@article {pmid41476222,
year = {2025},
author = {Shinohara, M and Gheni, G and Kawai, K and Morishima, M and Murayama, S and Saito, Y and Bu, G and Sato, N},
title = {Coordinated regional association of cathepsins and dipeptidyl peptidases with N-truncated Abeta42, Abeta40, and tau in Alzheimer's brain.},
journal = {Acta neuropathologica communications},
volume = {},
number = {},
pages = {},
doi = {10.1186/s40478-025-02146-1},
pmid = {41476222},
issn = {2051-5960},
support = {21H03391//Japan Promotion of Science/ ; JP 22H04923//Japan Promotion of Science/ ; MEXT24K02361//Japan Promotion of Science/ ; JP21wm0425019//AMED/ ; },
abstract = {Regional distributions of amyloid-β (Aβ) and tau accumulation have provided important insights into the pathomechanisms of Alzheimer's disease (AD). While such analyses have typically been conducted through histochemical or clinical imaging studies, we previously reported unique regional associations among Aβ species, tau and other proteins by biochemically analyzing multiple postmortem brain regions. Here, using a new cohort and novel ELISAs, we investigated the regional relationships of Aβ species, tau, neuroglial markers, cathepsins and dipeptidyl peptidases (DPP) across AD stages. Despite a relatively small sample size, this study replicated key prior findings, including a strong regional association between Aβ1-42 and the postsynaptic maker PSD95 particularly in the early stage, distinct regional distributions of Aβ1-42 and N-terminally truncated Aβ42 (Aβt-42), and a significant association between Aβt-42 and tau in AD. Moreover, this study observed that Aβ1-42 was associated with other synaptic proteins, but not neurofilament proteins. Notably, several proteases, particularly cathepsin B, cathepsin D and DPPIV, exhibited strong regional correlations with total Aβx-42, Aβt-42, Aβx-40, and tau accumulations in AD, forming coordinated regional distribution patterns. Such strong regional associations with late-stage Aβ species and tau were not observed for neuroglial markers. At the microscopic level, these proteases displayed abnormal morphologies proximity to Aβ and tau pathologies. Their coordinated regional distributions with Aβt-42, Aβx-40, and tau may indicate that these proteases cooperatively promote neurodegenerative cascades in AD.},
}

@article {pmid41476179,
year = {2025},
author = {Taheri, E and Raeeszadeh-Sarmazdeh, M},
title = {Evaluating the effect of minimal TIMP variants on protecting and transport across the rat brain microvascular cells (RBMEC).},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-025-30643-9},
pmid = {41476179},
issn = {2045-2322},
abstract = {Tissue inhibitors of metalloproteinases (TIMPs), endogenous inhibitors of matrix metalloproteinases (MMPs), can be tailored to regulate MMP activity and mitigate the disruptive effects of specific MMPs when dysregulated in diseases. MMPs, especially MMP-9, are major contributors to the degradation of extracellular matrix components, leading to BBB disruption in neurological disorders. The upregulation of MMPs undermines blood-brain barrier (BBB) integrity and drives neuroinflammation. Engineering minimal protein variants offers enhanced modularity, tissue penetration, and BBB permeability. Minimal TIMP variants were engineered, aiming to improve their therapeutic reach across both sides of the BBB, particularly when delivery to the brain is essential. In this study, we assessed the protective effects of mTC1 and mTC3 on BBB integrity using an in vitro model of rat brain microvascular endothelial cells (RBMECs). Barrier function was evaluated following treatment with recombinant MMP-9, either alone or co-treated with native TIMP-1, TIMP-3, or the engineered minimal variants. MMP-9 induced a dose-dependent increase in BBB permeability, reflected by a decrease in trans-endothelial electrical resistance (TEER) and increased paracellular transport of fluorescent tracers. Co-treatment with TIMP-1, TIMP-3, mTC1, or mTC3 significantly attenuated MMP-9-mediated disruption of tight junctions of RBMECs, preserving TEER values and reducing permeability. Immunofluorescence staining for tight junction proteins, ZO-1 and occludin, further validated the preservation of endothelial integrity in the presence of wild-type human TIMPs and engineered TIMP variants. These findings underscore the potential of engineered minimal TIMPs as molecular tools to stabilize the BBB and support their future application in mechanistic studies focused on BBB protection.},
}

@article {pmid41476127,
year = {2025},
author = {Aboubaker, DH and Elsayed, AAA and El-Gohary, A and El-Garf, IA and Ibrahim, BMM},
title = {Author Correction: Introduction of Cistanche phelypaea fatty acids as a new natural neurotrophic supplement by evaluating its effects in normal and Alzheimer's diseased rats.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {45801},
doi = {10.1038/s41598-025-34156-3},
pmid = {41476127},
issn = {2045-2322},
}

@article {pmid41475761,
year = {2026},
author = {Mei, J and Shi, X and Chen, M and Li, Z and Cui, Y and Fang, C and Wu, X and Chen, X and Zeng, K and Yang, L},
title = {Chitosan/selenium nanoparticles Pickering emulsion prolong quercetin retention time to ameliorates cognitive disorder: Focus on restoring the metabolic disorder and gut microbiota.},
journal = {Carbohydrate polymers},
volume = {375},
number = {},
pages = {124804},
doi = {10.1016/j.carbpol.2025.124804},
pmid = {41475761},
issn = {1879-1344},
mesh = {*Quercetin/chemistry/pharmacology/administration & dosage/pharmacokinetics ; Animals ; *Gastrointestinal Microbiome/drug effects ; *Chitosan/chemistry ; Emulsions/chemistry ; *Nanoparticles/chemistry ; *Selenium/chemistry ; Mice ; Male ; Mice, Inbred C57BL ; *Cognitive Dysfunction/drug therapy ; Brain/metabolism/drug effects ; },
abstract = {Gut microbiota influence brain inflammation and cognitive impairment by regulating lipid metabolism. The therapeutic efficacy of quercetin (Que) in Alzheimer's disease (AD) treatment is significantly limited by its poor water solubility and short residence time in vivo. Herein, Chitosan (CS) modified selenium nanoparticles was used to prepare a high-loading Pickering emulsion (Que-CS/Se-PE), improving bioaccessibility of Que. Simulated gastrointestinal fluid experiments demonstrate that Que-CS/Se-PE exhibits strong stability under acidic conditions. In vitro digestion studies indicate that Que-CS/Se-PE enables QUE to target intestinal fluids and release slowly. In vivo imaging revealed that the gastrointestinal retention time of Que-CS/Se-PE was up to 48 h. In HFD + D-gal-induced mice, Que-CS/Se-PE treatment reduced serum TC and brain TNF-α levels by 40.8 % and 31.5 %, respectively, indicating substantial improvement in lipid metabolism and neuroinflammation. Behavioral tests showed that Que-CS/Se-PE improved cognitive performance, with preference index elevated by 2.1-fold. Moreover, the relative abundances of Akkermansia, Lactobacillus, and Bacteroidota increased by 2.7-, 17.8-, and 4.7-fold, respectively. In conclusion, Que-CS/Se-PE exhibits interfacial stability, excellent adhesion, and sustained-release properties, significantly prolonging the retention time of quercetin in vivo and enhancing its bioavailability. Furthermore, it modulates lipid metabolism and gut microbiota, and finally ameliorates cognitive impairment in obesity and age-related AD.},
}

*Quercetin/chemistry/pharmacology/administration & dosage/pharmacokinetics
Animals
*Gastrointestinal Microbiome/drug effects
*Chitosan/chemistry
Emulsions/chemistry
*Nanoparticles/chemistry
*Selenium/chemistry
Mice
Male
Mice, Inbred C57BL
*Cognitive Dysfunction/drug therapy
Brain/metabolism/drug effects

@article {pmid41475447,
year = {2025},
author = {Guan, TC and Zeng, L and Liu, M and Liu, Y and Wu, YC and Mu, YG and Tan, EK and Zhou, ZD},
title = {RNA G-quadruplexes Mediated Protein Aggregation in Neurodegenerative Diseases.},
journal = {Ageing research reviews},
volume = {},
number = {},
pages = {103006},
doi = {10.1016/j.arr.2025.103006},
pmid = {41475447},
issn = {1872-9649},
abstract = {RNA G-quadruplexes (rG4s) are stable secondary structures formed by guanine-rich RNA sequences that have emerged as critical regulators of RNA metabolism. The rG4s are widespread in both coding and noncoding RNAs and have been implicated in regulation multiple post-transcriptional processes, including RNA stability, splicing, polyadenylation, nuclear export, localization, and translation. Recent findings real that rG4s play pathological roles in neurodegenerative diseases (NDs), including Alzheimer's disease (AD) and Parkinson's disease (PD). The rG4s function in stress granule dynamics, aberrant phase separation, and the nucleation of pathological protein assemblies, which is implicated in protein co-aggregation and pathological protein aggregation in NDs. Here, we provide an integrated synthesis of how rG4s influence protein aggregation through biophysical, cellular, and molecular mechanisms, with particular emphasis on rG4-driven perturbations of phase separation and aggregation pathways. The rG4s relevant disease pathogenesis, biomarker development, and therapeutic interventions in NDs are discussed. Furthermore, we highlight emerging translational opportunities, including the potential of rG4-targeting small molecules such as 5-aminolevulinic acid and other modulators, which may open new avenues for combating neurodegeneration.},
}

@article {pmid41475286,
year = {2025},
author = {Tan, B and Zhang, J and Dong, K and Li, Z and Yu, X and Zhang, SW and Luo, L and Yao, W and Wu, F},
title = {Neutrophil glycolysis mediates colitis-induced exacerbation of Alzheimer's disease.},
journal = {International immunopharmacology},
volume = {171},
number = {},
pages = {116127},
doi = {10.1016/j.intimp.2025.116127},
pmid = {41475286},
issn = {1878-1705},
abstract = {Alzheimer's disease (AD), the leading cause of dementia, is characterized by amyloid-β (Aβ) deposition, synaptic dysfunction, and progressive cognitive decline. Emerging evidence suggests that peripheral inflammation, particularly intestinal inflammation, can aggravate AD pathology through the gut-brain axis. As key mediators of intestinal inflammation and systemic immune activation, neutrophils have emerged as critical contributors to AD progression. In this study, we investigated how dextran sulfate sodium (DSS)-induced colitis influences Aβ pathology and synaptic integrity in 5 × FAD mice, focusing on the role of neutrophil glycolysis and neutrophil elastase (NE) activation. DSS-induced colitis significantly exacerbated AD-like pathology, as evidenced by pronounced body-weight loss, colon shortening, increased brain neutrophil infiltration, and elevated NE expression in the hippocampus, accompanied by enhanced Aβ plaque burden and reduced dendritic spine density. These findings indicate that DSS-triggered peripheral inflammation promotes central immune activation and accelerates Aβ pathology via metabolic reprogramming of neutrophils. Administration of the glycolytic inhibitor PFK-158 effectively suppressed NE expression and mitigated Aβ accumulation. Peripheral injection of PFK-158 attenuated neuroinflammation and partially restored dendritic structure, while intracerebroventricular infusion directly inhibited central neutrophil activation and improved hippocampal synaptic transmission, as reflected by enhanced field excitatory postsynaptic potentials (fEPSPs) and long-term potentiation (LTP). Collectively, these results demonstrate that DSS-induced colitis aggravates AD pathology by enhancing neutrophil glycolysis and NE release, linking peripheral metabolic inflammation to central neurodegeneration. Targeting neutrophil glycolytic activation with PFK-158 represents a promising therapeutic strategy to disrupt gut-brain inflammatory crosstalk and slow AD progression.},
}

@article {pmid41475015,
year = {2025},
author = {Cho, H and Song, J and Cho, H and Li, L and Liang, R and Miranda, R and Song, Q and Bian, J},
title = {Applications of Machine Learning for Cognitive Health in Older Individuals With HIV: Rapid Systematic Review.},
journal = {JMIR aging},
volume = {8},
number = {},
pages = {e80433},
doi = {10.2196/80433},
pmid = {41475015},
issn = {2561-7605},
mesh = {Humans ; *Machine Learning ; *HIV Infections/complications/psychology ; Aged ; *Cognition ; Middle Aged ; *Dementia/diagnosis ; *Cognitive Dysfunction/diagnosis ; },
abstract = {BACKGROUND: More than half of people with HIV are now older than 50 years, and they face an approximately 60% higher risk of developing dementia compared with the general population. In recent years, the application of artificial intelligence, particularly machine learning, combined with the growing availability of large datasets, has opened new avenues for developing prediction models that improve dementia detection, monitoring, and management.

OBJECTIVE: This systematic review aimed to synthesize the existing literature on the application of machine learning in dementia research among older people with HIV and identify directions for future research.

METHODS: A comprehensive search was conducted in PubMed, CINAHL, and Embase in September 2024, limited to studies published within the past 10 years. Eligible articles included original research involving people with HIV applying at least 1 machine learning technique and reporting dementia-related outcomes.

RESULTS: The search yielded 721 articles, of which 26 (3.6%) met the inclusion criteria. Most studies were retrospective and conducted in the United States (n=14, 53.8%), primarily focusing on neurocognitive impairment and HIV-associated neurocognitive disorders. Supervised machine learning techniques were most frequently used and demonstrated strong predictive performance. Common methodological challenges included small sample sizes, lack of external validation, limited participant diversity, and concerns about biological interpretability and generalizability.

