-derived metabolites have emerged as key mediators of the gut-brain axis, influencing cognitive function and neuroprotection. This study investigated whether Lactobacillus delbrueckii subsp. lactis CKDB001 alleviates scopolamine-induced memory impairment through metabolic modulation, and how its effects compare with those of donepezil. ICR mice were administered CKDB001 or donepezil for 4-5 weeks and evaluated through behavioral, microbiome, metabolomic, and molecular analyses. CKDB001 significantly improved spatial working memory in a dose-dependent manner, with the high-dose group showing improvements comparable to those of the donepezil-treated group, while passive avoidance showed a non-significant but positive trend. Both CKDB001 and donepezil modulated gut microbial composition, leading to a partial divergence from the scopolamine-disrupted community structure, with CKDB001 inducing dose-dependent intestinal colonization. Metabolomic profiling revealed that both treatments increased tryptophan-derived indole metabolites and altered lipid and short-chain fatty acid metabolite profiles, although these effects were more pronounced in CKDB001-treated mice. At the molecular level, both CKDB001 and donepezil reduced hippocampal tau phosphorylation, downregulated glycogen synthase kinase-3 (GSK-3) signaling, enhanced intestinal tight-junction proteins, and partially normalized acetylcholinesterase activity, with CKDB001 restoring AChE levels more closely toward the normal control. Together, these findings suggest that CKDB001 mitigates cognitive deficits through coordinated modulation of microbial, metabolic, and neuronal pathways, offering a microbiome-based therapeutic approach that may provide benefits comparable to donepezil with potentially fewer limitations.},
}

Animals
*Cognitive Dysfunction/chemically induced/metabolism/therapy/microbiology
Mice
Gastrointestinal Microbiome/drug effects
*Scopolamine/adverse effects
Male
*Lactobacillus delbrueckii/physiology
Mice, Inbred ICR
Donepezil/pharmacology
Hippocampus/metabolism/drug effects
*Probiotics/pharmacology

@article {pmid41465183,
year = {2025},
author = {Anthony, M and Xie, Y and O'Neil, JN and Teng, S},
title = {Structural Analysis of Missense Mutations on the Stability of APOE3 and APOE4.},
journal = {Genes},
volume = {16},
number = {12},
pages = {},
doi = {10.3390/genes16121509},
pmid = {41465183},
issn = {2073-4425},
support = {1R16GM159167-01/NH/NIH HHS/United States ; },
mesh = {*Mutation, Missense ; *Apolipoprotein E4/genetics/chemistry ; Humans ; Protein Stability ; Molecular Dynamics Simulation ; *Apolipoprotein E3/genetics/chemistry ; Alzheimer Disease/genetics ; Protein Folding ; Protein Conformation ; },
abstract = {Background/Objectives: Apolipoprotein E (APOE) plays a central role in lipid transport and neuronal cholesterol metabolism. Among its three major isoforms (APOE2, APOE3, and APOE4), the APOE4 variant is the strongest genetic risk factor for late-onset Alzheimer's disease (AD). However, the structural consequences of specific APOE mutations on protein stability remain poorly understood. Methods: Here, we performed computational saturation mutagenesis and molecular dynamics simulations on the non-lipidated N-terminal fragments of APOE3 and APOE4 to examine how missense mutations affect their structural stability. Results: Based on the folding energy (ΔΔG) calculations, mutations G165W and L155W were particularly destabilizing in APOE4. Molecular dynamics analyses showed that these mutations altered local flexibility and compactness, particularly within the helix 4 region, a key structural element for maintaining APOE's structural integrity. Conclusions: Our findings, which are state dependent and hypothesis generating, highlight isoform-dependent differences in protein stability and identify regions of structural vulnerability within APOE. These insights enhance our understanding of APOE's conformational dynamics and may inform future studies on its role in neurodegenerative disease mechanisms.},
}

*Mutation, Missense
*Apolipoprotein E4/genetics/chemistry
Humans
Protein Stability
Molecular Dynamics Simulation
*Apolipoprotein E3/genetics/chemistry
Alzheimer Disease/genetics
Protein Folding
Protein Conformation

@article {pmid41465142,
year = {2025},
author = {Machowska, M and Leszek, J and Mikołajczyk-Tarnawa, A and Głowacka, K and Trypka, E and Rąpała, M and Piechota, J and Wiela-Hojeńska, A},
title = {The Diagnostic Reliability of BIN1 and TOMM40 Genotyping in Assessing Dementia Risk.},
journal = {Genes},
volume = {16},
number = {12},
pages = {},
doi = {10.3390/genes16121469},
pmid = {41465142},
issn = {2073-4425},
support = {RPDS.01.02.01-02-0002/20//Regional Operational Programme of the Lower Silesian Voivodeship 2014-2020, co-financed by the European Union, European Regional Development Fund/ ; },
mesh = {Humans ; *Mitochondrial Precursor Protein Import Complex Proteins/genetics ; Male ; Female ; Aged ; *Cognitive Dysfunction/genetics/diagnosis ; *Tumor Suppressor Proteins/genetics ; Polymorphism, Single Nucleotide ; *Adaptor Proteins, Signal Transducing/genetics ; *Alzheimer Disease/genetics/diagnosis ; *Nuclear Proteins/genetics ; Genotype ; *Dementia/genetics/diagnosis ; *Membrane Transport Proteins/genetics ; Genetic Predisposition to Disease ; Case-Control Studies ; Aged, 80 and over ; Middle Aged ; },
abstract = {OBJECTIVES: Alzheimer's disease (AD) and other dementias represent a growing public health concern, highlighting the need for reliable biomarkers for early diagnosis and treatment monitoring. This study evaluated the potential utility of BIN1 and TOMM40 genotyping in diagnosing mild cognitive impairment (MCI) and early-stage dementia.

METHODS: The BIN1 rs744373 and TOMM40 rs2075650 polymorphisms were genotyped in a cohort of 105 individuals diagnosed with MCI or dementia and in 164 cognitively healthy controls. Genotype distributions were compared between the groups, and the potential role of these variants in diagnostic assessment was explored.

RESULTS: A significantly higher frequency of the TOMM40 rs2075650 GG genotype was observed in patients with AD compared with cognitively healthy controls. In contrast, no statistically significant differences in genotype distribution were found among individuals with mild MCI, vascular dementia, or mixed dementia. Furthermore, the distribution of BIN1 rs744373 alleles did not differ significantly across the analyzed groups.

CONCLUSIONS: Data on the effects of BIN1 rs744373 and TOMM40 rs2075650 polymorphisms in MCI and dementia remain limited and inconsistent. In our study, significant differences were observed only for the TOMM40 rs2075650 GG genotype and G allele, which were more frequent in Alzheimer's disease patients than in controls. No significant associations were found for MCI, vascular dementia, or mixed dementia, nor for the BIN1 rs744373 polymorphism. These results suggest that TOMM40 rs2075650 genotyping may serve as an additional marker for assessing AD risk.},
}

Humans
*Mitochondrial Precursor Protein Import Complex Proteins/genetics
Male
Female
Aged
*Cognitive Dysfunction/genetics/diagnosis
*Tumor Suppressor Proteins/genetics
Polymorphism, Single Nucleotide
*Adaptor Proteins, Signal Transducing/genetics
*Alzheimer Disease/genetics/diagnosis
*Nuclear Proteins/genetics
Genotype
*Dementia/genetics/diagnosis
*Membrane Transport Proteins/genetics
Genetic Predisposition to Disease
Case-Control Studies
Aged, 80 and over
Middle Aged

@article {pmid41465136,
year = {2025},
author = {Grech, VS and Lotsaris, K and Kefala, V and Rallis, E},
title = {From Skin to Brain: Key Genetic Mediators Associating Cutaneous Inflammation and Neurodegenerative Diseases.},
journal = {Genes},
volume = {16},
number = {12},
pages = {},
doi = {10.3390/genes16121463},
pmid = {41465136},
issn = {2073-4425},
abstract = {Chronic inflammatory skin diseases and neurodegenerative disorders share overlapping genetic, immunologic, and metabolic pathways that may predispose individuals to cognitive decline. This review synthesizes current human genomic, transcriptomic, and bioinformatic evidence linking psoriasis, rosacea, atopic dermatitis, and bullous pemphigoid with Alzheimer's and Parkinson's disease. Literature from PubMed, IEEE Xplore, and Google Scholar was examined, prioritizing studies integrating genomic, transcriptomic, and proteomic analyses. Among inflammatory dermatoses, psoriasis exhibits the strongest overlap with dementia genetics, with shared susceptibility loci including APOE, IL12B, and HLA-DRB5, and transcriptional regulators such as ZNF384 that converge on IL-17/TNF signaling. Rare-variant and pleiotropy analyses further implicate SETD1A and BC070367 in psoriasis-Parkinson's comorbidity. Rosacea demonstrates upregulation of neurodegeneration-related proteins SNCA, GSK3B, and HSPA8, together with shared regulatory hubs (PPARG, STAT4, RORA) driving NF-κB/IL-17/TNF-dependent inflammation. In atopic dermatitis, rare FLG variants interacting with BACE1 suggest a mechanistic bridge between barrier dysfunction and amyloidogenic processing. Bullous pemphigoid reveals an HLA-DQB1*03:01-mediated immunogenetic link hypothesis and cross-reactive autoantibodies targeting BP180 (collagen XVII) and BP230, highlighting an autoimmune route of neurocutaneous interaction. Other inflammatory and neurodegenerative diseases with currently weak or limited genetic evidence are also discussed, as they may represent emerging biological pathways or potential therapeutic targets within the skin-brain connection in the future. The aim of this work is to help clarify these genetic links and to advocate for the routine cognitive assessment of affected patients, enabling early detection, improved long-term quality of life, and the potential for timely therapeutic intervention.},
}

@article {pmid41464389,
year = {2025},
author = {Covelli, V and Visco, MA and Feyles, M and Sirotich, AC and Marelli, A},
title = {Narrative Medicine, Dementia, and Alzheimer's Disease: A Scoping Review.},
journal = {Healthcare (Basel, Switzerland)},
volume = {13},
number = {24},
pages = {},
doi = {10.3390/healthcare13243321},
pmid = {41464389},
issn = {2227-9032},
support = {H53D23009300001//PRIN 2022 PNRR programme/ ; },
abstract = {Background/Objectives: In recent years, Narrative Medicine (NM) has gained prominence in the context of neurodegenerative diseases, such as dementia, offering tools to understand the subjective experience of illness and to improve the care relationship. Methods: This scoping review, conducted following the PRISMA guidelines, analyzed the scientific literature from PubMed, PsycInfo, Web of Science, and Medline, encompassing 10 contributions focused on NM and patients with dementia or Alzheimer's disease. Results: The analysis identified three main themes: 1) narrative, memory, and personal identity, highlighting the role of narrative in preserving a sense of self; 2) personalization of care, oriented towards person-centeredness; 3) the use of narrative in a formative and reflective function as a tool to promote empathy, clinical awareness, and observation skills in the training of health professionals. Conclusions: NM confirms itself as a relational and reflexive paradigm, capable of humanizing care and promoting therapeutic pathways that are more inclusive and sensitive to the patient's subjectivity.},
}

@article {pmid41464340,
year = {2025},
author = {Alcaraz-Córdoba, A and López-Cano, M and Ibáñez-Masero, O and Ventura-Miranda, MI and Ruiz-Fernández, MD and Ortega-Galán, AM},
title = {Challenges and Social Implications of Informal Caregiving for People with Alzheimer's: A Qualitative Study.},
journal = {Healthcare (Basel, Switzerland)},
volume = {13},
number = {24},
pages = {},
doi = {10.3390/healthcare13243271},
pmid = {41464340},
issn = {2227-9032},
support = {TRFE-SI-2022/009//University of Almería/ ; },
abstract = {Aim: The aim of this study was to explore the experiences and challenges faced by informal caregivers of people with Alzheimer's, including the social and emotional aspects of their caregiving role. Methods: A descriptive qualitative study was conducted using one focus group discussion and eleven semi-structured interviews with informal caregivers of individuals diagnosed with Alzheimer's disease. The data collected were analyzed through thematic analysis using ATLAS.ti qualitative software version 23. Results: The results reveal two themes: (1) "Life centred on compassionate care for the other person", which reflects the role performed from a perspective of emotional and compassionate commitment to those in need of care, and (2) "Abandonment by caregivers", which expresses the emotional cost associated with caregiving. Conclusions: Informal caregivers of people with Alzheimer's disease undertake their roles guided by compassion, which involves substantial personal sacrifice. This commitment often leads to self-abandonment, impacting their emotional and physical health, social relationships, and personal aspirations. It is therefore crucial to implement psychosocial interventions grounded in compassion and to strengthen both formal and informal social support systems for caregivers.},
}

