@article {pmid41489328,
year = {2026},
author = {Brown, MJ and Murtala, NM and Amoatika, D and Kaur, A and Addo, PNO and Osinubi, MO and Miller, M and Ingram, LA},
title = {Erratum: Clinical and sociodemographic characteristics of Alzheimer's disease and related dementias among people with HIV.},
journal = {AIDS (London, England)},
volume = {40},
number = {1},
pages = {131},
doi = {10.1097/01.aids.0001173688.45352.98},
pmid = {41489328},
issn = {1473-5571},
}

@article {pmid41488982,
year = {2025},
author = {Ressa, R and Ettinger, J and Chowdhury, E and Graham, L and Ndirangu, K and Mancebo, JZ and Bodnar, C},
title = {A value assessment of patient-level outcomes and productivity loss for intravenous and subcutaneous lecanemab for patients with early Alzheimer's disease.},
journal = {Journal of medical economics},
volume = {29},
number = {1},
pages = {118-134},
doi = {10.1080/13696998.2025.2609499},
pmid = {41488982},
issn = {1941-837X},
mesh = {Humans ; *Alzheimer Disease/drug therapy ; Injections, Subcutaneous ; Markov Chains ; Patient Preference ; Administration, Intravenous ; Cost-Benefit Analysis ; Caregivers ; Efficiency ; Decision Support Techniques ; },
abstract = {AIMS: Intravenous (IV) lecanemab is approved for the treatment of patients with early Alzheimer's disease (AD); a subcutaneous (SC) option may offer additional benefits. We assessed the overall value of SC treatments, and direct/indirect outcomes associated with IV and SC lecanemab.

METHODS AND MATERIALS: For the narrative review, PubMed was searched (February 2025) for studies comparing patient preferences for IV/SC treatment administration published between 2015-2025. Study eligibility was determined using patient, intervention, comparator, outcomes, and study criteria. For the decision-analytic model, a Markov model was developed with four lecanemab treatment scenarios. Scenarios one to three included IV initiation (10 mg/kg biweekly) to month 18, followed by either IV initiation continued (10 mg/kg biweekly), SC maintenance (250 mg weekly) or IV maintenance (10 mg/kg every 4 weeks). Scenario four included SC initiation (500 mg weekly) for an 18-month period, followed by SC maintenance (250 mg weekly). Outcomes were administration time/frequency; patient, caregiver, and healthcare professional time; and caregiver productivity loss.

RESULTS: Forty-three publications reported patient treatment preferences. Most (88.4%) reported that patients preferred SC over IV. Key reasons for this were time savings (n = 13/43 studies; 30.2%), convenience (n = 11/43; 25.6%), treatment frequency (n = 12/43; 27.9%). Two studies (n = 2/43; 4.7%) reported an IV preference over SC; for three studies (n = 3/43; 7.0%), treatment preference was driven by administration frequency. Decision-analytic modeling of lecanemab treatment scenarios revealed that IV initiation to IV maintenance had the lowest number of administrations, whereas SC initiation to SC maintenance had the lowest number of treatment hours and caregiver productivity losses.

LIMITATIONS: Caution must be taken when generalizing these results for all AD patients.

CONCLUSIONS: SC treatments show value as a therapeutic option. IV and SC lecanemab availability may offer benefits to patients, caregivers, and society, and improve shared decision making.},
}

Humans
*Alzheimer Disease/drug therapy
Injections, Subcutaneous
Markov Chains
Patient Preference
Administration, Intravenous
Cost-Benefit Analysis
Caregivers
Efficiency
Decision Support Techniques

@article {pmid41488807,
year = {2025},
author = {Tang, F and Wei, J and Wong, ML and Lei, P},
title = {Tau protein: Physiological functions and multifaceted roles in neurodegenerative and psychiatric disorders.},
journal = {Genomic psychiatry : advancing science from genes to society},
volume = {},
number = {},
pages = {},
pmid = {41488807},
issn = {2997-2388},
abstract = {Tau, mainly expressed in neurons and less expressed in glial cells (astrocytes and oligodendrocytes) and peripheral tissues, is involved in the assembly and stabilization of microtubules, and other biological processes such as axonal transport, metal ion transport, etc. Dysfunction of tau, caused by mutations, hyperphosphorylation, aggregation, or reduced expression, is closely associated with tauopathies (e.g., Alzheimer disease) and psychiatric disorders. Tau-based biomarkers have emerged as predictive/diagnostic tools for these conditions. However, despite advancing to clinical trials, tau-targeted therapies have demonstrated limited efficacy in diseases. Therefore, this review aims to systematically summarize tau's physiological and pathological functions, the progress in tau-targeted therapies, and the development of tau as a disease biomarker, as well as to discuss critical gaps in understanding tau's pathophysiological roles and therapeutic translatability.},
}

@article {pmid41488805,
year = {2026},
author = {Klassen, P and Alexudis, C and Klose, V and de San José, NG and Huss, A and Bachhuber, F and Soylu, Ö and Fazeli, B and Erhart, D and Laible, M and Anderl-Straub, S and Jesse, S and Otto, M and Ludolph, AC and Tumani, H and Halbgebauer, S},
title = {Increased transmembrane protein 119 (TMEM119) levels in the cerebrospinal fluid of patients with mild cognitive impairment due to Alzheimer's disease suggest early microglial involvement.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {1},
pages = {e70240},
pmid = {41488805},
issn = {2352-8729},
abstract = {INTRODUCTION: We aimed to evaluate the potential of the microglial marker transmembrane protein 119 (TMEM119) in the cerebrospinal fluid (CSF) as a (differential) diagnostic biomarker for neurodegenerative diseases.

METHODS: Following assay validation, we used enzyme-linked immunosorbent assay to measure CSF TMEM119 in 174 patients from six diagnostic groups: Alzheimer's disease (AD, n = 35), amyotrophic lateral sclerosis (ALS, n = 33), cerebral microangiopathy (CM, n = 25), frontotemporal lobar degeneration (FTLD, n = 28), Lewy body diseases (n = 21), and non-neurodegenerative controls (n = 33).

RESULTS: CSF TMEM119 levels were elevated in the AD group compared to the control (p = 0.004), CM (p = 0.005), and FTLD (p = 0.023) groups. Levels were higher in both mild cognitive impairment (MCI-AD) and dementia (ADD) subgroups when compared to controls. For the discrimination of AD from controls, the area under the curve (AUC) was 0.78.

DISCUSSION: Our results indicate that CSF TMEM119 may have potential as a biomarker representing microglial involvement in early and later stages of AD.

HIGHLIGHTS: Elevated levels of TMEM119 were observed in the CSF of patients with AD.Increased CSF TMEM119 was seen in MCI-AD patients compared to controls.Elevated levels in MCI-AD underscore early microglial involvement in AD.In the AD group, an association was found between CSF TMEM119 and CSF total tau.CSF TMEM119 may provide valuable information on neuroinflammation.},
}

@article {pmid41488323,
year = {2025},
author = {Lotlikar, MS and Zellmer, JC and Bhattacharyya, R},
title = {Sigma receptors and mitochondria-associated ER membranes are converging therapeutic targets for Alzheimer's disease.},
journal = {Frontiers in neuroscience},
volume = {19},
number = {},
pages = {1733659},
pmid = {41488323},
issn = {1662-4548},
abstract = {Alzheimer's disease (AD) begins decades before clinical symptoms emerge. The "amyloid hypothesis" suggests that amyloid-β (Aβ) deposition initiates a cascade of tau hyperphosphorylation, neuroinflammation, and neuronal loss leading to cognitive decline. The recent success of anti-Aβ therapies such as Leqembi in prodromal or mild cognitive impaired patients underscores the importance of early intervention and Aβ clearance. However, safety and cost limitations highlight the need for alternative therapeutic strategies. Small-molecule modulators of Sigma-1 and Sigma-2 receptors (σ1R and σ2R) have emerged as promising candidates for AD treatment. σ1R agonists exhibit neuroprotective and anti-amnestic effects under pathological conditions without affecting normal cognition. Beyond AD, σ1R is implicated in several neurodegenerative diseases including ALS (amyotrophic lateral sclerosis), Parkinson's, and Huntington's diseases, stroke, and epilepsy. σ1R plays a key role at mitochondria-associated ER membranes (MAMs)-specialized lipid raft-like domains that form functional membrane contact sites between the endoplasmic reticulum (ER) and mitochondria. β-secretase (BACE1), γ-secretase, and their substrates APP and palmitoylated APP (palAPP) localize in the MAMs, promoting amyloidogenic Aβ production. MAMs serve as dynamic hubs for inter-organelle communication, calcium signaling, and lipid metabolism. The "MAM hypothesis" proposes that MAM dysregulation drives early AD pathology and persists throughout disease progression, contributing to neurofibrillary tangle formation, calcium imbalance, and neuroinflammation. This review aims to summarize the current understanding of σ1R-mediated regulation of MAMs and its neuroprotective mechanisms, highlighting potential therapeutic opportunities for targeting σ1R in AD and other neurodegenerative disorders.},
}

@article {pmid41488245,
year = {2025},
author = {Karatoprak, K and Cander, S},
title = {Effects of endocrine disruptors on the neurological system.},
journal = {Turkish journal of medical sciences},
volume = {55},
number = {7},
pages = {1657-1663},
pmid = {41488245},
issn = {1303-6165},
mesh = {*Endocrine Disruptors/adverse effects/toxicity ; Humans ; *Nervous System Diseases/chemically induced ; *Environmental Pollutants/adverse effects ; *Nervous System/drug effects ; Neurodegenerative Diseases/chemically induced ; Environmental Exposure/adverse effects ; },
abstract = {BACKGROUND/AIM: There is increasing interest in endocrine disrupting chemicals because of the potential effects on neurological health. These chemicals are widely found in various consumer products and industrial processes, and can lead to serious disorders of the endocrine system by disrupting hormone synthesis, expression, and function. The aim of this review was to examine epidemiological and experimental findings by investigating the link between exposure to endocrine disrupting chemicals and adverse neurological outcomes.

MATERIALS AND METHODS: In the preparation of this review, a PubMed literature search was conducted using the words "endocrine disruptors," "neuroendocrine effects," "neurobehavioral effects," and "neurodevelopmental effects" and articles containing relevant studies were examined.

RESULTS: Recent studies have shown a strong correlation between exposure to endocrine disrupting chemicals and the development of neurodegenerative diseases such as Alzheimer's and Parkinson's disease, and neurodevelopmental diseases such as autism spectrum disorder and attention deficit hyperactivity disorder. The effects of common pollutants such as pesticides, bisphenol A, polychlorinated biphenyls, and heavy metals on the endocrine system have been especially emphasized.

CONCLUSION: In conclusion, understanding the role played by endocrine disrupting chemicals in the development of neurological diseases will be of critical importance in the development of new strategies to prevent these diseases.},
}

*Endocrine Disruptors/adverse effects/toxicity
Humans
*Nervous System Diseases/chemically induced
*Environmental Pollutants/adverse effects
*Nervous System/drug effects
Neurodegenerative Diseases/chemically induced
Environmental Exposure/adverse effects

@article {pmid41488128,
year = {2025},
author = {Kearney, S and Yang, S and Wen, Z and Hou, B and Duong-Tran, D and Chen, T and Moore, J and Ritchie, M and Shen, L},
title = {Enabling Few-Shot Alzheimer's Disease Diagnosis on Biomarker Data with Tabular LLMs.},
journal = {ACM-BCB ... ... : the ... ACM Conference on Bioinformatics, Computational Biology and Biomedicine. ACM Conference on Bioinformatics, Computational Biology and Biomedicine},
volume = {2025},
number = {},
pages = {},
pmid = {41488128},
abstract = {Early and accurate diagnosis of Alzheimer's disease (AD), a complex neurodegenerative disorder, requires analysis of heterogeneous biomarkers (e.g., neuroimaging, genetic risk factors, cognitive tests, and cerebrospinal fluid proteins) typically represented in a tabular format. With flexible few-shot reasoning, multimodal integration, and natural-language-based interpretability, large language models (LLMs) offer unprecedented opportunities for prediction with structured biomedical data. We propose a novel framework called TAP-GPT, T abular A lzheimer's P rediction GPT, that adapts TableGPT2, a multimodal tabular-specialized LLM originally developed for business intelligence tasks, for AD diagnosis using structured biomarker data with small sample sizes. Our approach constructs few-shot tabular prompts using in-context learning examples from structured biomedical data and finetunes TableGPT2 using the parameter-efficient qLoRA adaption for a clinical binary classification task of AD or cognitively normal (CN). The TAP-GPT framework harnesses the powerful tabular understanding ability of TableGPT2 and the encoded prior knowledge of LLMs to outperform more advanced general-purpose LLMs and a tabular foundation model (TFM) developed for prediction tasks. To our knowledge, this is the first application of LLMs to the prediction task using tabular biomarker data, paving the way for future LLM-driven multi-agent frameworks in biomedical informatics.},
}

@article {pmid41488126,
year = {2025},
author = {Xu, FH and Duong-Tran, D and Huang, H and Saykin, AJ and Thompson, P and Davatzikos, C and Zhao, Y and Shen, L},
title = {Characterizing Amyloid Pathogenic Spread in Alzheimer's Disease Through A Network Diffusion Model.},
journal = {ACM-BCB ... ... : the ... ACM Conference on Bioinformatics, Computational Biology and Biomedicine. ACM Conference on Bioinformatics, Computational Biology and Biomedicine},
volume = {2025},
number = {},
pages = {},
pmid = {41488126},
abstract = {Early amyloid-β deposition is a hallmark of Alzheimer's disease (AD), though the exact nature of amyloid pathogenesis is not fully characterized. In this study, we designed a network diffusion model to simulate the spread of amyloid pathology through white matter brain networks of diagnostic subpopulations of healthy control (HC), mild cognitive impairment (MCI), and AD. Our network diffusion model was able to successfully model the spread of amyloid, recapturing regional distributions of amyloid observed in [18]F-florbetapir positron emission tomography (r=0.44-0.46, P<0.01). When tuning the optimal parameters, we found that the optimal diffusion time (t) provided a notion of temporal progression, where the HC group had the lowest time (t = 107.22 ± 16.67), followed by MCI (t = 122.78 ± 19.63), and lastly AD (t =136.20 ± 24.47). The optimal starting seeds were the brainstem in all three diagnostic groups, followed by the lateral orbitofrontal lobes for HC and MCI and the lingual gyri in AD. Our findings corroborate evidence from amyloid staging studies where amyloid starts in the primary neocortex and associative cortex. The significance of the white matter structural network in the diffusion process provides evidence for the trans-synaptic spread hypothesis of amyloid in AD. In conclusion, our study provides novel insights into the pathogenesis of amyloid in AD and its subsequent propagation throughout the brain.},
}

@article {pmid41488125,
year = {2025},
author = {Hou, B and Wang, Z and Zhou, Z and Tong, B and Wang, Z and Bao, J and Duong-Tran, D and Long, Q and Shen, L},
title = {Fair CCA for Fair Representation Learning: An ADNI Study.},
journal = {ACM-BCB ... ... : the ... ACM Conference on Bioinformatics, Computational Biology and Biomedicine. ACM Conference on Bioinformatics, Computational Biology and Biomedicine},
volume = {2025},
number = {},
pages = {},
pmid = {41488125},
abstract = {Canonical correlation analysis (CCA) is a technique for finding correlations between different data modalities and learning low-dimensional representations. As fairness becomes crucial in machine learning, fair CCA has gained attention. However, previous approaches often overlook the impact on downstream classification tasks, limiting applicability. We propose a novel fair CCA method for fair representation learning, ensuring the projected features are independent of sensitive attributes, thus enhancing fairness without compromising accuracy. We validate our method on synthetic data and real-world data from the Alzheimer's Disease Neuroimaging Initiative (ADNI), demonstrating its ability to maintain high correlation analysis performance while improving fairness in classification tasks. Our work enables fair machine learning in neuroimaging studies where unbiased analysis is essential. Code is available in https://github.com/ZhanliangAaronWang/FR-CCA-ADNI.},
}

@article {pmid41488046,
year = {2025},
author = {Liang, F and Sun, F and Guo, C and Zhong, H},
title = {Treadmill exercise alleviates Alzheimer's disease pathologies in APP/PS1 mice through modulation of microglial glucose metabolic reprogramming.},
journal = {Frontiers in aging neuroscience},
volume = {17},
number = {},
pages = {1734837},
pmid = {41488046},
issn = {1663-4365},
abstract = {OBJECTIVE: Our preliminary studies have demonstrated that exercise counteracts Alzheimer's disease (AD) by mitigating microglia-mediated neuroinflammation and enhancing microglial Aβ clearance. However, the underlying mechanism remains unclear. Given the crucial role of glucose metabolic reprogramming in regulating microglial functions, this study investigated the effects of treadmill exercise on microglial glucose metabolism and associated AD pathologies.

MATERIALS AND METHODS: Three-month-old male APP/PS1 transgenic mice were randomly assigned to a sedentary group (AD-SED) or an exercise group (AD-EXE). Age- and sex-matched C57BL/6 mice served as the wild-type control group (WT-SED). The AD-EXE group underwent a 3-month treadmill exercise intervention. Following the intervention, we assessed spatial learning and memory using the Morris water maze test, measured neuroinflammation and Aβ levels via Western blot and ELISA, and analyzed microglial glucose metabolism using LC-MS/MS targeted metabolomics and Seahorse assays.

RESULTS: APP/PS1 mice exhibited longer escape latencies during place navigation trial and fewer platform crossings during the spatial probe trial; these deficits were partially reversed by treadmill exercise. Furthermore, the exercise intervention significantly reduced hippocampal Aβ levels and suppressed neuroinflammation. Notably, microglia from 6-month-old APP/PS1 mice showed significant impairments in both glycolysis and oxidative phosphorylation (OXPHOS), with a metabolic profile primarily reliant on glycolysis. Treadmill exercise enhanced both glycolysis and OXPHOS, and shifted the metabolic phenotype from glycolytic-dominant toward oxidative phosphorylation, and restored metabolic homeostasis.

