@article {pmid41160464,
year = {2025},
author = {Kim, M and Kwon, H and Sohn, S and Lee, WJ and Cho, K and Kim, GW},
title = {Alzheimer's disease diagnosis and treatment: From pathophysiological insights to therapeutic advances in the era of precision neurology (2025 review).},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251391820},
doi = {10.1177/13872877251391820},
pmid = {41160464},
issn = {1875-8908},
abstract = {Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder marked by progressive cognitive decline, functional impairment, and ultimately, loss of independence. Traditional models centered on amyloid-β and tau pathology have expanded to encompass interconnected processes such as neuroinflammation, synaptic dysfunction, and gut-brain axis disruption, underscoring the multifactorial nature of the disease. In this review, we delivered that advances in diagnosis now integrate fluid biomarkers within the A/T/N/X framework, high-resolution neuroimaging, and artificial intelligence, enabling earlier and more precise disease characterization. On the therapeutic front, the approval of anti-amyloid monoclonal antibodies marks a paradigm shift toward disease-modifying approaches, yet challenges remain regarding efficacy, safety, and accessibility. Complementary strategies, including cognitive interventions and innovative drug delivery systems, highlight the need for multidimensional care that extends beyond pharmacology to improve patient quality of life. Furthermore, emerging avenues such as stem cell therapy, multitarget drug development, and precision medicine approaches illustrate a field in transition-shifting from symptomatic management toward personalized strategies aimed at altering the course of AD.},
}

@article {pmid41160460,
year = {2025},
author = {Cury, RM and da Silva, T and Cezar-Dos-Santos, F and Fakih, YRC and Narvaez, KAR and Gouvea, MC and Espínola, C and Ferreira, CF and de Castro, WAC and Pamplona, FA and Silva, EGD and Bicca, MA and Nascimento, FP},
title = {A randomized clinical trial of low-dose cannabis extract in Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251389608},
doi = {10.1177/13872877251389608},
pmid = {41160460},
issn = {1875-8908},
abstract = {BackgroundPreclinical and clinical evidence suggest that low-dose cannabinoids could ameliorate Alzheimer's disease (AD) signs and symptoms. We designed this trial to evaluate the safety and efficacy of low-dose THC-CBD balanced cannabinoid extract in the treatment of patients with AD-associated dementia.ObjectiveThe objective of this phase 2 trial was to evaluate the safety and efficacy of a balanced THC-CBD cannabinoid extract for symptomatic patients with AD.MethodsA Phase 2, randomized, double-blind, placebo-controlled, clinical trial including patients between 60 and 80 years-old diagnosed with AD-associated dementia. For 26 weeks, participants orally received either placebo or THC-CBD extract (0.350 mg/THC and 0.245 mg/CBD), daily.ResultsAt week 26, Mini-Mental State Exam total score was significantly higher in cannabis- when compared to placebo-treated patients, which was assessed using the mixed model analysis. No significant difference was detected between placebo and cannabis groups in terms of secondary outcomes and adverse events incidence.ConclusionsTo this date, this is the longest clinical trial evaluating cannabinoids effects on AD patients. We initially demonstrate that low-dose THC-CBD potentially can be an effective and safe therapeutic option for AD-related dementia. Nonetheless, larger and longer trials are necessary to confirm this finding and establish cannabinoid administration as therapy for AD dementia.Trial RegistrationThe Brazilian Registry of Clinical Trials (ReBEC) registration #U1111-1258-2058 - REBEC (ensaiosclinicos.gov.br).},
}