@article {pmid41464136,
year = {2025},
author = {Ali, SB and Ghannam, NE and Mancy, H and Elkilany, BG},
title = {Multimodal Self-Supervised Learning for Early Alzheimer's: Cross-Modal MRI-PET, Longitudinal Signals, and Site Invariance.},
journal = {Diagnostics (Basel, Switzerland)},
volume = {15},
number = {24},
pages = {},
doi = {10.3390/diagnostics15243135},
pmid = {41464136},
issn = {2075-4418},
support = {(PSAU/2025/03/33734)//Prince Sattam Bin Abdulaziz University/ ; },
abstract = {Background: The early and accurate identification of Alzheimer's disease (AD) is complicated by a number of factors, such as the diversity of imaging modalities, variability in scanners across multiple sites, and the long-term progression of neurodegeneration. Such modest gains and the range of diagnostic scenarios suggest that robust multimodal applications, which incorporate both structural, molecular, and longitudinal measurements, are required if realistic benefits are to be seen in actual clinical settings. Methods: We introduce a multimodal self-supervised learning (SSL) approach, which learns feature representations of MRI and PET jointly using the cross-modal alignment, longitudinal temporal consistency, and domain-invariant embedding optimization. The approach integrates contrastive learning, scanner harmonization strategies, and missing modality-aware fusion for handling real-world cohort diversity. Six widely used datasets were evaluated, which are made publicly available: ADNI, OASIS-3, AIBL, BioFINDER, TADPOLE, and MIRIAD. Results: The model performed in a state-of-the-art way on all benchmark tasks. On ADNI, it obtained a BACC of 93.0% and an AUC of 0.96 for the binary classification task (AD vs. CN), surpassing recent baselines such as DiaMond'25, SMoCo, and AnatCL with statistically significant performance gain. Strong cross-cohort generalizability was reported (78.0% BACC on OASIS-3 and 77.5% BACC on AIBL). For TADPOLE, for longitudinal prognosis (i.e., MCI → AD conversion), the model yielded an AUC of 0.85 and a C-index of 0.82, which shows better ascendency over previous SSL-based methods. High test-retest consistency was observed on MIRIAD (ICC = 0.91), indicating that instability in volume measurement due to atrophy progression was minimal. Conclusions: The proposed multimodal SSL framework offers effective transferable and domain-robust biomarkers for the early diagnosis of AD and prediction of MCI-to-AD progression. It has strong cross-dataset generalization.},
}

@article {pmid41464132,
year = {2025},
author = {Dobrin, N and Brehar, FM and Costea, D and Dumitru, AV and Ciurea, AV and Munteanu, O and Munteanu, LV},
title = {Anatomically Precise Microsurgical Resection of a Posterior Fossa Cerebellar Metastasis in an Elderly Patient with Preservation of Venous Outflow, Dentate Nucleus, and Cerebrospinal Fluid Pathways.},
journal = {Diagnostics (Basel, Switzerland)},
volume = {15},
number = {24},
pages = {},
doi = {10.3390/diagnostics15243131},
pmid = {41464132},
issn = {2075-4418},
abstract = {Background and Clinical Significance: Adults suffering from cerebellar metastases are often at high risk for rapid deterioration of their neurological status because the posterior fossa has limited compliance and the location of these metastases are close to the brain stem and important cerebrospinal fluid (CSF) pathways. In this paper, we present a longitudinal, patient-centered report on the history of an elderly individual who suffered from cognitive comorbidities and experienced a sudden loss of function in her cerebellum. Our goal in reporting this case is to provide a comparison between the patient's pre-operative and post-operative neurological examinations; the imaging studies she had before and after surgery; the surgical techniques utilized during her operation; and the outcome of her post-operative course in a way that will be helpful to other patients who have experienced a similar situation. Case Presentation: We report the case of an 80-year-old woman who initially presented with progressive ipsilateral limb-trunk ataxia, impaired smooth pursuit eye movement, and rebound nystagmus, but preserved pyramidal and sensory functions. Her quantitative bedside assessments included some of the components of the Scale for the Assessment and Rating of Ataxia (SARA), and a National Institute of Health Stroke Scale (NIHSS) score of 3. These findings indicated dysfunction of the left neocerebellar hemisphere and possible dentate nucleus involvement. The patient's magnetic resonance imaging (MRI) results demonstrated an expansive mass with surrounding vasogenic edema and marked compression and narrowing of the exits of the fourth ventricle which placed the patient's CSF pathways at significant risk of occlusion, while the aqueduct and inlets were patent. She then underwent a left lateral suboccipital craniectomy with controlled arachnoidal CSF release, preservation of venous drainage routes, subpial corticotomy oriented along the lines of the folia, stepwise internal debulking, and careful protection of the cerebellar peduncles and dentate nucleus. Dural reconstruction utilized a watertight pericranial graft to restore the cisternal compartments. Her post-operative intensive care unit (ICU) management emphasized optimal venous outflow, normoventilation, and early mobilization. Histopathology confirmed the presence of metastatic carcinoma, and staging suggested that the most likely source of the primary tumor was the lungs. Immediately post-operation, computed tomography (CT) imaging revealed a smooth resection cavity with open foramina of Magendie and Luschka, intact contours of the brain stem, and no evidence of bleeding or hydrocephalus. The patient's neurological deficits, including dysmetria, scanning dysarthria, and ataxic gait, improved gradually during the first 48 h post-operatively. Upon discharge, the patient demonstrated an improvement in her limb-kinetic subscore on the International Cooperative Ataxia Rating Scale (ICARS) and demonstrated independent ambulation. At two weeks post-operation, CT imaging revealed decreasing edema and stable cavity size, and the patient's modified Rankin scale had improved from 3 upon admission to 1. There were no episodes of CSF leakage, wound complications, or new cranial nerve deficits. A transient post-operative psychotic episode that was likely secondary to her underlying Alzheimer's disease was managed successfully with short-course pharmacotherapy. Conclusions: The current case study demonstrates the value of anatomy-based microsurgical planning, preservation of venous and CSF pathways, and targeted peri-operative management to facilitate rapid recovery of function in older adults who suffer from cerebellar metastasis and cognitive comorbidities. The case also demonstrates the importance of early multidisciplinary collaboration to allow for timely initiation of both adjuvant stereotactic radiosurgery and molecularly informed systemic therapy.},
}

@article {pmid41464118,
year = {2025},
author = {Al-Bakri, FH and Bejuri, WMYW and Al-Andoli, MN and Ikram, RRR and Khor, HM and Mispan, MS and Yunos, NM and Yusof, NFA and Fauadi, MHFM and Jaya, ASM and Moketar, NA and Yusop, N and Burhanudin, K and Marindah, TP and Bustamin, A and Zainuddin, Z and Wahyuni, D and Ariffin, UK and The Alzheimer's Disease Neuroimaging Initiative, },
title = {A Hybrid Explainable AI Framework (HXAI) for Accurate and Interpretable Diagnosis of Alzheimer's Disease.},
journal = {Diagnostics (Basel, Switzerland)},
volume = {15},
number = {24},
pages = {},
doi = {10.3390/diagnostics15243118},
pmid = {41464118},
issn = {2075-4418},
abstract = {Background/Objectives: In clinical practice, Explainable AI (XAI) enables non-specialists and general practitioners to make precise diagnoses. Current XAI approaches are limited, as many rely solely on either presenting explanations of clinical data or presenting explanations of MRI, or presenting explanations in unclear ways, reducing their clinical utility. Methods: In this paper, we propose a novel Hybrid Explainable AI (HXAI) framework. This framework uniquely integrates both model-agnostic (SHAP) and model-specific (Grad-CAM) explanation methods within a unified structure for the diagnosis of Alzheimer's disease. The dual-layer explainability constitutes the main originality of this study, as it provides the possibility of interpreting quantitative (at the feature level) and spatial (at the region level) data within a single diagnostic framework. Clinical features (e.g., Mini-Mental State Examination (MMSE), normalized Whole Brain Volume (nWBV), Socioeconomic Status (SES), age) are combined with MRI-derived features extracted via ResNet50, and these features are integrated using ensemble learning with a logistic regression meta-model. Results: The corresponding validation reflects the explainability accuracy of these feature-based explanations, with removal-based tests achieving 83.61% explainability accuracy, confirming the importance of these features. Model-specific information was used to explain MRI predictions, achieving 58.16% explainability accuracy of visual explanations. Conclusions: Our HXAI framework integrates both model-agnostic and model-specific approaches in a structured manner, supported by quantitative metrics. This dual-layer interpretability enhances transparency, improves explainability accuracy, and provides an accurate and interpretable framework for AD diagnosis, bridging the gap between model accuracy and clinical trust.},
}

@article {pmid41463637,
year = {2025},
author = {Vaida, C and Vanta, O and Rus, G and Pusca, A and Antal, T and Tohanean, N and Cailean, A and Jucan, D and Birlescu, I and Gherman, B and Pisla, D},
title = {Technical Validation of a Multimodal Cognitive-Haptic Sudoku Platform Under Simulated Tremor Conditions.},
journal = {Bioengineering (Basel, Switzerland)},
volume = {12},
number = {12},
pages = {},
doi = {10.3390/bioengineering12121340},
pmid = {41463637},
issn = {2306-5354},
support = {760071/23.05.2023, code CF 121/15.11.2022//NextGenerationEU/ ; },
abstract = {Neurological disorders such as Parkinson's and Alzheimer's diseases often involve overlapping motor and cognitive impairments that motivate integrated rehabilitation approaches. This study presents the technical validation of a dual-modality rehabilitation platform that combines haptic-based motor interaction with cognitive engagement through an adaptive Sudoku task in healthy adults under simulated tremor conditions. The system integrates a real-time tremor-filtering pipeline based on discrete wavelet denoising, Kalman smoothing, and wavelet packet decomposition, designed to attenuate high-frequency oscillations while preserving voluntary motion. The preclinical evaluation was carried out in two stages: (i) technical validation with healthy adults performing a standardized cognitive-haptic task under three conditions (no tremor, simulated tremor without filtering, simulated tremor with filtering) and (ii) extended usability testing with older participants without diagnosed neurological disorders. Quantitative evaluation focused on latency, performance degradation under simulated tremor, and partial restoration with filtering, while usability was assessed using the System Usability Scale (SUS). The platform achieved low end-to-end latency (41.4 ± 1.4 ms) and high usability (overall mean SUS = 81.4 ± 6.2), indicating stable performance and positive user feedback. Filtering significantly improved performance compared with unfiltered tremor but did not fully restore baseline performance, highlighting the current algorithm as a first-step compensation strategy rather than a complete solution. This work therefore demonstrates technical feasibility and interaction performance in healthy participants under simulated tremor; it does not assess clinical effectiveness and is intended to inform subsequent patient studies in populations with neurodegenerative diseases.},
}

@article {pmid41463559,
year = {2025},
author = {Danna, R and Kondle, S and Amar, O and Mabourakh, M and Chen, G and Fadol, WB and Mohieldin, AM},
title = {The Impact of Neurotoxin Proteins Trafficked by Primary Cilia and Extracellular Vesicles in Neurodegenerative Diseases.},
journal = {Biology},
volume = {14},
number = {12},
pages = {},
doi = {10.3390/biology14121787},
pmid = {41463559},
issn = {2079-7737},
support = {N/A//College of Graduate Studies, California Northstate University/ ; },
abstract = {Neurodegenerative diseases (NDDs), including Alzheimer's Disease (AD), Parkinson's Disease (PD), and Huntington's Disease (HD), share pathologic mechanisms including oxidative stress, mitochondrial dysfunction, and protein aggregation. However, they differ in age of onset and clinical progression. Emerging evidence highlights primary cilia (PC) as a key regulator of neuronal aging and the progression of these diseases. Dysfunctional PC may impair key signaling pathways, such as Sonic Hedgehog (Shh) and Wnt, promote oxidative stress, mitochondrial damage, and epigenetic instability. PC may also influence intercellular communication by regulating the biogenesis of exosomes and modulating tunneling nanotube (TNT) formation, both of which propagate toxic proteins between neurons. Mechanistically, the regulation of ciliary length is disrupted in AD, which leads to ciliary dysfunction that interferes with signaling pathways and promotes the aggregation of amyloid-beta. This amyloid-beta is then propagated through TNTs and exosomes, spreading neuronal damage. In PD, the accumulation of alpha-synuclein (α-syn) also impairs cilia function, thereby compromising the cell's response to oxidative stress. This results in the formation of abnormal TNTs and defective exosome-mediated clearance, ultimately contributing to neurodegeneration. Similarly, the mutant huntingtin protein aggregates within primary cilia in HD, morphologically disrupting them by obstructing intraflagellar transport. Damaged cilia are also associated with increased TNT formation and the exosomal release of toxic proteins, which leads to mitochondrial and epigenetic instability, ultimately promoting neuronal aging. Together, targeting ciliary function and its downstream regulation of TNTs and exosomes may provide a novel approach for slowing or halting disease progression across neurodegenerative diseases.},
}

@article {pmid41463495,
year = {2025},
author = {Lushnikov, KV and Serov, DA and Astashev, ME and Kozlov, VA and Melerzanov, A and Vedunova, MV},
title = {Brain Gamma-Stimulation: Mechanisms and Optimization of Impact.},
journal = {Biology},
volume = {14},
number = {12},
pages = {},
doi = {10.3390/biology14121722},
pmid = {41463495},
issn = {2079-7737},
support = {FSWR-2025-0009//Ministry of Science and Higher Education of the Russian Federation/ ; },
abstract = {The γ-rhythm plays a key role in coordinating the activity of the major brain systems and facilitating higher-level neurological processes. Several pathological conditions are associated with impaired generation or regulation of γ-oscillations. Modulating the γ-rhythm using periodic signals is considered a potential way to halt and/or treat such neurodegenerative processes. Despite the extensive knowledge gained in this field over the last 70 years, a unified theory linking the effectiveness of γ-stimulation to the characteristics of the stimulus and the stimulated remains elusive. In this review, we conducted a quantitative analysis of these relationships. The γ-stimulation effectiveness depends on species, age, frequency, and stimulus type. Here, we found with our analysis that experiments using white light were more effective than red and infrared. The range of effective central frequencies depends on age. We also showed that AD patients and mouse models respond differently to γ-stimulation, so the careful selection of study subjects is essential when assessing therapeutic potential. This review also provides an overview of the mechanisms of γ-stimulation and makes recommendations for optimizing the method based on these mechanisms. Our findings may be useful to understanding -stimulation mechanisms, planning future experiments for research groups and identifying potential therapeutic γ-stimulation regimens.},
}