CONCLUSIONS: Machine learning research on dementia among older people with HIV primarily targets HIV-associated neurocognitive disorders, with limited exploration of age-related neurodegenerative diseases such as Alzheimer disease and related dementias. The absence of longitudinal studies and external validation remains a key limitation. Future research should broaden the focus to all-cause dementia beyond HIV-specific conditions; apply advanced machine learning methods; and leverage large-scale longitudinal, multimodal datasets. Strengthening methodological rigor and enhancing real-world applications will be critical to improving early detection and effective management of cognitive health in this unique aging population.},
}

Humans
*Machine Learning
*HIV Infections/complications/psychology
Aged
*Cognition
Middle Aged
*Dementia/diagnosis
*Cognitive Dysfunction/diagnosis

@article {pmid41474988,
year = {2025},
author = {Kumar, A and Ramesh, M and Bhoi, J and Govindaraju, T},
title = {Papaverine-Derived Dual-Active Modulator Ameliorates Alzheimer's Disease Pathology in Aged APP/PSEN1 Transgenic Mice.},
journal = {Journal of medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.jmedchem.5c03360},
pmid = {41474988},
issn = {1520-4804},
abstract = {Alzheimer's disease (AD) therapeutics remain a challenge due to their complex pathology and multifactorial toxicity. Advanced stages of AD are marked by rapid cognitive decline, driven by amyloid plaques, neurofibrillary tangles, neuroinflammation, synaptic dysfunction, and neuronal loss. We report the design of dual-active, prodrug-like multifunctional modulators by conjugating papaverine with butyrate, a short-chain fatty acid (SCFA) with neuroprotective properties. The lead compound, P4B, undergoes enzymatic hydrolysis to release papaverine derivative P4H and butyrate, collectively inhibiting amyloid aggregation, Aβ-oligomer-induced membrane disruption, oxidative stress, and neuroinflammation. In vivo administration of P4B to aged APP/PSEN1 mice significantly reduced the amyloid burden, neuroinflammatory markers, and microglial activation in hippocampal and cortical regions. This work introduces an SCFA-based prodrug strategy to address the multifaceted toxicity of AD, offering a novel therapeutic paradigm with potential applicability to other neurodegenerative disorders.},
}

@article {pmid41474969,
year = {2026},
author = {Laaker, CJ and Vrba, SM and Port, JM and Hsu, M and Baenen, CM and Herbath, M and Priyathilaka, TT and Sandor, M and Fabry, Z},
title = {The cribriform plate: A dynamic central nervous system-immune hub.},
journal = {The Journal of experimental medicine},
volume = {223},
number = {2},
pages = {},
doi = {10.1084/jem.20251871},
pmid = {41474969},
issn = {1540-9538},
support = {NS126595/NH/NIH HHS/United States ; NS123449/NH/NIH HHS/United States ; 915125//American Heart Association/ ; T32GM135119//University of Wisconsin-Madison/ ; T32NS105602//University of Wisconsin-Madison/ ; T32GM140935//University of Wisconsin-Madison/ ; },
mesh = {Humans ; Animals ; *Central Nervous System/immunology ; *Olfactory Nerve/immunology/pathology ; Neuroinflammatory Diseases/immunology/pathology ; },
abstract = {Olfactory nerve bundles exit the brain through the cribriform plate (CP) with a rich perineural microenvironment (cpPME). This microenvironment facilitates interactions between cerebrospinal fluid, blood vessels, bone marrow, and lymphatic vessels. The immune niche of the cpPME changes in response to inflammation caused by stroke, autoimmunity, infection, and Alzheimer's disease. Neuroinflammation at the CP results in dysfunction of olfaction that might have diagnostic value in neurological disorders. Additionally, the proximity of the CP to the nasal mucosa allows targeted therapeutic interventions. A thorough understanding of the cpPME is essential for designing innovative diagnostics and treatments for neuroinflammatory diseases.},
}

Humans
Animals
*Central Nervous System/immunology
*Olfactory Nerve/immunology/pathology
Neuroinflammatory Diseases/immunology/pathology

@article {pmid41474679,
year = {2025},
author = {Duan, K and Yang, C and Wang, J and Zhao, L and Zhu, M},
title = {Global Burden of Neurological Diseases Attributable to Behavioral Risks, 1990-2021.},
journal = {Neuroepidemiology},
volume = {},
number = {},
pages = {1-21},
doi = {10.1159/000550275},
pmid = {41474679},
issn = {1423-0208},
abstract = {BACKGROUND: Behavioral risks contribute to the burden of neurological diseases, but changes from 1990 to 2021 remain unclear.

METHODS: Using the 2021 Global Burden of Disease database, we analyzed changes in age-standardized mortality (ASMR) and disability-adjusted life years (ASDR) for neurological diseases attributable to behavioral risks from 1990 to 2021, globally and regionally, including gender differences. The Joinpoint regression model estimated the annual percentage change of ASMR and ASDR. An age-period-cohort model separated the effects of age, period, and cohort, while a Bayesian model predicted changes from 2022 to 2035. Finally, cross-national inequality analysis evaluated the impact of socio-economic disparities on disease burden.

RESULTS: From 1990 to 2021, neurological diseases' burden increased, with stroke contributing most, followed by Alzheimer's disease and other dementias (ADOD), idiopathic epilepsy (IE), and multiple sclerosis (MS). ASMR and ASDR for ADOD, MS, and stroke declined. But ASMR for IE attributable to high alcohol use increased (Net drift= 0.28%), particularly among individuals aged 65-69 years (Local drift= 0.33%) and older, whereas stroke mortality associated with alcohol remained stable in the 20-30-year age group. By 2035, IE burden is projected to remain similar to 2021 levels. The disease burden was higher in males than females. Stroke burden varied by SDI level: tobacco and high alcohol use were more prominent in high SDI regions, while tobacco and dietary risks were significant in other SDI regions. Regional health inequalities were pronounced, with ADOD and MS burden concentrated in high-income groups, while stroke burden was concentrated in low-income groups.

CONCLUSION: Tobacco remains the primary risk for neurological diseases. Alcohol significantly affects IE in adults 65+ and stroke in those aged 20-30. Dietary risks contribute greatly to stroke in non-high SDI regions. Future efforts should strengthen behavioral risk control in males and reduce the increasingly concentrated stroke burden in low-income populations.},
}

@article {pmid41474270,
year = {2025},
author = {Le, VT and Yuune, JPT and Ou, YY},
title = {IFNg_DeepKG: A Novel Model for Identifying Interferon-Gamma-Inducing Epitopes Using Knowledge Graph RAG in Biomedical Applications.},
journal = {Journal of chemical information and modeling},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.jcim.5c02248},
pmid = {41474270},
issn = {1549-960X},
abstract = {The accurate and efficient computational identification of interferon-gamma-inducing epitopes (IFNgIE) is a critical bottleneck in the design of next-generation vaccines and immunotherapies. Existing computational models, while adept at learning sequence-based patterns, frequently fail to incorporate the rich biological context that governs an epitope's immunogenicity, such as its protein of origin, host, and disease association. To address this limitation, we propose IFNg_DeepKG, a new deep learning framework that synergistically integrates a pretrained protein language model (ESM2), a custom knowledge graph (KG) using a Retrieval-Augmented Generation (RAG) approach, and a multiscale convolutional neural network (MSCNN). The model's central innovation lies in its use of the RAG-KG to enrich sequence embeddings with external, biologically informed context, thereby significantly enhancing predictive performance. IFNg_DeepKG demonstrates superior performance on independent test data sets, achieving an AUC of 0.99 on the Human H_IFNgInd1 data set and 0.95 on the Mouse M_IFNgInd1 data set, a substantial increase over baseline models. With the more challenging independent data sets, the model demonstrated strong cross-species generalization, achieving AUCs of 0.94 (H_IFNgInd2) and 0.93 (M_IFNgInd2). The framework successfully identifies and classifies clinically relevant epitopes, including those associated with COVID-19 and Alzheimer's disease. By bridging the gap between sequence-based features and biological contexts, IFNg_DeepKG represents a significant advancement in computational immunology, offering a scalable and powerful platform for rational epitope discovery and precision medicine.},
}

@article {pmid41474009,
year = {2025},
author = {Wang, Z and Ranasinghe, JC and Chan, DCY and Gomm, A and Tanzi, RE and Zhang, C and Zhang, N and Huang, S},
title = {Machine Learning-Enhanced Hyperspectral Raman Imaging for Label-Free Molecular Atlas of Alzheimer's Brain.},
journal = {ACS applied materials & interfaces},
volume = {},
number = {},
pages = {},
doi = {10.1021/acsami.5c22623},
pmid = {41474009},
issn = {1944-8252},
abstract = {Label-free molecular imaging that enables the construction of a molecular atlas of biological tissues is vital for understanding complex physiological and pathological processes. Conventional bioimaging modalities, including positron-emission tomography (PET), magnetic-resonance imaging (MRI), immunoassays, and fluorescence microscopy, provide valuable structural and functional information but remain limited in molecular specificity, spatial resolution, and labeling requirements. Alzheimer's disease (AD), characterized by progressive neurodegeneration and region-specific brain deterioration, exemplifies this need. Here, we introduce a machine learning-enhanced hyperspectral Raman imaging framework that achieves label-free and molecularly resolved spatial mapping with submicrometer resolution, constructing a comprehensive molecular atlas of AD mouse brain slices. By integrating unsupervised and supervised machine learning (ML) algorithms with Raman hyperspectral imaging, this framework efficiently extracts spectral variance, molecular features, and region-dependent biochemical distributions. The resulting molecular maps reveal elevated Aβ42 accumulation and region-specific alterations in cholesterol and glycogen metabolism, particularly within the hippocampus and cortex. These results demonstrate the ability of ML-Raman imaging to capture molecular heterogeneity beyond classical Aβ pathology. The framework establishes an interpretable, data-driven approach for spatially resolved biochemical imaging, bridging optical spectroscopy and artificial intelligence for quantitative molecular characterization. Beyond neurodegenerative research, this methodology is broadly applicable to heterogeneous biological tissues and nanostructured materials, providing a versatile analytical platform for probing complex chemical and nanoscale interactions.},
}

@article {pmid41473658,
year = {2025},
author = {Li, M and An, C and Wang, X and Ren, M and Liu, S and Chen, R and Guo, Y and Wang, J and Fei, Y and Ma, D and Ma, K and Zhang, Y},
title = {Dexmedetomidine ameliorates cognitive and affective deficits by modulating neuroinflammation and neurogenesis in an Alzheimer's disease mouse model.},
journal = {Frontiers in aging neuroscience},
volume = {17},
number = {},
pages = {1724739},
pmid = {41473658},
issn = {1663-4365},
abstract = {Alzheimer's disease (AD) involves progressive cognitive decline and neuropsychiatric symptoms that are strongly linked to neuroinflammation and aberrant hippocampal neurogenesis. We examined whether dexmedetomidine (Dex), a clinically used selective α2-adrenergic agonist, could mitigate Aβ1-42-induced pathology in mice. After intracerebroventricular Aβ1-42 injection, animals were treated with Dex (25 or 50 μg/kg/day) for 7 days; a subgroup additionally received the α2 antagonist Yohimbine. Behavioral tests showed improved memory performance across recognition and spatial paradigms, accompanied by reduced anxiety-like behavior in exploratory assays. Histological analyses with Nissl and doublecortin (DCX) staining indicated preserved neuronal integrity, fewer degenerating cells, and normalization of pathological neurogenesis. At the molecular level, Dex suppressed the expression of pro-inflammatory and apoptotic genes (CXCL2, IL-1β, iNOS, SPHK1) and lowered hippocampal malondialdehyde, consistent with reduced oxidative stress and improved cellular resilience. Yohimbine partly reversed these effects, supporting α2-adrenergic involvement but leaving open the possibility of additional pathways contributing to the response. Overall, our results suggest that Dex protects against Aβ-driven injury through coordinated regulation of neuroinflammation, oxidative stress, and neurogenesis, underscoring its promise as a molecularly targeted candidate for early therapeutic strategies in AD management.},
}

@article {pmid41473656,
year = {2025},
author = {Huang, C and Lu, C and Liu, S and Dai, F and Mahmut, D and Gao, H and Ji, Y and Zhang, B},
title = {HALP, PIV, and SII as novel composite inflammatory indices for early detection and severity assessment of Alzheimer's disease.},
journal = {Frontiers in aging neuroscience},
volume = {17},
number = {},
pages = {1711176},
pmid = {41473656},
issn = {1663-4365},
abstract = {OBJECTIVE: This study aimed to evaluate the diagnostic and prognostic value of the Hemoglobin, Albumin, Lymphocyte, and Platelet (HALP) Score, the Pan-Immune-Inflammation Value (PIV), and the Systemic-Immune-Inflammation Index (SII) in Alzheimer's disease (AD), exploring their association with dementia severity and their potential utility in diagnosis and monitoring disease progression.

METHODS: In a retrospective case-control study, 261 AD patients and 176 healthy controls were enrolled. Propensity score matching (PSM) generated a balanced cohort of 176 patient-control pairs. Demographic, clinical, and hematologic variables were collected, including HALP, PIV, and SII, and dementia severity was assessed using the mini-mental state examination (MMSE). Univariate and multivariate logistic regression analyses were performed to identify independent risk factors for AD, while spearman's correlation and receiver operating characteristic (ROC) curve analysis with bootstrap internal validation were used to evaluate the biomarker's performance.

RESULTS: Following matching, AD patients exhibited significantly lower HALP and higher PIV and SII levels indicating a chronic pro-inflammatory state. HALP, PIV, and SII showed gradual but non-significant changes with dementia severity. HALP exhibited inverse correlation trend with dementia severity, though it did not reach statistical significance. Logistic regression identified education level and elevated neutrophil counts as independent risk factors of AD. ROC analysis revealed modest diagnostic performance for indices (AUC from 0.627 to 0.655), while combination of them did not significantly improve the diagnostic power.