CONCLUSION: Treadmill exercise promotes microglial glucose metabolic remodeling, which attenuates neuroinflammation and Aβ pathology, and restores spatial learning and memory deficits in APP/PS1 mice.},
}

@article {pmid41487996,
year = {2025},
author = {Camprubí-Ferrer, L and Yang, Y and Fernández-Calle, R and Boza-Serrano, A and García-Revilla, J and Frontiñán-Rubio, J and Deierborg, T},
title = {Galectin-3 shapes microglial phenotype through endogenous and exogenous mechanisms.},
journal = {Frontiers in cellular neuroscience},
volume = {19},
number = {},
pages = {1729776},
pmid = {41487996},
issn = {1662-5102},
abstract = {Galectin-3 (Gal3) is a multifunctional lectin expressed and released by microglia, where it influences diverse processes in both homeostasis and disease. To dissect its intracellular and extracellular roles, we generated Gal3-deficient BV2 microglial cells and systematically assessed how genetic deletion and exogenously added recombinant Gal3 shape microglial physiology. Gal3 deletion increased cell area, mitochondrial activity, and motility without affecting proliferation, linking endogenous Gal3 to microglial energetic control and dynamic cellular physiology. Endogenous Gal3 was required to maintain CD11b surface levels, and restrains TREM2 and Clec7a expression, whereas exogenous Gal3 promoted CD45 internalization and drove a paracrine TNFα release. Endogenous and exogenous Gal3 are synergistically needed for Syk phosphorylation and NOX2 expression. Internalization assays demonstrated that endogenous Gal3 constrained phagocytosis and endocytosis, while exogenous Gal3 enhanced endocytosis in a paracrine manner. In the Alzheimer's disease 5xFAD mouse model, where Gal3 deletion was reported to lower amyloid plaque burden, the absence of Gal3 does not affect microgliosis but elevates Clec7a levels around plaques. Together, these findings reveal Gal3 as a critical regulator of microglial homeostasis, uptake pathways, receptor expression, and inflammatory signaling. We have defined a novel microglial regulation based on endogenous and exogenous pools of Gal3. By identifying a novel Gal3-Clec7a interaction, this work highlights Gal3 as a key modulator of microglial phenotype and a potential target for therapeutic modulation of neuroinflammation.},
}

@article {pmid41487944,
year = {2026},
author = {Rus Prelog, P and Zupan, M and Gregorič Kramberger, M and Frol, S},
title = {The Concomitant Use of Selective Serotonin Reuptake Inhibitors and Anti-Amyloid Treatment in Alzheimer's Disease: Balancing Benefits and Risks.},
journal = {Dementia and geriatric cognitive disorders extra},
volume = {16},
number = {1},
pages = {1-3},
pmid = {41487944},
issn = {1664-5464},
}

@article {pmid41487496,
year = {2025},
author = {Cheng, R and Kim, J},
title = {Intranasal delivery of iron chelators and management of central nervous system disease.},
journal = {Frontiers in pharmacology},
volume = {16},
number = {},
pages = {1709259},
pmid = {41487496},
issn = {1663-9812},
abstract = {Brain iron dyshomeostasis plays a critical role in the pathology of multiple central nervous system (CNS) disorders, including neurodegenerative and neuropsychiatric diseases. Iron chelators such as deferoxamine (DFO) and deferiprone (DFP) have demonstrated therapeutic potential in mitigating disease progression in these conditions. However, systemic administration is hindered by poor blood-brain barrier (BBB) permeability, dose-limiting toxicity, and poor patient compliance due to frequent dosing regimens. In recent years, intranasal (IN) drug delivery has emerged as a promising strategy to bypass the BBB, providing a direct nose-to-brain delivery route via olfactory and trigeminal pathways while minimizing systemic exposure. This review provides a comprehensive summary of the current status of iron chelation therapy for CNS disorders with a focus on pharmacokinetics, efficacy, and translational potential of IN administration. While IN DFO has been extensively studied in preclinical models of Alzheimer's disease and stroke, recent developments have expanded the scope to other chelators such as DFP. We compare traditional systemic routes, including oral and intravenous, with intranasal administration, highlighting their respective advantages and limitations for CNS delivery. With ongoing advances in formulation and delivery technologies, IN iron chelators provide a promising alternative for the treatment of CNS disorders characterized by impaired iron homeostasis in the brain.},
}

@article {pmid41485354,
year = {2025},
author = {Lin, X and Tang, L and Hu, Z},
title = {Causal relationship between tractography-based brain white matter structural connectome and risk of psychiatric disorders: A bidirectional Mendelian randomization study.},
journal = {Psychiatry research. Neuroimaging},
volume = {357},
number = {},
pages = {112131},
doi = {10.1016/j.pscychresns.2025.112131},
pmid = {41485354},
issn = {1872-7506},
abstract = {AIM: This study sought to explore the causal link between 206 tractography-derived white matter connectivity metrics in the brain and the risk of nine psychiatric disorders, employing a bidirectional two-sample Mendelian randomization (MR) approach.

METHOD: Summary datasets of 9 psychiatric disorders including anxiety disorder, Alzheimer's disease (AD), major depressive disorder (MDD), autism spectrum disorder (ASD), bipolar disorder (BD), schizophrenia, Tourette syndrome(TS), attention-deficit hyperactivity disorder (ADHD), and cannabis use disorder (CUD) were used. MR analyses were performed using the inverse variance weighted (IVW), weighted median, MR-Egger, MR-PRESSO, and MR-robust adjusted profile score (MR-RAPS) method.

RESULTS: Forward MR analysis showed that the left-hemisphere dorsal attention network to the right-hemisphere limbic network connectome was causally associated with a 32 % higher risk of anxiety disorder [odds ratio(OR) = 1.32; 95 % confidence interval (CI): 1.16, 1.51). Reverse MR analysis indicated that AD was associated with a 7 % higher risk for the left-hemisphere limbic network to the right-hemisphere control network connectome(OR = 1.07; 95 % CI: 1.03, 1.10).

CONCLUSIONS: Our MR analysis reveals causal relationships between brain white matter structural connectivity and psychiatric disorders, advancing our knowledge of the neural mechanisms that contribute to psychiatric disorders and providing evidence for targeted interventions in psychiatric treatment.},
}

@article {pmid41483724,
year = {2025},
author = {Strain, JF and Rahmani, M and Phuah, CL and Dierker, D and Luo, J and Owen, C and Vlassenko, AG and Jafri, H and Bourgeat, P and Fripp, J and Jin, L and Moulder, K and Benzinger, T and Xiong, C and Lee, JM and Weiner, M and Masters, CL and Morris, JC and Womack, K and Goyal, MS and , },
title = {Regional growth rates of white matter hyperintensities are associated with beta-amyloid burden.},
journal = {Neurobiology of aging},
volume = {160},
number = {},
pages = {22-32},
doi = {10.1016/j.neurobiolaging.2025.12.006},
pmid = {41483724},
issn = {1558-1497},
abstract = {There is increasing evidence for an association between white matter hyperintensities (WMH) and brain beta-amyloid deposition. How WMH are longitudinally associated with brain beta-amyloid burden requires further investigation, particularly with respect to co-existent vascular risk factors and differences across white matter regions. We measured WMH on MRI and vascular risk factors in a combined neuroimaging data set of cognitively normal and individuals with dementia comprised of the ADNI, AIBL and OASIS3 studies, which includes harmonized centiloid estimates of beta-amyloid burden from PET imaging. WMH were measured using the TrUE-Net algorithm. Vascular risk factors were extracted from provided clinical data and used to calculate individual revised Framingham Stroke Risk Profile (FSRP) scores. Linear mixed effects modelling was used to determine the relationship between the growth rate of WMH and baseline beta-amyloid burden, controlling for age, sex, APOE4 status, and vascular risk factors. 1243 participants [49 % female, mean age 71.7 y (SD 7.6 y)] had at least 3 brain MRIs. Linear mixed models demonstrate robust independent cross-sectional relationships between WMH and baseline beta-amyloid burden (beta coefficient=0.27, p < 0.001), age (beta coefficient=0.04, p < 0.001) and vascular risk factors (beta coefficient=0.25, p < 0.001). Growth rates of WMH increased with baseline beta-amyloid burden (slope=0.021, p < 0.001) and decreased with anti-hypertensive medications (slope=-0.019, p = 0.002), above and beyond age, APOE4 status, and other vascular risk factors. The longitudinal association for beta-amyloid burden persisted in a similar analysis for parietal WM. Our study suggests that in Alzheimer disease research cohorts, WMH progression is associated with age and beta-amyloid burden, particularly in parietal white matter, and slowed by anti-hypertensive treatment.},
}

@article {pmid41483575,
year = {2025},
author = {Zhou, M and Tang, S and Zhang, Y and Fu, G and Yu, W and Wang, S and Cheng, S and Song, Z},
title = {Natural glycosides as multi-target neuroprotective agents in Alzheimer's disease: Bridging mechanistic insights and translational potential.},
journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology},
volume = {150},
number = {},
pages = {157738},
doi = {10.1016/j.phymed.2025.157738},
pmid = {41483575},
issn = {1618-095X},
abstract = {BACKGROUND: Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder defined by pathologies including amyloid-beta (Aβ) aggregation, tau hyperphosphorylation, and neuroinflammation. Natural glycosides, safe compounds derived from plants, have emerged as promising multi-target neuroprotective agents for treating this complex disease.

PURPOSE: This review synthesizes the mechanistic evidence for natural glycosides in AD, examining their effects on key pathological pathways like Aβ production, tau phosphorylation, cholinergic neurotransmission, and neuroinflammation. It also addresses significant translational challenges, including poor bioavailability and blood-brain barrier (BBB) penetration, and outlines potential delivery strategies.

RESULTS: Evidence indicates that natural glycosides exert multi-target effects, modulating Aβ and tau pathology while restoring cholinergic function. They also mitigate mitochondrial dysfunction, oxidative stress, and inhibit ferroptosis. Despite these benefits, their therapeutic application is currently hindered by poor oral bioavailability and limited penetration of the BBB.

CONCLUSION: Natural glycosides are credible multi-target candidates for AD therapy. Overcoming their pharmacokinetic limitations through brain-targeted delivery strategies, such as nanotechnology and intranasal approaches, is critical for their clinical success. Future research must prioritize advancing these compounds from preclinical studies to rigorous clinical trials to meet the urgent therapeutic need in AD.},
}

@article {pmid41482168,
year = {2025},
author = {Wang, X and Salminen, LE and Petkus, AJ and Frahmand, I and Millstein, J and Beavers, DP and Espeland, MA and Erus, G and Braskie, MN and Thompson, PM and Gatz, M and Chui, HC and Resnick, SM and Kaufman, JD and Rapp, SR and Shumaker, S and Brown, M and Younan, D and Chen, JC},
title = {Association between late-life air pollution exposure and medial temporal lobe atrophy in older women.},
journal = {Neurotoxicology},
volume = {112},
number = {},
pages = {103378},
doi = {10.1016/j.neuro.2025.103378},
pmid = {41482168},
issn = {1872-9711},
abstract = {Ambient air pollution exposures increase risk for Alzheimer's disease (AD) and related dementias, possibly due to structural changes in the medial temporal lobe (MTL). However, previous MRI studies examining exposure effects on the MTL were cross-sectional and mostly focused on the hippocampus, yielding mixed results. We addressed these limitations using longitudinal data collected from 653 cognitively unimpaired community-dwelling women from the Women's Health Initiative Memory Study with two MRI scans (Mage at MRI-1 =77.3 ± 3.5years). We used linear regressions to examine relationships between 3-year annual average exposures to fine particulate matter (PM2.5) and nitrogen dioxide (NO2) prior to MRI-1, and 5-year volume changes in the bilateral hippocampus, amygdala, parahippocampal gyrus (PHG), and entorhinal cortex (ERC), which were summed to operationalize MTL volume. Covariates included intracranial volume, sociodemographic, lifestyle, and clinical characteristics. For each interquartile increase of PM2.5 (3.26 µg/m[3]) and NO2 (6.77 ppb), adjusted MTL volume had greater shrinkage by 0.32 cm[3] (95 %CI=[-0.43,-0.21]) and 0.12 cm[3] (95 %CI=[-0.22,-0.01]), respectively. Exposure effects did not differ by APOE ε4 genotype, sociodemographic, or cardiovascular risk factors. Subregionally, higher PM2.5 was associated with greater PHG and ERC atrophy, and higher NO2 was associated with greater PHG atrophy. Brain associations with PM2.5 were not significant among women residing in locations that met air quality standards (PM2.5<9 µg/m[3]). Collectively, late-life PM2.5 and NO2 exposures were associated with greater MTL atrophy in cognitively unimpaired older women, especially in the PHG and ERC. These cortical MTL subregions are among the earliest affected by AD neuropathology - and may be preferentially vulnerable to air pollution neurotoxicity.},
}

@article {pmid41482167,
year = {2025},
author = {Bhardwaj, S and Bharti, A and Sharma, RS and Mishra, S and Kumar, P and Ethayathulla, AS and Singh, A and Mishra, V},
title = {Linking Particulate Matter Exposure and Neurological Disorders: Evidence from Epidemiology, Biomarkers and Mechanistic Studies.},
journal = {Neurotoxicology},
volume = {},
number = {},
pages = {103375},
doi = {10.1016/j.neuro.2025.103375},
pmid = {41482167},
issn = {1872-9711},
abstract = {Exposure to particulate matter (PM) including fine (PM2.5), coarse (PM10), and ultrafine particles (UFPM) has emerged as a critical environmental determinant of neurological disorders, including Alzheimer's and Parkinson's diseases, neurodevelopmental impairments, and cognitive decline. This review integrates evidence from 129 research articles (2002-2025) to elucidate the mechanistic, biomarker-based, and public health dimensions of PM-induced neurotoxicity. Mechanistic pathways include oxidative stress, neuroinflammation, mitochondrial dysfunction, and blood-brain barrier disruption, with documented structural and functional damage in brain regions such as the hippocampus and prefrontal cortex. PM2.5 serves as a carrier of neurotoxic metals (e.g., lead, cadmium, vanadium) and understudied organic toxicants (e.g., PAHs, pesticides), amplifying its pathogenic potential. Exposure occurs through the olfactory route, systemic circulation, and gut-brain axis, highlighting multiple entry points into the central nervous system. Biomarkers such as Aβ42, phosphorylated tau (p-tau), and α-synuclein are elevated in experimental models, but require greater validation in human PM-exposed populations. Children and older adults represent the most vulnerable groups due to developmental sensitivity and cumulative neuroinflammatory burden, yet remain underrepresented in cohort studies. Geographic disparities further limit generalizability, with low- and middle-income countries underrepresented despite experiencing the highest PM burdens. Future research must advance longitudinal, cohort and life-course studies, multi-omics biomarker discovery, and real-world mixture toxicology to identify intervention targets. These findings call for urgent integration of air pollution control into public health strategies targeting neurological diseases, emphasizing prevention through regulation, early detection, and equity-focused research frameworks.},
}

@article {pmid41482165,
year = {2025},
author = {He, D and Zhao, H and Zhu, Y and Kou, Y and Liu, T and Huang, H and Yang, H and Zhang, L and Deng, J and Xu, F and Wang, Q},
title = {USP53 promotes NOTCH2-induced neuroinflammation in Alzheimer's disease.},
journal = {Neurochemistry international},
volume = {},
number = {},
pages = {106109},
doi = {10.1016/j.neuint.2025.106109},
pmid = {41482165},
issn = {1872-9754},
abstract = {PURPOSE: This study aimed to investigate the role of USP53 and its associated signaling pathway associated with USP53 in Alzheimer's disease (AD).

METHODS: In vivo experiments were conducted in C57BL/6, 5XFAD, and USP53-knockout 5XFAD (USP53[-/-]) mice. In vitro experiments were performed using primary human microglia cells. mRNA expression was examined using quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR). Protein expression was measured using western blotting and immunofluorescence (IF). Immunoprecipitation (Co-IP) was used to detect protein-protein interactions. Morris Water Maze (MWM) was used to evaluate the learning ability and memory of mice.

RESULTS: USP53 was overexpressed in patients with AD. Knockout of USP53 downregulated the expression of CD68, glial fibrillary acidic protein (GFAP), ionized calcium binding adaptor molecule 1 (Iba1) and neuronal nuclear protein (NeuN), as well as the inflammatory mediators, interleukin-1 beta (IL-1β) and tumor necrosis factor alpha (TNF-α). The accumulation of Tau protein was reduced, and the learning ability and memory was improved in USP53[-/-] mice compared to 5XFAD mice. In vitro experiments demonstrated that protein-protein interaction existed between USP53 and NOTCH2 and that the inhibition of USP53 prevented amyloid-beta (Aβ)-induced deubiquitination of NOTCH2. Knockdown of USP53 reduced Aβ-induced elevation of inflammatory mediators and repressed Aβ-induced activation of IKKβ/NFκB signaling pathway in microglia.

CONCLUSION: USP53 promotes the activation of neuroinflammation and worsens learning ability and memory in AD mice, mediated by NOTCH2.},
}

@article {pmid41482153,
year = {2025},
author = {Yan, Y and Su, J and Xie, M and Kong, Y and Wang, C and Yuan, G and Fang, Y and Hwang, K and Kim, CY and Han, H and Zhang, Z},
title = {Low Intensity Ultrasound-facilitated exosome delivery promotes hippocampal neurogenesis in Alzheimer's disease.},
journal = {Brain stimulation},
volume = {},
number = {},
pages = {103015},
doi = {10.1016/j.brs.2025.103015},
pmid = {41482153},
issn = {1876-4754},
abstract = {BACKGROUND: Low-intensity ultrasound (LIUS) and human adipose-tissue mesenchymal stem cell-derived exosomes (hADSC-Exos) have shown neuroprotective potential, but their combined effects in Alzheimer's disease (AD) remain unclear.