@article {pmid41463342,
year = {2025},
author = {Karim, F and Ngo, A and Tucker, TE and Coronel, ADL and Mukherjee, J},
title = {Assessment of [[125]I]a-Bungarotoxin Binding to a7 Nicotinic Acetylcholinergic Receptors in Hippocampus-Subiculum of Postmortem Human Parkinson's Disease Brain.},
journal = {Biomolecules},
volume = {15},
number = {12},
pages = {},
doi = {10.3390/biom15121686},
pmid = {41463342},
issn = {2218-273X},
support = {3RF1AG029479-10/NH/NIH HHS/United States ; 5R01AG077700-02/NH/NIH HHS/United States ; },
mesh = {Humans ; *Parkinson Disease/metabolism/pathology ; *alpha7 Nicotinic Acetylcholine Receptor/metabolism ; *Bungarotoxins/metabolism ; Male ; Female ; Aged ; Iodine Radioisotopes/chemistry ; *Hippocampus/metabolism/pathology ; Aged, 80 and over ; Middle Aged ; Protein Binding ; alpha-Synuclein/metabolism ; Alzheimer Disease/metabolism ; },
abstract = {Parkinson's disease (PD) involves motor and cognitive impairment that nicotinic acetylcholine receptors (nAChRs) such as the α7 subtype are responsible for regulating. The hippocampus, abundant in α7 nAChRs, was quantitatively evaluated for [[125]I]α-bungarotoxin ([[125]I]α-Bgtx) binding to α7 nAChRs in postmortem human PD (n = 26; 12 male, 14 female) and cognitively normal (CN) (n = 29; 14 male, 15 female) brain slices. Anti-ubiquitin and anti-α-synuclein immunostained adjacent slices were analyzed using QuPath. Autoradiographs of [[125]I]α-Bgtx radioligand binding were analyzed in OptiQuant. Ubiquitin and α-synuclein distribution generally aligned with the distribution of α7 nAChRs detected by [[125]I]α-Bgtx. Binding of [[125]I]α-Bgtx in PD cases was significantly greater than CN with a 32% increase in gray matter binding. A weak positive correlation between age and [[125]I]α-Bgtx binding was found in both PD and CN. In comparison to Alzheimer's disease hippocampus, [[125]I]α-Bgtx binding in PD gray matter was higher by 41%. Differences in nAChR expression imply unique roles depending on the neurodegenerative pathology. PD may experience an increase in α7 nAChRs as a compensatory mechanism to the loss in neurons, highlighting its neuroprotective capabilities. [[125]I]α-Bgtx shows potential as a radioligand for α7 nAChRs to elucidate the complexities of PD pathology.},
}

Humans
*Parkinson Disease/metabolism/pathology
*alpha7 Nicotinic Acetylcholine Receptor/metabolism
*Bungarotoxins/metabolism
Male
Female
Aged
Iodine Radioisotopes/chemistry
*Hippocampus/metabolism/pathology
Aged, 80 and over
Middle Aged
Protein Binding
alpha-Synuclein/metabolism
Alzheimer Disease/metabolism

@article {pmid41463314,
year = {2025},
author = {Trentin, R and Moschin, E and Custódio, L and Moro, I},
title = {Bioactivity and Chemical Profiling of the Sea-Ice Microalga Microglena antarctica (Chlorophyceae).},
journal = {Biomolecules},
volume = {15},
number = {12},
pages = {},
doi = {10.3390/biom15121658},
pmid = {41463314},
issn = {2218-273X},
support = {UIDB/04326/2020//Fundação para a Ciência e a Tecnologia/ ; UIDP/04326/2020//Fundação para a Ciência e a Tecnologia/ ; LA/P/0101/2020//Fundação para a Ciência e a Tecnologia/ ; ALG-01-0145-FEDER-022121//operational programs CRESC Algarve 2020 and COMPETE 2020/ ; CEECIND/00425/2017//Fundação para a Ciência e a Tecnologia/ ; PNRA18-00078-B2//Italian National Program for Antarctic Research (PNRA)/ ; },
mesh = {*Microalgae/chemistry ; Antioxidants/pharmacology/chemistry ; *Enzyme Inhibitors/pharmacology/chemistry ; Antarctic Regions ; alpha-Amylases/antagonists & inhibitors ; Monophenol Monooxygenase/antagonists & inhibitors ; Plant Extracts/chemistry/pharmacology ; Methanol/chemistry ; },
abstract = {Antarctic algae have evolved in extreme environmental conditions, developing unique metabolic adaptations with significant biotechnological potential. In this study, we explored the bioactivity of the sea-ice microalga Microglena antarctica by preparing acetone and methanol extracts from biomass cultivated at 4, 8, and 16 °C. These extracts were screened for their in vitro antioxidant properties and inhibitory activities on enzymes related to Alzheimer's disease (acetylcholinesterase: AChE, butyrylcholinesterase: BChE), type 2 diabetes mellitus (T2DM, α-glucosidase, α-amylase), obesity (lipase), and hyperpigmentation (tyrosinase). Our screening revealed a high capacity of acetone extracts to scavenge the ABTS•[+] radical (EC50 ranging from 3.57 to 4.18 mg mL[-1]), along with strong copper chelating activity in both acetone and methanol extracts (EC50 values of 6.31 and 6.41 mg mL[-1]). Relevant inhibition towards α-amylase (IC50 values of 3.34 and 4.53 mg mL[-1]) and tyrosinase (with IC50 ranging from 3.82 to 5.47 mg mL[-1]) was reported for acetone and methanol extracts, respectively. UHPLC-HRMS-based profiling revealed the presence of lipidic molecules, such as glycolipids, phospholipids, and betaine lipids with polyunsaturated carbon chains, together with carotenoids, including canthaxanthin and adonixanthin, which are likely responsible for the observed bioactivities.},
}

*Microalgae/chemistry
Antioxidants/pharmacology/chemistry
*Enzyme Inhibitors/pharmacology/chemistry
Antarctic Regions
alpha-Amylases/antagonists & inhibitors
Monophenol Monooxygenase/antagonists & inhibitors
Plant Extracts/chemistry/pharmacology
Methanol/chemistry

@article {pmid41463129,
year = {2025},
author = {Eroglu, B and Velez, D and Jones, K and Deak, F and Eroglu, A},
title = {Amelioration of Alzheimer's Disease Pathology in Zebrafish by Photobiomodulation.},
journal = {Biomedicines},
volume = {13},
number = {12},
pages = {},
doi = {10.3390/biomedicines13123121},
pmid = {41463129},
issn = {2227-9059},
abstract = {Background/Objectives: The zebrafish is a widely used research model due to its characteristics, such as being transparent during development, sharing 70% of its genes with humans, and having conserved features of vertebrate aging, including deterioration of mitochondrial and cognitive functions. While affecting approximately 15% of the world population, neurodegenerative diseases, such as Alzheimer's disease (AD), are currently incurable, requiring testing of alternative treatment strategies. Hence, this study was conducted to test the hypothesis that an optimized photobiomodulation (PBM) therapy improves AD pathology through its multifaceted beneficial effects, including enhancing mitochondrial function and reducing oxidative stress and neuroinflammation. Methods: A pharmacological zebrafish model of AD was developed by adding small amounts (100 nM) of okadaic acid (OKA) directly to fish tanks for nine days. Next, some of OKA-treated and control zebrafish were subjected to an optimized near-infrared PBM therapy while others remain untreated. Results: When examined after OKA treatment, zebrafish brains displayed histological hallmarks of AD including, neurofibrillary tangles, vacuoles, and neuroinflammation. Behavioral tests using a T-maze revealed that OKA-treated zebrafish spent significantly less time in the reward arm than untreated controls (15.2% vs. 50%). In contrast, a sequential PBM therapy significantly reduced formation of neurofibrillary tangles, vacuoles, neuroinflammation, and improved mitochondrial biogenesis in brains of OKA-treated zebrafish while also improving their cognitive function as evidenced by being able to recall the reward arm and spending more time there similar to controls (55 and 57%, respectively). Conclusions: These findings suggest that (1) a fast, cost-effective zebrafish AD model can be developed using OKA treatment and (2) PBM therapy holds promise to ameliorate AD pathology.},
}

@article {pmid41463112,
year = {2025},
author = {Andreeva, TD and Todinova, S and Langari, A and Strijkova, V and Katrova, V and Taneva, SG},
title = {Amyloid Protein-Induced Remodeling of Morphometry and Nanomechanics in Human Platelets.},
journal = {Biomedicines},
volume = {13},
number = {12},
pages = {},
doi = {10.3390/biomedicines13123104},
pmid = {41463112},
issn = {2227-9059},
support = {КП-06-Н31/8//Bulgarian National Science Fund/ ; D01-352/2023//Funder Grant Number Bulgarian National Science Fund/ ; 449916462//German Research Foundation/ ; },
abstract = {Background/Objectives: The accumulation of specific amyloid proteins and peptides in the human brain is a hallmark of neurodegenerative disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD). Beyond the central nervous system, circulating peripheral blood cells are also exposed to these pathological proteins, which may contribute to the systemic disease manifestation. Human platelets (PLTs) were used as an in vitro model to investigate the impacts of amyloid Aβ1-42 peptide oligomers (Aβ42) and on-pathway α-synuclein (α-syn), two key amyloids implicated in AD and PD, on platelet biophysical properties. Methods: Using atomic force microscopy, imaging and force-distance modes, we analyzed changes in surface nanostructure, morphometric and nanomechanical signatures of PLTs, derived from healthy donors, following exposure to increasing concentrations of Aβ42 and α-syn. Results: Our findings show that platelet activation progresses with increasing amyloid concentration, characterized by cytoskeletal remodeling (filopodia-to-pseudopodia and lamellipodia transformation). While Aβ42 causes progressive decrease in the platelet membrane roughness, α-syn exhibits a biphasic effect-initial smoothing followed by a pronounced increase in the roughness at high concentrations. Both amyloids induce substantial increase in membrane stiffness (Young's modulus). Conclusions: The changes in PLTs' biophysical properties closely resemble the previously observed modification in PLTs derived from AD and PD patients, suggesting that amyloid proteins' interactions with PLTs may contribute to their dysfunction. Our results underscore the potential of platelets as peripheral indicators of neurodegeneration and point to their role in the systemic pathology of amyloid-associated diseases.},
}

@article {pmid41463053,
year = {2025},
author = {N F Guimarães, G and Dos Santos Cardoso, F and Gamboa, L and W Barrett, D and Gonzalez-Lima, F},
title = {Abdominal Photobiomodulation and the Gut-Brain Axis: A Systematic Review of Mechanistic and Translational Evidence.},
journal = {Biomedicines},
volume = {13},
number = {12},
pages = {},
doi = {10.3390/biomedicines13123042},
pmid = {41463053},
issn = {2227-9059},
abstract = {Background/Objectives: Bidirectional communication between the gut and brain is central to neurological and psychiatric health, and abdominal photobiomodulation (PBM) has emerged as a promising non-invasive way to modulate this axis by targeting intestinal mitochondria, epithelial integrity, and the microbiota. We systematically reviewed preclinical and clinical evidence on abdominal PBM, alone or in combined protocols, reporting microbiome, metabolic, or neurobehavioral outcomes. Methods: Following PRISMA 2020 recommendations, we searched MEDLINE, Scopus, Web of Science, and ScienceDirect through May 2025 for animal and human studies applying PBM to the abdomen and reporting gut-related, metabolic, or brain-related outcomes. Results: Nine studies met the eligibility criteria (five human, four animal). Human trials, mainly in Parkinson's and Alzheimer's disease, used 630-904 nm light and reported gains in mobility, balance, cognition, and olfaction; one trial also showed microbiota modulation with a decreased Firmicutes:Bacteroidetes ratio. Animal models revealed cognitive improvement, reduced neuroinflammation, dopaminergic neuroprotection, and microbial rebalancing. Mechanistic findings converged on enhanced mitochondrial bioenergetics, redox and anti-inflammatory signaling, vagal activation, and short-chain fatty acid-mediated effects. Conclusions: Current evidence, though limited by small samples, heterogeneous dosimetry, combined treatment sites, and few sham-controlled human trials, suggests that abdominal PBM can influence the gut-brain axis through converging mitochondrial, immune, and microbial mechanisms. Adequately powered randomized trials with standardized dosimetry, validated mechanistic biomarkers, and integrative multi-omics analyses are needed to clarify causal pathways and optimize translational applications.},
}

@article {pmid41463031,
year = {2025},
author = {Di Matteo, F and Vietri, M and D'Alessio, S and Ciaglia, T and Vestuto, EF and Pepe, G and Moltedo, O and Di Sarno, V and Musella, S and Ostacolo, C and Cominelli, F and Campiglia, P and Bertamino, A and Miranda, MR and Vestuto, V},
title = {Targeting Cathepsins in Neurodegeneration: Biochemical Advances.},
journal = {Biomedicines},
volume = {13},
number = {12},
pages = {},
doi = {10.3390/biomedicines13123019},
pmid = {41463031},
issn = {2227-9059},
abstract = {Background/Objectives: Cathepsins, lysosomal proteases crucial for neuronal proteostasis, mediate the clearance of misfolded and aggregated proteins. Their dysregulation is implicated in neurodegenerative and neuropsychiatric disorders such as Alzheimer's, Parkinson's, and Huntington's diseases. These conditions are characterized by toxic protein accumulation and impaired clearance, which exacerbate cellular stress responses, including the unfolded protein response (UPR), oxidative damage, and mitochondrial dysfunction. This review aims to summarize current knowledge on cathepsin roles in these pathways and assess their therapeutic potential. Methods: A comprehensive literature review was conducted, focusing on recent in vitro and in vivo studies investigating cathepsin function, inhibition, and modulation. Mechanistic insights and pharmacological approaches targeting cathepsins were analyzed, with attention to challenges in translating preclinical findings to clinical settings. Results: Cathepsins demonstrate a dual role: their proteolytic activity supports neuronal health by degrading toxic aggregates, but altered or insufficient activity may worsen proteotoxic stress. Studies reveal that cathepsins regulate autophagy, apoptosis, and neuroinflammation both intracellularly and extracellularly. Despite promising mechanistic data, clinical translation is hindered by issues such as poor inhibitor selectivity, limited brain penetration, and variability across preclinical models. Conclusions: Targeting cathepsins presents a promising strategy for treating neurodegenerative and neuropsychiatric disorders, but significant challenges remain. Future research should focus on improving drug specificity and delivery, and on developing standardized models to better predict clinical outcomes.},
}