CONCLUSION: HALP, PIV, and SII are promising blood-based biomarkers for AD diagnosis and progression monitoring. HALP may help track disease progression. These low cost, accessible composite inflammatory indices offer potential as adjunct tools for early detection and severity assessment in AD, especially in resource limited settings.},
}

@article {pmid41473450,
year = {2026},
author = {Khan, MB and Khan, S and Iqbal, T and Chinnam, S and Alzahrani, E and Gomha, SM and Zaki, MEA and Ogli, KKY},
title = {From concept to simulations: computational and experimental assessment of thiadiazole-thiazolidinone hybrid chalcones for anti-alzheimer potentials.},
journal = {3 Biotech},
volume = {16},
number = {1},
pages = {42},
pmid = {41473450},
issn = {2190-572X},
abstract = {UNLABELLED: A novel series of thiadiazole-linked thiazolidinone-chalcone derivatives was synthesized and comprehensively evaluated for their inhibitory potential against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Structural characterization was confirmed through [1]H-NMR, [13]C-NMR, and HREI-MS analyses. Among the synthesized compounds, analog 10 exhibited the most potent inhibitory activity with IC50 values of 3.10 ± 0.20 µM (AChE) and 3.80 ± 0.20 µM (BChE), surpassing the standard drug donepezil (IC50 = 5.50 ± 0.10 µM and 6.10 ± 0.20 µM, respectively). Other analogs demonstrated moderate to good activity within the range of 3.10-15.60 µM. In silico analyses, including molecular docking, pharmacophore modeling, molecular dynamics simulations, DFT calculations, and ADMET profiling, supported the experimental results and revealed stable binding conformations and favorable drug-like properties. The strong correlation between computational predictions and experimental data validated the proposed structure-activity relationship. These findings highlight compound 10 as a promising lead molecule for further optimization and development of effective and safe cholinesterase inhibitors for Alzheimer's disease therapy.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13205-025-04648-0.},
}

@article {pmid41473420,
year = {2026},
author = {Berry, BM and Davis, G and Reyes, Y and Yau, E and Stratton, L and Emery, M and Hill, C},
title = {Unforgettable: The power of community in the pursuit of health equity for Alzheimer's disease and other dementia.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {12},
number = {1},
pages = {e70195},
pmid = {41473420},
issn = {2352-8737},
abstract = {INTRODUCTION: The lack of racial/ethnic and socioeconomic diversity in research is an historic and ongoing crisis, especially for diseases like Alzheimer's disease and related dementias (ADRD), whose prevalence, incidence, and risk are highest among the populations most likely to be excluded. Targeted and culturally appropriate population education and engagement strategies are key to increasing participation and reducing health disparities and costs. Art-based knowledge translation (ABKT) uses art to disseminate information and resources related to research and its findings. The Alzheimer's Association applied ABKT in the form of a groundbreaking intervention called Unforgettable.

METHODS: Eligible communities were at least 35% Black/African American and/or Hispanic/Latino and had a strong local Alzheimer's Association chapter. Test market touring was used to refine the intervention's messaging. Highly tailored promotion and outreach was conducted by local chapters with national Alzheimer's Association support. A live concert, information tables, and an intermission talk provided additional promotion and messaging. Post-intervention surveys queried the intervention's messaging effectiveness and attendees' personal experiences around caregiving and research participation.

RESULTS: Three hundred thirty-four surveys were completed. Most respondents were women (89%), Black/African American (78%), and had never participated in a clinical trial (85%). Satisfaction with the intervention and its messaging was high. Barriers to clinical trial participation centered on fears of potential risks and overall lack of knowledge.

DISCUSSION: The success of Unforgettable demonstrates the potential for future partnerships and arts-based health education initiatives through ABKT. By continuing to integrate culturally relevant storytelling with public health outreach and education, the Alzheimer's Association and others can further the critical and urgent mission of ending ADRD disparities.

HIGHLIGHTS: Unforgettable is a groundbreaking intervention that leverages culturally resonant art and live performance to engage under-represented communities in Alzheimer's disease and related dementias (ADRD) research and clinical trials.Art-based knowledge translation was used in the development of Unforgettable, which refers to the practice of using art to disseminate, engage with, or communicate about research and its findings, reducing the knowledge-to-action gap.High satisfaction rates and increased awareness of ADRD research were reported by participants of Unforgettable, which highlights the need for integrating culturally relevant story-telling into interventions surrounding public health issues, such as ADRD.},
}

@article {pmid41473419,
year = {2026},
author = {Tonegawa-Kuji, R and Karavani, E and Danziger, M and Zhang, P and Hou, Y and Zhou, Y and Bykova, M and Pieper, AA and Rosen-Zvi, M and Cummings, J and Cheng, F},
title = {Critical evaluation of real-world evidence of repurposable medicines in the Alzheimer's disease drug development pipeline using a target trial emulation.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {12},
number = {1},
pages = {e70193},
pmid = {41473419},
issn = {2352-8737},
abstract = {INTRODUCTION: Repurposing Food and Drug Administration (FDA)-approved drugs could accelerate treatment development for Alzheimer's disease (AD).

METHODS: Using the MarketScan claims database (2011 to 2020), we applied a trial emulation approach in two base cohorts: (1) individuals with mild cognitive impairment (MCI cohort) and (2) individuals aged ≥70 years (over-70 cohort). We evaluated drugs represented in clinical trials for AD, comparing them with same-class or active comparators. Covariate-adjusted hazard ratios (HRs) were estimated using inverse-probability-weighted Cox models.

RESULTS: A total of 6 out of 38 (16%) drugs in the MCI cohort and 10 out of 53 (19%) drugs in the over-70 cohort were associated with a lower AD incidence versus same-class comparators. Active comparator analyses indicated that bupropion (vs escitalopram; HR 0.57, 95% confidence interval [CI] [0.49, 0.66]), trazodone (vs sertraline; HR 0.82, 95% CI [0.74, 0.91]), venlafaxine (vs escitalopram; 0.72, 95% CI [0.62, 0.84]), and zolpidem (vs lorazepam; HR 0.69, 95% CI [0.56, 0.85]) were associated with a lower AD incidence in the MCI cohort; these four plus liraglutide were associated with a lower incidence of AD dementia in the over-70 cohort (vs metformin; HR 0.74, 95% CI [0.59, 0.93]).

DISCUSSION: This is the first comprehensive set of trial emulations for FDA-approved drugs that are represented in AD trials. Findings may inform future trial designs.

HIGHLIGHTS: Repurposing FDA-approved drugs originally developed for other diseases could accelerate treatment development for AD.We identified repurposable drugs that are in current or complete clinical trials of AD and emulated trials for these agents using a large-scale insurance claims-based database.Among 54 drugs evaluated, 6/38 (16%) drugs in the MCI cohort and 10/53 (19%) in the over-70 cohort were associated with reduced AD incidence versus same-class comparators. Active comparator analyses indicated that bupropion, trazodone, venlafaxine, and zolpidem were associated with reduced AD incidence in the MCI cohort; these four plus liraglutide were associated with a lower incidence of AD dementia in the over-70 cohort.A minority of repurposed table drugs that are in current or completed clinical trials for AD and meet criteria for inclusion in this study showed no effect in our trial emulation studies.This is the first comprehensive set of trial emulations for FDA-approved drugs that are represented in AD trials. Building on our findings, integrating real-world evidence can inform future trials and accelerate drug development for AD.},
}

@article {pmid41473412,
year = {2025},
author = {Amine, JM and Mourad, M},
title = {Toward accurate Alzheimer's detection: transfer learning with ResNet50 for MRI-based diagnosis.},
journal = {Frontiers in neuroscience},
volume = {19},
number = {},
pages = {1664418},
pmid = {41473412},
issn = {1662-4548},
abstract = {INTRODUCTION: Alzheimer's disease (AD), the most prevalent form of dementia, affects more than 50 million individuals worldwide and demands accurate and timely diagnosis to improve patient outcomes. Traditional machine-learning approaches for AD detection using MRI often rely on manual feature extraction, which is labor-intensive and limits scalability. There is a growing need for automated, high-accuracy methods that can support clinical workflows and respond to the expected tripling of AD cases by 2050.

METHODS: This study proposes an automated feature-extraction approach using a pre-trained ResNet50 convolutional neural network (CNN) applied to brain MRI scans. Extracted deep features were classified using three different algorithms: Softmax, Support Vector Machine (SVM), and Random Forest (RF). Performance was evaluated on two benchmark datasets: ADNI and MIRIAD.

RESULTS: Among the tested models, the ResNet50-Softmax combination demonstrated the highest performance, surpassing state-of-the-art benchmarks (85.7%-98.59%). It achieved 99% sensitivity, 98% specificity, and an overall 99% accuracy on the ADNI dataset. On the MIRIAD dataset, the model also performed strongly, reaching 96% accuracy.

DISCUSSION: The results confirm that transfer learning using ResNet50 significantly enhances the accuracy and scalability of AD diagnosis from MRI data. By eliminating the need for manual feature extraction and offering near-perfect classification performance, this approach can streamline clinical neuroimaging workflows. These findings highlight the potential of deep learning models to support early diagnosis and meet the increasing global burden of Alzheimer's disease.},
}

@article {pmid41473353,
year = {2025},
author = {Coleman, MM and Haut, MW and Vieira Ligo Teixeira, C and Keith, CM and Mehta, RI and Phelps, HE and Worhunsky, P and Ward, M and Malone, J and Miller, M and Navia, RO and Marano, GD and Pockl, S and Rajabalee, N and McCuddy, WT and D'Haese, PF and Rezai, A and Wilhelmsen, K},
title = {Interaction of insula and hippocampus in memory dysfunction in Alzheimer's disease.},
journal = {Journal of Alzheimer's disease reports},
volume = {9},
number = {},
pages = {25424823251407323},
pmid = {41473353},
issn = {2542-4823},
abstract = {The insula, classically linked with emotion and perception, has recently been associated with memory function in Alzheimer's disease (AD). However, its role in memory remains unclear. This study investigated whether the insula contributes directly to memory consolidation or is indirectly involved in memory-related brain regions. We systematically increased diagnostic specificity in memory-impaired patients to assess the role of the insula in memory. Gyrification of the insula was associated with memory consolidation in Aβ+ individuals, only in combination with hippocampal atrophy. These findings suggest insular atrophy interacts with degeneration of the hippocampus in memory dysfunction in AD, but not necessarily in other pathologies.},
}

@article {pmid41473323,
year = {2025},
author = {Salian, VS and Veerareddy, V and Tang, X and Xiao, Y and Kalari, KR and Kashyap, PC and Kandimalla, KK},
title = {Molecular Mechanisms Underlying the Regulation of VCAM-1 Expression by the Short-Chain Fatty Acid Butyrate.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2025.12.15.694447},
pmid = {41473323},
issn = {2692-8205},
abstract = {Over the past decade, cerebrovascular inflammation has been increasingly recognized as a contributor to the progression of neurodegenerative diseases, particularly Alzheimer's disease (AD). One of the molecular hallmarks of cerebrovascular inflammation is the increased expression of vascular cell adhesion molecule (VCAM)-1 on blood-brain barrier (BBB) endothelial cells. Exposure to amyloid beta (Aβ) peptides, one of the primary hallmarks of AD, and pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α) induces VCAM-1 expression on the BBB endothelium, which facilitates extravasation of leukocytes into the brain thereby promoting an inflammatory response. Therefore, it is crucial to explore therapeutic agents that can inhibit VCAM-1 expression induced by Aβ and TNF-α. Short-chain fatty acids, such as butyrate, produced by the gut microbiota as byproducts of dietary fiber metabolism, are recognized for their anti-inflammatory properties. In this study, we successfully tested the hypothesis that butyrate mitigates Aβ and TNF-α-induced VCAM-1 expression in polarized human cerebral microvascular endothelial cell monolayers, a widely used BBB in vitro model. Our findings indicated that pre-treatment with butyrate significantly reduced Aβ42 and TNF-α mediated upregulation of VCAM-1. Furthermore, we have shown STAT3/GATA6 axis as a key mediator of anti-inflammatory effects of butyrate. These findings provide mechanistic insight into butyrate's protective role and highlight its potential to mitigate Aβ and TNF-α-induced cerebrovascular inflammation in AD.},
}

@article {pmid41473305,
year = {2025},
author = {Tang, X and Nelson, DA and Hernaez, M and Kandimalla, KK and Kalari, KR},
title = {NVUAtlas: A Comprehensive Single-Nucleus RNA-Seq Resource for the Human Neurovascular Unit in Alzheimer's Disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2025.12.03.692162},
pmid = {41473305},
issn = {2692-8205},
abstract = {BACKGROUND: Neurovascular unit (NVU) dysfunction is being recognized as one of the earliest contributors to Alzheimer's disease (AD) pathogenesis. However, systematic investigation of NVU dysfunction is currently limited by lack of access to molecular level information due to underrepresentation of vascular and mural cells in standard single-nucleus RNA sequencing (snRNA-seq) datasets. Consequently, existing transcriptomic atlases lack the resolution necessary to capture the coordinated intercellular signaling and dysfunction across vascular components of NVU, including endothelial cells and pericytes.

METHODS: We constructed the Human NVU Atlas by integrating 11 publicly available snRNA-seq datasets, including vascular-enriched samples, from the human prefrontal cortex. This comprehensive dataset aggregates over 4.2 million nuclei from 748 donors, including AD patients and age-matched controls. We utilized a unified probabilistic pipeline based on deep generative models (SCVI) to perform batch-aware integration and employed an ensemble of supervised and deep-learning classifiers to rigorously re-annotate cell types. Differential expression and ligand-receptor interaction analyses were subsequently performed to identify cell-type-specific disruptions in males versus females.

RESULTS: The atlas successfully curated vascular populations from 11 studies to assemble the largest publically available NVU cohort of endothelial cells (2.8%) and pericytes (1.9%) alongside astrocytes and neurons. Differential expression analysis revealed that while neurons predominantly exhibited gene downregulation in AD, vascular cells displayed a pattern of transcriptional hyperactivity with significant gene upregulation. We also identified pronounced sex-specific vulnerabilities; females exhibited distinct inflammatory signatures and downregulation of basement membrane collagen genes (e.g., COL4A1 , COL4A2) in pericytes, whereas these changes were not observed in males. Moreover, cell-cell interaction analysis revealed a widespread loss of collagen-integrin signaling between pericytes and neurons, suggesting the involvement of extracellular matrix disruptions in NVU dysfunction observed in AD.

CONCLUSION: The Human NVU Atlas provides a high-resolution, integrated transcriptomic framework for dissecting the cellular heterogeneity of the neurovascular unit. By uncovering sex-specific vascular mechanisms and disrupted intercellular communication, this resource highlights the critical role of vascular cells in AD progression and serves as a foundational reference for investigating cerebrovascular contribution to AD.},
}

@article {pmid41473135,
year = {2025},
author = {Andel, R and Sheardova, K and Pavlik, J and Vališ, M and Amlerova, J and Hort, J},
title = {Terrapino: a mobile application for Alzheimer's risk assessment and cognitive health promotion.},
journal = {Frontiers in digital health},
volume = {7},
number = {},
pages = {1719645},
pmid = {41473135},
issn = {2673-253X},
abstract = {OBJECTIVE: Mobile health technologies offer scalable opportunities to promote public health, including cognitive health, via education, engagement, and personalized health approach. This study describes the features of the Terrapino mobile application and its users to date, and provide initial evaluation of the ARA score.