@article {pmid41160443,
year = {2025},
author = {Lim, MJ and Cheung, CY and Chong, JR and Chua, J and Hilal, S and Lai, MK and Maier, AB and Schmetterer, L and Tan, BY and Venketasubramanian, N and Wong, TY and Xu, X and Yeo, BT and Zhou, JH and Chen, CL},
title = {HARMONISATION - A multimodal prospective study of vascular cognitive impairment in multi-ethnic Asians: Cohort profile, progress, current contributions, and future impact.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251389006},
doi = {10.1177/13872877251389006},
pmid = {41160443},
issn = {1875-8908},
abstract = {Vascular cognitive impairment (VCI) describes cerebrovascular disease (CeVD)-associated cognitive disorders regardless of pathogenesis, ranging from a prodrome to dementia. Heterogeneity in the etiology and severity of CeVD, and significant co-occurrence with Alzheimer's disease (AD) pathology has hampered investigations. Research into VCI is especially relevant in Asia, where cognitive impairment and dementia, often due to VCI, grows due to rapidly aging populations and high prevalence of vascular risk factors. This manuscript reviewed the rationale, unique positioning, design, methodology, and findings from the HARMONISATION study, a prospective observational study of VCI and AD in multi-ethnic Asians. HARMONISATION aimed to discover and validate novel biomarkers as effective diagnostic and prognostic tools, and translate findings into improved patient care, disease management and treatment-utilizing comprehensive multimodal clinical, neuroimaging, retinal, and blood biomarker data to address critical research gaps such as the etiology and clinical importance of mixed dementia, relationships between AD and CeVD pathology, and challenges of heterogenous CeVD pathology. HARMONIZATION recruited and deeply phenotyped 700 older multi-ethnic Asians with no cognitive impairment, mild cognitive impairment, and dementia for up to 5 years of follow-up. It has yielded developments in biomarker identification, validation, interactions and analysis methods; disease mechanisms and progression; clinical prognostics for VCI and AD; improved patient care and management; and enabled future development of novel interventions in Asians, and globally. An ongoing extension study will allow up to 10 years follow-up to further explore specific modifiable processes of VCI and the contributions of vascular events to cognitive impairment.},
}

@article {pmid41160347,
year = {2025},
author = {Brixner, DI and Zhao, C and Toyosaki, H and Frech, FH and Rosenbloom, MH},
title = {Initial Real-World Evidence for Lecanemab in the United States.},
journal = {Drugs & aging},
volume = {},
number = {},
pages = {},
pmid = {41160347},
issn = {1179-1969},
abstract = {BACKGROUND: Lecanemab is the first anti-amyloid monoclonal antibody with full approval in the US for the treatment of early Alzheimer's disease (AD). This observational study aimed to provide information about patient demographics, clinical characteristics, provider specialty, and lecanemab utilization patterns.

METHODS: This observational study used open administrative claims from the PurpleLab, a database encompassing medical and pharmacy claims derived from diverse sources, such as clearinghouses and Pharmacies. We included patients receiving one or more lecanemab doses between January 6, 2023 and October 31, 2024, and having continuous clinical activity ≥ 6 months prior to the first lecanemab infusion. The observation period ran from the first lecanemab infusion to the latest clinical activity or data availability. Treatment gaps were calculated as the number of gap days in lecanemab supply between consecutive infusions.

RESULTS: Among the study population (n = 4261), mean age was 75.2 years, 77.8% were White, 98.4% lived in urban settings, 81.7% were treated by neurologists, 77.3% had AD, and 31.7% had mild cognitive impairment. Mean follow-up period was 171.1 days. Lecanemab infusions averaged 1.9 per patient per month (SD 1.0), 16.3 days apart (SD 11.0), and 2.8% of patients experienced a treatment interruption ≥90 days.