@article {pmid41462981,
year = {2025},
author = {Harvey, J},
title = {Therapeutic Potential of Leptin in Neurodegenerative Disease.},
journal = {Biomedicines},
volume = {13},
number = {12},
pages = {},
doi = {10.3390/biomedicines13122969},
pmid = {41462981},
issn = {2227-9059},
abstract = {Alzheimer's disease (AD) is an age-related neurodegenerative disorder, characterised by the build-up of amyloid beta (Aβ) plaques and neurofibrillary tangles comprising hyper-phosphorylated tau. Increasing evidence indicates that in the early stages of AD, elevated levels of oligomeric forms of Aβ and phosphorylated tau (p-tau) gives rise to impaired synaptic function which ultimately drives AD-associated cognitive abnormalities. Thus, developing drugs that can limit the synaptic impairments that occur early in AD may have therapeutic benefits. Clinical evidence increasingly supports a link between lifestyle choices and AD risk. Indeed, there is an association between the circulating levels of the metabolic hormone leptin, mid-life obesity and disease risk, which has in turn stimulated interest in targeting the leptin system to treat AD. It is well-established that leptin readily accesses the brain, with the hippocampus, a key region that degenerates in AD, identified as a prime target for this hormone. Within the hippocampus, leptin has cognitive enhancing properties as it markedly influences the cellular events underlying hippocampal-dependent learning and memory, with significant impact on synaptic plasticity and trafficking of glutamate receptors at hippocampal excitatory CA1 synapses. Moreover, studies using a range of cell-based systems and animal models of disease indicate not only that leptin has powerful pro-cognitive effects, but also that leptin protects against the unwanted synapto-toxic effects of Aβ and tau, as well as enhancing neuronal cell viability. Moreover, recent studies have demonstrated that smaller leptin-based molecules replicate the full repertoire of protective features of whole leptin. Here we review the evidence that the leptin system is a potential novel avenue for drug discovery in AD.},
}

@article {pmid41462943,
year = {2025},
author = {Harun, ZZ and Abdul Azhar, A and Kim, YJ and Ibrahim, FW and Ng, MH and Tan, JK and Lokanathan, Y},
title = {Modulation of BDNF/TrkB Signalling Pathway in Alzheimer's Disease: Mechanistic Insights and the Role of Stem Cell Therapy.},
journal = {Biomedicines},
volume = {13},
number = {12},
pages = {},
doi = {10.3390/biomedicines13122931},
pmid = {41462943},
issn = {2227-9059},
support = {ETCM/0001//ALPS Global Holding Berhad/ ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disease, characterized by the accumulation of amyloid beta (aβ) plaques and neurofibrillary tangles, along with progressive deterioration of cognitive function. AD is the most common form of dementia and affects over 55 million people worldwide. Current treatments for AD are symptomatic-based rather than curative, which calls for the development of new therapeutic strategies. Stem cell therapy has shown promising results for neurodegenerative diseases, including AD. Brain-derived neurotrophic factor (BDNF) and its receptor, tropomyosin receptor kinase B (TrkB), and their downstream signalling cascades play crucial role in modulating neuronal survival, development and synaptic plasticity, which are vital for cognitive functioning, and this pathway is dysregulated in AD. While the BDNF/TrkB signalling pathway dysregulation and stem cell therapy are each widely studied in AD, the interplay between those two remains underexplored. This review focuses on the mechanistic insights of the BDNF/TrkB signalling pathway in normal physiological condition and AD, along with the effects of stem cell therapy on the pathway and its downstream cascades. The findings highlight the therapeutic outcomes in increasing BDNF/TrkB levels and functions, restoring synaptic plasticity, modulating downstream substrates activities and improving cognitive functions. In addition, challenges, limitations and future directions of stem cell therapy are discussed, underscoring the therapeutic benefits of this therapy for AD by modulating the BDNF/TrkB signalling pathway.},
}

@article {pmid41462898,
year = {2025},
author = {Bondar, AC and Iordache, MP and Coroescu, M and Buliman, A and Rusu, E and Budișteanu, M and Tanase, C},
title = {Unlocking the Sugar Code: Implications and Consequences of Glycosylation in Alzheimer's Disease and Other Tauopathies.},
journal = {Biomedicines},
volume = {13},
number = {12},
pages = {},
doi = {10.3390/biomedicines13122884},
pmid = {41462898},
issn = {2227-9059},
abstract = {Alzheimer's disease (AD) is the most prevalent cause of dementia, characterized by progressive cognitive decline, amyloid-β (Aβ) plaques, and neurofibrillary tangles composed of hyperphosphorylated tau protein. Other tauopathies, including frontotemporal lobar degeneration (FTLD), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD) share pathological hallmarks centered on abnormal tau biology. Increasing evidence highlights the role of post-translational modifications in modulating these pathogenic processes. Among these, glycosylation, the enzymatic attachment of glycans to proteins or lipids, has emerged as a critical regulator of protein folding, trafficking, aggregation, and clearance. Both N-linked glycosylation (N-glycosylation) and O-linked glycosylation (O-glycosylation) influence tau stability, Aβ processing, receptor signaling, synaptic integrity, and neuroinflammation. Dysregulated glycosylation patterns have been documented in brains and cerebrospinal fluid (CSF) of AD patients, suggesting biomarker potential and novel therapeutic targets. Moreover, glycosyltransferases and glycosidases show altered expression in neurodegeneration, linking metabolic and inflammatory pathways to tauopathy progression. This review synthesizes current evidence on the implications and consequences of glycosylation in AD and other tauopathies, integrating mechanistic, pathological, and clinical findings. We also discuss advances in glycoproteomics, the interplay between glycosylation and phosphorylation, and the translational potential of targeting glycosylation pathways for diagnosis and therapy.},
}

@article {pmid41462869,
year = {2025},
author = {Sarbu, M and Ica, R and Biricioiu, MR and Dehelean, L and Zamfir, AD},
title = {Glycosphingolipids in Dementia: Insights from Mass Spectrometry and Systems Biology Approaches.},
journal = {Biomedicines},
volume = {13},
number = {12},
pages = {},
doi = {10.3390/biomedicines13122854},
pmid = {41462869},
issn = {2227-9059},
support = {PN-IV-P2-2.1-TE-2023-0175//UEFISCDI/ ; UAV-IRG-1-2025-8//Aurel Vlaicu University of Arad, Romania/ ; },
abstract = {This narrative literature review synthesizes recent evidence on glycosphingolipid (GSL) dysregulation in dementia, emphasizing discoveries enabled by mass spectrometry (MS) and systems biology. Focusing on the research published within the last decade, we selected studies that are relevant to GSL alterations in dementia and notable for their methodological advances. The findings were conceptually integrated to emphasize key molecular, analytical, and systems-level aspects across the major dementia types. The results from MS-based glycolipidomics in Alzheimer's disease, dementia with Lewy bodies, frontotemporal dementia, Parkinson's disease dementia, and Huntington's disease consistently indicate altered GSL metabolism and shared molecular vulnerabilities in neuronal lipid regulation. At the same time, distinct GSL signatures differentiate individual dementias, reflecting the disease-specific mechanisms of neurodegeneration. The literature also reveals that recent advances in high-resolution MS and integrative analytical workflows have shifted GSL research from descriptive to mechanistic, facilitating the detailed mapping of species linked to neuroinflammation, protein aggregation, and synaptic dysfunction. Systems-level analyses combining MS data with other omics approaches increasingly depict GSLs as active regulators of neuronal function rather than inert membrane components. At the same time, emerging trends position GSLs as promising early biomarkers and potential therapeutic targets, while the growing use of artificial intelligence in MS data analysis is accelerating the detection of their subtle patterns, improving cross-disease comparisons. Together, these results reinforce the major role of MS-based platforms in discovering dementia-associated GSLs, identifying therapeutic targets, and influencing future strategies for diagnosis and treatment.},
}

@article {pmid41462867,
year = {2025},
author = {Fonseca, N and Nunes, M and Silva, PMA and Bousbaa, H and Ricardo, S},
title = {Galanthamine Fails to Reverse P-gp-Mediated Paclitaxel Resistance in Ovarian Cancer Cell Lines.},
journal = {Biomedicines},
volume = {13},
number = {12},
pages = {},
doi = {10.3390/biomedicines13122852},
pmid = {41462867},
issn = {2227-9059},
abstract = {Background: Ovarian cancer has the poorest prognosis of all gynecological malignancies, largely due to its chemoresistance, which poses significant treatment challenges. In this context, drug repurposing emerges as an innovative strategy that employs non-cancer treatments to interact with various signaling pathways, enhancing chemotherapy efficacy while minimizing toxicity. This study investigated the cytotoxic effects of galanthamine, currently used as an Alzheimer's disease, as a potential treatment for high-grade serous carcinoma, both individually and in combination with paclitaxel. Methods: The Presto Blue assay, viability marker assessments, immunocytochemical analysis of apoptosis, and a cumulative assay were employed to evaluate the functionality of P-glycoprotein. Results: The results indicated that galanthamine did not demonstrate cytotoxic or synergistic effects in either high-grade serous carcinoma cell line tested, suggesting that it is not a viable strategy for overcoming paclitaxel resistance in this context. The immunocytochemistry analysis indicated that galanthamine does not affect the expression of proteins related to cell viability and proliferation and is not associated with chemoresistance. Additionally, functional assays showed that galanthamine treatment did not affect its drug efflux function at the cellular level. Conclusions: Overall, the results indicate that galanthamine is unsuitable for reversing paclitaxel resistance despite some literature suggesting its potential interaction with P-glycoprotein.},
}

@article {pmid41462694,
year = {2025},
author = {Zhang, T and Zhang, S and Ma, J and Atiakshin, D and Han, S and Noda, M and Hiramatsu, M and Liu, J and Peng, Y and Long, J},
title = {Luteolin in Safflower Leaves Suppresses Microglial Inflammation Through FOXO3-Mediated Trem2 Transcription.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {14},
number = {12},
pages = {},
doi = {10.3390/antiox14121495},
pmid = {41462694},
issn = {2076-3921},
support = {No. 31870848, No. 82372899//National Natural Science Foundation of China/ ; 2024SF-ZDCYL-03-24//Key Research and Development Plan Project of Shaanxi Province, China/ ; G2022170026L//China National Foreign Experts Project/ ; No. 2023-JC-QN-0215//Natural Science Basic Research Program of Shaanxi/ ; No. xpt012025043//Basic Scientific Research Foundation of Xi'an Jiaotong University Young Academic Support Pro-gram/ ; },
abstract = {Neuroinflammation driven by microglial activation is a hallmark of Alzheimer's disease (AD). Triggering receptor expressed on myeloid cells 2 (TREM2) is a key regulator of microglial inflammation, yet strategies to modulate its expression remain limited. Safflower leaves, a vegetable rich in flavonoids-particularly luteolin-were previously shown to attenuate neuroinflammation, reduce oxidative stress, and ameliorate cognitive impairment in APP/PS1 mice. Here, we demonstrated that safflower leaves inhibit microglial inflammation and upregulate TREM2 in APP/PS1 mice. Luteolin, the major active flavonoid in safflower leaves, exerted anti-inflammatory effects in lipopolysaccharides (LPS)-activated microglia. Mechanistically, luteolin enhanced Trem2 transcription by activating forkhead box protein O3 (FOXO3), a novel transcriptional regulator of Trem2 identified through promoter analysis. FOXO3 binding to the Trem2 promoter was essential for this regulation, and luteolin further promoted FOXO3 nuclear translocation. Crucially, Trem2 knockdown attenuated luteolin's anti-inflammatory effects, confirming TREM2 as a key mediator. Overall, our study reveals the FOXO3-TREM2 axis as a potential therapeutic target for neuroinflammation and highlights luteolin present in safflower leaves as a candidate dietary intervention for AD, providing new mechanistic insights into the anti-inflammatory activity of this natural antioxidant.},
}

@article {pmid41462623,
year = {2025},
author = {Singh, DD and Yadav, DK and Shin, D},
title = {Antioxidant Natural Compounds Integrated with Targeted Protein Degradation: A Multi-Modal Strategy for Alzheimer's Disease Therapy.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {14},
number = {12},
pages = {},
doi = {10.3390/antiox14121426},
pmid = {41462623},
issn = {2076-3921},
support = {RS-2020-NR049589//National Research Foundation of Korea/ ; RS-2025-00555975//National Research Foundation of Korea/ ; GCU-202206050001//Gachon University/ ; },
abstract = {Alzheimer's disease (AD) Alzheimer's disease (AD) is a progressive neurodegenerative disorder marked by protein aggregation, oxidative stress, mitochondrial dysfunction, and chronic neuroinflammation, leading to cognitive decline. Current therapies remain largely symptomatic, highlighting the need for multi-target therapeutic strategies. Recent advances in antioxidant natural compounds and targeted protein degradation (TPD) technologies-particularly proteolysis-targeting chimeras (PROTACs), offer complementary mechanisms for disease modification. Natural antioxidants, including flavonoids, polyphenols, terpenoids, and alkaloids, confer neuroprotection by reducing reactive oxygen species, activating Nrf2 pathways, restoring mitochondrial function, and suppressing neuroinflammation. PROTACs, in contrast, selectively degrade pathological proteins such as hyperphosphorylated tau, amyloid-β, and APP fragments through the ubiquitin-proteasome system. The integrated "Antiox-PROTAC" approach combines these modalities to simultaneously mitigate oxidative stress and eliminate neurotoxic proteins. Natural compounds may act as warheads or scaffolds in PROTAC design, retaining antioxidant activity while enabling targeted degradation. Early preclinical findings demonstrate synergistic neuroprotective potential, though translational challenges remain, including blood-brain barrier permeability, bioavailability, and delivery optimization. Future directions involve hybrid molecules, nanoparticle-based delivery, and personalized therapeutic strategies. Overall, the Antiox-PROTAC paradigm represents a next-generation, multi-modal framework with the potential to modify disease progression and enhance cognitive outcomes in Alzheimer's disease.},
}