METHODS: Between December 2022 and December 2024, 8,395 users completed the Alzheimer's Risk Assessment survey, a comprehensive questionnaire developed to collect comprehensive, evidence-based information about Alzheimer's disease risk and protective factors including sociodemographics, health and health history information, lifestyle habits, subjective memory complaints and perceived stress. Most (95%) used the original, Czech version, but English and Spanish versions are also available.

RESULTS: Users were 18-103 years old (mean 57.1 ± 14.5 years), with 46.4% aged 60 years or older. Most (72%) were women and nearly half held a college degree. Despite relatively high education, lifestyle and health characteristics resembled general population trends, suggesting broad accessibility and reach. In a random forest machine learning models, hypertension, going for walks, playing sports and exercising, education, depression, memory complaints, meditation, vegetable intake and the use of olive oil emerged as most influential variables predicting the overall Alzheimer's Risk Assessment score, whether estimated for the entire sample or for those aged 60 + years. The models explained upwards of 80% of variance in the risk score.

CONCLUSIONS: This initial examination suggests good feasibility to engage large numbers of individuals in cognitive health promotion through a mobile platform. The early data also suggests good validity of the Alzheimer's Risk Assessment score collected within the application. The initial findings support future efforts to test the application's capacity to contribute to efforts to cognitive health promotion which can be tested through longitudinal research in the upcoming years.},
}

@article {pmid41473097,
year = {2025},
author = {Kang, MH and Kang, MA and Jeon, HJ and Shin, HC and Moon, H and Lee, DG and Park, HM},
title = {Evaluation of the safety and efficacy of a donepezil depot injection in dogs with canine cognitive dysfunction.},
journal = {Frontiers in veterinary science},
volume = {12},
number = {},
pages = {1724060},
pmid = {41473097},
issn = {2297-1769},
abstract = {Canine cognitive dysfunction (CCD) is an age-related neurodegenerative disorder for which effective treatments remain limited, and objective diagnostic and therapeutic assessment tools using biomarkers or neuroimaging are still lacking compared with human Alzheimer's disease. This study evaluated the safety and efficacy of a long-acting donepezil depot injection in dogs with CCD, using behavioral scores and serum neurofilament light chain (NfL) as primary outcomes, with baseline MRI for diagnostic support. Thirty-two dogs with clinically diagnosed CCD were randomly assigned to a high-dose group (n = 11), a low-dose group (n = 11), or a control group (n = 10). Diagnosis was established based on the Canine Cognitive Dysfunction Rating Scale (CCDR), the CAnine DEmentia Scale (CADES), and DISHAA scoring, and baseline MRI was performed in selected dogs with owner consent. A single intramuscular injection of donepezil depot was administered on day 0, and evaluations were conducted on days 14 and 28. The high-dose group showed significant improvements in CCDR, CADES, and DISHAA at both 14 and 28 days, whereas the low-dose group improved primarily at day 28, with earlier effects limited to CADES (p < 0.05). At day 28, both treatment groups had significantly lower serum NfL levels than controls (p < 0.05), while within-group values remained stable. Quality-of-life scores improved in activity, sociability, overall condition, and global QoL. Adverse events were mild and transient. These findings suggest that a single intramuscular injection of long-acting donepezil depot demonstrates favorable safety and potential efficacy in dogs with CCD, with improvements in behavioral scores and NfL supporting its therapeutic potential and highlighting the value of integrating clinical and biomarker-based assessments in future CCD management.},
}

@article {pmid41472916,
year = {2026},
author = {Zheng, Y and Sharma, H and Betke, M and Cherry, JD and Mez, JB and Beane, JE and Kolachalama, VB},
title = {FourierMIL: Fourier Filtering-based Multiple Instance Learning for Whole Slide Image Analysis.},
journal = {International journal of computer vision},
volume = {134},
number = {1},
pages = {26},
pmid = {41472916},
issn = {0920-5691},
abstract = {Recent advancements in computer vision, including convolutional neural networks, multilayer perceptrons, graph-based methods and transformer architectures, have significantly improved image classification. However, applying these techniques to digital pathology, particularly gigapixel whole-slide images (WSIs), presents unique challenges due to their vast size and heterogeneity. We introduce FourierMIL, a multiple instance learning framework that leverages the discrete Fourier transform to efficiently capture global and local dependencies in WSIs. Unlike conventional approaches, FourierMIL is adaptable to diverse digital stains and pathology tasks. To evaluate its versatility, we tested FourierMIL on three distinct challenges using public and private datasets. (1) Metastasis detection in hematoxylin and eosin (H&E)- stained lymph node WSIs from CAncer MEtastases in LYmph nOdes challeNge (CAMELYON16) dataset. (2) Lung cancer classification (adenocarcinoma versus squamous cell carcinoma) using The Cancer Genome Atlas (TCGA) and the Clinical Proteomic Tumor Analysis Consortium (CPTAC) datasets. (3) Alzheimer's disease pathology identification in phospho-tau monoclonal antibody (AT8)- stained WSIs from the Understanding Neurologic Injury and Traumatic Encephalopathy (UNITE), the Framingham Heart Study (FHS), and the Boston University Alzheimer's Disease Research Center (ADC) cohorts. FourierMIL outperformed state-of-the-art methods across all tasks, demonstrating its robustness as an attention-free solution for diverse applications in digital pathology.},
}

@article {pmid41472887,
year = {2025},
author = {Anagnostou, E and Armenis, G},
title = {Eye movement abnormalities in Alzheimer's disease and other neurodegenerative dementias: insights from current evidence and priorities for future research.},
journal = {Frontiers in ophthalmology},
volume = {5},
number = {},
pages = {1754941},
pmid = {41472887},
issn = {2674-0826},
abstract = {Eye movement abnormalities are increasingly recognized as early and sensitive markers of neurodegenerative dementias, particularly Alzheimer's disease (AD). Disruptions in saccadic, antisaccadic, smooth pursuit, fixation, and naturalistic eye movement tasks reflect dysfunction in frontal, parietal, subcortical, and cerebellar circuits that are vulnerable to neurodegeneration. Studies have consistently demonstrated that AD patients show prolonged saccadic latencies, increased antisaccade error rates, reduced smooth pursuit gain, and fixation instability. Such deficits correlate with cognitive impairment, disease severity, and neuroimaging biomarkers of cortical atrophy. Comparisons with frontotemporal dementia (FTD), dementia with Lewy bodies (DLB), and posterior cortical atrophy (PCA) highlight overlapping yet distinct oculomotor profiles, suggesting diagnostic and prognostic value. Eye-tracking methodologies offer non-invasive, cost-effective tools that could complement neuropsychological and imaging assessments. However, methodological variability remains a barrier to clinical implementation. This review integrates evidence from foundational and recent studies to provide a comprehensive account of oculomotor dysfunction in AD and other dementias, emphasizing the translational potential of eye movement biomarkers in clinical practice and research.},
}

@article {pmid41472841,
year = {2025},
author = {Wang, Y and Bone, R and Fleisher, W and Gresenz, CR and Mitchell, J and van der Klaauw, W and Wang, C and Singh, L},
title = {Using Under-Represented Subgroup Fine Tuning to Improve Fairness for Disease Prediction.},
journal = {Biomedical engineering systems and technologies, international joint conference, BIOSTEC ... revised selected papers. BIOSTEC (Conference)},
volume = {2},
number = {},
pages = {240-253},
pmid = {41472841},
abstract = {The role of artificial intelligence is growing in healthcare and disease prediction. Because of its potential impact and demographic disparities that have been identified in machine learning models for disease prediction, there are growing concerns about transparency, accountability and fairness of these predictive models. However, very little research has investigated methods for improving model fairness in disease prediction, particularly when the sensitive attribute is multivariate and when the distribution of sensitive attribute groups is highly skewed. In this work, we explore algorithmic fairness when predicting heart disease and Alzheimer's Disease and Related Dementias (ADRD). We propose a fine tuning approach to improve model fairness that takes advantage of observations from the majority groups to build a pre-trained model and uses observations from each underrepresented subgroup to fine tune the pre-trained model, thereby incorporating additional specific knowledge about each subgroup. We find that our fine tuning approach performs better than other algorithmic fairness fixing methods across all subgroups even if the subgroup distribution is very imbalanced and some subgroups are very small. This is an important step toward understanding approaches for improving fairness for healthcare and disease prediction.},
}

@article {pmid41472721,
year = {2025},
author = {Meynadasy, MA and Sachs-Ericsson, N and Cushing, SD and Sheffler, JL and Kabbaj, M and Wilber, A},
title = {Psychiatric Risk Factors for Progression From Mild Cognitive Impairment to Alzheimer's Disease: A Systematic Review.},
journal = {The American journal of geriatric psychiatry. Open science, education, and practice},
volume = {8},
number = {},
pages = {17-32},
pmid = {41472721},
issn = {2950-3868},
abstract = {Mild Cognitive Impairment (MCI), the intermediate stage between healthy aging and dementia, is a window for identification of risk factors for progression to Alzheimer's Disease (AD). Rodents modeling aspects of AD-related pathophysiology are useful for examining mechanisms underlying AD risk factors. We provide a systematic update of human literature on psychiatric risk factors for progression from MCI to AD and use these findings to motivate a targeted review of related rodent literature. We searched databases to identify human studies published since a previous systematic review. We included articles if longitudinal, assessed MCI at baseline and AD at follow-up, and reported on risk factors for progression of MCI to AD. We categorized articles by risk factor type and included those examining psychiatric factors. Results were synthesized based on psychopathology examined and methods used. Relevant rodent literature was reviewed and incorporated. We found seventeen papers examining psychiatric risk factors for MCI progression to AD; we found cross species support for the role of depression as an important risk factor. We discuss hypotheses to explain the role of depression and suggest investigating transdiagnostic factors related to depression and AD (e.g., sleep, stress) that lend themselves to investigation across species.},
}

@article {pmid41472708,
year = {2025},
author = {Oxendine, JD and Sirkis, DW and Jonson, C and Yokoyama, JS},
title = {Single-nucleus RNA-seq reveals no increase in T cells in Alzheimer's disease prefrontal cortex or hippocampus.},
journal = {Frontiers in cellular neuroscience},
volume = {19},
number = {},
pages = {1681881},
pmid = {41472708},
issn = {1662-5102},
abstract = {BACKGROUND: Alzheimer's disease (AD) has long been associated with hallmark protein aggregates, yet increasing evidence suggests immune involvement may contribute to its progression. Prior studies have found increased T cell presence in AD brain tissue, raising the possibility of neuroimmune crosstalk.

METHODS: We used single-nucleus RNA sequencing data from the Religious Orders Study and Memory and Aging Project (ROSMAP), the largest available postmortem AD cohort, to investigate T cell dynamics in prefrontal cortex (PFC) and hippocampus.

RESULTS: Contrary to prior findings, we observed no significant increase in T cell frequency in individuals with pathologically confirmed AD in either region. We replicated these findings in dorsolateral PFC (DLPFC) using the Seattle Alzheimer's Disease Brain Cell Atlas (SEA-AD). Notably, although we confirmed a prior finding of T cell expansion in middle temporal gyrus (MTG), the strength of this association was affected by donor age. Additionally, we detected no change in gene expression in T cells in the brain parenchyma from individuals with AD.

IMPACT: These results suggest that T cell enrichment in AD may be regionally restricted and not as widespread as previously assumed. Our findings underscore the importance of brain region selection, analytical approach, and dataset composition in interpreting immune cell dynamics in neurodegenerative disease.},
}

@article {pmid41472502,
year = {2025},
author = {Stewart, CC and Yu, L and Kapasi, A and Bennett, DA and Boyle, PA},
title = {APOE ε4 and Decline in Health and Financial Literacy in Advanced Age.},
journal = {Journal of the American Geriatrics Society},
volume = {},
number = {},
pages = {},
doi = {10.1111/jgs.70291},
pmid = {41472502},
issn = {1532-5415},
support = {R01 AG017917/AG/NIA NIH HHS/United States ; R01 AG033678/AG/NIA NIH HHS/United States ; R01 AG034374/AG/NIA NIH HHS/United States ; R01 AG060376/AG/NIA NIH HHS/United States ; },
abstract = {BACKGROUND: Health and financial literacy decline in aging, but it is unclear why. In this study, we hypothesized that older people who are carriers of the APOE ε4 allele exhibit a steeper decline in literacy over time.

METHODS: Participants were 851 community-dwelling older adults without dementia at analytic baseline (188 ε4 carriers and 663 noncarriers). Literacy was assessed at baseline and each year thereafter for up to 14 years.

RESULTS: In a linear mixed-effects model adjusted for age, gender, and education, ε4 was associated with a lower starting level of literacy (b = -3.60, SE b = 1.00, p < 0.001) and, critically, a roughly 40% steeper decline in literacy over time (b = -0.41, SE b = 0.14, p = 0.004). The association between ε4 and literacy decline persisted after adjusting for global cognition at baseline (b = -0.35, SE b = 0.14, p = 0.012) and among a subgroup of participants with no cognitive impairment at baseline (b = -0.34, SE b = 0.14, p = 0.016).