CONCLUSIONS: Lecanemab utilization followed US FDA-approved prescribing information. Disparities for minority and rural-based populations were observed suggesting opportunities to improve access for underserved populations.},
}

@article {pmid41160319,
year = {2025},
author = {Sarikamis Johnson, B and Ercin, N and Kalkan Cakmak, R and Besli, N and Beker, M and Beker, MC and Celik, U},
title = {Exploring the effects of squalene in the PERK/ATF4/eIF2α/CHOP signalling pathway in an in vitro Alzheimer Disease model and in silico approach.},
journal = {Metabolic brain disease},
volume = {40},
number = {8},
pages = {300},
pmid = {41160319},
issn = {1573-7365},
support = {123Z925//Scientific and Technological Research Council of Türkiye/ ; 2021-067//University of Health Sciences, Türkiye/ ; },
mesh = {Humans ; *Alzheimer Disease/metabolism/drug therapy ; Activating Transcription Factor 4/metabolism ; eIF-2 Kinase/metabolism ; *Signal Transduction/drug effects ; Eukaryotic Initiation Factor-2/metabolism ; Endoplasmic Reticulum Stress/drug effects ; Transcription Factor CHOP/metabolism ; *Squalene/pharmacology/therapeutic use ; Unfolded Protein Response/drug effects ; Reactive Oxygen Species/metabolism ; Molecular Docking Simulation ; Amyloid beta-Peptides ; Oxidative Stress/drug effects ; Mesenchymal Stem Cells/drug effects/metabolism ; Cells, Cultured ; Peptide Fragments ; },
abstract = {Recent studies emphasize the pivotal role of endoplasmic reticulum (ER) stress in Alzheimer's disease (AD), highlighting the need for further investigation into this critical link. In response to ER stress, cells increase reactive oxygen species (ROS) production, leading to heightened oxidative stress. This interplay has sparked interest in antioxidant molecules such as squalene (SQ) as potential therapeutic agents. The primary objective of this study was to examine the impact of SQ on the unfolded protein response (UPR) pathway triggered by ER stress in an in vitro AD model. Herein, molecular docking analysis was performed to evaluate SQ interactions with target proteins, followed by in vitro assays. Human bone marrow-derived mesenchymal stem cells were differentiated into neuronal-like cells and characterized via immunostaining. The cells were then exposed to Aβ1-42 toxicity to establish an in vitro AD model. To assess the effects of SQ treatment following Aβ1-42 exposure, UPR-related proteins (BIP, p-PERK, PERK, eIF2α, p-eIF2α, ATF4, CHOP) were analysed by Western blotting; ROS levels were quantified to evaluate oxidative stress, and a TUNEL assay was performed to assess apoptosis. Our findings indicate that SQ alters protein expression within the UPR pathway in the AD experimental model. Notably, amyloid-β levels were significantly reduced in the SQ-treated group (p˂0.001). Furthermore, SQ reduced ROS levels. These results suggest that SQ holds potential as a therapeutic agent for mitigating amyloid-β toxicity.},
}

Humans
*Alzheimer Disease/metabolism/drug therapy
Activating Transcription Factor 4/metabolism
eIF-2 Kinase/metabolism
*Signal Transduction/drug effects
Eukaryotic Initiation Factor-2/metabolism
Endoplasmic Reticulum Stress/drug effects
Transcription Factor CHOP/metabolism
*Squalene/pharmacology/therapeutic use
Unfolded Protein Response/drug effects
Reactive Oxygen Species/metabolism
Molecular Docking Simulation
Amyloid beta-Peptides
Oxidative Stress/drug effects
Mesenchymal Stem Cells/drug effects/metabolism
Cells, Cultured
Peptide Fragments