@article {pmid41462581,
year = {2025},
author = {Wang, X and Tian, S and Xiao, H and Chen, C and Ning, F and Lin, Y},
title = {Vascular risk factor variability and cognitive impairment in older adults a community-based retrospective study.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {45057},
pmid = {41462581},
issn = {2045-2322},
support = {21-1-4-rkjk-1-nsh//Qingdao Municipal Bureau of Science and Technology/ ; 21-1-4-rkjk-1-nsh//Qingdao Municipal Bureau of Science and Technology/ ; 21-1-4-rkjk-1-nsh//Qingdao Municipal Bureau of Science and Technology/ ; 21-1-4-rkjk-1-nsh//Qingdao Municipal Bureau of Science and Technology/ ; 21-1-4-rkjk-1-nsh//Qingdao Municipal Bureau of Science and Technology/ ; 21-1-4-rkjk-1-nsh//Qingdao Municipal Bureau of Science and Technology/ ; },
}

@article {pmid41462458,
year = {2025},
author = {Palacios, ER and Shapland, CY and Wolf, LJ and Nordestgaard, LT and Anderson, E and Slaney, C and Bernie, D and Mitchell, D and Kehoe, PG and Griffith, GJ and Tilling, K},
title = {Dissecting the effect of long-term exposure to air pollution on risk of dementia in UK Biobank.},
journal = {Environmental health : a global access science source},
volume = {24},
number = {1},
pages = {96},
pmid = {41462458},
issn = {1476-069X},
support = {108899/B/15/Z/WT_/Wellcome Trust/United Kingdom ; MC UU 00032/2/MRC_/Medical Research Council/United Kingdom ; MC UU 00032/06/MRC_/Medical Research Council/United Kingdom ; MC UU 00032/2/MRC_/Medical Research Council/United Kingdom ; 10.46540/3100-00007B//Beckett-Fonden/ ; MR/W011581/1//UK Research and Innovation/ ; MC UU 00032/1//MQ Mental Health Research/ ; },
mesh = {Humans ; United Kingdom/epidemiology ; *Air Pollution/adverse effects ; *Particulate Matter/adverse effects/analysis ; *Environmental Exposure/adverse effects ; *Air Pollutants/adverse effects/analysis ; *Dementia/epidemiology/chemically induced ; Aged ; Male ; Female ; Biological Specimen Banks ; Risk Factors ; Middle Aged ; Nitric Oxide/adverse effects/analysis ; Aged, 80 and over ; Nitrogen Dioxide ; UK Biobank ; },
abstract = {Mounting evidence links air pollution to dementia, the most prevalent cause of cognitive impairment in older people. Here we investigated individual and compound effects of particulate matters (PM10, PM2.5, PMcoarse, PMabs) and nitric oxides (NO2, NO) on risk of all-cause dementia, and its most common subtypes, Alzheimer's disease (AD) and vascular dementia (VAD), using data from UK Biobank. We addressed factors that hinder causal interpretation of associations previously shown in the literature and their translation into clear public health policies. Specifically: 1) spatial confounding by area-level covariates, 2) collinearity among and identification of the most relevant air pollutants, and 3) the time window for pollution exposure. Furthermore, we used chronic obstructive pulmonary disease (COPD) and frequency of oily fish intake in positive and negative control analyses. We found NO2 to be the strongest risk factor for dementia, especially when considering participants with longer permanence at residential address as proxy for longer periods ([Formula: see text] years) of exposure (all-cause dementia hazard ratio HR=1.06, 1.02-1.11 per 9.86 [Formula: see text] interquartile range). There was stronger evidence of an effect on risk for AD than VAD. Positive control analysis did not provide any evidence against causality, although the analyses of spatial confounding and negative control analyses revealed the presence of some residual bias, thus warranting care in the interpretation of the results. Together, our results highlight that targeting air pollution, in particular NO2 levels, could inform preventive public health policies for dementia.},
}

Humans
United Kingdom/epidemiology
*Air Pollution/adverse effects
*Particulate Matter/adverse effects/analysis
*Environmental Exposure/adverse effects
*Air Pollutants/adverse effects/analysis
*Dementia/epidemiology/chemically induced
Aged
Male
Female
Biological Specimen Banks
Risk Factors
Middle Aged
Nitric Oxide/adverse effects/analysis
Aged, 80 and over
Nitrogen Dioxide
UK Biobank

@article {pmid41462362,
year = {2025},
author = {Lukacsovich, D and Wang, L and Young, JI and Zhang, W and Gomez, L and Schmidt, MA and Gardener, H and Agudelo, C and Dueker, N and Elfassy, T and Gibbs, C and Scott, SS and Martin, ER and Kunkle, BW and Chen, XS and Blanton, S and Rundek, T and Wang, L},
title = {DNA methylation signatures of Life's Essential 8 and their implications for dementia.},
journal = {Alzheimer's research & therapy},
volume = {17},
number = {1},
pages = {266},
pmid = {41462362},
issn = {1758-9193},
mesh = {Humans ; *DNA Methylation/genetics ; Male ; Female ; *Dementia/genetics ; Aged ; Middle Aged ; Genome-Wide Association Study ; Cohort Studies ; Biomarkers ; Adult ; Aged, 80 and over ; Hispanic or Latino/genetics ; White ; },
abstract = {BACKGROUND: As dementia cases continue to rise, effective prevention strategies are urgently needed. However, objective biomarkers that directly reflect lifestyle factors remain limited. Life's Essential 8 (LE8) is a composite of modifiable cardiovascular health metrics, and lower LE8 has been consistently associated with increased risk of dementia. In this study, we aimed to identify DNA methylation biomarkers associated with LE8 scores and investigate their relevance for dementia risk.

METHODS: We performed an epigenome-wide association study of 273 stroke-free, self-identified Hispanic adults aged 40 and older from the Northern Manhattan Study (NOMAS), a community-based urban cohort study. DNA methylation (DNAm) was assessed using Illumina MethylationEPIC arrays. Robust linear models identified CpGs associated with LE8 score, a composite score on eight health metrics including diet quality, physical activity, nicotine exposure, sleep health, body mass index, blood lipids, blood glucose, and blood pressure. Differentially methylated regions were identified by combining P-values in sliding windows while accounting for spatial correlations across the genome. We also performed functional annotation, pathway analyses, and integrative analyses with gene expression, genetic variants, brain-blood correlations, and comparisons with previous dementia studies to identify the most biologically meaningful DNAm sites.

RESULTS: After adjusting for age, sex, APOE ε4, immune cell composition, and ancestry, we found 11 CpGs with suggestive evidence of association with LE8 (P-value < 1 × 10[-5]) and 37 differentially methylated regions that passed multiple-testing correction. These LE8-associated loci mapped to genes and pathways that support vascular integrity and regulate inflammation, key biological processes relevant to both cardiovascular disease and dementia. Integrative analyses highlighted several CpGs in the HOXA5 gene promoter with converging evidence supporting their potential as dementia biomarkers, including strong blood-brain DNAm correlations, association with gene expression and genetic variants, and prior associations with Alzheimer's disease neuropathology.

CONCLUSIONS: Our comparison with published results showed that a number of LE8-associated DNA methylation sites are associated with dementia, highlighting the possible connection between cardiovascular health and dementia risk and pointing to potential actionable targets for dementia prevention. Moreover, DNAm biomarkers have clinical potential as objective measures to identify individuals at elevated risk, stratify participants based on biologically informed risk profiles, and monitor epigenetic responses to lifestyle interventions in dementia prevention trials. Future studies in larger and more diverse cohorts are needed to validate and refine these methylation biomarkers for clinical applications.},
}

Humans
*DNA Methylation/genetics
Male
Female
*Dementia/genetics
Aged
Middle Aged
Genome-Wide Association Study
Cohort Studies
Biomarkers
Adult
Aged, 80 and over
Hispanic or Latino/genetics
White

@article {pmid41462345,
year = {2025},
author = {Ryoo, N and Park, JY and Lee, C and Ho, S and Hong, YJ and Jeong, JH and Park, KH and Wang, MJ and Choi, SH and Kim, S and Youn, YC and Kim, E and Kim, S and Yang, DW},
title = {EEG-based detection of early functional brain changes in subjective cognitive decline: a prospective cohort study.},
journal = {Alzheimer's research & therapy},
volume = {17},
number = {1},
pages = {265},
pmid = {41462345},
issn = {1758-9193},
support = {RS-2024-00350834//National Research Foundation of Korea/ ; RS-2024-00350834//National Research Foundation of Korea/ ; RS-2024-00350834//National Research Foundation of Korea/ ; RS-2024-00350834//National Research Foundation of Korea/ ; RS-2023-00224524//The Korea Creative Content Agency/ ; RS-2023-00224524//The Korea Creative Content Agency/ ; RS-2023-00224524//The Korea Creative Content Agency/ ; HI18C0530//The ministry of health and welfare, South Korea/ ; HI18C0530//The ministry of health and welfare, South Korea/ ; HI18C0530//The ministry of health and welfare, South Korea/ ; HI18C0530//The ministry of health and welfare, South Korea/ ; HI18C0530//The ministry of health and welfare, South Korea/ ; HI18C0530//The ministry of health and welfare, South Korea/ ; HI18C0530//The ministry of health and welfare, South Korea/ ; HI18C0530//The ministry of health and welfare, South Korea/ ; HI18C0530//The ministry of health and welfare, South Korea/ ; HI18C0530//The ministry of health and welfare, South Korea/ ; },
mesh = {Humans ; *Cognitive Dysfunction/physiopathology/diagnosis ; Male ; *Electroencephalography/methods ; Female ; Prospective Studies ; *Brain/physiopathology ; Aged ; Machine Learning ; Middle Aged ; Cohort Studies ; Alzheimer Disease/physiopathology ; Aged, 80 and over ; },
abstract = {BACKGROUND: Subjective cognitive decline (SCD) has been recognized as a preclinical stage of Alzheimer's disease. However, the identification of early functional brain changes remains challenging. This study investigated the functional brain changes in SCD using longitudinal EEG and evaluate the feasibility of EEG features as scalable biomarkers for identifying amyloid burden and cognitive decline using an interpretable machine learning framework.

METHODS: We analyzed 120 individuals with SCD enrolled in a multicenter prospective cohort (the CoSCo study) at baseline and after a 2-year follow-up. Participants were classified as amyloid-positive (A + SCD) or amyloid-negative (A - SCD). Spectral power and graph theory-based network analyses were conducted. Also, we trained machine learning classifiers to distinguish between the groups and interpreted the predictions of classifiers using SHAP.

RESULTS: At both baseline and follow-up, the A + SCD group exhibited elevated low-frequency (delta and theta) activity and reduced alpha activity compared to the A - SCD group. The EEG-based classifiers distinguished A + SCD from A-SCD individuals with high performance, outperforming a classifier based on demographic data. The results of SHAP analysis confirmed the importance and relative contribution of selected EEG features.

CONCLUSIONS: Longitudinal EEG, when combined with interpretable machine learning, can detect and track the functional alterations of brain related to amyloid pathology in preclinical AD. Our findings support the feasibility of EEG as a non-invasive, scalable, and sensitive biomarker for risk stratification, before overt cognitive impairment emerges.

TRIAL REGISTRATION: This study was registered at the Clinical Research Information Service (CRIS) (cris.nih.go.kr/cris; # KCT0003397, Registration Date: December 21, 2018).},
}

Humans
*Cognitive Dysfunction/physiopathology/diagnosis
Male
*Electroencephalography/methods
Female
Prospective Studies
*Brain/physiopathology
Aged
Machine Learning
Middle Aged
Cohort Studies
Alzheimer Disease/physiopathology
Aged, 80 and over

@article {pmid41462331,
year = {2025},
author = {Brar, A and Issar, A and Tylinski Sant'Ana, T and Mollayeva, T},
title = {The effects of sex and gender attributes on clinical outcomes: a systematic review.},
journal = {Biology of sex differences},
volume = {16},
number = {1},
pages = {108},
pmid = {41462331},
issn = {2042-6410},
support = {GBHI ALZ UK-23-971123//Global Brain Health Institute, Alzheimer's Association, and Alzheimer's Society UK Pilot Award for Global Brain Health Leaders/ ; CRC-2021-00074//Canada Research Chairs Program for Neurological Disorders and Brain Health/ ; },
mesh = {Humans ; Male ; *Sex Characteristics ; Female ; *Gender Identity ; },
abstract = {BACKGROUND: Biological sex and sociocultural gender may influence changes in health status critical to clinical decision-making, yet scientific evidence of their effects on clinically relevant outcomes remain uncertain. We aimed to systematically review research on sex and gender effects on clinical outcomes and to assess the consistency and significance of associations between sex, gender, and clinical outcomes.

METHODS: We searched Medline, Embase, PsycInfo, CINAHL, and Web of Science from each database's inception to November 20, 2023, and included English language peer-reviewed research utilizing standardized measures of sex and gender attributes in adults to measure their association with clinically relevant outcomes. We performed a risk of bias assessment and certainty assessment using criteria set a priori. We created visualizations of results with links to study quality and sex and gender attributes, which facilitated certainty assessment. We reported results across sex and gender-related attributes and measures.

RESULTS: Of the 12,964 unique records identified, 19 studies with a total of 643,093 participants (54% male) were included in data synthesis. Four studies measured attributes of sex (testosterone, sex-specific polygenic score), and 15 studies measured attributes of gender (gender identity, roles, and adherence to masculine norms). We observed great heterogeneity in the direction and significance of the associations, resulting in evidence of moderate certainty only for the association between testosterone level and depression, and erectile function. We regarded all other evidence as very low in certainty.