CONCLUSIONS: ε4 contributes to literacy decline among older adults, presumably due in part to the accumulation of neuropathologies associated with ε4. We discuss the potential clinical implications of ε4-related literacy decline.},
}

@article {pmid41471981,
year = {2025},
author = {Kuczyńska-Wiśnik, D and Stojowska-Swędrzyńska, K and Laskowska, E},
title = {Bacterial Adaptation to Stress Induced by Glyoxal/Methylglyoxal and Advanced Glycation End Products.},
journal = {Microorganisms},
volume = {13},
number = {12},
pages = {},
pmid = {41471981},
issn = {2076-2607},
support = {531/D010-D241-25//University of Gdańsk/ ; },
abstract = {Glyoxal (GO) and methylglyoxal (MGO) are highly toxic metabolic byproducts that induce carbonyl stress in bacteria and eukaryotes. Their accumulation in cells is linked to non-enzymatic glycosylation (glycation) of proteins, nucleic acids, and lipids, leading to the formation of advanced glycation end products (AGEs). In humans, AGEs are associated with several health problems, such as diabetes, Alzheimer's disease, cancer, and aging. Recent studies indicate that, despite their short lifespan, bacteria are also affected by AGEs formation. In this review, we summarize the pathways and mechanisms that help bacteria cope with GO, MGO, and AGEs. We also discuss the impact of dietary AGEs on gut microbiota and the antibacterial activity of host-derived GO/MGO. Recent studies highlight three main areas for future research: the role of AGEs in dysbiosis, the regulation of protein activities by MGO/GO-dependent modifications, and the potential use of glyoxalase pathway inhibitors to combat pathogens. This last point is especially important due to the rising prevalence of multidrug-resistant strains and the failure of antibiotic therapies.},
}

@article {pmid41471945,
year = {2025},
author = {Felicetti, A and Azzolino, D and Piro, PP and Lopes, GCD and Rezaeinezhad, N and Lovero, R and Bocchio-Chiavetto, L and Colella, M and Passarelli, PC},
title = {The Oral-Brain Axis in Alzheimer's Disease: From Microbial Dysbiosis to Neurodegeneration.},
journal = {Microorganisms},
volume = {13},
number = {12},
pages = {},
pmid = {41471945},
issn = {2076-2607},
abstract = {Alzheimer's disease (AD), the most prevalent form of dementia, still lacks a clearly defined pathogenesis and effective disease-modifying therapies, prompting growing interest in peripheral drivers of neurodegeneration. Among these, chronic oral dysbiosis has emerged as a potential risk factor. Disruption of the oral ecosystem in periodontitis promotes systemic inflammation and the circulation of bacterial products capable of influencing brain homeostasis. By integrating molecular findings with epidemiological data linking periodontitis, tooth loss, and poor oral health to increased AD risk, this review examines how oral dysbiosis contributes to systemic inflammation as part of a broader network of interacting factors involved in AD pathophysiology. It describes how inflammatory, gut-microbial, genetic, and barrier-related processes intersect with oral dysbiosis and jointly contribute to the acceleration of AD progression. Building on this systemic perspective, the review highlights emerging oral biomarkers and oral-gut microbiota-targeted therapies as potential tools to address current gaps in early diagnosis and intervention. Overall, this work advances current understanding by integrating previously fragmented evidence and highlighting the key conceptual and methodological gaps that must be addressed to clarify causality and to guide the development of preventive and therapeutic approaches targeting oral health in the context of AD.},
}

@article {pmid41471921,
year = {2025},
author = {Jiménez-Pareyón, GR and Cristóbal-Luna, JM and García-Martínez, Y and Garfias-Noguez, C and Ramírez-Damián, M and Torres-Maravilla, E and Sánchez-Pardo, ME},
title = {Psychobiotics at the Frontiers of Neurodegenerative and Neuropsychiatric Research.},
journal = {Microorganisms},
volume = {13},
number = {12},
pages = {},
pmid = {41471921},
issn = {2076-2607},
support = {SIP20250920//Politécnico Nacional-Secretaría de Investigación y Posgrado/ ; },
abstract = {Neurodegenerative and neuropsychiatric disorders remain a major public health concern due to their progressive nature, high prevalence, and considerable socioeconomic burden. Conventional treatments often fall short, facing limitations such as pharmacoresistance, adverse effects, and limited efficacy, underscoring the need for complementary approaches. Recent advances highlight the central role of the gut-brain axis (GBA) in neurological health, positioning psychobiotics and probiotic strains with potential mental health benefits, as candidates in adjunctive therapy. This review integrates current evidence on the GBA's involvement in conditions such as Alzheimer's disease, Parkinson's disease, depression, and anxiety. We examine how psychobiotics may modulate neuroinflammation, oxidative stress, and neurotransmitter signaling, thereby contributing to cognitive and emotional regulation. Both preclinical and clinical studies are discussed, with emphasis on biomarker changes, quality-of-life outcomes, and neuropsychiatric comorbidities. We also explore recent innovations, including precision psychobiotics, microbiota-drug synergies, and their relevance to overlapping metabolic and neurodegenerative pathologies. Finally, we address the major translational challenges in the field, strain selection, methodological standardization, biomarker integration, and ethical design, highlighting key perspectives for advancing psychobiotics research toward clinical application.},
}

@article {pmid41471864,
year = {2025},
author = {Cao, S and Shi, X and Chen, Y and Liu, T and Hu, J and Dong, X and Chen, H and Dai, J and Yin, H},
title = {Gut Microbiota-Targeted Photobiomodulation Ameliorates Alzheimer's Pathology via the Gut-Brain Axis: Comparable Efficacy to Transcranial Irradiation.},
journal = {Microorganisms},
volume = {13},
number = {12},
pages = {},
pmid = {41471864},
issn = {2076-2607},
support = {62175261//National Natural Science Foundation of China/ ; 2023YFB3609103//National Key R&D Program of China/ ; 2021-I2M-1-058//Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences/ ; 24JCZDJC00240//Natural Science Foundation of Tianjin/ ; },
abstract = {Alzheimer's disease (AD) is a major neurodegenerative disorder with limited effective and affordable therapies. Photobiomodulation (PBM) offers a safe, non-invasive treatment strategy, yet conventional transcranial PBM (tc-PBM) is restricted by low skull penetration. To overcome this limitation, gut microbiota-targeted PBM (gm-PBM) has been proposed to modulate the gut-brain axis, though its efficacy and mechanisms remain unclear. Here, six-month-old APPswe/PS1dE9 mice received gm-PBM or tc-PBM (810 nm, 25 mW/cm[2], 20 min/day for 4 weeks). Behavioral testing revealed that both treatments improved spatial learning and memory, while histological analyses showed reduced amyloid-β deposition and microglial shift toward an anti-inflammatory phenotype. Notably, gm-PBM specifically enriched short-chain fatty acid-producing bacteria, elevated propionate, butyrate, and secondary bile acids, and restored intestinal barrier integrity, whereas tc-PBM induced minimal microbiota changes. These findings suggest that gm-PBM confers neuroprotective effects comparable to or exceeding tc-PBM through modulation of the gut microbiota-metabolism-immune axis, highlighting its potential as a non-invasive and cost-effective therapeutic approach for AD.},
}

@article {pmid41471791,
year = {2025},
author = {Ali, A and Lin, CL and Wang, CK},
title = {Neuroprotective Effect of Fresh Gac Fruit Parts Against β-Amyloid-Induced Toxicity and Its Influence on Synaptic Gene Expression in HT-22 Cell Model.},
journal = {Molecules (Basel, Switzerland)},
volume = {30},
number = {24},
pages = {},
pmid = {41471791},
issn = {1420-3049},
mesh = {*Amyloid beta-Peptides/toxicity ; *Neuroprotective Agents/pharmacology/chemistry ; *Fruit/chemistry ; Animals ; *Plant Extracts/pharmacology/chemistry ; *Synapses/drug effects/metabolism/genetics ; Reactive Oxygen Species/metabolism ; Mice ; Cell Line ; *Gene Expression Regulation/drug effects ; Cell Survival/drug effects ; Humans ; },
abstract = {Neurodegenerative diseases (NDs) have emerged as a significant global health crisis, disproportionately affecting the aging population. As longevity increases, the incidence, healthcare costs, and caregiver burden associated with NDs are escalating at an alarming rate. As of recent data, NDs such as Alzheimer's disease (AD) are not only significant health burdens but also reflect a complex interplay between socio-economic factors and healthcare systems worldwide. Gac fruit (Momordica cochinchinensis) is a rich source of bioactive compounds that has been used as food and traditional medicine. Gac fruit ameliorates memory deficits, enhances beta amyloid (Aβ)1-42 clearance, and induces neurite outgrowth. In this study, we examined the anti-neurodegenerative and synaptic improvement effect of fresh gac fruit parts extracts (FGPEs) produced from different solvents. Results showed that the 80% ethanol extract of peel (PE-EtOH) and ethyl acetate extract of seed (SE-EtOAc) significantly protected HT-22 cells by attenuating Aβ-induced cell death, intracellular reactive oxygen species (ROS) production, mitochondrial dysfunction, and synaptic dysfunction. PE-EtOH protected synaptic functions by significantly increasing the postsynaptic density protein-95 (PSD-95) and reducing the neurexin 2 mRNA expression. In contrast, SE-EtOAc increased the PSD-95 and neurexin 3 and reduced the neurexin 2 expressions. These findings indicate that PE-EtOH and SE-EtOAc could have great potential in ameliorating Aβ-induced toxicity in an HT-22 cell model.},
}

*Amyloid beta-Peptides/toxicity
*Neuroprotective Agents/pharmacology/chemistry
*Fruit/chemistry
Animals
*Plant Extracts/pharmacology/chemistry
*Synapses/drug effects/metabolism/genetics
Reactive Oxygen Species/metabolism
Mice
Cell Line
*Gene Expression Regulation/drug effects
Cell Survival/drug effects
Humans

@article {pmid41471783,
year = {2025},
author = {Balewski, Ł and Kornicka, A},
title = {Recent Advances in Synthetic Isoquinoline-Based Derivatives in Drug Design.},
journal = {Molecules (Basel, Switzerland)},
volume = {30},
number = {24},
pages = {},
pmid = {41471783},
issn = {1420-3049},
support = {01-62025/0008403/643//Gdańsk Medical University/ ; },
mesh = {*Isoquinolines/chemistry/pharmacology/chemical synthesis ; Humans ; *Drug Design ; Antineoplastic Agents/pharmacology/chemistry/chemical synthesis ; Animals ; Signal Transduction/drug effects ; },
abstract = {Compounds based on an isoquinoline scaffold (benzo[c]pyridine) display a broad spectrum of biological activities. In recent years, studies have focused mainly on their anticancer properties. Their antiproliferative effects are associated with diverse mechanisms that include targeting PI3K/Akt/mTOR signaling pathways and reactive oxygen species or inducing apoptosis and cell cycle arrest. Furthermore, isoquinolines may inhibit microtubule polymerization, topoisomerase, or tumor multidrug resistance. Recent studies have also shown that these compounds may act as effective antimicrobial, antifungal, antiviral, and antiprotozoal agents. Moreover, it has also been demonstrated that isoquinoline derivatives exhibit potent anti-Alzheimer effects, alleviating central nervous system functions. Additionally, they possess anti-inflammatory and antidiabetic properties. Due to the presence of donor nitrogen, the isoquinoline core constitutes an appropriate ligand that may be employed for the development of metal complexes with improved pharmacological properties. A number of chelates containing copper, iridium, or platinum were found to exhibit prominent biological activity, which places them in a leading position for the development of effective medications. This review summarizes the recent development of synthetic isoquinoline-based compounds with proven pharmacological properties in the period of 2020-2025. Also, other biomedical applications for synthetic isoquinoline derivatives are provided.},
}

*Isoquinolines/chemistry/pharmacology/chemical synthesis
Humans
*Drug Design
Antineoplastic Agents/pharmacology/chemistry/chemical synthesis
Animals
Signal Transduction/drug effects

@article {pmid41471435,
year = {2025},
author = {Singh, A and Supriya, S and Siuly, S and Wang, H},
title = {CONECT: Novel Weighted Networks Framework Leveraging Angle-Relation Connection (ARC) and Metaheuristic Algorithms for EEG-Based Dementia Classification.},
journal = {Sensors (Basel, Switzerland)},
volume = {25},
number = {24},
pages = {},
doi = {10.3390/s25247439},
pmid = {41471435},
issn = {1424-8220},
mesh = {Humans ; *Electroencephalography/methods ; *Dementia/classification/diagnosis/physiopathology ; *Algorithms ; Signal Processing, Computer-Assisted ; },
abstract = {Accurate and robust classification of dementia subtypes using non-invasive electroencephalography (EEG) signals remains a critical challenge for clinicians and researchers in the field of neuroscience. Traditional methods often rely on limited spectral features, overlooking the rich structural and geometric information inherent in EEG dynamics. CONECT (Complex Network Conversion and Topology), a novel framework, is introduced and built upon four core innovations. First, EEG time series are transformed into weighted networks using a novel Angle-Relation Connection (ARC) rule, a geometry-based approach that links time points based on angular monotonicity. Secondly, a tunable edge-weighting function is introduced by integrating amplitude, temporal, and angular components, providing adaptable heuristics adaptable to the most promising biomarker, i.e., curvature-driven features in dementia. Additionally, two new graph-based EEG features, the Weighted Angular Irregularity Index (WAII) and the Curvature-Based Edge Feature Index (CBEFI), are proposed as potential biomarkers to capture localized irregularity and signal geometry, respectively. For the first time in a dementia EEG classification study using the OpenNeuro ds004504 dataset (raw), Ant Colony Optimization (ACO) is applied as a feature selection technique to select the most discriminative features and improve model classification and transparency. The classification results demonstrate CONECT's potential as a promising, interpretable, and geometry-informed framework for accurate and practical dementia subtype diagnosis.},
}

Humans
*Electroencephalography/methods
*Dementia/classification/diagnosis/physiopathology
*Algorithms
Signal Processing, Computer-Assisted

@article {pmid41471381,
year = {2025},
author = {Sharaf, YM and Nazeam, JA and Abu-Elfotuh, K and Gowifel, AMH and Atwa, AM and Mohamed, EK and Hamdan, AME and Almotairi, R and Hamdan, AM and Osman, SM and El Hefnawy, HM},
title = {Lemon Juice-Assisted Green Extraction of Strawberry Enhances Neuroprotective Phytochemicals: Insights into Alzheimer's-Related Pathways.},
journal = {Pharmaceuticals (Basel, Switzerland)},
volume = {18},
number = {12},
pages = {},
doi = {10.3390/ph18121892},
pmid = {41471381},
issn = {1424-8247},
abstract = {Background/Objective: Alzheimer's disease (AD) is a neurodegenerative condition characterized by oxidative stress, neuroinflammation, amyloidogenesis, and tau-related pathology. This study investigated the macronutrient and phytochemical composition of strawberry (S), lemon (L), and lemon juice-assisted strawberry (S/L) extracts and evaluated their neuroprotective efficacy relative to selenium (Se) in an aluminum chloride (AlCl3)-induced rat model of AD. Methods: Macronutrients and phenolics were quantified in S, L, and S/L, and the extracts were profiled using high-performance liquid chromatography and electrospray ionization tandem mass-spectrometry. Male Sprague-Dawley rats received AlCl3 with or without S, L, S/L, or Se, and their cognitive performance was assessed using the Morris water maze, Y-maze, and conditioned avoidance tests. Markers of oxidative status, inflammation, cholinergic function, apoptotic signaling, and Wnt3/β-catenin pathway activity were quantified in the brain tissue, and cortico-hippocampal morphology was examined. Results: The S/L extract showed the highest carbohydrate, protein, and lipid content. The total phenolic content was highest in S/L (60.46 mg gallic acid equivalents/g), followed by L (55.08) and S (44.75), with S/L also being the richest in gallic, ellagic, and chlorogenic acids. S/L attenuated AlCl3-induced cognitive deficits, restored antioxidant status, suppressed neuroinflammation, improved cholinergic indices, modulated apoptotic signaling, and downregulated amyloidogenic and NLRP3 inflammasome markers, consistent with histological evidence of neuronal preservation. Conclusions: Lemon juice-assisted extraction enhanced the macronutrient and phenolic richness and multitarget neuroprotection of strawberries. S/L co-extracts represent promising functional food-derived adjuvants for AD management and support integrative compositional-mechanistic profiling to optimize natural product-based interventions.},
}