@article {pmid41160288,
year = {2025},
author = {Motamedzadeh, A and Karimzad, Y and Ferdosi, F and Nabavizadeh, F and Rahmati-Dehkordi, F and Dadgostar, E and Aschner, M and Validad, A and Kazemi, B and Tamtaji, OR},
title = {Potential of Benfotiamine in the treatment of neuropsychological disorders.},
journal = {Molecular biology reports},
volume = {53},
number = {1},
pages = {26},
pmid = {41160288},
issn = {1573-4978},
mesh = {Humans ; *Thiamine/analogs & derivatives/pharmacology/therapeutic use ; Oxidative Stress/drug effects ; *Neuroprotective Agents/pharmacology/therapeutic use ; Animals ; *Mental Disorders/drug therapy/metabolism ; Signal Transduction/drug effects ; Thiamine Deficiency/drug therapy/metabolism ; },
abstract = {Neuropsychiatric disorders pose significant health challenges. Current drug therapies are often inadequate, highlighting the urgent need for new and effective treatments. Thiamine deficiency has been implicated in the pathophysiology of various neuropsychiatric disorders. In this context, benfotiamine, a synthetic thiamine derivative, has gained increasing attention for its potential therapeutic effects across a range of neuropsychiatric conditions. Emerging evidence supports the neuroprotective effects of benfotiamine, which are mediated through its modulation of diverse cellular and molecular pathways, i.e., Tau phosphorylation, amyloid β, oxidative stress, neuroinflammation, as well as synaptic plasticity via the glycogen synthase kinase-3β (GSK3β) signaling pathway. In this narrative review, we provide a comprehensive overview of the cellular and molecular pathways modulated by benfotiamine in the context of neuropsychiatric disorders. Specifically, we highlight its effects on oxidative stress, inflammatory signaling, mitochondrial function, glucose metabolism, and advanced glycation end-product (AGE) formation, all of which contribute to its neuroprotective and potentially therapeutic properties.},
}

Humans
*Thiamine/analogs & derivatives/pharmacology/therapeutic use
Oxidative Stress/drug effects
*Neuroprotective Agents/pharmacology/therapeutic use
Animals
*Mental Disorders/drug therapy/metabolism
Signal Transduction/drug effects
Thiamine Deficiency/drug therapy/metabolism

@article {pmid41158654,
year = {2025},
author = {Chiba, T and Hattori, Y and Asakura, K and Sano, Y and Saito, S and Minami, M and Yamamoto, H and Ihara, M},
title = {Taxifolin for prevention of COGnitive impairment (T-COG trial): a study protocol for a randomized, double-blind, placebo-controlled trial.},
journal = {Frontiers in nutrition},
volume = {12},
number = {},
pages = {1686381},
pmid = {41158654},
issn = {2296-861X},
abstract = {BACKGROUND: In 2023 and 2024, the novel anti-β-amyloid antibodies lecanemab and donanemab have been approved for treatment of mild cognitive impairment and mild dementia in several countries, including Japan and the United States. Although they successfully eliminate accumulated β-amyloid, they merely delay cognitive deterioration and do not improve cognitive function. This suggests that β-amyloid elimination is insufficient for cognitive improvement. Therefore, novel treatments with pleiotropic neuroprotective effects are warranted. Taxifolin, a bioactive flavonoid, shows pleiotropic effects, such as inhibition of amyloid-β aggregation and oligomerization and hippocampal neuroinflammation, as well as stimulation of brain lymphatic vessel formation in our previous experimental studies. Furthermore, our preliminary observational study showed that oral administration of taxifolin was associated with cognitive improvement in patients with mild cognitive impairment or mild dementia.

METHODS: This is a randomized, double-blind, placebo-controlled, crossover trial involving 60 patients with mild cognitive impairment or mild dementia. All participants will take 100-mg taxifolin or placebo capsules orally once daily for 12 weeks. The washout period will be 6 weeks. The primary objective is to determine the effect of taxifolin on cognitive impairment using the Montreal Cognitive Assessment. The main secondary objectives are to evaluate the impact of taxifolin on (i) prevention further cognitive decline, as evaluated by changes in the scores for total Alzheimer's Disease Assessment Scale-Cognitive Subscale 14 and trail making test and (ii) changes in white matter hyperintensity volume and number of cerebral microbleeds on brain magnetic resonance imaging.

DISCUSSION: This T-COG trial may provide valuable insights into new therapeutic approaches, considering that taxifolin has multitarget neuroprotection, which could prevent further cognitive decline, along with its highly safe profile and inexpensive cost.