CONCLUSION: Research findings regarding the effects of sex and gender attributes on clinical outcomes is variable. However, results suggest that neither sex nor gender attributes should be ignored when investigating clinically relevant outcomes. To enhance certainty, future research should delve into sex and gender attributes concurrently, taking into account that clinical disorders are not evenly distributed across sexes and genders. This approach would provide needed evidence to drive precision medicine and person-centered care.

PROSPERO: CRD42023456917.

FUNDING: Global Brain Health Institute, Alzheimer's Association, and Alzheimer's Society UK Pilot Award for Global Brain Health Leaders (GBHI ALZ UK-23-971123); Canada Research Chairs Program for Neurological Disorders and Brain Health (CRC-2021-00074).},
}

Humans
Male
*Sex Characteristics
Female
*Gender Identity

@article {pmid41462276,
year = {2025},
author = {Yin, T and Yesiltepe, M and Metkar, S and Ramon, A and Greenig, M and Sormanni, P and D'Adamio, L},
title = {The NewroBus platform: engineered humanized anti-TfR1 nanobodies for efficient brain delivery.},
journal = {Cell communication and signaling : CCS},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12964-025-02605-1},
pmid = {41462276},
issn = {1478-811X},
support = {R01AG073182/AG/NIA NIH HHS/United States ; },
abstract = {BACKGROUND: Delivery of biologic therapeutics to the central nervous system (CNS) is hindered by the blood-brain barrier (BBB), which restricts large molecule passage. Receptor-mediated transcytosis via transferrin receptor 1 (TfR1) provides a physiological route for selective BBB transport. This study aimed to develop human-specific nanobodies that engage TfR1 without disrupting transferrin function, enabling safe and efficient CNS delivery of therapeutic biologics.

METHODS: Single-domain camelid antibodies targeting human TfR1 were isolated, humanized, and optimized through computational and artificial intelligence-guided algorithms to improve humanness, solubility, and stability. Binding kinetics were quantified by surface plasmon resonance using a 1:1 Langmuir model. In vivo BBB permeability and safety were assessed in rats genetically humanized for TfR1 and transferrin following intravenous or subcutaneous administration.

RESULTS: Optimized TfR1-binding nanobodies exhibited high affinity for human TfR1, with equilibrium dissociation constants (KD) in the picomolar range. These nanobodies crossed the BBB efficiently without interfering with transferrin binding or iron homeostasis and were therefore designated NewroBus. When fused to humanized tumor necrosis factor alpha (TNFα)-neutralizing nanobodies, NewroBus heterodimers maintained BBB permeability and achieved sustained cerebrospinal fluid and serum levels for at least three days after subcutaneous dosing. Chronic administration of representative constructs in humanized rats did not alter hematologic parameters, indicating absence of TfR1-related hematotoxicity.

CONCLUSIONS: Humanized TfR1 nanobodies (NewroBus) enable efficient, TfR1-dependent transcytosis of biologics across the BBB while preserving iron transport and safety. Their high binding affinity, favorable pharmacokinetic properties, and modular fusion capacity position NewroBus as a versatile platform for CNS delivery of therapeutic proteins.},
}

@article {pmid41462232,
year = {2025},
author = {Shaikh, MR and Jeyabose, A and Arjunan, RV},
title = {Deep learning for Alzheimer's disease: advances in classification, segmentation, subtyping, and explainability.},
journal = {Biomedical engineering online},
volume = {24},
number = {1},
pages = {150},
pmid = {41462232},
issn = {1475-925X},
mesh = {*Alzheimer Disease/diagnostic imaging/classification/diagnosis ; *Deep Learning ; Humans ; *Image Processing, Computer-Assisted/methods ; Magnetic Resonance Imaging ; },
abstract = {Alzheimer's disease (AD) poses urgent significant challenges for early detection and personalized prognostication. Deep learning (DL) is now regarded as a pivotal technology for extracting subtle imaging and non-imaging biomarkers; yet translating these advances into clinical practice demands a coherent framework. In this review, we first survey input modalities from structural and functional MRI to PET, genetic profiles, and cognitive tests and the key public cohorts that supply multimodal data. We then categorize DL architectures into three complementary pillars: (1) end-to-end classification networks for direct diagnosis; (2) multimodal fusion strategies that integrate heterogeneous biomarkers; and (3) automated segmentation pipelines for precise anatomical delineation. We also examine subtyping algorithms that uncover latent AD phenotypes via clustering and decision-tree models. In order to fill the gap between high-performance DL and real-world adoption, we detail explainable AI methods that render model decisions transparent, and we review performance benchmarks including accuracy, sensitivity/specificity, Dice and Jaccard indices to contextualize efficacy. Finally, we discuss clinical translation, covering prospective validation, workflow integration, and regulatory/privacy considerations, before outlining challenges and future directions such as data heterogeneity, interpretability-accuracy trade-offs, early/preclinical detection, and federated learning. Our roadmap highlights the interdisciplinary collaborations and technical innovations needed to deliver robust, trustworthy, and scalable DL-based tools for Alzheimer's care.},
}

*Alzheimer Disease/diagnostic imaging/classification/diagnosis
*Deep Learning
Humans
*Image Processing, Computer-Assisted/methods
Magnetic Resonance Imaging

@article {pmid41462042,
year = {2025},
author = {Okhovat, M and Layman, CE and Davis, BA and Pederson, A and O'Niel, A and Holden, S and Kessler, K and Acharya, SN and Wheeler, KJ and Nevonen, KA and Herrera, J and Ward, S and Vigh-Conrad, K and Adey, A and Raber, J and Carbone, L},
title = {Epigenetic and transcriptomic alterations precede amyloidosis in the Alzheimer's disease App[NL-G-F] knock-in mouse model.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {44934},
pmid = {41462042},
issn = {2045-2322},
support = {R21 AG079158-01A1/GF/NIH HHS/United States ; DOD HT94252410812//U.S. Department of Defense/ ; 1R21AG065681-01A1//National Institute of Aging (NIA), NIH/ ; },
mesh = {Animals ; *Alzheimer Disease/genetics/pathology/metabolism ; Disease Models, Animal ; *Epigenesis, Genetic ; Mice ; *Amyloidosis/genetics/pathology/metabolism ; DNA Methylation ; *Transcriptome ; *Amyloid beta-Protein Precursor/genetics ; Mice, Transgenic ; Hippocampus/metabolism/pathology ; Humans ; Gene Knock-In Techniques ; Brain/metabolism/pathology ; Male ; },
abstract = {Understanding Alzheimer's disease (AD) from its earliest stages is essential for uncovering initial mechanisms of pathology and developing interventions. Here, we use the humanized App[NL-G-F] mouse model, which develops early amyloid pathology along a predictable timeline, to characterize epigenetic changes in the brain and blood at early pre-symptomatic, as well as later, stages of disease progression. We identified alterations in chromatin accessibility, gene expression, and DNA methylation before and after amyloidosis, in the absence of advanced age. Despite broadly stable hippocampal cell composition, App[NL-G-F] mice exhibit major gene expression differences preceding amyloid plaque deposition, particularly in pathways related to mitochondrial function and protein biosynthesis. In later stages of pathology, immune pathways were upregulated, consistent with established neuroinflammatory processes in AD. Extensive DNA methylation changes were also detected in both blood and hippocampus at early and late pathology stages. Many blood methylation differences at early stages overlapped brain cis-regulatory elements and mapped near differentially expressed hippocampal genes, with enrichment in neuronal development and synaptic pathways, underscoring a potential link between blood methylation and brain physiology and supporting the potential of blood DNA methylation as an early biomarker of amyloidosis. Notably, five genes, including Rbfox1 and Camta1, showed coordinated epigenetic dysregulation in both brain and blood prior to amyloidosis, highlighting them as potential early blood-based biomarkers.},
}

Animals
*Alzheimer Disease/genetics/pathology/metabolism
Disease Models, Animal
*Epigenesis, Genetic
Mice
*Amyloidosis/genetics/pathology/metabolism
DNA Methylation
*Transcriptome
*Amyloid beta-Protein Precursor/genetics
Mice, Transgenic
Hippocampus/metabolism/pathology
Humans
Gene Knock-In Techniques
Brain/metabolism/pathology
Male

@article {pmid41462008,
year = {2025},
author = {Yang, L and Li, H and Li, M and Fu, A and Bai, S and Li, J and Yang, L and He, G},
title = {Preparation of a Near-infrared Probe Based on Triphenylamine Thiophene and its Use for the Fluorescence Imaging of H2S in Living Cells.},
journal = {Journal of fluorescence},
volume = {},
number = {},
pages = {},
pmid = {41462008},
issn = {1573-4994},
support = {232102310008, 242102311060//Key Scientific and Technological Project of Henan Province/ ; 242102311019//Key Scientific and Technological Project of Henan Province/ ; ZDSYS2023008//Open Program of Henan Key Laboratory of Biological Psychiatry/ ; No. XTkf04//Open Program of Henan Collaborative Innovation Center of Prevention and treatment of mental disorder/ ; },
abstract = {Hydrogen sulfide (H2S) functions as a critical gaseous signaling molecule, and dysregulated levels are linked to various pathological conditions, such as diabetes, cardiovascular disorders, Alzheimer's disease, and malignant tumors. To facilitate disease monitoring and improve the understanding of related mechanisms, it is imperative to establish a rapid and precise method for detecting H2S. In this work, we have designed a new near-infrared fluorescent probe, designated TPA-YL, for H2S sensing. TPA-YL probe utilizes triphenylamine thiophene dye as a fluorophore, and 2,4-dinitrobenzenesulfonyl (DNS) as the response site for H2S. In the presence of H2S, the responsive group in TPA-YL undergoes thiolysis, and near-infrared fluorescence from the fluorophore is "turned on". The resulting fluorescence signal exhibits a good linear relationship with H2S up to 50 µM (limit of detection, 17 nM). The advantages of TPA-YL include: a long emission wavelength (642 nm); a large Stokes shift (188 nm); high selectivity; as well as remarkable sensitivity (under physiological conditions). Furthermore, the TPA-YL probe has been effectively applied for visualizing both externally supplied and internally generated H2S in HeLa cells via fluorescence imaging. Thus, this probe provides a promising strategy for studying the role of H2S in intricate physiological and pathological mechanisms. We develop a novel near-infrared fluorescent probe (TPA-YL) for the detection of H2S. In the presence of H2S, the responsive group in TPA-YL undergoes thiolysis, and near-infrared fluorescence from the fluorophore is "turned on". TPA-YL enables H2S detection in both in vitro and in vivo settings.},
}

@article {pmid41461937,
year = {2025},
author = {Alzarea, SI},
title = {An integrative computational approach for identification of NLRP3 inhibitors through machine learning, docking, dynamics and DFT analysis.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-025-34068-2},
pmid = {41461937},
issn = {2045-2322},
support = {DGSSR-2025-FC-01044//Al Jouf University/ ; },
abstract = {Neuroinflammation, mediated by NLR family pyrin domain containing 3 (NLRP3) inflammasome, plays a crucial role in the development of many central nervous system (CNS) diseases such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, and stroke. Despite extensive efforts, there are no clinically approved NLRP3 inhibitors due to issues like poor selectivity, undesirable drug-like properties, and safety concerns. In this study, a machine learning-based virtual screening strategy was used to identify phytochemicals that inhibit the NLRP3 NACHT domain, a key region involved in ATP-driven oligomerization and inflammasome activation. A carefully curated set of 1,956 active compounds and 5,476 inactive ones was employed to train various classifiers, with the Random Forest model demonstrating the best predictive performance (AUC = 0.83). This enhanced model was applied to analyze the MPD3 phytochemical library, resulting in 183 drug-like candidates. Molecular docking revealed that PubChem 348,482, ZINC14583344, and PubChem 11,027,076 showed excellent binding affinities (-10.6 to - 11.3 kcal/mol), forming strong interactions with key residues (Ala228, Arg578, Glu629) known to influence NLRP3 conformational dynamics. ADMET analysis confirmed favorable pharmacokinetic and safety profiles, while molecular dynamics simulations over more than 100 ns verified the stability of the protein-ligand complexes through consistent RMSD, RMSF, and hydrogen bonding patterns of ZINC14583344. MM-GBSA free energy calculations further identified ZINC14583344 (-23.99 kcal/mol) as the most promising candidate. Additionally, Density Functional Theory (DFT) analysis indicated that ZINC14583344 has a smaller HOMO-LUMO gap, higher softness, and greater electrophilicity, suggesting superior reactivity and receptor binding flexibility. Conversely, PubChem 348,482 displayed a higher dipole moment and nucleophilicity, indicating stronger hydrogen bonding and electrostatic interactions with polar residues. Collectively, these findings highlight ZINC14583344 and PubChem 348,482 as promising scaffolds for developing selective NLRP3 inhibitors, providing a basis for therapeutic strategies against neuroinflammation-related CNS disorders.},
}