@article {pmid41471360,
year = {2025},
author = {Chen, Y and Ma, H and Jin, M and Zhang, S and Qu, S and Wang, G and Aa, J},
title = {Pharmacokinetic and Pharmacodynamic Evaluation of PZ-2891, an Anti-Alzheimer's Disease Agonist of PANK2.},
journal = {Pharmaceuticals (Basel, Switzerland)},
volume = {18},
number = {12},
pages = {},
doi = {10.3390/ph18121871},
pmid = {41471360},
issn = {1424-8247},
support = {2017ZX09301013//National Key Special Project of Science and Technology for Innovation Drugs of China/ ; BK20192005//Leading Technology Foundation Research Project of Jiangsu Province/ ; 2021-I2M-5-011//CAMS Innovation Fund for Medical Sciences/ ; },
abstract = {Background/Objectives: Alzheimer's disease (AD) is a neurodegenerative disorder with a high incidence but limited agents. Herein, PZ-2891 was discovered as a novel anti-AD candidate. Both in vivo and in vitro pharmacodynamic (PD) studies and pharmacokinetic (PK) properties were investigated and illustrated in this research. Methods: A computer-generated random number table was used to divide mice into various groups randomly. Injecting Aβ into the mice hippocampus to mimic AD-like pathologies, neurobehavioral tests, including the Morris maze, Y maze, open field test (OFT) and novel object recognition (NOR), were operated to evaluate the cognitive improvement in PZ-2891. D-galactose (D-gal), okadaic acid (OA) and lipopolysaccharide (LPS) were employed to trigger neural injuries in vitro. A reliable analytic method was developed to profile PZ-2891's PK properties in SD rats through a triple quadrupole liquid chromatography-mass spectrometry (LC-MS/MS) instrument. Results: PZ-2891 markedly alleviated cognitive impairment in the Aβ-induced model mice. It also protected nerve cells from oxidative stress and inflammatory injuries and significantly reduced AD-typical pathological biomarkers. The PK results showed that PZ-2891 was exposed rapidly in both plasma and brain, with a brain-to-blood ratio of around 0.59, Cmax of around 454.50 ± 151.35 ng/mL, Tmax of around 0.49 ± 0.15 h and oral bioavailability of around 19.74 ± 6.78%. Conclusions: These findings suggest that PZ-2891, an agonist of PANK2, is a novel and potential candidate agent for AD with excellent efficacy and PK properties.},
}

@article {pmid41471351,
year = {2025},
author = {Makhaeva, GF and Utepova, IA and Rudakova, EV and Kovaleva, NV and Boltneva, NP and Zyryanova, EY and Musikhina, AA and Lazarev, VF and Vladimirova, SA and Guzhova, IV and Ganebnykh, IN and Astakhova, TY and Timokhina, EN and Chupakhin, ON and Charushin, VN and Richardson, RJ},
title = {1-Azinyl-1'-Alkenylferrocenes with Anticholinesterase, Antioxidant, and Antiaggregating Activities as Multifunctional Agents for Potential Treatment of Alzheimer's Disease.},
journal = {Pharmaceuticals (Basel, Switzerland)},
volume = {18},
number = {12},
pages = {},
doi = {10.3390/ph18121862},
pmid = {41471351},
issn = {1424-8247},
support = {24-63-00016//Russian Science Foundation/ ; },
abstract = {Background/Objectives: This study focused on synthesizing novel alkenyl derivatives of azinylferrocenes and evaluating their potential as Alzheimer's disease (AD) therapeutics. Methods: 1-Azinyl-1'-acetylferrocenes were obtained by regioselective acetylation of azinylferrocenes, followed by the Wittig reaction or reduction of 1-azinyl-1'-acetylferrocenes and subsequent dehydration of the resulting alcohols. The synthesized compounds underwent the following biological activity testing relevant to AD: inhibition of acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and off-target carboxylesterase (CES); antioxidant capacity (ABTS and FRAP assays); inhibition of Aβ42 self-aggregation (thioflavin method); blocking AChE-induced β-amyloid aggregation (propidium displacement); and cytotoxicity in SH-SY5Y and MSC-Neu cells (MTT assay). Results: Quinoline and bipyridine derivatives demonstrated effective cholinesterase inhibition, especially quinoline 7b (AChE IC50 3.32 μM; BChE IC50 3.68 μM), while acridine derivatives were poor inhibitors. Quantum chemical (QC) calculations predicted that acridine derivatives were especially prone to form stable dimers. Molecular docking into protein targets generated by an AlphaFold3 reproduction code showed that these dimers were too bulky to access enzyme active sites, yet they could bind to protein surfaces to inhibit Aβ42 self-aggregation and displace propidium from the AChE peripheral anionic site. All compounds showed high antioxidant activity in ABTS and FRAP assays, with quinoline derivatives being 2-4 times more potent than Trolox. QC calculations supported these findings. Quinoline and bipyridine derivatives also exhibited low cytotoxicity and scant CES inhibition. Conclusions: Overall, the synthesized ferrocenes, particularly the quinoline and bipyridine derivatives, appear promising for further research as multifunctional therapeutic agents targeting AD due to their anticholinesterase, antiaggregating, and antioxidant activities combined with low toxicity.},
}

@article {pmid41471285,
year = {2025},
author = {Stanciu, GD},
title = {Beyond Conventional Pharmacotherapy: Unraveling Mechanisms and Advancing Multi-Target Strategies in Alzheimer's Disease.},
journal = {Pharmaceuticals (Basel, Switzerland)},
volume = {18},
number = {12},
pages = {},
doi = {10.3390/ph18121797},
pmid = {41471285},
issn = {1424-8247},
abstract = {Alzheimer's disease (AD) remains the most prevalent form of dementia worldwide, representing a major and escalating global health burden [...].},
}

@article {pmid41471143,
year = {2025},
author = {Ortiz-Islas, E and Montes, P and Rodríguez-Pérez, CE and Ruiz-Sánchez, E and Sánchez-Barbosa, T and Pichardo-Rojas, D and Zavala-Tecuapetla, C and Carvajal-Aguilera, K and Campos-Peña, V},
title = {Correction: Ortiz-Islas et al. Evolution of Alzheimer's Disease Therapeutics: From Conventional Drugs to Medicinal Plants, Immunotherapy, Microbiotherapy and Nanotherapy. Pharmaceutics 2025, 17, 128.},
journal = {Pharmaceutics},
volume = {17},
number = {12},
pages = {},
doi = {10.3390/pharmaceutics17121625},
pmid = {41471143},
issn = {1999-4923},
abstract = {References [...].},
}

@article {pmid41471108,
year = {2025},
author = {Treder, N and Bączek, T},
title = {Sialic Acid in Neurodegenerative and Psychiatric Disorders: From Molecular Regulation to Targeted Nanocarrier-Based Therapy.},
journal = {Pharmaceutics},
volume = {17},
number = {12},
pages = {},
doi = {10.3390/pharmaceutics17121593},
pmid = {41471108},
issn = {1999-4923},
abstract = {In recent years, the exploration of molecular and cellular mechanisms underlying central nervous system (CNS) disorders has expanded beyond classical neurotransmitter- and receptor-based approaches toward a more integrated view including immune, metabolic, and glycosylation processes. Among these, sialic acid and its derivatives have emerged as critical regulators of neuronal communication, immune modulation, and synaptic plasticity. Their involvement ranges from maintaining neurochemical homeostasis under physiological conditions to contributing to the onset and progression of neurodegenerative and psychiatric diseases. Given the central role of sialylation in cellular recognition, receptor signaling, and blood-brain barrier (BBB) interactions, understanding these pathways provides valuable insight for the development of advanced therapeutic and diagnostic strategies. This review highlights recent evidence linking altered sialic acid metabolism and polysialylation to Alzheimer's disease and other neurodegenerative and psychiatric disorders. It further discusses the potential of sialic acid-related mechanisms as novel molecular targets and their integration into innovative nanocarrier-based drug delivery systems designed to improve brain penetration, selectivity, and therapeutic efficacy. Finally, current challenges and future perspectives in translating sialic acid-based approaches into clinical applications are addressed.},
}

@article {pmid41471079,
year = {2025},
author = {Trasca, DM and Dorin, PI and Carmen, S and Varut, RM and Singer, CE and Radivojevic, K and Stoica, GA},
title = {Artificial Intelligence in Biomedicine: A Systematic Review from Nanomedicine to Neurology and Hepatology.},
journal = {Pharmaceutics},
volume = {17},
number = {12},
pages = {},
doi = {10.3390/pharmaceutics17121564},
pmid = {41471079},
issn = {1999-4923},
abstract = {Background/Objectives: This review evaluates the expanding contributions of artificial intelligence (AI) across biomedicine, focusing on cancer therapy and nanomedicine, cardiology and medical imaging, neurodegenerative disorders, and liver disease. Core AI concepts (machine learning, deep learning, artificial neural networks, model training/validation, and explainability) are introduced to frame application domains. Methods: A systematic search of major biomedical databases (2010-2025) identified English-language original studies on AI in these four areas; 203 articles meeting PRISMA 2020 criteria were included in a qualitative synthesis. Results: In oncology and nanomedicine, AI-driven methods expedite nanocarrier design, predict biodistribution and treatment response, and enable nanoparticle-enhanced monitoring. In cardiology, algorithms enhance ECG interpretation, coronary calcium scoring, automated image segmentation, and noninvasive FFR estimation. For neurological disease, multimodal AI models integrate imaging and biomarker data to improve early detection and patient stratification. In hepatology, AI supports digital histopathology, augments intraoperative robotics, and refines transplant wait-list prioritization. Common obstacles are highlighted, including data heterogeneity, lack of standardized acquisition protocols, model transparency, and the scarcity of prospective multicenter validation. Conclusions: AI is emerging as a practical enabler across these biomedical fields, but its safe and equitable use requires harmonized data, rigorous multicentre validation, and more transparent models to ensure clinical benefit while minimizing bias.},
}

@article {pmid41471033,
year = {2025},
author = {Park, YC and Seol, E and Lee, J and Hong, JH and Jung, JG and Sunwoo, J},
title = {Pharmacokinetic Evaluation of GB-5001, a Long-Acting Injectable Formulation of Donepezil, in Healthy Korean Participants: Population Pharmacokinetics with Phase 1 Study.},
journal = {Pharmaceutics},
volume = {17},
number = {12},
pages = {},
doi = {10.3390/pharmaceutics17121517},
pmid = {41471033},
issn = {1999-4923},
support = {Not applicable//G2GBIO Inc./ ; },
abstract = {Background/Objectives: Oral donepezil, an acetylcholinesterase (AChE) inhibitor for Alzheimer's disease, faces adherence challenges. Long-acting injectable (LAI) formulations like GB-5001 aim to enhance adherence by reducing dosing frequency. This Phase 1, open-label, active-controlled, dose-escalation study evaluated the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of GB-5001 in healthy male adults. Methods: Participants were assigned to cohorts receiving GB-5001A or GB-5001D (LAI formulations) via intramuscular (IM) or subcutaneous (SC) injection, or oral Aricept[®]. Safety, PK, and PD (AChE inhibition) were assessed. The influence of CYP2D6 phenotype was explored, and modeling/simulation was performed. Results: Fifty healthy male participants completed the study. After IM administration, GB-5001A (70 mg, 140 mg, 280 mg) showed dose-dependent increases in exposure (AUCinf and Cmax), resulting in significantly extended exposure compared to oral Aricept[®] 10 mg. No serious adverse events were reported; the most common AEs were mild injection site reactions, which occurred in all treatment groups except the GB-5001A IM 70 mg group and the Aricept group. GB-5001A also demonstrated sustained AChE inhibition. Conclusions: GB-5001A, an LAI donepezil, showed favorable safety, dose-proportional PK, and sustained plasma exposure. It achieved a 3-4-fold longer half-life than oral donepezil. These findings, supported by modeling, highlight GB-5001A's potential as a once-monthly IM alternative for Alzheimer's disease treatment.},
}