OBJECTIVE: To evaluate the safety and efficacy of intranasal hADSC-Exos alone or combined with LIUS in APP/PS1 mice, and explore underlying molecular mechanisms.

METHODS: Female APP/PS1 mice (30 weeks) were randomized into five groups (n=6). Treatments included intranasal hADSC-Exos, LIUS, or both for 2 months. Behavioral tests, histology, and hippocampal RNA-seq were performed.

RESULTS: LIUS enhanced Exo uptake in HT22 cells by ∼8% without toxicity. Combined treatment improved learning and memory (escape latency ↓45 s→20 s; P<0.01), increased neurogenesis markers (GFAP/SOX2, DCX, Ki67), and reduced amyloid and microglial activation. RNA-seq identified 93 specific DEGs in the combination group, with enrichment in synaptic and mitochondrial pathways. Fos and Kcnj13 were top DEGs and both downregulated after therapy (P<0.05).

CONCLUSIONS: Intranasal hADSC-Exos combined with LIUS is safe, enhances brain delivery, and synergistically improves cognition and neurogenesis in AD mice. The Fos-Kcnj13 axis may mediate these effects, suggesting a promising noninvasive therapeutic strategy.},
}

@article {pmid41482111,
year = {2025},
author = {Zheng, R and Liu, X and Liao, Z and Wan, R and Qiu, G and Li, M and Tang, C and Zhou, R and Song, J},
title = {Electroacupuncture ameliorates tau-driven cognitive decline by modulating NF-κB/NLRP3 inflammasome signaling in P301S mice.},
journal = {Experimental neurology},
volume = {398},
number = {},
pages = {115637},
doi = {10.1016/j.expneurol.2025.115637},
pmid = {41482111},
issn = {1090-2430},
abstract = {Alzheimer's disease (AD) progression is driven by a vicious cycle wherein pathological Tau hyperphosphorylation promotes microglial activation and NF-κB/NLRP3 inflammasome signaling, leading to excessive secretion of proinflammatory cytokines that reciprocally exacerbate Tau pathology. While pharmacological NLRP3 inhibitors hold therapeutic potential for AD, critical barriers-including poor blood-brain barrier penetration, suboptimal target selectivity, and safety concerns-persist. This study investigated whether electroacupuncture (EA), a non-pharmacological neuromodulatory approach, could disrupt this Tau-inflammasome cycle. Using P301S Tau transgenic mice, two EA regimens were tested at the GV20 (Baihui) acupoint: 6-month-old mice receiving a 1-month EA intervention, and 6-month-old mice undergoing a prolonged 3-month EA intervention. Cognitive function was evaluated via Y-maze, novel object recognition (NOR), and Morris water maze (MWM) tests, while corticospinal function was assessed using tail-suspension limb-clasping scoring. Hippocampal Tau pathology and inflammatory signaling were analyzed by Western blot and immunohistochemistry, targeting total Tau, phosphorylated Tau, NF-κB, NLRP3, caspase-1, IL-1β, IL-18, TNF-α, and microglial morphology. Short-term (1-month) EA treatment significantly improved spatial working memory and recognition memory. Mechanistically, EA reduced p-Tau levels, suppressed NF-κB activation (decreased p-P65/P65 ratio), downregulated NLRP3 inflammasome components (NLRP3, cleaved caspase-1) and proinflammatory cytokines (IL-1β, IL-18 and TNF-α), and mitigated microglial hyperactivation. Importantly, long-term (3-month) EA treatment persistently suppressed p-Tau accumulation and neuroinflammation, thereby consolidating cognitive benefits even in P301S mice with severe corticospinal dysfunction. These findings establish EA as a multi-targeted immunomodulatory strategy that attenuates Tau-driven neuroinflammation through the TNF-α/NF-κB/NLRP3 signaling axis, highlighting its potential as a safe, non-pharmacological adjunct or alternative therapy for AD and related tauopathies.},
}

@article {pmid41482107,
year = {2025},
author = {Chen, X and Yao, H and Ma, S and Zhu, H and Xu, Y and Zhu, Y and Ying, Y and Wang, L and Zhang, Q and Zheng, C and Zhou, Y and Tong, Z and Huang, K and Shentu, Y},
title = {FGF22/FGFR2/YAP modulates ferroptosis to suppress neurodegeneration and cognitive impairment in Alzheimer's disease.},
journal = {Experimental neurology},
volume = {398},
number = {},
pages = {115630},
doi = {10.1016/j.expneurol.2025.115630},
pmid = {41482107},
issn = {1090-2430},
abstract = {Ferroptosis, a programmed cell death triggered by iron accumulation and lipid peroxidation, has been increasingly recognized as a critical mechanism underlying neurodegenerative processes, including Alzheimer's disease (AD). The mechanosensitive regulator YAP is implicated in AD progression and ferroptosis. Here we confirmed that FGF22, a fibroblast growth factor, amelitorated cognitive deficits in β-Amyloid (1-42) (Aβ1-42) treated AD model mice through the FGFR2/YAP pathway, which was further ascertained by various biochemical analyses. Additionally, FGF22 treatment effectively reduced ferroptosis and neuronal apoptosis, thereby attenuating synaptic impairments and neuronal injury in the AD model mice and Aβ1-42-exposed HT22 cells. Collectively, the data presented herein implicate FGF22 as a potential neuroprotective agent in AD models, with its efficacy likely mediated through engaging of the FGFR2/YAP signaling axis.},
}

@article {pmid41482106,
year = {2025},
author = {Kaur, A and Singh, S and Singh, M and Silakari, P and Mannan, A and Vishwas, S and Kumar, P and Subramaniyan, V and Singh, TG},
title = {Demethyleneberberine attenuates combined cognitive and metabolic dysfunctions in an insulin-resistance-induced Alzheimer's disease rat model: Synthesis, in-silico and in-vivo insights.},
journal = {Experimental neurology},
volume = {},
number = {},
pages = {115634},
doi = {10.1016/j.expneurol.2025.115634},
pmid = {41482106},
issn = {1090-2430},
abstract = {In this study, we evaluated the therapeutic potential of DMB, a berberine derivative known for its enhanced bioavailability and reduced toxicity. DMB was synthesized and administered orally at doses of 5 and 10 mg/kg in an in vivo rat model of insulin resistance-induced Alzheimer's disease (AD). This model was established using a combination of a high-fat diet (HFD), streptozotocin (35 mg/kg; intraperitoneally), and amyloid-β25-35. In-silico docking studies revealed that DMB exhibits a high binding affinity for key proteins implicated in both AD and diabetes, including insulin receptors, leptin receptors, protein tyrosine phosphatase 1B (PTP1B), HMG-CoA reductase, acetylcholinesterase (AChE), and butyrylcholinesterase (BChE). Molecular dynamics simulations confirmed the stable binding and inhibitory potential of Demethyleneberberine (DMB) against Insulin Receptor Tyrosine Kinase and AChE. Pharmacological network analysis indicated that DMB modulates multiple pathways involved in metabolic and cognitive decline, suggesting its promise as a therapeutic candidate for insulin resistance-induced AD. Neurobehavioral assessments demonstrated that DMB significantly (p < 0.001) improved cognitive function, ameliorated metabolic disruptions (elevated blood glucose and insulin levels), and normalized pro-inflammatory markers (Tumor Necrosis Factor-alpha (TNF-α), Interleukin 1-beta (IL-1β)) and oxidative stress parameters (Thiobarbituric Acid Reactive Substances (TBARS), glutathione (GSH), superoxide dismutase (SOD), and catalase (CAT). Additionally, DMB reduced levels of AD-related biomarkers, including BACE-1 (β-secretase 1), amyloid-β, and acetylcholinesterase, indicating its capacity to mitigate oxidative stress and amyloidogenesis. This multidisciplinary approach, integrating in vivo and in-silico methodologies, provides a comprehensive understanding of DMB's neuroprotective effects and underscores its potential as a therapeutic agent for both AD and diabetes.},
}

@article {pmid41482105,
year = {2025},
author = {Hegnet, E and Häkli, S and Koivisto, H and Miettinen, PO and Jin, N and Gureviciene, I and Tanila, H},
title = {Age and sex dependent hippocampal neuronal hyperactivity in Alzheimer model mice.},
journal = {Experimental neurology},
volume = {},
number = {},
pages = {115632},
doi = {10.1016/j.expneurol.2025.115632},
pmid = {41482105},
issn = {1090-2430},
abstract = {Both seizures and epileptiform discharges have been reported in various amyloid plaque- forming mouse models of Alzheimer's disease (AD). These mice also show premature mortality possibly related to epileptic seizures. Yet, the relationship between epileptic manifestations and amyloid pathology remains elusive. We utilized deltaFosB as a marker for sustained neuronal hyperactivity to localize the epileptic focus and compared it with age and sex differences in premature mortality between APP/PS1, 5xFAD and wildtype littermate mice and epileptiform discharges (EDs) during sleep in cortex and hippocampus. APP/PS1 mice showed elevated FosB/deltaFosB (shortly FosB) staining in the dentate granule (DG) cells and CA1-CA3 pyramidal cells. These were also the origins of identified epileptiform discharges (EDs) in LFP recordings. APP/PS1 mice showed much higher premature mortality than 5xFAD mice, females more than males. FosB staining intensity in APP/PS1 mice was robustly elevated compared to wildtype mice and peaked at 3 months of age. In contrast, FosB intensity in 5xFAD was lower than in wildtype mice at 1 and 3 months of age, showing a modest elevation at 10 months. In APP/PS1 mice between 1.5 and 3 months of age, the DG amyloid load correlated positively with FosB intensity. Furthermore, the DG FosB intensity showed a positive correlation with the frequency of EDs during sleep. These findings suggest that FosB staining intensity can be used as a proxy for local epileptiform activity in AD model mice and help unveil cellular and molecular basis of AD related neuronal hyperactivity and epilepsy.},
}

@article {pmid41482083,
year = {2025},
author = {Gonzalez, T and Govers, R},
title = {A possible role for glucose transporter inhibition in the genistein-induced amelioration of a high glucose C. elegans Alzheimer disease model.},
journal = {Free radical biology & medicine},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.freeradbiomed.2025.12.040},
pmid = {41482083},
issn = {1873-4596},
abstract = {Wang and colleagues (Wang, et al, Free Rad Biol Med, 242 (2026) 167-187) have found in in silico and in vitro experiments, that multifaceted molecule genistein inhibits many of the detrimental effects of high glucose in a C. elegans-based Alzheimer disease model that expresses β-amyloid in a temperature-dependent fashion. Genistein inhibits, amongst many other pathophysiogical parameters, the glucose-induced aggregation of β-amyloid. While these findings are of interest, a few possible explanations are missing. Here, we hypothesize that genistein may inhibit some of the high glucose effects through its previously described inhibitory interaction with glucose transporters.},
}

@article {pmid41480628,
year = {2026},
author = {Bhowmick, T and Basu, R and Mitra, AK and Ali, SA and Kumer, A and Dhara, B},
title = {Post-Covid Alzheimer and Its Remediation via PROTACs Therapy: A Comprehensive Review.},
journal = {Health science reports},
volume = {9},
number = {1},
pages = {e71631},
pmid = {41480628},
issn = {2398-8835},
abstract = {BACKGROUND AND AIMS: Alzheimer's disease (AD) is a progressive neurodegenerative disorder of aging characterized by memory loss and cognitive decline, associated with amyloid-β toxicity, tau hyperphosphorylation, and neurofibrillary tangle formation. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) affects the central nervous system and has been linked to neurological manifestations and accelerated neurodegeneration, including in individuals without pre-existing AD. Emerging evidence suggests COVID-19 may increase levels of hyperphosphorylated tau, potentially worsening AD severity. This review synthesizes current knowledge on COVID-19-AD interactions and evaluates proteolysis-targeting chimeras (PROTACs) as an emerging therapeutic strategy.

METHODS: Narrative synthesis of recent literature on SARS-CoV-2-related neuropathology, tau pathology in AD, and the design and preclinical development of PROTACs targeting disease-relevant proteins via the ubiquitin-proteasome system.

RESULTS: Reports indicate COVID-19 can precipitate or exacerbate neurodegenerative processes and is associated with increased tau phosphorylation and other biomarkers of neuronal injury. Conventional AD therapies remain limited in efficacy. PROTACs-heterobifunctional molecules that recruit target proteins to E3 ligases for proteasomal degradation-do not require classical active-site binding and have demonstrated preclinical potential for degrading pathogenic proteins, supporting their exploration against tau-driven pathology in AD.

CONCLUSIONS: COVID-19 may intensify AD pathogenesis through mechanisms that include tau hyperphosphorylation, underscoring the need for targeted interventions. PROTACs offer a mechanistically distinct, protein-degradation-based approach with promise for modifying tau-mediated disease; rigorous preclinical and clinical studies are warranted to establish feasibility, safety, and therapeutic impact in AD.},
}

@article {pmid41480618,
year = {2025},
author = {Hu, G and Gogzheyan, C and Panja, S and Sil, S and Gendelman, HE},
title = {Extracellular vesicle-based therapies for neurodegenerative diseases.},
journal = {NeuroImmune pharmacology and therapeutics},
volume = {4},
number = {4},
pages = {377-390},
pmid = {41480618},
issn = {2750-6665},
abstract = {Extracellular vesicles (EVs) are mediators of neurodegeneration and emerging therapeutic tools for central nervous system disorders. On the one hand, they help spread beta amyloid, tau, α-synuclein, TDP-43, and mutant SOD1, contributing to the signs and symptoms of Alzheimer's, Parkinson's, Amyotrophic lateral sclerosis, and Huntington's Diseases. By activating glial cells, they promote chronic neuroinflammation through carrying cytokines, inflammasomes, and chemokines. On the other hand, EVs' ability to transport neuroregulatory products and cross the blood-brain barrier makes them ideal vehicles for drug delivery. Their function can be surface-modified to deliver targeted therapies, including anti-inflammatory and neuroprotective regulatory RNAs, proteins, and lipids, as well as factors that help maintain neural homeostasis. Notably, we suggest that colostrum-derived EVs, enriched with growth factors and immune-regulatory microRNAs, offer a natural, scalable, and biocompatible source for neuroprotective treatment. Although EVs can act as "Janus-faced" entities - serving both as disease initiators and versatile therapeutic vehicles - controlling their activity can enable immune-based therapeutics for neurodegenerative diseases.},
}

@article {pmid41480584,
year = {2025},
author = {Xue, H and Zhao, Q and Zhao, Z and Li, R and Li, G},
title = {Construction of neural system disease models from the perspective of cellular biomechanics and their application in teaching practice.},
journal = {Frontiers in bioengineering and biotechnology},
volume = {13},
number = {},
pages = {1715222},
pmid = {41480584},
issn = {2296-4185},
abstract = {BACKGROUND: Neurological diseases such as Alzheimer's, Parkinson's, and multiple sclerosis present significant challenges to healthcare systems due to their complex pathophysiological mechanisms. Recent advancements in cellular biomechanics have opened new avenues for modeling these diseases, providing insights into how mechanical forces influence cellular behavior and contribute to disease progression.

METHODS: This study explores the construction of neurological disease models from a cellular biomechanics perspective and their integration into educational practices. We combined biomechanical principles with traditional biological models to develop multiscale representations of neurological disorders, encompassing cellular, tissue, and organ levels. The models were applied in teaching through the design of interactive scenarios, including virtual simulations and 3D-printed anatomical structures, to promote active student engagement.

RESULTS: The integration of biomechanical models enhanced the understanding of disease mechanisms and facilitated the identification of key intervention targets. Teaching strategies incorporating these models improved student comprehension of neurological diseases, as evidenced by evaluation outcomes. The models also supported the development of personalized rehabilitation programs, demonstrating potential for clinical translation.