@article {pmid41461739,
year = {2025},
author = {Palachai, N and Buranrat, B and Pariwatthanakun, C and Noisa, P and Mairuae, N},
title = {Neuroprotective effects of Cratoxylum formosum (L.) leaf extract on β-amyloid-induced injury in human neuroblastoma SH-SY5Y cells.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {44730},
pmid = {41461739},
issn = {2045-2322},
support = {//the Faculty of Medicine, Mahasarakham University/ ; //Thai Traditional Medical Knowledge Fund/ ; },
mesh = {Humans ; *Amyloid beta-Peptides/toxicity ; *Plant Extracts/pharmacology/chemistry ; *Plant Leaves/chemistry ; *Neuroprotective Agents/pharmacology/chemistry ; Cell Line, Tumor ; Oxidative Stress/drug effects ; Reactive Oxygen Species/metabolism ; Cell Survival/drug effects ; *Neuroblastoma/metabolism/pathology/drug therapy ; Cyclic AMP Response Element-Binding Protein/metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; *Peptide Fragments/toxicity ; Caspase 3/metabolism ; Apoptosis/drug effects ; Phosphorylation/drug effects ; },
abstract = {In Alzheimer's disease (AD), Amyloid beta peptide (Aβ), the primary constituent of senile plaques, has been documented as triggering oxidative stress and leading to the death of neuronal cells. Therefore, this research aims to investigate how the Cratoxylum formosum (L.) leaf extract mitigates oxidative stress and cellular damage induced by Aβ in SH-SY5Y cells. The SH-SY5Y cells were treated with Cratoxylum formosum (L.) extract both with and without Aβ25-35. Neuroprotection was evaluated through viability and lactate dehydrogenase (LDH) assays, accompanied by an analysis of various mechanisms including caspase-3/7 activity, levels of reactive oxygen species (ROS), phosphorylation of protein kinase B (Akt), extracellular signal-regulated kinase 1/2 (ERK1/2), and cAMP-responsive element binding protein (CREB), expression of B-cell lymphoma 2 (Bcl-2) proteins, as well as catalase (CAT) and superoxide dismutase (SOD) activities. Results indicated an escalation in oxidative stress in cells exposed to Aβ, evidenced by increased ROS levels. Aβ further exacerbated caspase-3/7 activity, LDH release, and a decline in cell viability. Conversely, treatment with Cratoxylum formosum (L.) extract exhibited a concentration-dependent reduction in Aβ-induced neurotoxicity, manifesting in enhanced cell survival, reduced LDH release and ROS production, and suppression of caspase-3/7 activity. Moreover, it led to increased phosphorylation of Akt, ERK1/2, CREB, upregulated expression of Bcl-2 proteins, and enhanced activity of SOD and CAT. High-performance liquid chromatography (HPLC) analysis identified chlorogenic acid, 1,5-dicaffeoylquinic acid, and ferulic acid as the major phenolic constituents of Cratoxylum formosum (L.) extract. These results imply that the extract may provide protective effects against Aβ-induced neurotoxicity, although further studies are required to clarify its role in AD.},
}

Humans
*Amyloid beta-Peptides/toxicity
*Plant Extracts/pharmacology/chemistry
*Plant Leaves/chemistry
*Neuroprotective Agents/pharmacology/chemistry
Cell Line, Tumor
Oxidative Stress/drug effects
Reactive Oxygen Species/metabolism
Cell Survival/drug effects
*Neuroblastoma/metabolism/pathology/drug therapy
Cyclic AMP Response Element-Binding Protein/metabolism
Proto-Oncogene Proteins c-akt/metabolism
*Peptide Fragments/toxicity
Caspase 3/metabolism
Apoptosis/drug effects
Phosphorylation/drug effects

@article {pmid41461684,
year = {2025},
author = {Saremi, M and Safari, S and Alikhani, MY and Komaki, A and Siadat, SD and Asghari, B},
title = {Evidence for neuroprotection by Bacillus coagulans ATCC 7050 via synaptic plasticity and oxidative balance in Alzheimer's disease.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {44690},
pmid = {41461684},
issn = {2045-2322},
support = {Grant Number: 140303292888//Vice Chancellor for Research and Technology, Hamadan University of Medical Sciences/ ; },
mesh = {Animals ; *Alzheimer Disease/metabolism/physiopathology ; *Oxidative Stress/drug effects ; Male ; *Neuronal Plasticity/drug effects ; Rats ; Rats, Wistar ; *Bacillus coagulans/physiology ; Disease Models, Animal ; Hippocampus/metabolism ; Amyloid beta-Peptides ; *Probiotics/pharmacology/administration & dosage ; Long-Term Potentiation ; *Neuroprotection ; Superoxide Dismutase/metabolism ; Memory, Short-Term ; Glutathione Peroxidase/metabolism ; Malondialdehyde/metabolism ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, synaptic impairment, and oxidative stress. Probiotics with antioxidant and anti-inflammatory properties have been proposed as potential adjunctive strategies. This study examined whether oral administration of Bacillus coagulans ATCC 7050 could attenuate hippocampal oxidative stress, modulate synaptic plasticity, and influence spatial working memory in an Aβ1-42-induced rat model of AD. Adult male Wistar rats were assigned to Sham, AD, BC (probiotic only), and AD + BC groups. Working memory was assessed by Y-maze, synaptic function by perforant path-dentate gyrus long-term potentiation (LTP) recordings, and oxidative status by hippocampal malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione peroxidase (GPx) assays. AD rats exhibited reduced alternation percentage, impaired LTP (fEPSP slope and PS amplitude), elevated MDA, and decreased SOD and GPx activities versus Sham. B. coagulans treatment improved alternation percentage without affecting total entries, preserved PS amplitude from 30 min post-HFS, reduced MDA, and restored SOD activity, with partial GPx recovery. fEPSP slope remained reduced. These findings suggest B. coagulans ATCC 7050 mitigates oxidative stress, preserves neuronal excitability, and improves working memory in an Aβ-based AD model, supporting further investigation of its potential as a safe adjunct in early-stage disease.},
}

Animals
*Alzheimer Disease/metabolism/physiopathology
*Oxidative Stress/drug effects
Male
*Neuronal Plasticity/drug effects
Rats
Rats, Wistar
*Bacillus coagulans/physiology
Disease Models, Animal
Hippocampus/metabolism
Amyloid beta-Peptides
*Probiotics/pharmacology/administration & dosage
Long-Term Potentiation
*Neuroprotection
Superoxide Dismutase/metabolism
Memory, Short-Term
Glutathione Peroxidase/metabolism
Malondialdehyde/metabolism

@article {pmid41461311,
year = {2025},
author = {Li, R and Wu, X and Yao, J and Chen, J and Shui, X and Zheng, X and Tian, W and Wang, L and Zhou, Y and Zhang, T and Chen, D and Liu, Y and Lee, TH},
title = {Selective degradation of DAPK1 via a novel hydrophobic tagging attenuates tau pathology in Alzheimer's disease.},
journal = {Journal of advanced research},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jare.2025.12.037},
pmid = {41461311},
issn = {2090-1224},
abstract = {INTRODUCTION: The upregulation of death-associated protein kinase 1 (DAPK1) is involved in tau hyperphosphorylation, neuronal apoptosis and cognitive dysfunction, which are key pathological features of Alzheimer's disease (AD). This result suggests that DAPK1 is novel therapeutic target for AD.

OBJECTIVES: This study aimed to evaluate the efficacy and mechanism of action of CJ1, a novel hydrophobic tagging (HyT)-based degrader, in targeting DAPK1 and alleviating in AD.

METHODS: A library of HyT-based bifunctional molecules was synthesized and systematically screened for their ability to degrade DAPK1 in vitro. CJ1 emerged as the most potent candidate degrader of DAPK1, and its capacity to induce DAPK1 degradation via the proteasome system was further evaluated. Its effects on tau phosphorylation and neuronal viability were evaluated in multiple cellular models. The in vivo efficacy of systemic CJ1 administration was assessed in two tau-related pathology (tauopathy) mouse models, AAV-hTau-P301L and hTau transgenic mice. Behavioral, biochemical, and histological analyses were performed to evaluate cognitive function, tau pathology, neuroinflammation, neurodegeneration, and safety.

RESULTS: CJ1 selectively promoted the posttranslational degradation of DAPK1 by the proteasome system without affecting DAPK1 mRNA expression. In vitro studies demonstrated that CJ1 significantly reduced tau phosphorylation at multiple AD-related sites. In vivo, CJ1 effectively penetrated the BBB, decreased the levels of both the soluble and insoluble forms of hyperphosphorylated tau, and suppressed the formation of neurofibrillary tangles. Additionally, CJ1 treatment restored synaptic and dendritic structures, enhanced spatial learning and memory, attenuated neuroinflammatory responses, preserved neuronal populations, and produced no evidence of systemic toxicity.

CONCLUSION: CJ1 functions as a potent and selective degrader of DAPK1, exerting neuroprotective effects by reducing tau hyperphosphorylation and preserving neuronal structural integrity. These findings support DAPK1 as a promising therapeutic target and suggest that further preclinical studies are warranted to evaluate CJ1 as a potential treatment for tauopathies associated with AD.},
}

@article {pmid41461066,
year = {2025},
author = {Zhang, Y and Zhu, X and Yang, S and Wong, AKC and Chen, X},
title = {Digital Health Technologies Applied in Patients With Early Cognitive Change: Scoping Review.},
journal = {Journal of medical Internet research},
volume = {27},
number = {},
pages = {e82881},
doi = {10.2196/82881},
pmid = {41461066},
issn = {1438-8871},
mesh = {Humans ; Telemedicine ; *Digital Technology ; *Cognitive Dysfunction/diagnosis/therapy ; *Biomedical Technology ; Digital Health ; },
abstract = {BACKGROUND: Digital health technologies (DHTs) have the potential to revolutionize the screening, diagnostic support, monitoring, and intervention for early cognitive change. However, the full spectrum of their application and the existing evidence base in this specific patient population have not been systematically delineated.

OBJECTIVE: This study aimed to review and synthesize the applications, roles, and challenges of DHTs in patients with early cognitive change.

METHODS: This scoping review was conducted in accordance with established methodological frameworks for scoping reviews and followed the PRISMA-ScR (Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews) and PRISMA-S (PRISMA Statement for Reporting Literature Searches in Systematic Reviews) guidelines. A systematic search was conducted across 5 electronic databases: PubMed, Embase, Web of Science, APA PsycINFO, and the Cochrane Library. The search covered the period from each database's inception until September 30, 2025. Studies were selected, and data were extracted using the population-concept-context framework, focusing on digital health interventions for patients with early cognitive change.

RESULTS: This scoping review identified 193 studies (from 8346 initial articles, screened down to 5623 after deduplication) evaluating DHTs for early cognitive change, with a marked publication surge post 2020. Studies predominantly focused on mild cognitive impairment and subjective cognitive decline. Among the 170 studies that reported the age of participants, the mean age of the participants was 74.09 (SD 7.98) years. Furthermore, six categories of DHTs emerged: (1) artificial intelligence or big data, (2) internet of things, (3) virtual reality or augmented reality, (4) robotics, (5) mobile apps or computerized cognitive training, and (6) telemedicine. Outcomes most frequently assessed included cognitive function, mental health, and feasibility. Notably, only 23 studies measured quality of life, with limited long-term (6-12 months) follow-up. Physiological markers, social support, sleep quality, and self-efficacy were explored but less frequently.

CONCLUSIONS: DHTs demonstrate significant potential in the management of patients with early cognitive impairment, particularly playing crucial roles in screening, intervention, monitoring, and auxiliary diagnosis. This scoping review underscores that DHTs, through personalized interventions and continuous care, can effectively improve patient outcomes while innovatively incorporating the caregiver perspective. However, their practical application faces challenges in balancing technological complexity with user-friendliness. Future research needs to address five key issues: (1) the lack of long-term efficacy evidence, (2) insufficient coverage of individuals with subjective cognitive decline and caregiver populations, (3) a dearth of empirical evidence on the combined application of multiple DHTs, (4) the failure of personalized programs to fully account for individual differences, and (5) the absence of effective solutions to address data and ethical risks. There is an urgent need to establish a long-term efficacy evaluation system for DHTs through rigorous methodological validation.},
}

Humans
Telemedicine
*Digital Technology
*Cognitive Dysfunction/diagnosis/therapy
*Biomedical Technology
Digital Health

@article {pmid41460923,
year = {2025},
author = {Korada, S and Tam, OH and Greco, HC and Hammell, MG and Dubnau, J and Sher, RB},
title = {LINE-1 retrotransposition in a mouse TDP-43 model of neurodegeneration marks motor cortex neurons for cell-intrinsic and cell non-autonomous programmed cell death.},
journal = {PLoS genetics},
volume = {21},
number = {12},
pages = {e1012007},
doi = {10.1371/journal.pgen.1012007},
pmid = {41460923},
issn = {1553-7404},
abstract = {A key pathological feature of Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD) is the loss of nuclear localization and accumulation of cytoplasmic inclusions of TAR-DNA binding protein 43 (TDP-43). TDP-43 is a nucleic acid-binding protein involved in transcriptional repression, mRNA splicing, and the regulation of retrotransposable elements (RTEs) and endogenous retroviruses (ERVs). RTEs/ERVs are mobile virus-like genetic elements that constitute about 45% of our genome and encode the capacity to replicate through an RNA intermediate and insert cDNA copies at de novo chromosomal locations. A causal role of RTEs/ERVs has been demonstrated in Drosophila in mediating both intracellular toxicity of TDP-43 and the intercellular spread of toxicity from glia to neurons. RTEs/ERVs are inappropriately expressed in postmortem tissues from ALS, FTD, and Alzheimer's Disease (AD) patients, but the role of RTEs/ERVs has not yet been examined in a vertebrate model of TDP-43 pathology. We utilized established transgenic mouse models that overexpress moderate levels of human wild-type TDP-43 or a mutant version with a specific ALS-causal Q331K amino acid substitution, together with a LINE-1-EGFP retrotransposon indicator line. We found that TDP-43 animals exhibit broad expression of RTEs/ERVs with LINE-1 retrotransposition in glia and neurons in the motor cortex. Expression begins with onset of neurological phenotypes, earlier in hTDP-43-Q331K animals and later in hTDP-43-WT. The LINE-1-EGFP retrotransposition reporter transiently labels spatially clustered groups of neurons and glia at the time of onset of motor symptoms, while EGFP-labeled neurons undergo cell death and are therefore lost over time. Unlabeled cells also die as a function of distance from the clusters of LINE-1-EGFP labeled neurons and glial cells. Together, these findings support the hypothesis that TDP-43 pathology triggers RTE/ERV expression in the motor cortex, that such expression marks cells for programmed cell death, with cell non-autonomous effects on nearby neurons and glial cells.},
}