CLINICAL TRIAL REGISTRATION: https://jrct.mhlw.go.jp, jRCTs051250004.},
}

@article {pmid41157961,
year = {2025},
author = {Cruz-Aguilar, MA and Hernández-Arteaga, E and Ramírez-Salado, I and Hernández-González, M and Guevara, MA},
title = {Melatonin reorganizes the sleep EEG spectral power in Alzheimer's disease: a preliminary principal component analysis-based comparison of placebo and treatment effects.},
journal = {Neurological research},
volume = {},
number = {},
pages = {1-16},
doi = {10.1080/01616412.2025.2578344},
pmid = {41157961},
issn = {1743-1328},
abstract = {OBJECTIVES: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-β plaque accumulation, tau pathology, and cortical atrophy, leading to widespread synaptic dysfunction and cognitive decline. Sleep disturbances are highly prevalent in AD and are thought to both reflect and exacerbate underlying neurodegenerative processes. Melatonin, an indoleamine synthesized by the pineal gland, is central to the regulation of circadian rhythms and sleep - wake cycles. In healthy individuals, melatonin enhances non-rapid eye movement (NREM) sleep and attenuates beta activity during wakefulness. In AD populations, it has been associated with improved sleep quality and potential neuroprotective effects against amyloid-related pathology. Electroencephalography (EEG) offers a non-invasive method to monitor neurophysiological changes associated with AD. Principal component analysis (PCA), a dimensionality reduction technique, enables the identification of latent neural patterns within complex EEG data.

METHODS: In this preliminary study, PCA was applied to EEG recordings from eight individuals with mild-to-moderate AD during both wakefulness and sleep under placebo and melatonin conditions. EEG derivations included bipolar (F7-T3, F8-T4, F3-F4, O1-O2) and referential (C3-A1, C4-A2) configurations.

RESULTS: Preliminary PCA suggests that melatonin administration may induce a stage-dependent reorganization of EEG spectral activity, characterized by a relative enhancement of slow-frequency activity and an apparent increase in spectral segregation during NREM sleep.

DISCUSSION: These preliminary findings suggest that melatonin could optimize stage-specific neural dynamics, supporting its therapeutic potential in AD-related sleep disruption.},
}

@article {pmid41156471,
year = {2025},
author = {Zhang, J and Zhang, J},
title = {Natural Small-Molecule Bergapten Ameliorates Amyloid-β Pathology and Neuroinflammation in Alzheimer's Disease.},
journal = {Nutrients},
volume = {17},
number = {20},
pages = {},
doi = {10.3390/nu17203218},
pmid = {41156471},
issn = {2072-6643},
support = {2022QH2300//Fujian Medical University/ ; },
mesh = {Animals ; *Alzheimer Disease/drug therapy/metabolism/pathology ; Mice ; *Amyloid beta-Peptides/metabolism ; Microglia/drug effects/metabolism ; Molecular Docking Simulation ; *Neuroinflammatory Diseases/drug therapy ; Disease Models, Animal ; Male ; Maze Learning/drug effects ; MAP Kinase Signaling System/drug effects ; Memory/drug effects ; *Anti-Inflammatory Agents/pharmacology ; },
abstract = {BACKGROUND: The pathogenesis of Alzheimer's disease (AD) is complex, and effective treatments remain elusive. Growing evidence suggests that dietary factors may play a significant role in preventing or alleviating AD. Bergapten (BG), a natural compound with anti-inflammatory properties, has been studied; however, its specific role in neuroinflammation and AD pathogenesis remains unclear.

METHODS: Through public databases and bioinformatics tools, the possible molecular mechanisms of BG's effects on AD were analyzed. Six-month-old 5×FAD mice underwent intragastric administration of BG for 30 consecutive days. Learning and memory abilities were assessed using the novel object recognition (NOR) test and the Morris water maze (MWM) test. Immunofluorescence staining, Western blot and q-PCR was conducted to assess the underlying mechanisms. In vitro experiments used Aβ-stimulated BV2 microglial cells for BG intervention.