@article {pmid41470875,
year = {2025},
author = {Fekete, M and Jarecsny, T and Lehoczki, A and Major, D and Fazekas-Pongor, V and Csípő, T and Lipécz, Á and Szappanos, Á and Pázmándi, EM and Varga, P and Varga, JT},
title = {Mediterranean Diet, Polyphenols, and Neuroprotection: Mechanistic Insights into Resveratrol and Oleuropein.},
journal = {Nutrients},
volume = {17},
number = {24},
pages = {},
doi = {10.3390/nu17243929},
pmid = {41470875},
issn = {2072-6643},
support = {TKP2021-NKTA-47//TKP2021-NKTA-47/ ; RRF-2.3.1-21-2022-00003//Ministry of Innovation and Technology under the National Cardiovascular Laboratory Program/ ; },
mesh = {*Diet, Mediterranean ; Humans ; *Iridoid Glucosides/pharmacology ; *Iridoids/pharmacology ; *Resveratrol/pharmacology ; *Neurodegenerative Diseases/prevention & control ; *Polyphenols/pharmacology ; *Neuroprotective Agents/pharmacology ; *Neuroprotection ; Parkinson Disease/prevention & control ; },
abstract = {Background: Neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease, are among the leading causes of disability and mortality worldwide. Dietary patterns have emerged as modifiable risk factors that may influence disease onset and progression. The Mediterranean diet (MedDiet), rich in fruits, vegetables, whole grains, legumes, fish, and extra virgin olive oil, has been consistently associated with better cognitive outcomes and reduced risk of neurodegeneration. Aim: This narrative review summarizes current evidence on the role of the MedDiet in slowing the progression of neurodegenerative diseases, with a particular focus on polyphenols such as resveratrol and oleuropein as key bioactive mediators. Methods: We synthesized findings from epidemiological studies, clinical trials, and mechanistic research to provide an integrated overview of how adherence to the MedDiet and its polyphenol components affects neurodegenerative disease trajectories. Results: Epidemiological studies suggest that higher MedDiet adherence is associated with slower cognitive decline, reduced conversion from mild cognitive impairment to Alzheimer's disease, and better motor and non-motor outcomes in Parkinson's disease. Mechanistically, the MedDiet modulates oxidative stress, neuroinflammation, mitochondrial function, vascular health, and the gut-brain axis. Polyphenols such as resveratrol and oleuropein exert neuroprotective effects through antioxidant activity, modulation of amyloid aggregation, mitochondrial biogenesis, and activation of signaling pathways (e.g., SIRT1). Clinical studies, although limited, indicate beneficial effects of polyphenol-rich interventions on cognitive and metabolic biomarkers. Conclusions: Current evidence supports the Mediterranean diet as a promising dietary strategy to slow the progression of neurodegenerative diseases. Polyphenols, including resveratrol and oleuropein, may play a role in mediating these effects. Further well-designed, long-term clinical trials are needed to establish causal relationships, optimize dosage, and explore biomarker-driven personalized nutrition approaches.},
}

*Diet, Mediterranean
Humans
*Iridoid Glucosides/pharmacology
*Iridoids/pharmacology
*Resveratrol/pharmacology
*Neurodegenerative Diseases/prevention & control
*Polyphenols/pharmacology
*Neuroprotective Agents/pharmacology
*Neuroprotection
Parkinson Disease/prevention & control

@article {pmid41470866,
year = {2025},
author = {Pham, J and Refesse, M and Saeed, A and Latunde-Dada, GO},
title = {Haem Oxygenase-1, Ferroptosis and Disorders-A Narrative Review.},
journal = {Nutrients},
volume = {17},
number = {24},
pages = {},
doi = {10.3390/nu17243921},
pmid = {41470866},
issn = {2072-6643},
mesh = {*Ferroptosis/physiology ; Humans ; *Heme Oxygenase-1/metabolism ; Iron/metabolism ; Reactive Oxygen Species/metabolism ; Animals ; Neoplasms ; Antioxidants/metabolism ; NF-E2-Related Factor 2/metabolism ; Lipid Peroxidation ; },
abstract = {Ferroptosis is a non-apoptotic form of cell death that is driven by iron and reactive oxygen species (ROS). This process is characterised by lipid peroxidation, which damages cell membranes and distinguishes it from other types of cell death. Excess iron promotes ferroptosis through Fenton chemistry, leading to increased ROS production. While glutathione peroxidase 4 has been identified as a key regulator of this process, other factors, such as the ferroptosis suppressor protein 1 (FSP1), suggest that regulation is more complex. Ferroptosis has been associated with several degenerative diseases, including Alzheimer's disease, Parkinson's disease, acute kidney injury, liver disorders, and cancer. The enzyme haemoxygenase-1 (HO-1) plays dual roles: it can promote ferroptosis by releasing iron or provide protection through its antioxidant effects in various organs and tissues. HO-1 increases iron levels through the catabolism of haem which can heighten sensitivity to ferroptosis by influencing iron trafficking and ferritin expression. Conversely, HO-1 has demonstrated nephroprotective effects in cases of renal injury and other disorders. HO-1's involvement in regulating iron metabolism and its antioxidant capabilities can lead to differing outcomes, highlighting key players in the ferroptosis process. The Nrf2/HO-1 axis is crucial for its antioxidant properties in various disorders. Moreover, dietary sources can enhance HO-1 induction through Nrf2 regulation. Hence, HO-1 acts as both a modulator and a mediator, presenting new therapeutic targets for cancer, neurodegeneration, and kidney and liver diseases.},
}

*Ferroptosis/physiology
Humans
*Heme Oxygenase-1/metabolism
Iron/metabolism
Reactive Oxygen Species/metabolism
Animals
Neoplasms
Antioxidants/metabolism
NF-E2-Related Factor 2/metabolism
Lipid Peroxidation

@article {pmid41470855,
year = {2025},
author = {Gunning, JA and Converse, MF and Gudarzi, B and Lotfallah, W and Racette, SB},
title = {Dietary Patterns Influence Chronic Disease Risk and Health Outcomes in Older Adults: A Narrative Review.},
journal = {Nutrients},
volume = {17},
number = {24},
pages = {},
doi = {10.3390/nu17243910},
pmid = {41470855},
issn = {2072-6643},
support = {T32DK137525/DK/NIDDK NIH HHS/United States ; },
mesh = {Humans ; Chronic Disease/prevention & control/epidemiology ; Risk Factors ; Aged ; *Diet/adverse effects ; Cardiovascular Diseases/prevention & control ; Neoplasms/prevention & control ; Diabetes Mellitus, Type 2/prevention & control ; Aging ; *Feeding Behavior ; },
abstract = {The global population is aging rapidly and the prevalence of age-related noncommunicable diseases is increasing. Favorable dietary patterns have the power to reduce the risk or progression of various age-related chronic diseases, including obesity, hypertension, cardiovascular disease, type 2 diabetes, several types of cancer, and some neurodegenerative diseases. In contrast, adverse dietary patterns may contribute to the onset or progression of many chronic diseases or their risk factors. A diet rich in wholesome, nutrient-dense, minimally processed foods, such as a Mediterranean-style diet, may promote health and prevent disease through its abundance of antioxidants, fiber, omega-3 fatty acids, and micronutrients. Conversely, a diet high in nutrient-poor and ultra-processed foods may accelerate disease onset and progression by promoting inflammation and affecting metabolic pathways adversely. This narrative review summarizes the literature from clinical trials and large population-based studies on protective dietary patterns and adverse dietary patterns that influence risk of cardiovascular disease and related risk factors, cancer, Alzheimer's disease and related dementias, type 2 diabetes, frailty, and liver disease.},
}

Humans
Chronic Disease/prevention & control/epidemiology
Risk Factors
Aged
*Diet/adverse effects
Cardiovascular Diseases/prevention & control
Neoplasms/prevention & control
Diabetes Mellitus, Type 2/prevention & control
Aging
*Feeding Behavior

@article {pmid41470842,
year = {2025},
author = {Salinas, LMB and Marroquin, M and Mendez, M and Omaña-Guzmán, I and Lopez-Alvarenga, JC},
title = {How the Intake of Pulses May Impact Metabolic Disorders and Dementia Risk: A Narrative Review.},
journal = {Nutrients},
volume = {17},
number = {24},
pages = {},
doi = {10.3390/nu17243898},
pmid = {41470842},
issn = {2072-6643},
mesh = {Humans ; *Dementia/prevention & control/epidemiology ; *Metabolic Diseases/prevention & control/epidemiology ; Gastrointestinal Microbiome ; *Diet ; Risk Factors ; Antioxidants ; },
abstract = {We present a narrative review focusing on pulses' geographical origin and distribution, their impact on human evolution and history, and their influence on human health. Pulses, including dry peas, beans, and lentils, are renowned for their richness in chemical antioxidants. Despite containing antinutrients, processing techniques preserve their health advantages. Epidemiological research has consistently demonstrated that the consumption of pulses is associated with favorable effects on metabolism. This evidence is further supported by molecular and clinical research, which has elucidated potential nutrigenomic mechanisms and effects on gut microbiota composition underlying their health benefits. However, the literature lacks randomized controlled clinical trials investigating the effects of pulses on health outcomes. Despite this limitation, our review provides valuable insights into the potential beneficial effects of pulses in ameliorating metabolic disorders and reducing the risk of dementia and Alzheimer's disease. Acknowledging the current limitations, we identify areas for further research to generate additional evidence. Specifically, well-designed randomized controlled trials are needed to thoroughly assess the efficacy of pulses in preventing metabolic diseases. Addressing these research gaps will enhance our understanding of the health benefits associated with pulse consumption and facilitate evidence-based dietary recommendations to improve public health outcomes.},
}

Humans
*Dementia/prevention & control/epidemiology
*Metabolic Diseases/prevention & control/epidemiology
Gastrointestinal Microbiome
*Diet
Risk Factors
Antioxidants

@article {pmid41470813,
year = {2025},
author = {Araújo-Rodrigues, H and Garzón-García, L and Salsinha, AS and Relvas, JB and Tavaria, FK and Santos-Buelga, C and González-Paramás, AM and Pintado, ME},
title = {Neuroprotective Effects of Mushroom Biomass Digestive Fractions and Gut Microbiota Metabolites in Microglial and Caenorhabditis elegans Models of Neurodegeneration.},
journal = {Nutrients},
volume = {17},
number = {24},
pages = {},
doi = {10.3390/nu17243867},
pmid = {41470813},
issn = {2072-6643},
support = {UID/50016/2025//Fundação para a Ciência e Tecnologia/ ; 2020.05798.BD//Fundação para a Ciência e Tecnologia/ ; Project SA106P24//Consejería de Educación de la Junta de Castilla y León/ ; Summer Fellowship.//Federation of European Biochemical Societies/ ; PID2019-106167RB-I00//MCIN/AEI/10.13039/501100011033/ ; MCIN/AEI/10.13039/501100011033//PRE2020-095876/ ; TRANSCOLAB PLUS research project (0112_TRANSCOLAB_PLUS_2_P), entitled "Cross-border 842 Collaborative Laboratory for the green transition of the Agri-Food and Agro-industrial sector"//European Regional Development Fund-ERDF-through the INTERREG VI-A 844 Spain-Portugal Cooperation Program (POCTEP) 2021-2027/ ; P40 OD010440/CD/ODCDC CDC HHS/United States ; },
mesh = {Animals ; Caenorhabditis elegans/drug effects ; *Gastrointestinal Microbiome ; *Neuroprotective Agents/pharmacology ; Humans ; Reactive Oxygen Species/metabolism ; *Microglia/drug effects/metabolism ; *Agaricales/chemistry/metabolism ; Disease Models, Animal ; *Neurodegenerative Diseases ; Biomass ; Fatty Acids, Volatile/pharmacology/metabolism ; Animals, Genetically Modified ; gamma-Aminobutyric Acid/pharmacology ; Cell Survival/drug effects ; Amyloid beta-Peptides/metabolism ; },
abstract = {Background: The accumulation of β-amyloid plaques, neurofibrillary tangles, and neuroinflammation are key hallmarks of Alzheimer's disease (AD). Reactive oxygen species (ROS) act as major triggers and amplifiers of neuroinflammatory responses, contributing to immune dysregulation and neuronal damage. Despite extensive research, no effective therapy halts or reverses AD progression, emphasizing the need for alternative preventive strategies, including the use of natural compounds. Objectives: This study evaluated the neuroprotective effects of simulated digestive fractions (permeate fraction) of mushroom biomass (MB)-Trametes versicolor (TV), Hericium erinaceus (HE), and Pleurotus ostreatus (PO)-and key gut microbiota-derived metabolites, such as short-chain fatty acids (SCFAs) and γ-aminobutyric acid (GABA) on ROS production in human microglial cells (HMC3) and in transgenic Caenorhabditis elegans models exhibiting hyperphosphorylated Tau and β-amyloid-induced toxicity. Methods: Cell viability and ROS production were assessed in HMC3 cells treated with mushroom fractions and metabolites. Chemotaxis and paralysis assays were performed in transgenic C. elegans strains expressing hyperphosphorylated Tau or β-amyloid proteins. Results: Mushroom digestive fractions and SCFAs significantly decreased ROS levels in HMC3 cells. Moreover, mushroom digestive fractions, butyric acid, and GABA improved behavioral outcomes in C. elegans, enhancing chemotaxis and delaying paralysis. These effects were dose-dependent and varied among mushroom species and metabolites. Conclusions: Mushroom-derived digestive fractions and microbiota-related metabolites exhibit neuroprotective activity by modulating oxidative stress and mitigating neurodegeneration-associated behaviors. Diets enriched with such MBs may support preventive strategies for neurodegenerative diseases. Further research is required to elucidate the molecular mechanisms underlying these protective effects and their translational potential for human neurodegenerative diseases.},
}

Animals
Caenorhabditis elegans/drug effects
*Gastrointestinal Microbiome
*Neuroprotective Agents/pharmacology
Humans
Reactive Oxygen Species/metabolism
*Microglia/drug effects/metabolism
*Agaricales/chemistry/metabolism
Disease Models, Animal
*Neurodegenerative Diseases
Biomass
Fatty Acids, Volatile/pharmacology/metabolism
Animals, Genetically Modified
gamma-Aminobutyric Acid/pharmacology
Cell Survival/drug effects
Amyloid beta-Peptides/metabolism

@article {pmid41470118,
year = {2025},
author = {Liampas, I and Siokas, V and Marogianni, C and Tsika, A and Dastamani, M and Stamati, P and Dardiotis, E},
title = {Associations Between Cognitive Performance and Motor Signs in Older Adults with Alzheimer's Dementia.},
journal = {Medicina (Kaunas, Lithuania)},
volume = {61},
number = {12},
pages = {},
pmid = {41470118},
issn = {1648-9144},
mesh = {Humans ; Female ; Aged ; Male ; *Alzheimer Disease/complications/physiopathology/psychology ; Cross-Sectional Studies ; Aged, 80 and over ; *Cognition/physiology ; Neuropsychological Tests ; Executive Function/physiology ; Middle Aged ; },
abstract = {Background and Objectives: The interplay between motor tasks and cognition in Alzheimer's dementia (AD) remains insufficiently characterised. We hypothesised that prefrontal-mediated cognitive functions could contribute to motor impairments in older adults with AD. Materials and Methods: Cross-sectional data from the National Alzheimer's Coordinating Centre (NACC) were analysed. Our sample included older adults (≥60 years) with a baseline diagnosis of AD. The Unified Parkinson's Disease Rating Scale Part-III was used to assess the presence or absence of motor signs. Episodic memory, language, confrontation naming, attention, processing speed, and executive function were assessed using a neuropsychological battery. Binary logistic models examined the relationship between cognitive performance and motor manifestations. Results: Of 44,713 NACC participants, 5124 individuals with complete covariate data were included in the analysis, 1339 with and 3785 without motor signs. Participants were predominantly female (~55%), with an average age of 76.5 ± 7.9 years and mean education of 14.2 ± 3.7 years. The presence of motor manifestations was related to slower processing speed (Trail Making Test-Part A) and impaired executive function (Trail Making Test-Part B). No covariate modified these associations. Among specific motor domains, impaired chair rise was related to executive dysfunction, whereas postural instability, impaired posture-gait, and bradykinesia were related to slower mental processing. Hypophonia, masked facies, resting tremor, action-postural tremor and rigidity were not associated with any cognitive measure. Conclusions: Processing speed and, to a lesser extent, executive function emerged as the main cognitive functions associated with motor manifestations in older adults with AD. Further research is needed to clarify the nature of this association, including potential causal pathways.},
}