@article {pmid41460854,
year = {2025},
author = {Musfee, FI and Agarwal, S and Maroufy, V and Liu, C and McCormick, JB and Fisher-Hoch, S and Savitz, SI},
title = {Cardiometabolic indicators of cognitive impairment in the Cameron County Hispanic Cohort.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251408098},
doi = {10.1177/13872877251408098},
pmid = {41460854},
issn = {1875-8908},
abstract = {BackgroundCognitive impairment (CI) and its related risk factors (e.g., diabetes and stroke) are highly prevalent among Hispanic/Latinos (H/L); however, prior research in H/L focused on aging individuals (≥65 years old).ObjectiveTo comprehensively assess the associations between a wide-range of cardiometabolic health indicators and CI using a prospective study design in a younger cohort of H/L (majority <65 years old) from the Cameron County Hispanic Cohort (CCHC).MethodsWe identified a total of 1240 CCHC subjects with complete Mini-Mental Status Exam (MMSE) data at study baseline and at 5-year follow-up. The outcome (i.e., CI) was based on MMSE scores of less than 24. We conducted univariate associations for multiple cardiometabolic indicators with CI; and mixed logistic regression models to estimate odds ratios for the associations between cardiometabolic indicators and CI adjusted for age, education, prior stroke, and APOE gene.ResultsThe majority (89.9%) of the participants were <65 years old. A total of 117 subjects had CI at baseline (9.4%). Baseline study cohort showed that Individuals with CI were older with a lower education performance, and were more likely to be diabetic with lower mean levels of Low-density Lipoprotein, and a higher mean systolic blood pressure. Diabetes significantly increased the odds for CI (OR:2.11, 95%CI:1.26-3.52) from the adjusted multivariate mixed logistic models.ConclusionsThis analysis showed that diabetes was an important indicator for CI regardless of age, education, or APOE gene status. These findings highlight the higher burden of cardiometabolic risk factors on CI in the CCHC cohort.},
}

@article {pmid41460835,
year = {2025},
author = {Mishio Bawa, E and Amoatika, DA and Miller, MC and Olatosi, BA and Donelle, L and Levkoff, SE and Hardin, JW and Li, X and Bonilha, L and Friedman, DB and Adams, SA},
title = {Mapping the mortality-to-incidence ratios of Alzheimer's Disease and Related Dementias (ADRDs): Evidence from the South Carolina Alzheimer's disease registry.},
journal = {PloS one},
volume = {20},
number = {12},
pages = {e0339785},
doi = {10.1371/journal.pone.0339785},
pmid = {41460835},
issn = {1932-6203},
mesh = {Humans ; South Carolina/epidemiology ; *Alzheimer Disease/mortality/epidemiology ; Registries ; Incidence ; Female ; Male ; Aged ; *Dementia/mortality/epidemiology ; *COVID-19/epidemiology ; Aged, 80 and over ; Rural Population ; Middle Aged ; },
abstract = {INTRODUCTION: Mortality-to-incidence ratios (MIRs) are useful in assessing disease burdens and illustrating disparities. Unlike cancer, MIRs have not been applied to ADRDs. Therefore, we estimated and mapped the MIRs for ADRDs to show disparities in South Carolina.

METHODS: Using data from the South Carolina Alzheimer's Disease Registry (2017-2021), ADRD MIRs were calculated by demographic and geospatial characteristics. To account for the influence of the COVID-19 pandemic, data from 2015 to 2019 were also examined. MIRs were calculated as age-adjusted mortality rates divided by age-adjusted incidence rates.

RESULTS: Overall, Black people and rural individuals consistently experienced higher MIRs, with the COVID-19 pandemic increasing this disparity gap. MIRs greater than 1.00 were only observed among Black people. The MIR for 31 out of 46 counties exceeded the state average.

DISCUSSION: Estimating and mapping ADRDs has aided in identifying specific areas with the greatest burden of ADRD in South Carolina for targeting interventions.},
}

Humans
South Carolina/epidemiology
*Alzheimer Disease/mortality/epidemiology
Registries
Incidence
Female
Male
Aged
*Dementia/mortality/epidemiology
*COVID-19/epidemiology
Aged, 80 and over
Rural Population
Middle Aged

@article {pmid41460672,
year = {2025},
author = {Sun, L and Wei, G and Ji, F and Ding, Y and Fan, J and Xu, Y and He, C and Zhou, Y and Liu, Z and Sun, Z and Zhou, D},
title = {Proteome-wide association study identifies novel Alzheimer's disease-associated proteins.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251409352},
doi = {10.1177/13872877251409352},
pmid = {41460672},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease (AD) is a progressive neurodegenerative disease with limited prevention and treatment options.ObjectiveWe aimed to identify proteins with genetically regulated plasma levels associated with AD and its related phenotypes.MethodsWe conducted a proteome-wide association study (PWAS) using Olink-based plasma proteomes (N = 45,540) from the UK Biobank Pharma Proteomics Project (UKB-PPP) and a large-scale genome-wide association study for AD (N case = 85,934, N control = 401,577). To validate and expand these findings, we conducted longitudinal analyses of AD and mild cognitive disorder (MCD) over a 13.7-year follow-up, along with genetic-based PWAS analyses and cross-sectional studies on hippocampal volume. Protein-protein interaction networks were constructed to explore mechanistic association.ResultsWe identified 30 AD-associated plasma proteins by PWAS, including 17 previously reported and 13 novel candidates (including FES, LRP11, and HDGF). Longitudinal cohort studies supported the role of PILRB and FES in AD and/or MCD. Additionally, the genetically determined higher levels of LRP11 were found to be associated with an increased hippocampal volume, including its subdivisions, along with a reduced risk of AD. In contrast, higher plasma levels of HDGF were linked to a decreased hippocampal volume, accompanied by an increased risk of AD. Protein-protein interaction analysis linked PILRA, PILRB, FES, and LRP11 to several pathological proteins associated with AD, including BIN1, ABCA7, and SORL1.ConclusionsThis study identified 13 novel candidates, with potential roles in hippocampal volume and AD risk, providing insights into disease mechanisms.},
}

@article {pmid41460671,
year = {2025},
author = {Nakano, M and Kondo, K and Ishiki, K and Moniruzzaman, M and Mitsuishi, Y and Kadota, A and Watanabe, S and Yamashita, K and Miura, M and Iwanaga, S and Sato, T and Nishimura, M and Miura, K},
title = {Plasma biomarkers for Alzheimer's disease in middle-aged and older Japanese men: A population-based cross-sectional study.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251409337},
doi = {10.1177/13872877251409337},
pmid = {41460671},
issn = {1875-8908},
abstract = {BackgroundThe diagnostic value of blood-based biomarkers for Alzheimer's disease (AD) neuropathology has been demonstrated in individuals with cognitive impairment; however, evidence for reliable preclinical stage diagnostic methods remains insufficient.ObjectiveTo identify confounding variables that may obscure the interpretation of these biomarkers, we examined their associations with various physiological indices including age, renal function, and cognitive function in Japanese men from the general population.MethodsPlasma were collected from 845 randomly selected Japanese men participants (aged >40 years) to measure 40- and 42-amino acid amyloid-β (Aβ40 and Aβ42), total tau (T-tau), tau phosphorylated at threonine 181 (P-tau181), and neurofilament light chain (NfL) using an automated immunoassay system. Cognitive function was assessed using the Cognitive Abilities Screening Instrument (CASI). Linear regression models were constructed to estimate association strengths with correction for possible confounding variables.ResultsPlasma Aβ40, Aβ42, T-tau, P-tau181, NfL, and P-tau181/T-tau increased with age and declining glomerular filtration rate (eGFR), whereas Aβ42/Aβ40 decreased with age. Higher T-tau and P-tau181 were associated with lower CASI scores after adjusting for age and eGFR. Individuals in older age groups with Aβ42/Aβ40 ratios less than or equal to a cutoff ("amyloid-positive") also exhibited higher P-tau181, NfL, and P-tau181/T-tau than amyloid-negative individuals, with no significant difference in mean CASI score.ConclusionsOur results confirm that plasma AD biomarkers are significantly influenced by age and renal clearance rate. Notably, higher T-tau and P-tau181 were associated with preclinical cognitive impairment. Additionally, a lower Aβ42/Aβ40 was associated with asymptomatic tau pathology and neurodegeneration.},
}

@article {pmid41460670,
year = {2025},
author = {Hu, Y and Lu, X and Han, Z and Shi, Y and Wang, Y and Lu, Q and Wang, Y and He, Y and Lu, Y and Chen, F and Chen, H and Zhang, N},
title = {Hong Kong Brief Cognitive Test for identifying symptomatic Alzheimer's disease and other types of dementia.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251405903},
doi = {10.1177/13872877251405903},
pmid = {41460670},
issn = {1875-8908},
abstract = {BackgroundThe Hong Kong Brief Cognitive Test (HKBC) has demonstrated high discriminative ability for patients with cognitive impairment in both Cantonese- and Mandarin-speaking populations.ObjectiveTo evaluate the diagnostic efficacy of the HKBC in identifying dementia and mild cognitive impairment (MCI) due to Alzheimer's disease (AD) and other common types of dementia.MethodsSixty-one patients with dementia due to AD, 30 patients with MCI due to AD, 47 patients with subcortical ischemic vascular dementia (SIVD), 50 patients with frontotemporal lobar degeneration (FTLD), 17 patients with Lewy body dementia (LBD), and 37 cognitively unimpaired controls (CUCs) were recruited and completed the HKBC, the Mini-Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA). The diagnostic performance of each test was analyzed via receiver operating characteristic curve analysis. Impairment in cognitive domains on the HKBC was analyzed in patients with symptomatic AD.ResultsScores of the HKBC, MMSE and MoCA were significantly lower in patients with all types of dementia, AD (dementia and MCI), and non-AD dementia (SIVD, FTLD, and LBD) than in CUCs. The most appropriate cutoff scores of the HKBC were 24 for identifying AD and LBD, 22 for identifying SIVD and FTLD, and 26 for identifying MCI due to AD from CUCs. HKBC memory and language scores were significantly lower in patients with MCI due to AD than in CUCs.ConclusionsThis study demonstrated that the HKBC could efficiently identify patients with common types of dementia and was sensitive in screening early AD.},
}

@article {pmid41460669,
year = {2025},
author = {Sayed, A and Zhu, J and Thoma, F and Cohen, AD and Reis, S and Lopez, OL and Sultan, I and McKennan, C and Muluktla, SR and Pascoal, T and Saeed, A},
title = {Impact of coronary interventions on dementia diagnosis by race: Insights from a multi-hospital heart-brain registry.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251409341},
doi = {10.1177/13872877251409341},
pmid = {41460669},
issn = {1875-8908},
abstract = {BackgroundRacial and ethnic disparities have been reported with coronary artery disease as well as dementia and Alzheimer's disease (AD) related diagnoses.ObjectiveTo investigate the disparities concerning coronary interventions and the incidence of non-vascular and AD-related dementia diagnoses within a multi-site healthcare network.MethodsUtilizing the EMR-acquired Heart-Brain registry in a multi-site healthcare network in Western Pennsylvania, we analyzed patients with coronary artery disease (CAD) who underwent percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG) between 2010 and 2020. We assessed the incidence of 'likely' non-vascular dementia, including AD-related diagnosis, over a median follow-up of six years. Baseline covariates were summarized using means and medians. Multivariable adjusted Cox regression hazard ratios (HR [95% CI]) were used to examine the association between incident 'non-vascular dementia and AD-related diagnosis with the type of coronary intervention, stratified by self-reported race.ResultsAmong 47,210 patients, 71.6% (n = 33,822) underwent PCI and 28.4% (n = 13,388) underwent CABG. Overall, the risk of likely non-vascular dementia diagnosis was higher among Black patients (HR = 1.26 [1.02-1.56]; p = 0.035). In stratified analysis by procedure, Black patients with CABG history had greater risk of non-vascular dementia (HR = 1.85, 95% CI [1.29-2.66]; p = 0.020), and AD related diagnosis (HR = 1.73, 95% CI [1.16-2.58]; p = 0.007); than White patients.ConclusionsBlack patients who undergo CABG may be at a higher risk of non-vascular dementia incidence. More research is needed to evaluate the mechanisms of this finding and develop precise risk mitigation strategies to prevent dementia risk.},
}

@article {pmid41460665,
year = {2025},
author = {Yoshida, Y and Michihata, N and Tanito, M and Hiratsuka, Y and Nakao, S and Yasunaga, H},
title = {Association between open angle glaucoma and early onset Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251410501},
doi = {10.1177/13872877251410501},
pmid = {41460665},
issn = {1875-8908},
abstract = {BackgroundThe association between open-angle glaucoma (OAG) and early-onset Alzheimer's disease (EOAD) remains unclear.ObjectiveTo investigate the association between OAG and EOAD.MethodsWe conducted a case-control study using a Japanese nationwide administrative claims database. Individuals aged 40-64 with a diagnosis of Alzheimer's disease (AD) and a prescription for AD medications were defined as EOAD cases (n = 2344). The index date was the first AD medication prescription. Controls (n = 9376) were matched to cases in a 4:1 ratio by age and sex using risk set sampling. OAG exposure was defined as a diagnosis ≥12 months before the index date. Conditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs).ResultsOAG was present in 15.8% of EOAD cases and 12.5% of controls. A significant association was observed between OAG and EOAD (OR, 1.22; 95% CI, 1.06-1.40; p = 0.006). EOAD was associated with diabetes (OR, 1.56; 95% CI, 1.37-1.77; p < 0.001), hypertension (OR, 1.15; 95% CI, 1.02-1.29; p = 0.021), depression (OR, 7.81; 95% CI, 6.76-9.02; p < 0.001), and excessive alcohol use (OR, 2.35; 95% CI, 1.72-3.21; p < 0.001). In sex-stratified analyses, the association between OAG and EOAD was significant in males (OR, 1.32; 95% CI, 1.09-1.60; p = 0.005) but not in females (OR, 1.11; 95% CI, 0.90-1.37; p = 0.321).ConclusionsIndividuals with OAG may be associated with an increased risk of EOAD, and careful monitoring of cognitive symptoms may help facilitate early detection and intervention.},
}