CONCLUSION: The application of cellular biomechanics in neurological disease modeling enriches both research and educational practices. By bridging biomechanical insights with clinical and teaching applications, this approach prepares future healthcare professionals to address complex neurological disorders more effectively. Interdisciplinary collaboration among biomechanics, education, and clinical medicine is essential to advance neurological rehabilitation and improve patient outcomes.},
}

@article {pmid41480432,
year = {2025},
author = {Reyes-Long, S and Roldan-Valadez, E and Cortes-Altamirano, JL and Clavijo-Cornejo, D and Alfaro-Rodriguez, A},
title = {Insights From a Scoping Review and Bibliometric Analysis of Trends and Advances in Biomarker Research: The Role of MicroRNAs in Cognitive Decline Across Neurodegenerative Diseases.},
journal = {Cureus},
volume = {17},
number = {12},
pages = {e98237},
pmid = {41480432},
issn = {2168-8184},
abstract = {MicroRNAs (miRNAs) are small non-coding RNA molecules that negatively regulate gene expression and are implicated in the pathogenesis of neurodegenerative diseases, such as Alzheimer's disease (AD) and Parkinson's disease (PD). This study aims to provide a bibliometric analysis of the most influential research on miRNAs related to cognitive decline in AD and PD. Searches were run in Scopus on July 23, 2024 (verification July 29, 2024) for records 2014-2021; journal indicators were retrieved from Clarivate Journal Citation Reports (JCR) at the time of extraction. Selection was based on total citations; citations per year were calculated for interpretation. The search initially identified 7,722 articles related to miRNAs and cognitive decline in AD and PD. After applying predefined inclusion and exclusion criteria, the top 100 most-cited articles, published between 2015 and 2021, were selected for detailed analysis. Citation metrics and bibliometric data were extracted and analyzed to determine trends, influential journals, key authors, and leading institutions. The analysis revealed a peak in publications in 2014, with 28 articles contributing to a total of 5,339 citations. Among the top 100 articles, 60 were classified as Citation Classics (≥100 citations), and 40 were identified as Hyperclassics (≥250 citations). The leading journals were Molecular Neurobiology, Progress in Neurobiology, and PLoS ONE, collectively accounting for 2,944 citations (14.7% of the total). Harvard Medical School emerged as the top contributing institution, with four highly cited articles totaling 683 citations (3.3% of the total). Geographically, the United States led the research landscape with 31 articles, representing 32.1% (6,593 citations) of the total citations. This bibliometric analysis highlights the significant role of miRNAs in cognitive decline related to AD and PD. Review articles comprised 65% of the Hyperclassics, emphasizing their impact in consolidating and advancing knowledge. The findings underscore the importance of continuous innovation, interdisciplinary collaboration, and global research efforts in the development of miRNAs as biomarkers for early diagnosis and monitoring of cognitive decline in neurodegenerative diseases.},
}

@article {pmid41480410,
year = {2026},
author = {Tang, S and Luo, W and Wu, S and Yuan, M and Wen, J and Zhong, G and Shen, L and Jiang, W and Cheng, C and Wu, X and Xiao, X},
title = {Hippocampus-targeted BDNF gene therapy to rescue cognitive impairments of Alzheimer's disease in multiple mouse models.},
journal = {Genes & diseases},
volume = {13},
number = {2},
pages = {101649},
pmid = {41480410},
issn = {2352-3042},
abstract = {Brain-derived neurotrophic factor (BDNF) can protect neurons from apoptosis and maintain normal synaptic structures, indicating a significant potential for Alzheimer's disease (AD) treatment. However, the method of in vivo BDNF delivery requires further optimization, and the therapeutic efficacy of BDNF in AD animal models needs to be further evaluated. Here, we demonstrated that a newly engineered adeno-associated virus (AAV) serotype termed AAVT42 showed better tropism for neurons than AAV9 in the central nervous system (CNS). We analyzed the therapeutic potentials of AAVT42-delivered BDNF in three AD mouse models: amyloid precursor protein/presenilin-1 (APP/PS1), rTg4510, and 3 × Tg. Long-term BDNF expression in the hippocampus mitigated neuronal degeneration or loss in these AD mice, and alleviated their cognitive impairment, with no discernible effect on amyloid-β deposition or tau phosphorylation. Furthermore, transcriptomic analysis in 3 × Tg mice revealed that BDNF orchestrated the up-regulation of genes associated with neuronal structural organization and synaptic transmissions, such as Neuropeptide Y (Npy), Corticotropin-releasing hormone (Crh), Tachykinin precursor 1 (Tac1), and the down-regulation of Bone morphogenetic proteins (Bmps). Our study highlighted the efficacy of AAVT42 in gene delivery to CNS and validated the therapeutic benefits of BDNF in treating AD, which will be useful for future translational research on AD treatment using an AAV delivery system.},
}

@article {pmid41480321,
year = {2025},
author = {Durairajan, SSK and Singh, AK and Sulaiman, SM and Patnaik, S and Krishnamoorthi, S and Iyaswamy, A and Vellingiri, B and Yang, CB and Williams, LL},
title = {Molecular links between inflammatory bowel disease and Alzheimer's disease through immune signaling and inflammatory pathways.},
journal = {World journal of gastroenterology},
volume = {31},
number = {48},
pages = {111301},
pmid = {41480321},
issn = {2219-2840},
mesh = {Humans ; *Alzheimer Disease/immunology/pathology ; Animals ; Gastrointestinal Microbiome/immunology ; Signal Transduction/immunology ; Dysbiosis/immunology/microbiology ; Disease Progression ; Amyloid beta-Peptides/metabolism/immunology ; Brain/immunology/pathology ; Brain-Gut Axis/immunology ; *Inflammatory Bowel Diseases/immunology/complications ; *Colitis, Ulcerative/immunology/complications ; Anti-Inflammatory Agents/therapeutic use ; Disease Models, Animal ; *Crohn Disease/immunology/complications ; Inflammation/immunology ; },
abstract = {Inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn's disease (CD), has been increasingly associated with the progression of neurodegenerative disorders, particularly Alzheimer's disease (AD). Emerging data from population-based meta-analyses and in vivo experimental models demonstrate that systemic inflammation associated with IBD exacerbates disruption of the gut-brain axis (GBA). This disruption promotes the deposition of amyloid-β (Aβ) plaques, and cognitive decline. Together, these effects contribute to the progression of AD. Chronic colitis, a hallmark of IBD, accelerates Aβ pathology and induces cognitive impairment in transgenic mouse models, providing direct evidence of the detrimental effects of gut inflammation on neurodegeneration. Although numerous clinical and meta-analytical studies have examined the prevalence of AD in IBD patients, the molecular mechanisms underlying this association remain inadequately understood. In particular, the roles of immune regulation and GBA interactions require further investigation. This review aims to critically compile current evidence that elucidates the shared pathophysiological mechanisms underlying this association, such as chronic systemic inflammation, gut dysbiosis, and dysregulated immune responses. Although anti-inflammatory therapies, probiotics, and modulation of the gut microbiota have the potential to reduce the risk of AD and slow its progression, age-related gut inflammation and dysbiosis can aggravate AD pathology. This underscores the necessity for treatments that specifically target IBD-associated inflammation to limit AD progression. In addition, this review also meticulously examines how immune signaling and regulatory pathways in IBD, such as triggering receptor expression via myeloid cell receptor activation; NLRP3 inflammasome-driven inflammation; disrupted interleukin (IL)-1β, IL-6, and tumor necrosis factor-alpha (TNF-α) signaling; and elevated C-reactive protein levels, contribute to increased amyloidogenesis. This paper proposes a comprehensive framework for therapeutic strategies targeting IBD-related inflammation and elucidates their potential to attenuate the progression of AD.},
}

Humans
*Alzheimer Disease/immunology/pathology
Animals
Gastrointestinal Microbiome/immunology
Signal Transduction/immunology
Dysbiosis/immunology/microbiology
Disease Progression
Amyloid beta-Peptides/metabolism/immunology
Brain/immunology/pathology
Brain-Gut Axis/immunology
*Inflammatory Bowel Diseases/immunology/complications
*Colitis, Ulcerative/immunology/complications
Anti-Inflammatory Agents/therapeutic use
Disease Models, Animal
*Crohn Disease/immunology/complications
Inflammation/immunology

@article {pmid41480285,
year = {2025},
author = {García-Gutiérrez, F and Matias-Guiu, JA and Ayala, JL},
title = {Deep multimodal learning for domain-level cognitive decline prediction in Alzheimer's disease.},
journal = {Frontiers in artificial intelligence},
volume = {8},
number = {},
pages = {1731062},
pmid = {41480285},
issn = {2624-8212},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is characterized by significant variability in clinical progression; however, few studies have focused on developing models to predict cognitive decline. Anticipating these trajectories is essential for patient management, care planning, and developing new treatments. This study explores the potential of artificial intelligence (AI) techniques to model neurocognitive trajectories from multimodal neuroimaging data and further investigates different data representation frameworks.

METHODS: Using information from 653 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI), we developed models to predict future clinical diagnoses and cognitive decline, both quantitatively (rate of decline) and qualitatively (presence or absence of decline). Input features included structural T1-weighted magnetic resonance imaging (MRI), [[18]F]-fluorodeoxyglucose positron emission tomography (FDG-PET), [[18]F]-florbetapir PET (AV45-PET), neuropsychological assessments, and demographic variables. Several information representation strategies were explored, including tabular data models, convolutional neural networks (CNNs), and graph neural networks (GNNs). Furthermore, to maximize the use of all available information, we proposed a modeling framework that performed modality-specific pre-training to learn feature embeddings, which were then integrated through a late-fusion layer to produce a unified representation for downstream prediction.

RESULTS: The modeling strategies demonstrated good predictive performance for future clinical diagnoses, consistent with previous studies (F1 = 0.779). Quantitative models explained approximately 29.4%-36.0% of the variance in cognitive decline. In the qualitative analysis, the models achieved AUC values above 0.83 when predicting cognitive deterioration in the memory, language, and executive function domains. Architecturally, CNN- and GNN-based models yielded the best performance, and the proposed pre-training strategy consistently improved predictive accuracy.

CONCLUSIONS: This study demonstrates that AI techniques can capture patterns of cognitive decline by exploiting multimodal neuroimaging data. These findings contribute to the development of more precise phenotyping approaches for neurodegenerative patterns in AD.},
}

@article {pmid41480277,
year = {2025},
author = {Imarah, AO and Hasan, N and Alabbasi, MG},
title = {ZnO-modified carbon paste electrode for electrochemical sensing of dopamine in the presence of tyrosine.},
journal = {ADMET & DMPK},
volume = {13},
number = {6},
pages = {3010},
pmid = {41480277},
issn = {1848-7718},
abstract = {BACKGROUND AND PURPOSE: Dopamine, 3,4-dihydroxyphenylalanine, functions as a catecholamine neurotransmitter in the brain, sending messages to other neurons to regulate information transmission to other areas of the brain, govern movement, and alter brain activity. Tyrosine undergoes an enzymatic process in the pharmaceutical industry to produce dopamine. Thus, it is crucial to measure both tyrosine and dopamine in bodily fluids simultaneously.

EXPERIMENTAL APPROACH: In this work, we demonstrate the production of ZnO nanoparticles using a straightforward solvothermal technique. A straightforward, quick, and sensitive electrochemical sensing platform for dopamine detection was then created using the produced ZnO nanoparticles.

KEY RESULTS: Cyclic voltammetry comparison revealed that the ZnO/carbon paste electrode considerably enhanced the dopamine oxidation process compared to the unmodified carbon paste electrode (CPE). With a low detection limit of 0.003 μM, the ZnO/CPE sensor's linear response for voltammetric dopamine determination was found to be between 0.01 and 480.0 μM.

CONCLUSION: The modified CPE effectively demonstrates its great accuracy in tyrosine-induced dopamine detection.},
}

@article {pmid41479956,
year = {2025},
author = {Massara, M and Vedovelli, L and Masina, F and M J Edelstyn, N and Silvia Bisiacchi, P and Di Rosa, E},
title = {From cigarettes to compulsions: a longitudinal study in de novo Parkinson's disease.},
journal = {Frontiers in psychology},
volume = {16},
number = {},
pages = {1708535},
pmid = {41479956},
issn = {1664-1078},
abstract = {INTRODUCTION: Parkinson's disease (PD) is the second most common neurodegenerative disorder after Alzheimer's disease. Among the environmental and lifestyle factors associated with disease onset, cigarette smoking represents one of the most paradoxical. While substantial evidence has demonstrated a protective effect of smoking against the development of PD, smoking appears to worsen symptomatology, particularly by exacerbating impulsive-compulsive behaviors (ICBs) in people with PD (PwPD). However, longitudinal studies examining the effects of cigarette smoking on the progression of PD remain limited. Moreover, recent studies often involve mixed samples of treated and untreated PwPD, potentially confounding the impact of dopamine replacement therapy with that of smoking on ICBs.

METHODS: In the present study, we investigated a cohort of de novo PwPD, tracking their motor, cognitive, affective, and behavioral outcomes over 5 years, to better clarify the role of smoking in disease progression. Data were obtained from the Parkinson's Progression Markers Initiative and included 166 PwPD (119 non-smokers and 47 former smokers) and 79 healthy controls (48 non-smokers and 31 former smokers).

RESULTS: Our results revealed that a significantly higher percentage of former-smoker PwPD (28%) exhibited at least one ICB compared to non-smoker PwPD (13%; Pearson's [2](1) = 5.45, p = 0.02). No other significant differences between non-smokers and former smokers emerged in motor or non-motor symptoms, either in PwPD or in healthy individuals.

DISCUSSION: In conclusion, the novelty of our findings lies in showing that smoking-related influences on impulsive-compulsive behaviors in PD are most evident at the de novo stage, before any dopaminergic treatment. This temporal specificity may help resolve previous inconsistencies in the literature and underscores the importance of distinguishing between environmental and pharmacological effects on symptom development.},
}

@article {pmid41479611,
year = {2025},
author = {Dadgostar, M and Hanford, LC and Green, JR and Richburg, BD and Cannon, AT and Barnett, NV and Salat, DH and Arnold, SE and Eshghi, M},
title = {Kinematic correlates of early speech motor changes in cognitively intact APOE-ε4 carriers: a preliminary study using a color-word interference task.},
journal = {Frontiers in neurology},
volume = {16},
number = {},
pages = {1649729},
pmid = {41479611},
issn = {1664-2295},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is the most prevalent form of dementia and a major public health challenge. In the absence of a cure, accurate and innovative early diagnostic methods are essential for proactive life and healthcare planning. Speech metrics have shown promising potential for identifying individuals with mild cognitive impairment (MCI) and AD, prompting investigation into whether speech motor features can detect elevated risk even prior to cognitive decline. This preliminary study examined whether speech kinematic features measured during a color-word interference task could distinguish cognitively normal APOE-ε4 carriers (ε4[+]) from non-carriers (ε4[-]).

METHODS: Sixteen cognitively normal older adults (n = 9 ε4[+], n = 7 ε4[-]) completed a sentence-based color-word interference task while three-dimensional electromagnetic articulography recorded lower-lip movements. Lip movement duration (s), average speed (mm/s), and range of movement (mm³) were extracted for three sentence segments: pre-interference, during-interference, and post-interference. Difference measures (ΔDuring-Pre, ΔDuring-Post) were computed to quantify task-related modulation. Descriptive statistics and independent t-tests were used to examine group-level trends. For classification, a support vector machine (SVM) with a degree-2 polynomial kernel and leave-one-out cross-validation evaluated all feature combinations derived from the 15 kinematic measures.

RESULTS: Although no group differences reached statistical significance after accounting for multiple testing, several features showed moderate effect sizes. The optimal SVM model achieved 87.5% cross-validated accuracy (precision 88.9%, sensitivity 88.9%, specificity 85.7%) using three features: (1) lip movement duration during the pre-interference segment, (2) average lip speed during interference, and (3) the change in lip movement range from pre- to during-interference segments (ΔDuring-Pre).

DISCUSSION: These findings suggest that lip kinematic responses to mild cognitive-motor interference may capture subtle neuromotor differences associated with APOE-ε4 status in cognitively intact older adults. The identified features point to potential alterations in anticipatory motor planning, interference susceptibility, and articulatory adaptability in ε4[+] individuals. However, the small sample size, risk of overfitting, and sex imbalance limit interpretability. Thus, these results should be viewed as hypothesis-generating. Larger, sex-balanced, and longitudinal studies are needed to validate these candidate markers and clarify their role in multimodal early AD risk stratification.},
}

@article {pmid41479608,
year = {2025},
author = {Wang, J and Xia, K and Yang, D and Wu, J and Liu, L and Huang, Y and Shan, Q and Zhang, H and Wang, Y},
title = {Trends in mortality from Alzheimer's disease and related dementias with hyperlipidemia in the United States from 1999 to 2020-a CDC WONDER database study.},
journal = {Frontiers in neurology},
volume = {16},
number = {},
pages = {1705607},
pmid = {41479608},
issn = {1664-2295},
abstract = {BACKGROUND: The co-occurrence of Alzheimer's disease and related dementias (ADRD) with hyperlipidemia represents a growing public health burden amid population aging. Although both conditions have been independently linked to increased morbidity and mortality, national trends in ADRD-related mortality involving hyperlipidemia remain poorly characterized.

METHODS: We conducted a retrospective, population-based study using mortality data from the U.S. Centers for Disease Control and Prevention Wide-ranging Online Data for Epidemiologic Research (CDC WONDER) from 1999 to 2020. Deaths with co-listed International Classification of Diseases, Tenth Revision codes for ADRD and hyperlipidemia were identified. Age-standardized mortality rates (ASMR) were calculated per 100,000 persons using the 2000 U.S. standard population. Joinpoint regression was employed to estimate annual percentage change (APC) and average annual percentage change (AAPC) with 95% confidence intervals (CI).

RESULTS: Between 1999 and 2020, the number of deaths related to ADRD with hyperlipidemia increased from 519 to 21,969, with the ASMR rising from 0.19 to 5.32 per 100,000 (AAPC: 15.25%; 95% CI: 14.37-17.31). A sharp rise in mortality was observed after 2018 across nearly all subgroups. Males had a steeper increase than females (AAPC: 16.31% vs. 14.97%). Non-Hispanic Black individuals had the highest ASMR in 2020 (5.53 per 100,000), while Asian/Pacific Islanders had the most rapid increase (AAPC: 21.80%). Regionally, the South showed the highest burden, while the Northeast exhibited the fastest growth (AAPC: 17.77%). Rural areas had a higher ASMR than metropolitan areas (6.29 vs. 5.09 per 100,000), with comparable upward trends. Notably, individuals aged ≥85 years accounted for over half of all deaths by 2020 and exhibited the highest age-specific mortality rates.

CONCLUSION: ADRD-related mortality involving hyperlipidemia has significantly risen in the U.S. over two decades, with notable disparities across demographics and geography, underscoring the need for public-health relevance and coordination to be evaluated in future analytic studies targeting cardiometabolic and cognitive health in high-risk populations.},
}

@article {pmid41479607,
year = {2025},
author = {Yu, H and Lee, H and Lee, M and Kim, D and Pirpamer, L and Duering, M and Moy, S and Helmer, KG and Kim, REY and , },
title = {Multi-center evaluation of Neurophet AQUA for brain MRI segmentation: T1 compared with FreeSurfer and T2-FLAIR compared with ground truth.},
journal = {Frontiers in neurology},
volume = {16},
number = {},
pages = {1672133},
pmid = {41479607},
issn = {1664-2295},
abstract = {INTRODUCTION: Accurate segmentation of brain regions in magnetic resonance imaging (MRI) is essential for diagnosing and managing neurological diseases. FreeSurfer is a widely used tool for brain MRI segmentation, but its limitations in speed and usability pose challenges in clinical practice. Neurophet AQUA, an advanced automated segmentation tool, aims to overcome these challenges by offering rapid and reliable segmentation. This study evaluates two segmentation pipelines: (1) a T1-based brain region segmentation pipeline, comparing the performance and reliability of Neurophet AQUA and FreeSurfer v7.3.2 using the standard recon-all pipeline in segmenting gray matter, white matter, and subcortical structures; and (2) a T2-FLAIR-based white matter lesion segmentation pipeline of Neurophet AQUA, assessing the detection of white matter hyperintensities (WMH).