Humans
Female
Aged
Male
*Alzheimer Disease/complications/physiopathology/psychology
Cross-Sectional Studies
Aged, 80 and over
*Cognition/physiology
Neuropsychological Tests
Executive Function/physiology
Middle Aged

@article {pmid41470021,
year = {2025},
author = {Azami, H and McAndrews, MP and Rostaghi, M and Zomorrodi, R and Brooks, H and Blumberger, DM and Fischer, CE and Flint, A and Herrmann, N and Kumar, S and Gallagher, D and Mah, L and Mulsant, BH and Pollock, BG and Rajji, TK and , },
title = {Multiscale dispersion entropy of resting-state EEG in older adults with Alzheimer's disease, mild cognitive impairment, and remitted major depressive disorder.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251410962},
doi = {10.1177/13872877251410962},
pmid = {41470021},
issn = {1875-8908},
abstract = {BackgroundMultiscale dispersion entropy (MDEnt) is a nonlinear EEG measure that quantifies brain complexity across time scales, reflecting both local and global brain dynamics. Previous research indicates lower complexity at short time scales in Alzheimer's disease (AD) compared to mild cognitive impairment (MCI) and healthy controls (HCs), with MCI also showing lower values than HCs. Major depressive disorder (MDD) has also been preliminarily linked to reduced complexity during acute episodes.ObjectiveTo assess whether MDEnt at short time scales can distinguish AD from MCI and HCs, and to examine complexity differences across additional groups, remitted MDD (rMDD) and rMDD + MCI, while exploring associations with cognitive performance.MethodsThe study included 316 older adults: 44 HCs, 46 with rMDD, 114 with MCI, 71 with rMDD + MCI, and 41 with AD. Resting-state, eyes-closed EEGs were analyzed using MDEnt at 24 ms (short) and 60 ms (long) time scales. Cognitive function was measured with the Montreal Cognitive Assessment and a composite cognitive score.ResultsShort time scale complexity was lowest in AD, followed by MCI, and highest in HCs; rMDD presence had no impact. Only AD showed reduced complexity at long time scales. Complexity at both time scales was significantly correlated with cognitive performance.ConclusionsThis study highlights the value of MDEnt to assess complexity at short time scale and differentiate individuals with AD, MCI, or HCs. Reduced complexity in these individuals may underlie their cognitive impairment. In contrast, our study suggests that any MDD impact on complexity is likely related to active depressive symptoms.},
}

@article {pmid41470020,
year = {2025},
author = {Ailabouni, NJ and Hanjani, LS and Weir, KR and Reeve, E and Abdulla, A and Bohill, R and Brandt, N},
title = {Empowerment to have a conversation with healthcare professionals: Co-designing the PRIME (PReparing people living with dementia and carers to Initiate conversations about their MEdicines) tool.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251406907},
doi = {10.1177/13872877251406907},
pmid = {41470020},
issn = {1875-8908},
abstract = {BackgroundEmpowering people living with memory problems, including Alzheimer's disease, dementia, or mild cognitive impairment, and their carers to be engaged in the shared decision-making process about their medicines could reduce their risk of experiencing medicine-related harm. More co-designed resources to support them are needed.ObjectiveTo co-design and test a conversation-starter tool to empower people living with memory problems and their carers (consumers) to have a conversation with their healthcare professional (HCP) about their medicines.MethodsWe employed a consumer participation method with an eleven-member Steering Group consisting of six consumers and five HCPs from Australia and Maryland, United States of America. We conducted one-on-one interviews with consumers and HCPs to test the tool. We analyzed data deductively using the integrated-Promoting Action on Research Implementation in Health Services (i-PARIHS) framework and the Communication-Health Information Processing (C-HIP) model. Inductively, we also drew emergent themes that did not fit within the i-PARIHS.ResultsWe successfully co-designed the PRIME tool and recruited 35 participants (26 consumers; 9 HCPs) to improve the tool's readability and comprehensibility. We identified four major themes including: Theme 1: Variable consumer self-advocacy; Theme 2: Value of the tool; Theme 3: Changing behavior, empowerment, and motivation; Theme 4: Future use, dissemination, and implementation.ConclusionsOur participants valued the PRIME tool as an empowerment resource. They believed it would remind them of their permission to ask questions about their medicines. This may lead to a closer alignment of medicines with a person's goals of care.},
}

@article {pmid41470019,
year = {2025},
author = {Botella, M and Estanga, A and Ros, N and Saldias, J and Cañada, M and García-Sebastián, M and Larrea, JÁ and Echeverria, M and Garrido, A and Altuna, M},
title = {Neuropsychiatric signatures across the Alzheimer's disease continuum in Down syndrome and sporadic forms: A biomarker-driven comparison.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251407121},
doi = {10.1177/13872877251407121},
pmid = {41470019},
issn = {1875-8908},
abstract = {BackgroundNeuropsychiatric symptoms (NPS) are increasingly recognized as core features of Alzheimer's disease (AD), often emerging preclinically. Adults with Down syndrome (DS) represent a genetically determined population at high risk for AD (DS-associated AD, DSAD), yet their neuropsychiatric profiles remain undercharacterized and seldom compared with sporadic AD (sAD).ObjectiveTo delineate and compare NPS profiles across the AD continuum in adults with and without DS, examining their relationships with amyloid-tau (AT) biomarker status, neuroimaging, and neurophysiological markers.MethodsWe conducted a cross-sectional study of 293 adults (138 with DS, ≥ 18 years; 155 non-DS, ≥ 50 years) stratified by cognitive stage. NPS were assessed via Neuropsychiatric Inventory (NPI). A subset underwent cerebrospinal fluid biomarker analysis, MRI, and EEG. Linear models explored NPI associations with AT status, MRI/EEG findings, sex, and psychotropic medication use.ResultsNPS severity increased with cognitive decline in both cohorts; affective and behavioral domains were most prevalent. Individuals with DS showed significantly higher NPI total scores across all stages, particularly disinhibition and aberrant motor behaviors during dementia. Positive AT biomarker status and abnormal EEG/MRI findings independently associated with greater NPI burden, including in cognitively unimpaired individuals. Polypharmacy and female sex were additional predictors in DS. Caregiver distress paralleled NPI severity.ConclusionsThis study identifies shared and syndrome-specific NPS trajectories in DSAD and sAD, with clear associations to AD biomarkers and neurophysiological dysfunction. Findings support NPS as early indicators of AD pathology and underscore the importance of personalized, developmentally informed behavioral assessment and care.},
}

@article {pmid41469954,
year = {2025},
author = {Falzarano, FB and Cimarolli, VR and Riffin, C and Czaja, SJ and Boerner, K},
title = {Preliminary evaluation of a tailored difficulty index for long-distance family caregivers of older adults with dementia.},
journal = {BMC geriatrics},
volume = {25},
number = {1},
pages = {1074},
pmid = {41469954},
issn = {1471-2318},
support = {K99AG073509/AG/NIA NIH HHS/United States ; R21AG069019/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *Caregivers/psychology ; Female ; Male ; Aged ; *Dementia/psychology/therapy/diagnosis ; Pilot Projects ; Aged, 80 and over ; Middle Aged ; Psychometrics/methods ; Feasibility Studies ; Time Factors ; },
abstract = {BACKGROUND: The bulk of research focused on family caregiving for persons with Alzheimer's Disease and Related Dementias (ADRD) has been limited to those in close proximity to their care-recipient. The unique needs of the growing number of long-distance caregivers (LDCs) remain understudied and unaddressed. Existing measures of caregiver strain, which were primarily developed for and with geographically proximate caregivers, do not adequately capture the unique challenges faced by LDCs (e.g., difficulties with ensuring and monitoring care from afar). Thus, the current study aims to evaluate the suitability and psychometric properties of a caregiving difficulty index tailored for LDCs.

METHODS: Data were from 40 participants enrolled in a pilot feasibility trial of a psycho-educational intervention for burdened LDCs of older adults with ADRD. Participants completed several measures assessing sociodemographic characteristics, caregiver burden, strain (i.e., family and work conflict, role captivity), and the 9-item difficulty index. An exploratory factor analysis (EFA) was conducted to examine the index's underlying factor structure. Pearson's correlations were used to assess the relationship among the final items and other validated measures of burden and strain. Cronbach's alphas were calculated for the total index and each subscale to evaluate internal consistency.

RESULTS: EFA findings revealed that retention of eight out of the original nine items yielded the best model fit, with items loading onto two distinct components capturing general caregiving and distance-specific challenges. Cronbach's alphas were 0.79 for the total measure and between 0.67-0.80 for its subscales. Overall difficulty scores were also significantly positively related to caregiver burden (r = 0.42) and strain (rs = 0.31-0.44). Results provide initial evidence supporting the index's reliability and validity.

CONCLUSION: Findings provide preliminary support for the potential suitability of the 8-item index for use with LDCs and underscore the importance of tailored assessments to adequately measure the unique challenges associated with the long-distance caregiving experience.},
}

Humans
*Caregivers/psychology
Female
Male
Aged
*Dementia/psychology/therapy/diagnosis
Pilot Projects
Aged, 80 and over
Middle Aged
Psychometrics/methods
Feasibility Studies
Time Factors

@article {pmid41469943,
year = {2025},
author = {Kim, E and Lee, J and Han, D},
title = {Tau proteoforms as plasma biomarkers in Alzheimer's disease: mechanisms, measurement, and Medicine.},
journal = {Expert review of proteomics},
volume = {},
number = {},
pages = {},
doi = {10.1080/14789450.2025.2611853},
pmid = {41469943},
issn = {1744-8387},
abstract = {INTRODUCTION: Blood-based tau proteoforms have emerged as specific, scalable biomarkers of Alzheimer's pathology, addressing the limitations of symptom-based diagnosis, neuroimaging, and invasive cerebrospinal fluid (CSF) testing. This review synthesizes advances in tau phosphorylation and truncation biology, evaluates translation from CSF to plasma with state-of-the-art proteomics, and outlines the analytical standards and cross-matrix calibration needed for clinical adoption.

AREAS COVERED: We conducted a literature search in PubMed and Google Scholar. We reviewed studies published between January 2005 and September 2025 investigating tau proteoforms in Alzheimer's disease.

EXPERT OPINION: Blood-based tau proteoforms are poised to move Alzheimer's diagnostics from specialized imaging to accessible frontline testing, with plasma p-tau217 approaching positron emission tomography (PET) and CSF performance and multi-analyte panels with glial fibrillary acidic protein (GFAP) or neurofilament light (NfL) improving differential diagnosis while reducing invasiveness and cost. Building on the first FDA-cleared plasma assay(Lumipulse G p-tau217/Aβ1-42 Ratio) in May 2025, we anticipate a dual pathway over the next decade in which referral centers use high-plex mass spectrometry(MS) panels for phosphoforms and truncations, while primary care adopts automated high-throughput immunoassays (e.g Chemiluminescent enzyme immunoassay (CLEIA)) for triage, supported by harmonized Standard Operating Procedures (SOPs), cross-matrix calibration, and robust reference materials.},
}

@article {pmid41419947,
year = {2025},
author = {Conca, F and Esposito, V and Polito, C and Santi, GC and Gibbons, DM and Caminiti, SP and Boccalini, C and Morinelli, C and Berti, V and Mazzeo, S and Bessi, V and Marcone, A and Iannaccone, S and Sorbi, S and Perani, D and Cappa, SF and Catricalà, E},
title = {Mapping the neural correlates of the effect of psycholinguistic variables on picture naming performance: a FDG-PET study across neurodegenerative diseases.},
journal = {Alzheimer's research & therapy},
volume = {17},
number = {1},
pages = {272},
pmid = {41419947},
issn = {1758-9193},
abstract = {BACKGROUND: Picture naming performance is influenced by the properties of the stimuli and of the words to be retrieved, such as word length and lexical frequency. Significant inconsistencies, however, remain regarding the brain regions mediating these effects in neurodegenerative patients. In the present study, we addressed this issue by correlating regional cerebral metabolism with several naming-related variables in a large cohort of neurodegenerative patients, who are likely to exhibit naming impairments due to different mechanisms of cognitive dysfunction.

METHODS: A total of 178 patients classified within the Frontotemporal (FTD) and Alzheimer’s Disease (AD) spectra were administered a picture naming test validated for the Italian language (CaGi) and underwent a FDG-PET scan. Principal Component Analysis on 10 psycholinguistic variables resulted in the extraction of four components, labelled as word-form, visual, lexical, and semantic, according to the variables populating each of them. Using an item-level approach, the influence of each component on patients' performance was assessed and correlated with brain metabolism data from 11 left hemispheric Regions of Interest.

RESULTS: A simple word form and lexical structure were associated with better naming performance. The imaging findings reveal a distributed neural network, with fusiform gyrus supporting both visual and semantic features. Inferior frontal and posterior temporal/parietal gyri represented an interface between lexico-semantic and phonological properties. The anterior temporal lobe contributed to all the stages of picture naming. The two dementia spectra activated different areas in response to the same variables, in particular for the visual and semantic components, suggesting the presence of disease-specific compensatory mechanisms.

CONCLUSIONS: Our results suggest a distributed neural network showing both commonalities and specificities in how picture and word properties influence naming performance. The network also seems capable of compensatory changes in the face of the extension of neurodegenerative processes.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13195-025-01936-y.},
}

@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