METHODS: Four main datasets were used. For the T1-based segmentation pipeline, the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset was used to compare the segmentation results of Neurophet AQUA and FreeSurfer, with quality assessed by expert evaluation. The MarkVCID dataset was used to evaluate the scan-rescan repeatability and inter-scanner reproducibility of Neurophet AQUA. For the T2-FLAIR-based pipeline, WMH segmentation performance was assessed using 2D and 3D FLAIR sequences from the ADNI dataset by comparing the segmentations to ground truth (GT) labels and calculating Dice similarity coefficients (DSC).

RESULTS: Segmentation quality and reliability showed that Neurophet AQUA and FreeSurfer achieved comparable performance in most regions, with no significant differences. However, Neurophet AQUA had significantly faster processing time. In intracranial volume (ICV) measurements, Neurophet AQUA showed better repeatability than FreeSurfer in both rescans (ICC: 0.999 vs. 0.991) and inter-scanner settings (ICC: 0.983 vs. 0.866). AQUA also demonstrated consistent WMH segmentation across 2D and 3D FLAIR images.

CONCLUSION: Neurophet AQUA demonstrated high segmentation accuracy and excellent repeatability in rescanned measurements, as well as exploratory evidence of inter-scanner reproducibility on T1-weighted MRI, showing comparable performance to established tools such as FreeSurfer. It also showed consistent WMH segmentation across FLAIR types. Neurophet AQUA is highly suitable for clinical applications that require accurate analysis, high repeatability and reproducibility, and rapid brain MRI processing, making it particularly well-suited for multicenter research studies.},
}

@article {pmid41479572,
year = {2025},
author = {Radchenko, AI and Kuzubova, EV and Apostol, AA and Mitkevich, VA and Andreeva, LA and Limborska, SA and Stepenko, YV and Shmigerova, VS and Solin, AV and Korokin, MV and Pokrovskii, MV and Myasoedov, NF and Makarov, AA},
title = {The Potential of the Peptide Drug Semax and Its Derivative for Correcting Pathological Impairments in the Animal Model of Alzheimer's Disease.},
journal = {Acta naturae},
volume = {17},
number = {4},
pages = {110-120},
pmid = {41479572},
issn = {2075-8251},
abstract = {Alzheimer's disease, first described over a century ago, is currently among the most common neurodegenerative diseases whose significance is increasingly growing with the aging of populations. Throughout the entire period of its study, no remedies have been found that would be effective in treating - or at least significantly slowing - the pathological process, while being sufficiently safe. In this regard, significant attention is paid to the development and application of natural peptide drugs lacking side effects. The present study assessed the effect of the known neuroprotective peptide Semax and its derivative on the behavioral characteristics and development of amyloidosis in transgenic APPswe/PS1dE9/Blg mice acting as a model of Alzheimer's disease. The open field, novel object recognition, and Barnes maze tests demonstrated that both Semax and its derivative improved cognitive functions in mice. Histological examination showed that these peptides reduced the number of amyloid inclusions in the cortex and hippocampus of the animals' brains. These findings demonstrate the high potential of Semax and its derivatives when used to develop therapeutic and corrective strategies for Alzheimer's disease.},
}

@article {pmid41479568,
year = {2025},
author = {Sukhorukov, VS and Egorova, AV and Romanenko, AS and Ryabova, MS and Krasilnikova, AP},
title = {Mitophagy in Age-Dependent Neurodegeneration.},
journal = {Acta naturae},
volume = {17},
number = {4},
pages = {64-71},
pmid = {41479568},
issn = {2075-8251},
abstract = {Mitochondrial dysfunction is one of the pathogenetic mechanisms of neuronal damage during aging. The high energy dependence of neurons makes them particularly vulnerable to age-related changes accompanied by oxidative stress and impaired energy metabolism. The maintenance of a pool of functional mitochondria is regulated by mitophagy, which ensures the utilization of damaged organelles, thereby preventing the progression of mitochondrial dysfunction. Brain aging is accompanied by a reduced level of activity of metabolic processes, aggravated mitochondrial dysfunction, and an increased risk of developing neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. This review highlights the molecular and signaling pathways of mitophagy and its dysregulation during physiological and pathological aging, which is of particular interest for identifying pharmaceutical targets and developing potential therapies for neurodegenerative conditions.},
}

@article {pmid41479443,
year = {2025},
author = {Zhang, ZS and Lin, RR and Liu, X and Li, MJ and Lu, S and Tao, QQ and , },
title = {Osteoporosis-mediated exacerbation of the amyloid-β pathology: Involvement of serum calcium.},
journal = {Journal of Alzheimer's disease reports},
volume = {9},
number = {},
pages = {25424823251409408},
pmid = {41479443},
issn = {2542-4823},
abstract = {Alzheimer's disease (AD) and osteoporosis (OP) are two common age-related degenerative diseases with similar epidemiological characteristics, yet their complex relationship and specific mechanistic intersections remain unclear. In this study, 775 individuals were divided into OP and non-OP groups. Results showed that OP was associated with elevated serum calcium levels and severer amyloid-β (Aβ) pathology. Regression analysis indicated a positive correlation between serum calcium and Aβ PET levels. Mediation analysis further elucidated that serum calcium involved in the OP-mediated exacerbation of Aβ pathology. These findings suggested that serum calcium may be a bridge in the complex association between OP and AD.},
}

@article {pmid41479437,
year = {2026},
author = {Shouri Bidgoli, A and Darvishpour, A},
title = {Emotionally Personalized Doll Therapy for Behavioral Symptoms in an 88-Year-Old Woman With Alzheimer's Disease: A Case Report.},
journal = {Clinical case reports},
volume = {14},
number = {1},
pages = {e71769},
pmid = {41479437},
issn = {2050-0904},
abstract = {Behavioral and psychological symptoms of dementia (BPSD), such as agitation, sleep disturbance, and repetitive speech, are common in Alzheimer's disease (AD) and significantly burden both patients and caregivers. Doll therapy (DT) has been explored as a nonpharmacological approach in institutional care, but the potential role of emotionally personalized dolls in home care remains underreported. We describe an 88-year-old woman with AD who presented with persistent nocturnal agitation, repetitive vocalizations, and restlessness despite stable pharmacological management. During a household rearrangement, she reencountered her granddaughter's childhood doll. She quickly developed a strong emotional attachment and engaged with the doll in caregiving behaviors (cradling, rocking, singing, and feeding gestures). Within days, her agitation and repetitive speech markedly decreased. Sleep continuity improved, daytime activity increased, and her emotional expression became richer. She was more cooperative at mealtimes, demonstrated modest motor gains, and on several occasions verbalized urinary needs. Hallucinatory speech diminished substantially. Notably, she refused interaction with other dolls, suggesting that the personal and emotional significance of this specific doll was central to the observed improvement. This case highlights the potential therapeutic value of integrating emotionally personalized objects into dementia care at home. Personalized doll therapy may help activate residual emotional memory and attachment systems, leading to meaningful behavioral improvements without changes in medication. While promising, these findings are limited to a single case and warrant further investigation through systematic studies.},
}

@article {pmid41479381,
year = {2025},
author = {Singh, NK and Varshney, N},
title = {Therapeutic Applications of Natural Flavonoids Against Alzheimer's Disease-like Pathology: Special Focus on PI3K/Akt and Nrf2 Signaling Pathways.},
journal = {Current neurovascular research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672026423088251205120807},
pmid = {41479381},
issn = {1875-5739},
abstract = {The PI3K/AKT and Nrf2 signaling systems are essential for neurogenesis, synaptic plasticity, and cellular survival, and their dysregulation has been linked to the progression of Alzheimer's disease (AD). Due to its complex pathophysiology, currently approved therapeutic agents only provide symptomatic relief and are often associated with serious side effects. Researchers have increasingly focused on natural bioactive compounds as potential therapies, with flavonoids emerging as promising candidates due to their diverse neuroprotective properties. These polyphenolic compounds exhibit notable anti-inflammatory, anti-apoptotic, and antioxidant effects, making them attractive therapeutic agents against AD. A key mechanism by which flavonoids exert neuroprotection is through modulation of the PI3K/AKT and Nrf2 signaling pathways. By enhancing neuronal resilience, reducing oxidative stress, inhibiting apoptosis, and regulating autophagy, flavonoids can mitigate neurodegenerative processes associated with AD. Additionally, they attenuate Aβ accumulation and tau hyperphosphorylation, both of which contribute to neuronal dysfunction, via PI3K/AKT activation and Nrf2 pathway regulation. In preclinical AD models, numerous flavonoids-including epicatechin, kaempferol, quercetin, and luteolin- have demonstrated neuroprotective effects through regulation of the PI3K/AKT and Nrf2 pathways. Despite these encouraging findings, further research is needed to determine optimal dosages, strategies for enhancing bioavailability, and the long-term effects of flavonoid-based therapies in AD. Future studies should focus on translating preclinical evidence into clinical trials, which could improve patient outcomes and quality of life. A deeper understanding of the molecular mechanisms underlying flavonoid activity, particularly their interaction with PI3K/AKT and Nrf2 pathways, may pave the way for novel neuroprotective therapies.},
}

@article {pmid41478788,
year = {2025},
author = {Sah, SS and Kumbhalwar, A},
title = {Comment on "Housing Assistance and Health Care Access Among Older Adults With Alzheimer's Disease and Related Dementias: Evidence From Multisource Linked Survey-Administrative Data".},
journal = {The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jagp.2025.12.005},
pmid = {41478788},
issn = {1545-7214},
}

@article {pmid41478541,
year = {2025},
author = {Zafar, I and Khan, MS and Jamal, A and Shafiq, S and Bahwerth, FS and Khan, NU},
title = {Precision therapeutic strategies for Alzheimer's disease: Amyloid β-targeted foundations and multimodal next-generation approaches.},
journal = {Molecular and cellular neurosciences},
volume = {},
number = {},
pages = {104070},
doi = {10.1016/j.mcn.2025.104070},
pmid = {41478541},
issn = {1095-9327},
abstract = {Alzheimer's disease (AD) is the leading cause of dementia and a significant unmet medical challenge, pathologically characterized by amyloid β (Aβ) aggregation, tau hyperphosphorylation, synaptic dysfunction, and chronic neuroinflammation. Although Aβ has long been a central therapeutic target, clinical translation has historically been hindered by late-stage intervention, inadequate blood-brain barrier (BBB) penetration, and the molecular heterogeneity of AD. Recent advances with Aβ-targeted monoclonal antibodies, particularly lecanemab and donanemab, have provided the first clinical evidence of disease modification, demonstrating robust amyloid clearance and measurable slowing of cognitive decline in early-stage AD. These results validate the Aβ hypothesis but also highlight persistent barriers, including amyloid-related imaging abnormalities (ARIA), questions about the durability of benefit, challenges in patient stratification, and the high economic burden of biologics. To overcome these limitations, next-generation strategies are emerging that extend beyond single-pathway targeting toward multimodal and precision-based frameworks. Innovative approaches include tau-directed therapies to prevent the propagation of neurofibrillary tangles, immunomodulatory strategies to enhance microglial clearance of aggregated proteins, and neuroprotective interventions to counteract oxidative and inflammatory stress. Concurrently, nanotechnology-based drug delivery systems are being engineered to efficiently traverse the BBB and deliver multifunctional payloads, while artificial intelligence (AI)- driven discovery platforms are accelerating target identification, biomarker integration, and patient stratification. Future perspectives emphasize the importance of preclinical-stage intervention, long-term efficacy trials, and the adoption of personalised treatment paradigms that integrate genomic, biomarker, and digital profiling to optimise outcomes. Collectively, these advances signal a paradigm shift in AD therapeutics, positioning Aβ-targeted therapies as a foundation while paving the way for combination strategies that more effectively address the disease's multifactorial nature.},
}

@article {pmid41478533,
year = {2025},
author = {Plantera, L and Didio, A and Ceglarek, U and Bechmann, I},
title = {Proteomic comparison of human brain tissue preservation methods.},
journal = {Journal of proteomics},
volume = {325},
number = {},
pages = {105589},
doi = {10.1016/j.jprot.2025.105589},
pmid = {41478533},
issn = {1876-7737},
abstract = {This study investigated the impact of tissue preservation methods on protein profiles analyzed by reversed-phase liquid chromatography-high-resolution mass spectrometry (LC-HRMS) using data-independent acquisition (DIA). Proteomic profiles from formalin-fixed, formalin-fixed and paraffin-embedded (FFPE), and fresh-frozen human brain tissues (cortex and hippocampus, n = 6) were compared, including an FFPE-specific protein extraction kit (n = 4). Formalin-fixed samples more closely resembled fresh-frozen profiles than FFPE or FFPE-Kit samples, while still showing high correlation and overlap with FFPE tissues in principal component analyses. A core set of 1753 proteins was consistently detected across all sample preparation methods. A total of 35 proteins were identified exclusively in fresh-frozen samples, but without functional enrichment. Quantitative comparisons to the proteome of fresh-frozen tissue revealed an underrepresentation of cellular processes, energy metabolism, signaling, and transport related to protein properties such as length, location, and hydrophobicity. In contrast, neuronal development and phagosome-related pathways were overrepresented in fixed tissues. In a pilot study comparing low (Braak 0-II, n = 4) and high (Braak IV-VI, n = 4) Alzheimer's disease (AD) stages using formalin-fixed samples, we identified 12 potential protein biomarkers, primarily nucleosomal proteins and carboxypeptidase M (CPM). These findings suggest that formalin-fixed brain tissue provides reliable proteomic information, making it a valuable resource for neurodegenerative disease research. SIGNIFICANCE: Proteomics offers enormous potential for investigating the molecular regulation of the human brain. Valuable tissue samples are often preserved in formalin or additionally with paraffin for later analysis. The potential value of these preserved samples for proteomic analysis has already been recognized. However, tissue preservation poses a challenge for proteome analysis. Consequently, several studies have compared different protein extraction protocols for fixed samples. In addition, studies have been published comparing protein extraction from FFPE samples with fresh-frozen samples. To our knowledge, this is the first study to compare protein extraction across all three tissue preservation methods with subsequent functional analysis using samples obtained from the same donors, thereby eliminating inter-donor variability and enabling a direct comparison of preservation effects. This study validates a protein extraction protocol from formalin-fixed samples, laying the groundwork for future research into potential biomarkers in formalin-fixed samples.},
}

@article {pmid41478467,
year = {2025},
author = {Feng, L and Zou, L and Wen, X and Zhang, L and Zhao, Y and Ren, W and Wang, T and Chen, J and Wang, X and Tian, Z},
title = {The medial septal-medial habenula cholinergic circuit: A new mechanism of exercise improving cognitive function in AD mice.},
journal = {Journal of sport and health science},
volume = {},
number = {},
pages = {101118},
doi = {10.1016/j.jshs.2025.101118},
pmid = {41478467},
issn = {2213-2961},
abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressively and incurably neurodegenerative disorder with cognitive dysfunction (e.g., memory decline). Exercise intervention, such as aerobic and resistance training, has increasingly been accepted as a feasible strategy to improve cognitive function. However, the potential neurobiological mechanism of exercise-induced cognitive benefits requires further investigation, especially the combined regime (i.e., aerobic + resistance training) recommended by the World Health Organization guidelines on physical activity. Against this background, we aimed to investigate whether the medial septum (MS)-medial habenula (MHb) cholinergic circuit mediated the effects of combined (aerobic and resistance) exercise intervention on cognitive function in AD mice.

METHODS: Six-week-old male C57BL/6J wild-type (WT) mice were randomly divided into the sham-operated control group (Sham), the AD model group (AD), the early exercise with pre-AD group (Ex+AD), the post-AD with exercise group (AD+Ex), and the exercise with both pre-AD and post-AD group (Ex+AD+Ex), with 10 mice in each group. Five-month-old male C57BL/6J background 5 × FAD transgenic AD mice were randomly divided into 6 groups: WT control group (WT), 5 × FAD group (FAD), 5 × FAD + exercise intervention group (FAD+Ex), chemical inhibition of the MS + exercise intervention group (FAD+MS (i) +Ex), chemical inhibition of the MHb group (FAD+MHb (i) +Ex), and chemical activation of MS + chemical inhibition of MHb + exercise intervention group (FAD+MS (q) +MHb (i) +Ex), with 8 mice in each group. The mice in the exercise intervention groups were subjected to aerobic treadmill training combined with resistance ladder climbing. The projection relationship between MS and MHb cholinergic neurons was examined using neuroanatomical tracing experiments. Cognitive function was assessed using the Morris water maze, novel object recognition test, and Y-maze test. Neuronal damage was evaluated by hematoxylin and eosin staining and Nissl staining in the MS and MHb regions, as well as immunofluorescence staining for amyloid-β (Aβ), choline acetyltransferase (ChAT), hyperphosphorylated microtubule-associated protein tau (p-Tau), neurofilament light chain (NFL), α-synuclein (α-Syn), retinoic acid-related orphan receptor β (RORβ), neuronal nuclei (NeuN), and microtubule-associated protein 2 (MAP2), and Western blotting for Aβ, ChAT, p-Tau, NFL, α-Syn, and RORβ. Mitochondrial structure and function in MS and MHb neurons were assessed by transmission electron microscopy and Western blotting for mitochondrial transcription regulator A (TFAM), nuclear respiratory factor 1 (NFR1), and adenosine triphosphate (ATP) synthase subunit β (ATPB) protein expression levels.

RESULTS: Exercise training significantly alleviated cognitive dysfunction and neuronal damage in the MS region of Aβ mice, especially exercise preconditioning. Cholinergic neurons in the MS region of mice projected to the MHb region. Moreover, the MS-MHb cholinergic circuit mediated the beneficial effects of exercise on ameliorating neuronal damage and improving cognitive function in 5 × FAD mice.

CONCLUSION: Exercise, mediated by the MS-MHb cholinergic circuit, improved neuronal damage and cognitive function in AD mice. This study provides scientific evidence for the potential application of exercise in the prevention and control of AD and offers new insights for future clinical intervention strategies from the perspective of neuroscience.},
}

@article {pmid41478465,
year = {2025},
author = {Bandarupalli, T and Noonan, C and Hansen, K and Weaver, R and Baumann, K and Banks, WA and Erickson, MA and Rhea, EM},
title = {Acute peripheral versus central inhibition of insulin receptors differentially alters cytokine and blood-brain barrier responses to an inflammatory stimulus.},
journal = {Brain, behavior, and immunity},
volume = {133},
number = {},
pages = {106251},
doi = {10.1016/j.bbi.2025.106251},
pmid = {41478465},
issn = {1090-2139},
abstract = {The blood-brain barrier (BBB)'s role in protecting the brain from exposure to harmful circulating factors has led to its disruption being implicated in neurodegenerative diseases such as vascular dementia and Alzheimer's disease. Insulin resistance, defined by an impaired response to insulin, is a common feature of metabolic disorders and neurodegenerative diseases. Importantly, individuals can possess peripheral insulin resistance independent of central insulin resistance and vice versa. States of insulin resistance, like diabetes mellitus for peripheral insulin resistance and Alzheimer's disease for central insulin resistance, are associated with inflammation and BBB disruption. However, the contributions of acute impairment of insulin receptor signaling solely in the periphery versus the brain to inflammation and BBB disruption are not clear. As central vs peripheral insulin resistance could have different effects on inflammation, we characterized the effects of acute central versus peripheral insulin receptor inhibition with or without an inflammatory insult, using lipopolysaccharide (LPS) as a prototypic immune stimulus. Male CD-1 mice were treated with an insulin receptor antagonist (S961), peripherally (intraperitoneal) or centrally (intranasal). This treatment was then followed by an intraperitoneal administration of either saline or LPS 30 min later, at a single 3 mg/kg dose known to cause inflammation and BBB disruption. Assays of BBB disruption and brain and serum collection were done 28 h after the injections. Metabolic hormones, cytokines, and the acute phase protein serum amyloid a (SAA) were then measured in serum and brain homogenates. In the absence of LPS, central S961 reduced serum hormones including ghrelin, gastric inhibitory peptide (GIP), and glucagon. Peripheral S961 significantly increased many cytokines in both brain and blood, whereas central S961 decreased serum SAA and increased a few cytokines. BBB integrity was not affected by S961 alone, but central S961 decreased LPS-induced BBB disruption and also lowered serum levels of SAA. These findings highlight the differential effects of peripheral versus central insulin receptor inhibition on cytokine responses and BBB integrity in the presence and absence of acute inflammation, elucidating differences in the molecular mechanisms for insulin receptor signaling depending on the location of signaling dysfunction. The results suggest a potential neuroprotective role of acute central insulin inhibition during acute inflammation.},
}

@article {pmid41478424,
year = {2025},
author = {Zhang, Y and Chen, L and Jin, J and Xin, Y and Wang, J and Zhang, A},
title = {Therapeutic application of fecal microbiota transplantation for neurological diseases: Exploring novel mechanisms and perspectives.},
journal = {Experimental neurology},
volume = {},
number = {},
pages = {115631},
doi = {10.1016/j.expneurol.2025.115631},
pmid = {41478424},
issn = {1090-2430},
abstract = {Recently, fecal microbiota transplantation (FMT) has garnered widespread attention as an emerging therapeutic approach in the field of neurological disorders. In this study, we review the research progress of FMT in treating neurological disorders. First, the development, safety, and efficacy of FMT are introduced. Subsequently, the application and potential mechanisms of FMT in neurodegenerative diseases (such as Parkinson's disease and Alzheimer's disease), neurodevelopmental disorders (such as autism spectrum disorder and attention deficit hyperactivity disorder), and other neurological conditions are elaborated in detail. Particularly, we explore the pivotal role of the microbiota-gut-brain axis in FMT for treating neurological disorders, as well as how FMT influences neurological function by regulating the gut microbiota and its metabolites, immune system and inflammatory responses, and neurotransmitters. However, FMT also faces numerous challenges in the treatment of neurological disorders, such as ethical issues, safety concerns, and standardization problems. Therefore, this review also prospects the future development directions of FMT in the treatment of neurological diseases, including personalized therapy and combination therapies. FMT may be a feasible and promising option for treating various neurological disorders, but a comprehensive understanding of its working principles and continuous improvement of its application in clinical practice are still ongoing.},
}

@article {pmid41478423,
year = {2025},
author = {Moallem, EZ and Vekaria, HJ and Macheda, T and Hawkins, MR and Roberts, KN and Patel, SP and Sullivan, PG and Bachstetter, AD},
title = {Traumatic brain injury exacerbates mitochondrial dysfunction in APP/PS1 knock-in mice through time-dependent pathways.},
journal = {Experimental neurology},
volume = {398},
number = {},
pages = {115629},
doi = {10.1016/j.expneurol.2025.115629},
pmid = {41478423},
issn = {1090-2430},
abstract = {Cerebral hypometabolism occurs in both traumatic brain injury (TBI) and Alzheimer's disease (AD), but whether these conditions act through distinct or overlapping mechanisms is unclear. TBI disrupts cerebral metabolism via blood-brain barrier damage, altered glucose transporter expression, calcium buffering abnormalities, and oxidative damage to metabolic enzymes. AD-related hypometabolism is linked to amyloid-β (Aβ) effects on mitochondria, including impaired respiration, oxidative stress, and altered mitophagy, fusion, and fission. We tested whether TBI-induced mitochondrial dysfunction exacerbates Aβ-mediated impairment using a closed-head injury (CHI) model in APP/PS1 knock-in (KI) mice. Injuries were delivered at 4-5 months of age, before plaque formation and mitochondrial deficits in KI mice. Bioenergetics were measured at 1, 4, and 8 months post-injury in hippocampus and cortex using Seahorse assays on isolated mitochondria. At 1 month, genotype-by-injury interactions revealed greater dysfunction in KI mice than either condition alone, with males more vulnerable than females. At 4-8 months, amyloid-mediated effects predominated, while TBI-specific changes were no longer apparent, suggesting recovery or convergence onto shared mechanisms. These results indicate that TBI can temporarily worsen mitochondrial dysfunction in the context of early amyloidosis, with sex influencing vulnerability. Findings provide insight into the temporal relationship between TBI and amyloid-induced mitochondrial deficits and support the importance of sex as a biological variable in neurodegenerative disease progression.},
}

@article {pmid41478422,
year = {2025},
author = {Vranceanu, AM and Puttre, H and Stone, S and Pollak, KI and Kutner, JS and Ritchie, CS},
title = {Developing and testing a program to strengthen the dementia palliative care trial workforce.},
journal = {Journal of pain and symptom management},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jpainsymman.2025.12.020},
pmid = {41478422},
issn = {1873-6513},
abstract = {OBJECTIVE: To describe the development and early outcomes of the National Institute on Aging (NIA)-funded Dementia Palliative Care Clinical Trials Training Program (DEM-PCCT).

BACKGROUND: Nonpharmacological palliative care interventions can improve the lives of people living with dementia and their care partners, yet evidence remains limited. We developed DEM-PCCT to train investigators and enhance evidence-based dementia palliative care interventions. DEM-PCCT represents the first national program to integrate dementia-specific palliative care training with structured grant development, NIH stage model-based didactics, experiential trainings and longitudinal evaluation of scholar productivity-addressing a critical gap.

METHODS: DEM-PCCT is a 10-month program where scholars participate in monthly virtual sessions and a one-week in-person didactic and experiential program. The curriculum to supports participants' research grant development and submission. Participants evaluate curriculum components and report their confidence, comfort and knowledge with conducting dementia clinical trials pre- and post-training. We also track grant submissions, published manuscripts and feasibility outcomes.

RESULTS: Three cohorts of interdisciplinary scholars (N = 53) have started and 2 have completed DEM-PCCT. Program feasibility and satisfaction were high. Confidence and comfort conducting dementia clinical trials significantly improved (p-value < .05 for both). Most scholars submitted at least one research grant application by program completion, and secured funding. Scholars report continued productivity in grants and publications.

CONCLUSION: DEM-PCCT is a novel national training model that advances dementia palliative care by combining didactic training, experiential learning and structured grant development. Thus, DEM-PCCT builds the scientific workforce and serves as a model to accelerate evidence-based dementia palliative care interventions.},
}

@article {pmid41478196,
year = {2025},
author = {Haider, SZ and Iqbal, MW and Sun, X and Alghamdi, HA and Yuan, Q and Zhu, D and Nawaz, MZ},
title = {Unraveling the metabolic potential of Moringa oleifera derived metabolites in combating Parkinson's and Alzheimer's disease.},
journal = {Bioorganic chemistry},
volume = {169},
number = {},
pages = {109442},
doi = {10.1016/j.bioorg.2025.109442},
pmid = {41478196},
issn = {1090-2120},
abstract = {Moringa oleifera is a nutrient-rich medicinal plant recognized for its broad-spectrum therapeutic potential. However, the specific bioactive metabolites and their molecular mechanisms in curing and preventing these diseases remain inadequately explored. The present study unveiled how moringa metabolites interact with specific molecular targets linked to various diseases and explored their potential as natural therapeutic agents against these diseases. The study first constructed a metabolite library based on compounds identified through multiple analytical techniques, including GC-MS, LC-MS, HPLC, UFLC, and NMR, as reported in previous studies. Then utilized a comprehensive computational approach integrating virtual screening, ADMET analysis, molecular docking, and dynamics simulations, and MM-GBSA/MM-PBSA methods to predict and evaluate the binding affinities and stabilities of moringa-derived metabolites against disease-related proteins. In total, 72 metabolites derived from moringa were screened against the ten genes, the overexpression of which was reported in five related disease conditions, including Alzheimer's, Parkinson's, Kidney Stones, Multiple Sclerosis, and Asthma diseases. These metabolites demonstrated strong interactions with genes associated specifically with Alzheimer's and Parkinson's diseases. To enhance the reliability and translational relevance of the computational predictions, experimentally validated inhibitors lanabecestat (APP inhibitor), GNE0877 (LRRK2 inhibitor), and olaparib (PARP1 inhibitor) were included as positive controls to benchmark the binding affinity and interaction stability of moringa metabolites. Our findings revealed that metabolites delta-tocopherol and gamma-tocopherol exhibit potential to inhibit poly (ADP-ribose) polymerase 1 (PARP1), while 1-acetyl-4,4-bis[4-(3-bromopropoxy)-3,5-dimethoxyphenyl] piperidine and 9,9'-bianthracene showed potential in inhibiting leucine-rich repeat kinase 2 (LRRK2); overexpression of both genes is linked to Parkinson's disease. Additionally, the metabolite 1-acetyl-4,4-bis[4-(3-bromopropoxy)-3,5-dimethoxyphenyl] piperidine also demonstrated potential in inhibiting the amyloid precursor protein (APP) associated with Alzheimer's disease. The identified metabolites displayed strong binding affinities, favorable ADMET properties, and stable interactions during molecular dynamics simulations compared to their respective control compound, positioning them as promising natural therapeutic agents against Alzheimer's and Parkinson's diseases. The study underscores the relevance of integrating computational methodologies to explore the therapeutic potential of bioactive plant compounds.},
}

@article {pmid41478158,
year = {2025},
author = {Bezerra, IC and Viana, JO and Bisneto, JSR and Cavalcante, GG and Barbosa de Luna, JG and da Silva, AJ and Weber, KC and Machado, G and de Lima Filho, JL and Gubert, P},
title = {Computational insights into terpene-induced modulation of amyloid-β peptide (Aβ1-42) aggregation-favoring conformations.},
journal = {Journal of molecular graphics & modelling},
volume = {143},
number = {},
pages = {109268},
doi = {10.1016/j.jmgm.2025.109268},
pmid = {41478158},
issn = {1873-4243},
abstract = {Alzheimer's disease (AD) is characterized by progressive neurodegeneration, with aggregation of amyloid-β (Aβ1-42) playing a central role. Natural terpenes have emerged as promising therapeutic candidates due to their bioactivity. Here, we investigated caryophyllene and copaene interactions with Aβ1-42 via molecular docking, molecular dynamics simulations, and MM/PBSA calculations. Both terpenes bound effectively to distinct Aβ1-42 pockets, altering structural flexibility and disrupting aggregation-prone regions, mainly within the C-terminal and central hydrophobic domains. Inter-residue distance matrices showed increased separation between peptide segments, reducing compactness and potentially hindering β-sheet nucleation. Secondary structure analysis revealed decreased β-sheet content and preservation of α-helices, especially for caryophyllene in pocket 1 and copaene in pocket 2. Binding free energy analysis confirmed favorable thermodynamics dominated by hydrophobic interactions. These findings suggest caryophyllene and copaene interfere with early Aβ1-42 aggregation steps, supporting their potential as natural scaffolds for anti-amyloid drug development in AD.},
}

@article {pmid41477991,
year = {2025},
author = {Hu, H and Cheng, Q and Li, D and Li, Y and Li, X and Chen, Y and Guo, Y and Tian, S and Jiang, Y and Chen, Y and Liu, Y and Li, S},
title = {Ponicidin ameliorates Alzheimer's disease through dual inhibition of RIPK1-mediated neuroinflammation and necroptosis.},
journal = {International immunopharmacology},
volume = {171},
number = {},
pages = {116095},
doi = {10.1016/j.intimp.2025.116095},
pmid = {41477991},
issn = {1878-1705},
abstract = {Ponicidin (Pon), a diterpenoid isolated from Rabdosia rubescens, exhibits a broad range of pharmacological activities, including anti-inflammatory effects. However, its therapeutic potential in Alzheimer's disease (AD), particularly in modulating receptor-interacting protein kinase 1 (RIPK1)-mediated neuroinflammation and necroptosis, remains underexplored. This study aims to investigate the mechanism through which Pon targets RIPK1 to alleviate AD pathogenesis. The interaction between Pon and RIPK1 was confirmed using bio-layer interferometry (BLI) and drug affinity responsive target stability (DARTS) assays. In vitro, the effects of Pon on inflammatory responses and necroptosis were evaluated in BV2 microglial cells (BV2 cells) and HT22 hippocampal neuronal cells (HT22 cells) using Enzyme-linked immunosorbent assay (ELISA), Reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR), Western blotting (WB), and flow cytometry. In vivo, Pon's therapeutic efficacy was assessed in the 5 × FAD transgenic mouse model of AD through behavioral tests, histological analysis, and biochemical assays. Pon was found to bind RIPK1 with high affinity (KD = 135 nM) and enhance RIPK1's resistance to proteolytic degradation. In microglial cells, Pon effectively inhibited the release of pro-inflammatory cytokines interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α) by disrupting the RIPK1-janus kinase 1 (JAK1)-signal transducer and activator of transcription 1 (STAT1) signaling pathway. In neurons, Pon suppressed RIPK1-mediated necroptosis by blocking the RIPK1-RIPK3-mixed lineage kinase domain-like protein (MLKL) cascade. Behavioral analysis of 5 × FAD mice revealed that Pon treatment significantly improved cognitive function, reduced amyloid-beta (Aβ) plaque deposition, and alleviated neuroinflammation and necroptosis in the brain. Pon exerts dual neuroprotective effects by targeting RIPK1, mitigating both neuroinflammation and necroptosis, two critical pathological processes in AD. These findings underscore Pon's potential as a disease-modifying therapy for AD and provide a foundation for the clinical development of natural product-derived RIPK1 inhibitors in neurodegenerative diseases.},
}

@article {pmid41477919,
year = {2025},
author = {Hamada, N and Bernier, MO and Lumniczky, K and Laurier, D},
title = {Health effects of ionizing radiation exposure in the brain: MELODI perspectives on potential implications of emerging evidence for radiation protection.},
journal = {Mutation research. Reviews in mutation research},
volume = {797},
number = {},
pages = {108582},
doi = {10.1016/j.mrrev.2025.108582},
pmid = {41477919},
issn = {1388-2139},
abstract = {There is a growing body of epidemiological evidence for elevated risks of a variety of multifactorial diseases such as cancer, neurodegenerative diseases (e.g., Parkinson's disease and dementia) and cerebrovascular diseases (e.g., stroke) following radiation exposure of the brain. Implications of available scientific evidence for radiation protection need to be assessed, e.g., in terms of radiation effect classification (tissue reactions vs stochastic effects), dose and dose-rate effectiveness, target identification (at levels of cells, tissues and organs inside/outside the brain) for dose monitoring and risk management, radiation weighting approach for the mixed radiation field, and individual differences in radiation responses (e.g., with sex, age, populations, genetics, epigenetics, comorbidity, co-exposure). On the other hand, whole brain irradiation has clinically been tested to treat neurodegenerative diseases, particularly Alzheimer's disease. Action of radiation seems to represent a double-edged sword (i.e., detrimental to the healthy brain vs therapeutic to the diseased brain) not only for cancer, but also for non-cancer diseases. Justification of radiation exposure and optimization of radiation protection would therefore be of critical importance. This paper gives a brief overview of emerging evidence for radiation effects in the brain, and considers its potential implications for radiation protection.},
}

@article {pmid41477717,
year = {2025},
author = {Osypov, AA and Mukhina, KA and Lyubanskaya, AD and Nikiforova, AB and Korchagina, VM and Mitkevich, VA and Popova, IY},
title = {[The Role of NOX2-Mediated Oxidative Stress in Initiation of Acute Amyloid Toxicity].},
journal = {Molekuliarnaia biologiia},
volume = {59},
number = {6},
pages = {971-978},
doi = {10.7868/S3034555325060076},
pmid = {41477717},
issn = {0026-8984},
mesh = {*NADPH Oxidase 2/metabolism/genetics/antagonists & inhibitors ; Animals ; *Oxidative Stress/drug effects ; Mice ; *Amyloid beta-Peptides/toxicity ; *Alzheimer Disease/pathology/genetics/metabolism ; *Brain/metabolism/pathology/drug effects ; Mice, Inbred BALB C ; Male ; },
abstract = {Although the role of NADPH oxidase 2 (NOX2) in the development of Alzheimer's disease (AD) is widely recognized, its contribution to the initial stages of amyloid-induced pathology remains unclear. Intraventricular administration of β-amyloid (Aβ) causes acute amyloid toxicity, leading to neurodegenerative changes similar to AD. The acute phase, lasting several days, is a critical time window for studying early pathological mechanisms. In this work, we assessed the level of oxidative stress in the brain of BALB/c mice at the early stages of amyloid toxicity and the role of NOX2 in these processes. Analysis of key markers of oxidative stress in various fractions of brain homogenate on day 4 after Aβ administration showed that individual parameters demonstrated only a tendency to change, without reaching statistical significance. However, principal component analysis (PCA) revealed a clear separation between the Aβ-treated and control groups, indicating the need for a comprehensive rather than isolated analysis of biochemical changes at early stages of pathology. It is noteworthy that the centroids of the groups in PCA were located along the same straight line, and the group receiving Aβ together with the NOX2 inhibitor occupied an intermediate position between the control and Aβ groups. This indicates partial suppression of oxidative stress through NOX2. At the same time, the NOX2 inhibitor completely prevented Aβ-induced microgliosis in the hippocampus, confirming that the concentration used was sufficient to suppress NOX2-dependent microglial activation. The in vivo data demonstrate that oxidative stress induced by Aβ administration may not be entirely mediated by NOX2, although this mechanism plays an important role in the initiation of the pathological process in AD.},
}

*NADPH Oxidase 2/metabolism/genetics/antagonists & inhibitors
Animals
*Oxidative Stress/drug effects
Mice
*Amyloid beta-Peptides/toxicity
*Alzheimer Disease/pathology/genetics/metabolism
*Brain/metabolism/pathology/drug effects
Mice, Inbred BALB C
Male

@article {pmid41477715,
year = {2025},
author = {Zernov, N and Melenteva, D and Popugaeva, E},
title = {[Benzopyran Derivative Improves Synaptic Plasticity, Exploration Interest and Alleviates Amyloidogenesis and Astrogliosis in 5*FAD Mice].},
journal = {Molekuliarnaia biologiia},
volume = {59},
number = {6},
pages = {938-956},
doi = {10.7868/S3034555325060053},
pmid = {41477715},
issn = {0026-8984},
mesh = {Animals ; Mice ; *Neuronal Plasticity/drug effects ; *Alzheimer Disease/drug therapy/pathology/genetics/metabolism/physiopathology ; Mice, Transgenic ; Hippocampus/metabolism/drug effects/pathology/physiopathology ; *Gliosis/drug therapy/genetics/pathology/metabolism ; Female ; Disease Models, Animal ; Humans ; Long-Term Potentiation/drug effects ; *Plaque, Amyloid/drug therapy/pathology/genetics/metabolism ; },
abstract = {Current Alzheimer's disease (AD) therapies offer only symptomatic relief and fail to halt disease progression, underscoring the urgent need for novel therapeutic strategies. We have previously shown that selective positive allosteric modulator of TRPC6, benzopyran derivative (C20), exhibits synaptoprotective properties at nanomolar concentrations, restores synaptic plasticity in 5xFAD mice, and enhances hippocampus-dependent memory. Here, we further evaluate the preclinical efficacy and safety of C20, focusing on its effects on chronic toxicity, mutagenicity, amyloidosis, astrogliosis, synaptic plasticity, and behavior in a transgenic AD model. Chronic and acute toxicity studies were performed on female wild type mice. The Ames test was conducted using Salmonella typhimurium and E. coli strains to evaluate the mutagenic potential of C20. 8 months old 5xFAD were used as model of AD. Electrophysiological recordings were applied to study long term potentiation in hippocampal slices of 5xFAD mice following intraperitoneal injections of C20. Behavioral testing included the open field test. Immunohistochemical analyses were performed to quantify amyloid plaques and astrogliosis in the hippocampus. Chronic and acute toxicity studies revealed no significant adverse effects on mice weight and survival, indicating that C20 is well-tolerated at the tested dose. The Ames test confirmed that C20 is almost non-mutagenic. Behavioral testing demonstrated that C20- treated mice exhibited increased exploration in the open field test. Immunohistochemical analyses detected a significant reduction in amyloid plaques and astrogliosis. Our findings suggest that C20 is a safe and effective therapeutic candidate for AD, with the potential to restore synaptic plasticity, improve cognitive function, and reduce pathological hallmarks of the disease.},
}

Animals
Mice
*Neuronal Plasticity/drug effects
*Alzheimer Disease/drug therapy/pathology/genetics/metabolism/physiopathology
Mice, Transgenic
Hippocampus/metabolism/drug effects/pathology/physiopathology
*Gliosis/drug therapy/genetics/pathology/metabolism
Female
Disease Models, Animal
Humans
Long-Term Potentiation/drug effects
*Plaque, Amyloid/drug therapy/pathology/genetics/metabolism

@article {pmid41477671,
year = {2025},
author = {Hammerschlag, BL and Butts, B and Likos, KD and Verble, DD and Nimmagadda, N and Wharton, W},
title = {Pilot: Salivary lactoferrin as a potential preclinical Alzheimer's disease biomarker.},
journal = {Journal of Alzheimer's disease reports},
volume = {9},
number = {},
pages = {25424823251409391},
pmid = {41477671},
issn = {2542-4823},
abstract = {Alzheimer's disease (AD) research increasingly emphasizes accessible biomarkers for early detection. Lactoferrin, an iron-binding glycoprotein present in saliva, has been associated with AD pathology with mixed results. In this pilot study, saliva samples from 17 middle-to-older-aged Black and non-Hispanic White adults at risk for AD were measured. After adjusting for demographic variables, salivary lactoferrin (sLF) concentrations correlated significantly with Digit Span Memory Test scores (p = 0.013) and modestly with visuospatial performance (p = 0.194), with no racial differences observed. These preliminary results support further large-scale studies to assess sLF as a potential noninvasive biomarker for AD.},
}

@article {pmid41477670,
year = {2025},
author = {Shimokawa, H and Akishita, M and Asada, T and Katayama, S and Hattori, Y and Yakushiji, Y and Taki, Y and Murai, H and Boku, Y and Tsujimoto, M and Umegaki, H and Ogawa, T and Matsumoto, S and Ono, K and Imon, Y and Tsunemi, T and Iwata, A and Hanajima, R and Hisahara, S and Uehara, T and Ishiguro, T and Nakaoku, Y and Ishii, K and Ishiki, A and Nagai, Y and Teramukai, S and Ihara, M and Fukushima, M},
title = {Baseline characteristics of patients with early Alzheimer's disease enrolled in the pivotal trial of low-intensity pulsed ultrasound (LIPUS-AD).},
journal = {Journal of Alzheimer's disease reports},
volume = {9},
number = {},
pages = {25424823251407541},
pmid = {41477670},
issn = {2542-4823},
abstract = {BACKGROUND: We demonstrated that low-intensity pulsed ultrasound (LIPUS) therapy tended to ameliorate cognitive declines in patients with early Alzheimer's disease (AD) in the pilot trial. Thus, we have started the pivotal trial in a randomized, double-blind, placebo-controlled manner (LIPUS-AD).

OBJECTIVE: We here report the clinical characteristics of AD patients enrolled in the trial.

METHODS: The major inclusion criteria included age 50-90 years of both sex, Clinical Dementia Rating (CDR) global score of 0.5∼1.0 and Japanese version of the Mini-Mental State Examination (MMSE-J) score greater than 20 at screening, positive brain Aβ-PET, and no symptomatic brain hemorrhage, infarction, or edema on brain MRI.

RESULTS: A total of 231 subjects were finally enrolled. As compared with the pilot trial, they were characterized by older age and higher prevalence of dyslipidemia. They had lower scores of ADAS-J-cog and Modified Hachinski Ischemic Scale (MHIS), while other cognitive scores were comparable with the pilot trial. Use of cholinesterase inhibitors was less as compared with the pilot trial. APOE ε4 polymorphism is present in 58% of the subjects, including heterozygote in 44% and homozygote in 14%. Brain MRI measurements showed that hippocampus volume was distributed with a peak at 5700-5999 mm[3] without left and right difference, and brain Aβ-PET showed that centiloid scale distributed with a peak at 90-99.9 and standardized uptake value ratio (SUVR) with a peak at 0.7-0.79. There were weak but significant correlations between ADAS-J-cog14 and those brain MRI and Aβ-PET measurements.

CONCLUSIONS: Clinical characteristics of subjects in the LIPUS-AD trial largely mimic those in the pilot trial, addressing efficacy and safety of the LIPUS therapy in early AD.Clinical Trial Gov. No.: NCT05983575, jRCT No.: jRCT2032230125.},
}

@article {pmid41477669,
year = {2025},
author = {Sha, Y and Jia, C and Liang, M and Wu, J and Zhang, T and Zhu, Y and Yuan, J and Li, Q and Huang, Z and Cui, R and Ni, J},
title = {Higher cerebellum florbetapir uptake in cerebral amyloid angiopathy compared to Alzheimer's disease: A dual florbetapir and FDG PET study.},
journal = {Journal of Alzheimer's disease reports},
volume = {9},
number = {},
pages = {25424823251409418},
pmid = {41477669},
issn = {2542-4823},
abstract = {BACKGROUND: Amyloid-β (Aβ) is the primary amyloidogenic protein involved in various diseases associated with cognitive dysfunction, including Alzheimer's disease (AD) and cerebral amyloid angiopathy (CAA).

OBJECTIVE: This cross-sectional study aimed to investigate the characteristics of [18]F-florbetapir PET, which detects Aβ deposition, and [18]F-FDG PET, which measures glucose metabolism in patients with CAA and AD.

METHODS: 30 patients with AD, 37 with probable CAA, and 14 control subjects (CSs) underwent [18]F-florbetapir and [18]F-FDG PET imaging within a one-month period. Region of interest and voxel-wise analyses were performed to compare Aβ deposition and glucose metabolism patterns among the three study groups. Standardized uptake value ratios were calculated using brainstem as the reference region for [18]F-florbetapir and [18]F-FDG PET, respectively.

RESULTS: Patients with CAA exhibited significantly higher [18]F-florbetapir uptake in the cerebellum, global cerebral cortex, and various cortical regions compared to CSs. Compared to patients with AD, those with CAA showed predominantly higher [18]F-florbetapir uptake in the cerebellum but lower uptake in the insular cortex and posterior cingulate gyrus. Glucose hypometabolism patterns in CAA did not differ significantly from those observed in AD.

CONCLUSIONS: Distinct Aβ deposition patterns, particularly the increased amyloid burden in the cerebellum, could serve as a valuable biomarker for differentiating CAA from AD.},
}

@article {pmid41477538,
year = {2025},
author = {Campos, VLM and Serafim, AP},
title = {Pharmacological Interventions for Excoriation Behaviors in Alzheimer's Disease: An Empty Systematic Review of Clinical Trials.},
journal = {Clinical neuropsychiatry},
volume = {22},
number = {6},
pages = {498-506},
pmid = {41477538},
issn = {2385-0787},
abstract = {OBJECTIVE: skin-picking behaviors are often maintained in association with mood changes, but can also manifest as separate manifestations particularly in Alzheimer's disease (AD). Verifying the effect of interventions on its remission may contribute to reducing stress in patients and caregivers. This systematic review sought to evaluate the eficacy of pharmacological interventions for skin-picking behaviors in elderly individuals with AD.

METHOD: according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA 2020), searches were conducted in ClinicalTrials.gov,Embase, Lilacs, Open Science Framework, PsycNET, PubMed, Scopus, SciELO, SciELO Preprints and Web of Science, with no language or date restrictions. Inclusion criteria were clinical trials with participants aged ≥ 40 years with AD, evaluating pre/ post-test outcomes with standardized instruments.

RESULTS: of the 87 records found, none met the eligibility criteria, configuring an empty review. Two studies related to the topic were excluded because they were not clinical trials (a single case report and a case series), involving five patients treated with antipsychotics (risperidone, pimozide and thioridazine) and antidepressants (paroxetine). The absence of eligible studies suggests a gap in the literature and the lack of robust evidence on the pharmacological efficacy on these behavioral symptoms in this population.

CONCLUSIONS: future clinical trials are needed to support specific therapeutic recommendations, since the evidence suggested by studies that are not clinical trials, evaluated in addition to the main objective of this review, is primary and limited.},
}

@article {pmid41477525,
year = {2025},
author = {Zheng, M and Hong, X and Liao, P and Huang, H and Zhang, Y and Xu, W and Li, H},
title = {Plant-Derived Exosome-Like Nanoparticles: A Promising Therapeutic for Neurological Disorders and Drug Delivery.},
journal = {International journal of nanomedicine},
volume = {20},
number = {},
pages = {15769-15791},
pmid = {41477525},
issn = {1178-2013},
mesh = {Humans ; *Exosomes/chemistry ; *Nanoparticles/chemistry ; Animals ; *Nervous System Diseases/drug therapy ; Blood-Brain Barrier/metabolism ; *Drug Delivery Systems/methods ; *Plants/chemistry ; },
abstract = {Neurological disorders, including ischemic stroke, Alzheimer's disease, and Parkinson's disease, exhibit high incidence rates and pose significant health challenges. Current pharmacological treatments often fail to adequately address clinical needs due to obstacles such as limited penetration of the blood-brain barrier and suboptimal efficacy. Plant-derived exosome-like nanoparticles (PELNs) have emerged as promising therapeutic agents due to their superior biocompatibility, low toxicity, ability to traverse the blood-brain barrier, and abundance of lipids, microRNAs, and other bioactive compounds. This review provides a comprehensive overview of recent advancements in PELNs preparation technologies, elucidates the mechanisms of action of their principal bioactive components, and explores their therapeutic applications across various neurological disorders, thereby offering a theoretical foundation for the development of related treatment strategies. Nonetheless, researches on PELNs continue to encounter significant challenges. At the production level, there is an absence of standardized isolation protocols, and the yields remain inadequate to satisfy clinical requirements. Clinically, the efficacy in humans has yet to be established, and the available safety data are insufficient. Technically, the lack of standardized storage conditions and the susceptibility of biological stability to external factors further complicate the field. This review delineates these challenges to offer insights for advancing both fundamental research and the clinical translation of PELNs.},
}

Humans
*Exosomes/chemistry
*Nanoparticles/chemistry
Animals
*Nervous System Diseases/drug therapy
Blood-Brain Barrier/metabolism
*Drug Delivery Systems/methods
*Plants/chemistry

@article {pmid41477168,
year = {2025},
author = {Xiao, Y and Li, H and Han, X and Liu, Y and Sun, J and Sun, C and Wang, Y and Ye, T and Cheng, X},
title = {Qi-Fu-Yin ameliorates physiological frailty in male 5xFAD mice through remodeling the gut microbiota and modulating the cerebral cortex metabolism.},
journal = {Frontiers in aging neuroscience},
volume = {17},
number = {},
pages = {1622286},
pmid = {41477168},
issn = {1663-4365},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is a neurodegenerative disease that can only be managed rather than cured, bringing a substantial burden to society. Frailty and cognition are intertwined in a cycle of decline, affecting the prognosis of AD. Qi-Fu-Yin (QFY) is a classic prescription in traditional Chinese medicine for dementia. While most studies have focused on cognitive impairment, research on physiological frailty remains relatively scarce in AD, especially in 5xFAD mice. We aimed to investigate the impacts of QFY on the physiological frailty of male 5xFAD mice.

METHODS: Male 5xFAD mice received QFY, followed by grip strength test, rotarod test, grading score of frailty, lipofuscin staining, SA-β-gal and Aβ co-staining. The metabolite alteration and the intestinal flora composition were analyzed by non-targeted metabolomics and 16S rRNA sequencing. Moreover, Spearman's correlation analysis was used to integrate behavioral results, differentially expressed metabolites, and altered bacterial genera.

RESULTS: We discovered that QFY improved grip strength, riding time, score of frailty, lipofuscin deposition, SA-β-gal, and Aβ in male 5xFAD mice. The results of untargeted metabolomics showed that metabolites such as proline, PS (18:1/18:0), and PFSA-CI were downregulated in the male 5xFAD mice compared with C57BJ/6JXSJL mice, while PE (18:1/18:1) was upregulated. QFY treatment reversed these changes, restoring metabolite levels toward those of C57BJ/6JXSJL mice. Arginine and proline metabolism, alanine, aspartate and glutamate metabolism, and butyrate metabolism were filtered out as the important metabolic pathways between the C57BJ/6JXSJL mice and the male 5xFAD mice, as well as between the 5xFAD mice and the 5xFAD mice with QFY treatment. Moreover, Ruminococcaceae, Subdoligranulum, Bacteroides, Alistipes, Rikenellaceae_RC9_gut_group, and Odoribacter, which were lower in male 5xFAD mice, were improved after QFY intervention.

DISCUSSION: The differential intestinal flora might improve the metabolism of brain tissue as well as muscle strength and coordination through Short-chain fatty acids (SCFAs). The differential metabolites caused by QFY intervention also have an improving effect on physiological frailty. We suggest that QFY exerts protective impacts against the physiological frailty in AD by adjusting the muscle-gut-brain axis.},
}

@article {pmid41477167,
year = {2025},
author = {Garcia, ML and Denton, AR and Jackson, NL and Scofield, MD and McMahon, LL},
title = {Pharmacologically increasing O-GlcNAcylation increases complexity of astrocytes in the dentate gyrus of TgF344-AD rats.},
journal = {Frontiers in aging neuroscience},
volume = {17},
number = {},
pages = {1690410},
pmid = {41477167},
issn = {1663-4365},
abstract = {BACKGROUND: Alzheimer's disease (AD) pathology begins two or three decades prior to the onset of cognitive symptoms and is characterized by amyloid-β (Aβ) and hyperphosphorylated tau (pTau) accumulation, reactive glial cells, increased inflammation, and neuronal degeneration in later stages. Preclinical studies report that increasing the post-translational modification, O-GlcNAcylation, involving the addition of a single N-acetylglucosamine (GlcNAc) moiety to serine or threonine residues, can reduce amyloidogenic processing of amyloid precursor protein (APP) and compete with serine phosphorylation on tau, decreasing hyperphosphorylated tau accumulation. Protein O-GlcNAcylation can have anti-inflammatory effects, suggesting the possibility that increasing O-GlcNAcylation may decrease reactive gliosis and other pathological changes in AD.

METHODS: This study aimed to assess the possible beneficial effects of pharmacologically enhancing O-GlcNAcylation by inhibiting O-GlcNAcase (OGA), the enzyme responsible for the removal of O-GlcNAc moieties, on progressive AD pathology using female TgF344-AD rats. The selective OGA inhibitor thiamet-G [TMG; 10 mg/kg, subcutaneously (s.c.)] was administered three times per week for 3 months starting at 6 months of age, a time point when Aβ pathology is evident in the hippocampus. Western blot analysis was used to measure protein levels of GFAP, Iba-1, and Aβ. Immunohistochemistry and confocal imaging were used to assess Aβ plaques, astrocyte and microglia complexity, and degeneration of tyrosine hydroxylase-positive (TH+) axons.

RESULTS: In TgF344-AD rats, we found significantly increased astrocyte complexity, defined as increased process length and branches, increased numbers of microglia, loss of noradrenergic axons (NA), and significant Aβ plaques compared to WT, confirming previous work by us and others. Notably, pharmacologically increasing O-GlcNAcylation further increased astrocyte complexity in TgF344-AD rats, specifically those located in close proximity to Aβ plaques, while microglia morphology and Aβ staining were unaffected. O-GlcNAcylation was not able to lessen the loss of TH + axons in TgF344-AD rats, although fewer dystrophic axons were observed, suggesting a possible beneficial effect.

DISCUSSION: Our findings demonstrate that increasing O-GlcNAcylation in TgF344-AD rats using a cyclical treatment protocol at a time when Aβ pathology is already significant does not provide broad beneficial effects on Aβ accumulation, microglial reactivity, or noradrenergic axon loss, although there appears to be fewer dystrophic axons. Importantly, increasing O-GlcNAcylation in TgF344-AD rats has dual beneficial effects on astrocyte reactivity. Astrocytes in close proximity to Aβ plaques are more complex with longer processes and more branches compared to those in saline-treated TgF344-AD rats at the same distance, enabling them to surround plaques and protect nearby neurons. Astrocytes located at more distal locations from plaques are less reactive than those at the same distance in saline-treated TgF344-AD rats, permitting a less pathological local environment for nearby neurons. Our findings offer new insights into the possible mechanisms that might contribute to the beneficial therapeutic effects of increasing O-GlcNAcylation during progressive AD pathology.},
}

@article {pmid41476954,
year = {2026},
author = {Verón, GL and Juantorena, GE and Keller, G and Crivelli, L and Kamienkowski, JE},
title = {Eye tracking as a diagnostic tool in Alzheimer's disease, mild cognitive impairment, and related dementias: a systematic review.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {1},
pages = {e70238},
pmid = {41476954},
issn = {2352-8729},
abstract = {UNLABELLED: Alzheimer's disease (AD) pathology begins years before symptoms emerge, making early detection essential. Eye tracking offers a rapid, non-invasive means of identifying early cognitive decline through oculomotor disturbances. This Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)- and Population, Intervention, Comparison, and Outcome (PICO)-guided systematic review evaluated studies from PubMed, ACM Digital Library, and Google Scholar on eye tracking in mild cognitive impairment (MCI), AD, and related dementias. Seventy-one studies met the inclusion criteria. Antisaccade tasks consistently distinguished AD and MCI from healthy controls, with impaired accuracy, longer latencies, and reduced gain. Non-saccadic paradigms (e.g., visual search, free viewing) indicated diminished exploratory behavior in AD, with mixed findings in MCI. A major limitation was the lack of cohorts defined by current biological criteria, hindering clinical translation. In a subset, classical machine-learning (ML) models and deep neural networks reported accuracies of 0.72 to 0.97. Overall, antisaccade tasks show strong promise for early AD screening; future work should adopt biologically defined cohorts and scalable, accessible eye-tracking technologies.

HIGHLIGHTS: Antisaccade tasks best distinguish AD and MCI from HCs.Visual search/free-view tasks showed diminished exploratory behavior in AD.Most studies lack biomarker-based AD criteria, creating a major research gap.},
}

@article {pmid41476782,
year = {2025},
author = {Zhu, Y and Liu, H and He, M and Xu, Z and Sun, L and Wu, Z and Niu, X and Huang, S and Wang, J and Ran, X},
title = {Epidemiology and Risk Factors Characteristics of Alzheimer's Disease in Southwestern China: A Cross-Sectional Study.},
journal = {Clinical interventions in aging},
volume = {20},
number = {},
pages = {2685-2704},
pmid = {41476782},
issn = {1178-1998},
mesh = {Humans ; *Alzheimer Disease/epidemiology ; China/epidemiology ; Female ; Male ; Risk Factors ; Aged ; *Cognitive Dysfunction/epidemiology ; Cross-Sectional Studies ; Aged, 80 and over ; Middle Aged ; Prevalence ; Rural Population ; Sex Factors ; Age Factors ; Educational Status ; Comorbidity ; Logistic Models ; },
abstract = {BACKGROUND: To address the regional heterogeneity of Alzheimer's disease, a large-scale epidemiological study of 12,421 elderly individuals was conducted in southwestern China to depict its unique risk characteristics.

METHODS: A total of 12,421 subjects were selected via cluster sampling from southwestern China after low quality data were filtered out. On the basis of investigations and medical imaging examinations, three groups were distinguished: the AD, mild cognitive impairment (MCI), and normal control groups. The risk factors for AD and MCI were analysed via a multivariate logistic regression model.

RESULTS: This study identifies a high burden of cognitive impairment in southwestern China, with 22.07% of adults aged ≥60 years exhibiting cognitive decline and 5.81% diagnosed with Alzheimer's disease rates surpassing national and global averages. Key risk factors included age >80 years, female sex, low education, rural residence, surgical history, and urological comorbidities. These findings underscore the need for region-specific prevention strategies, prioritizing older, less-educated rural women through combined cognitive and vascular interventions, while integrating cognitive screening into primary care in underserved areas for early detection and intervention.

CONCLUSION: Elderly individuals in southwestern China exhibit a high prevalence of cognitive impairment, with AD associated with complex risk factors including established contributors like advanced age, dementia family history, alcohol abuse, and multisystem comorbidities-while notably identifying surgical history and urolithiasis as region specific risk signals. These findings underscore regional, environmental, and ethnic influences on AD pathogenesis, requiring tailored prevention/treatment. Future priorities include integrating brief cognitive screening into primary care, targeting high-risk groups (eg, undereducated rural elderly women), and establishing prospective cohorts to clarify causal links between urolithiasis, surgical history, and cognitive decline for refined region-adapted AD prevention.},
}

Humans
*Alzheimer Disease/epidemiology
China/epidemiology
Female
Male
Risk Factors
Aged
*Cognitive Dysfunction/epidemiology
Cross-Sectional Studies
Aged, 80 and over
Middle Aged
Prevalence
Rural Population
Sex Factors
Age Factors
Educational Status
Comorbidity
Logistic Models

@article {pmid41476670,
year = {2025},
author = {Mygind, L and Jensen, G and Neesgaard, V and Krohn, KT and Puig, ST and Boysen, A and Petersen, S and Lambertsen, KL and Metaxas, A and Kemp, M and Møller-Jensen, J and Finsen, B},
title = {E.coli-derived CsgA-peptides stimulate cytokine production in microglia and lead to transient changes in neocortical Aβ-levels in pre-plaque APP SWE /PS1 ΔE9 and wild type mice.},
journal = {Brain, behavior, & immunity - health},
volume = {50},
number = {},
pages = {101128},
pmid = {41476670},
issn = {2666-3546},
abstract = {Epidemiological and pre-clinical data propose that infections can accelerate the cognitive decline in Alzheimer's disease (AD) and other dementias. The implication of infectious agents, and especially the role of E.coli and other amyloid-peptide producing bacteria, on the development and progression of cerebral amyloidosis and neuroinflammation, both key neuropathological characteristics of AD, has only been studied to a limited extent. In this study, recombinant bacterial amyloid surface protein CsgA was injected intracisternally in pre-plaque 8-11-week-old APP SWE /PS1 ΔE9 mice and age-matched wild type (WT) mice. Although less potent than bacterial lipopolysaccharide, CsgA significantly increased the gene expression of inflammatory cytokines, such as tumor necrosis factor, in the neocortex of both APP SWE /PS1 ΔE9 and WT mice, and in cultured microglia. CsgA exposure also induced transient changes in neocortical amyloid-beta (Aβ) peptide levels, increasing the highly fibrillogenic Aβ42 in the guanidine-fraction in APP SWE /PS1 ΔE9 mice and decreasing Aβ40 in the PBS-fraction in WT mice. The changes in Aβ levels had dissipated 24 h post-injection. In line with the only transient changes in Aβ levels and inflammatory gene expression, CsgA did not impact on long term spatial memory in pre-plaque APP SWE /PS1 ΔE9 mice. Our findings highlight a contribution of bacterial amyloid proteins on neuroinflammation and a possible contribution in influencing Aβ-homeostasis during infections. However, findings need to be further elaborated in older APP SWE /PS1 ΔE9 mice in which Aβ plaques are abundant and an inflammatory response already established. Also, the impact of CsgA and other bacterial amyloids should be examined after repeated and/or continuous administration and at different concentrations.},
}

@article {pmid41476457,
year = {2026},
author = {Modali, VA and Pavanya, M and Arjunan, RV and Cenitta, D and Sampathila, N and Kamath, R and Chadaga, K},
title = {AlzStack: Forecasting early-onset Alzheimer's with an explainable AI system using multiple data balancing techniques.},
journal = {Global epidemiology},
volume = {11},
number = {},
pages = {100235},
pmid = {41476457},
issn = {2590-1133},
abstract = {Alzheimer's disease (AD) is a degenerative neurological disease that progresses over time, making early detection crucial for effective intervention and better patient prognosis. Traditional diagnostic methods such as cognitive assessments, neuroimaging, and biomarker analysis can be time-consuming, costly, and inconsistent. We introduce AlzStack, a soft voting ensemble model to classify AD from a richly detailed dataset containing 2149 patients across demographic, medical, lifestyle, and cognitive variables. To resolve class imbalance, we implemented a pipeline 5-fold cross-validation, randomized search for hyper parameter tuning and advanced resampling methods such as SMOTE (Synthetic Minority Oversampling Technique), ADASYN, BorderlineSMOTE, and SVMSMOTE. Soft Vote Classifier surpassed both stacking ensembles and hard voting with an AUC value of 94.27 %, accuracy of 93.26 %, precision of 89.17 %, a recall of 92.11 %, and F1-score value of 90.61 %.A secondary experiment with only resampling methods applied to data to all base models served as a baseline for comparison confirming the superior performance of cross-validation AlzStack configuration. To improve interpretability, we utilized a wide range of Explainable Artificial Intelligence (XAI methods) and these approaches yielded global and local explanations about model behavior, emphasizing key features like MMSE scores, functional measures, and behavioral markers. Combining robust predictive performance with explainable decision-making makes AlzStack is a healthcare decision-support algorithm for the early detection of AD.},
}

@article {pmid41476306,
year = {2025},
author = {Baskaran, A and Wasilewicz, A and Rollinger, JM and Grzelczyk, J and Gałązka-Czarnecka, I and Budryn, G and Strzała, T and Graf, TN and Oberlies, NH and Boratyński, F and El-Sayed, ER},
title = {Natural pigments from the endophyte Aspergillus westerdijkiae and evaluation of their bioactivities.},
journal = {Microbial cell factories},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12934-025-02905-8},
pmid = {41476306},
issn = {1475-2859},
support = {2021/43/P/NZ9/02 241//This research is part of project No. 2021/43/P/NZ9/02 241 co-funded by the National Science Centre and the European Union Framework Programme for Research and Innovation Horizon 2020 under the Marie Skłodowska-Curie grant agreement no. 945339./ ; 2021/43/P/NZ9/02 241//This research is part of project No. 2021/43/P/NZ9/02 241 co-funded by the National Science Centre and the European Union Framework Programme for Research and Innovation Horizon 2020 under the Marie Skłodowska-Curie grant agreement no. 945339./ ; 2021/43/P/NZ9/02 241//This research is part of project No. 2021/43/P/NZ9/02 241 co-funded by the National Science Centre and the European Union Framework Programme for Research and Innovation Horizon 2020 under the Marie Skłodowska-Curie grant agreement no. 945339./ ; 2021/43/P/NZ9/02 241//This research is part of project No. 2021/43/P/NZ9/02 241 co-funded by the National Science Centre and the European Union Framework Programme for Research and Innovation Horizon 2020 under the Marie Skłodowska-Curie grant agreement no. 945339./ ; 2021/43/P/NZ9/02 241//This research is part of project No. 2021/43/P/NZ9/02 241 co-funded by the National Science Centre and the European Union Framework Programme for Research and Innovation Horizon 2020 under the Marie Skłodowska-Curie grant agreement no. 945339./ ; 2021/43/P/NZ9/02 241//This research is part of project No. 2021/43/P/NZ9/02 241 co-funded by the National Science Centre and the European Union Framework Programme for Research and Innovation Horizon 2020 under the Marie Skłodowska-Curie grant agreement no. 945339./ ; 2021/43/P/NZ9/02 241//This research is part of project No. 2021/43/P/NZ9/02 241 co-funded by the National Science Centre and the European Union Framework Programme for Research and Innovation Horizon 2020 under the Marie Skłodowska-Curie grant agreement no. 945339./ ; 2021/43/P/NZ9/02 241//This research is part of project No. 2021/43/P/NZ9/02 241 co-funded by the National Science Centre and the European Union Framework Programme for Research and Innovation Horizon 2020 under the Marie Skłodowska-Curie grant agreement no. 945339./ ; 2021/43/P/NZ9/02 241//This research is part of project No. 2021/43/P/NZ9/02 241 co-funded by the National Science Centre and the European Union Framework Programme for Research and Innovation Horizon 2020 under the Marie Skłodowska-Curie grant agreement no. 945339./ ; 2021/43/P/NZ9/02 241//This research is part of project No. 2021/43/P/NZ9/02 241 co-funded by the National Science Centre and the European Union Framework Programme for Research and Innovation Horizon 2020 under the Marie Skłodowska-Curie grant agreement no. 945339./ ; 2021/43/P/NZ9/02 241//This research is part of project No. 2021/43/P/NZ9/02 241 co-funded by the National Science Centre and the European Union Framework Programme for Research and Innovation Horizon 2020 under the Marie Skłodowska-Curie grant agreement no. 945339./ ; },
abstract = {BACKGROUND: The growing consumer preference for natural and sustainable products has heightened interest in biopigments across pharmaceutical, cosmetic, and food industries. In this study, we investigate endophytic fungi as a viable and eco-friendly source for the production of bioactive natural pigments.

METHODS AND RESULTS: A promising strain, Aspergillus westerdijkiae 17P, was isolated from Betula pendula and assessed for its pigment-producing potential and associated bioactivities. The biomass extract was fractionated, and the resulting components were evaluated for antimicrobial, antioxidant, anticancer, neuroprotective, and peroxisome proliferator-activated receptor gamma (PPAR-γ) agonist activities. Among the fractions, 17P2 exhibited broad-spectrum antimicrobial effects, notable antioxidant activity (83% DPPH radical scavenging at 1000 mg/mL), and cytotoxicity against MCF-7 and HepG2 cancer cell lines, with IC₅₀ values of 250 mg/mL. Isothermal titration calorimetry (ITC) demonstrated strong binding affinities of 17P2 to acetylcholinesterase (Kd = 1.63 µM) and butyrylcholinesterase (Kd = 0.03 µM), indicating potential anti-Alzheimer's properties. Additionally, significant interactions with monoamine oxidase A and PPAR-γ suggest possible antidepressant and antidiabetic applications. Four major pigment fractions (17P1-17P4) were purified and structurally characterized using UHPLC-MS and NMR, revealing key metabolites such as aluminium and iron aspergillic acid complexes, penicillic acid, and preussin. Notably, gamma irradiation at 2000 Gy significantly enhanced the red, yellow, and orange pigments yield compared to the non-irradiated control cultures.

CONCLUSIONS: Collectively, these findings position A. westerdijkiae 17P as a valuable and versatile biotechnological resource for the sustainable production of multifunctional fungal pigments with potential industrial and therapeutic applications.},
}

@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 = {115},
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 regulating multiple post-transcriptional processes, including RNA stability, splicing, polyadenylation, nuclear export, localization, and translation. Recent findings reveal 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 (5-ALA) 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},
pmid = {41475015},
issn = {2561-7605},
support = {K01 AG090118/AG/NIA NIH HHS/United States ; K99 HL169940/HL/NHLBI NIH HHS/United States ; R34 MH135768/MH/NIMH NIH HHS/United States ; R35 GM151089/GM/NIGMS NIH HHS/United States ; },
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},
support = {R01 AG080623/AG/NIA NIH HHS/United States ; R56 AG053272/AG/NIA NIH HHS/United States ; },
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},
support = {F31 AG079619/AG/NIA NIH HHS/United States ; R01 AG070094/AG/NIA NIH HHS/United States ; T32 MH093311/MH/NIMH NIH HHS/United States ; },
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.},
}