RESULTS: Bioinformatics analysis revealed the MAPK signaling pathway as the top-ranked pathway. Molecular docking studies further demonstrated strong binding interactions between BG and key proteins within the MAPK pathway. In behavioral studies, NOR test and MWM test demonstrated that BG treatment improved learning and memory abilities in 5×FAD mice. Additionally, BG treatment significantly reduced Aβ deposition, pro-inflammatory cytokine levels, and inhibited excessive microglial activation in these mice. Consistent with in vivo findings, BG effectively decreased pro-inflammatory cytokines in Aβ-stimulated BV2 microglial cells. Mechanistic studies revealed that BG attenuates neuroinflammatory responses by inhibiting the MAPK signaling pathway both in vivo and in vitro.

CONCLUSIONS: Our findings suggest that BG mitigates AD pathological features by suppressing MAPK-mediated neuroinflammation and represents a promising natural small molecule for the prevention and treatment of AD.},
}

Animals
*Alzheimer Disease/drug therapy/metabolism/pathology
Mice
*Amyloid beta-Peptides/metabolism
Microglia/drug effects/metabolism
Molecular Docking Simulation
*Neuroinflammatory Diseases/drug therapy
Disease Models, Animal
Male
Maze Learning/drug effects
MAP Kinase Signaling System/drug effects
Memory/drug effects
*Anti-Inflammatory Agents/pharmacology

@article {pmid41155570,
year = {2025},
author = {Atanasova, M},
title = {Small-Molecule Inhibitors of Amyloid Beta: Insights from Molecular Dynamics-Part B: Natural Compounds.},
journal = {Pharmaceuticals (Basel, Switzerland)},
volume = {18},
number = {10},
pages = {},
doi = {10.3390/ph18101457},
pmid = {41155570},
issn = {1424-8247},
support = {Grant No BG16RFPR002-1.014-0018//the Centre of Excellence in Informatics and ICT funded by the Research, Innovation and Digitalization for Smart Transformation Programme 2021-2027 and co-financed by the European Union/ ; agreement D01-98/26.06.2025//the National Road Map/ ; },
abstract = {Alzheimer's disease (AD) is the most common form of dementia, characterized by progressive memory loss and cognitive decline. Its key pathological hallmarks include extracellular amyloid plaques composed of amyloid beta (Aβ) peptides and intracellular neurofibrillary tangles formed by hyperphosphorylated tau protein. Although numerous studies have investigated the complex pathology of AD, its underlying mechanisms remain incompletely understood. The amyloid cascade hypothesis continues to be the leading model of AD pathogenesis. It suggests that Aβ aggregation is the initial trigger of neurotoxicity, setting off a cascade of pathological events including inflammation, oxidative stress, tau hyperphosphorylation, synaptic dysfunction, and, ultimately, dementia. Molecular dynamics (MD) is a powerful tool in structure-based drug design (SBDD). By simulating biomolecular motions at the atomic level, MD provides unique insights into molecular properties, functions, and inhibition mechanisms-insights often inaccessible through other experimental or computational techniques. When integrated with experimental data, MD further deepens our understanding of molecular interactions and biological processes. Natural compounds, known for their pleiotropic pharmacological activities, favorable safety profiles, and general tolerability (despite occasional side effects), are increasingly explored for their potential in both the treatment and prevention of various diseases, including AD. In this review, we summarize current findings from MD simulations of natural compounds with anti-amyloidogenic potential. This work builds upon our previous publication, which focused on endogenous compounds and repurposed drugs. The review is structured as follows: an overview of the amyloid cascade hypothesis; a discussion of Aβ oligomeric structures and their stabilizing interactions; a section on molecular dynamics, including its challenges and future directions; and a comprehensive analysis of the inhibitory mechanisms of natural compounds, categorized by their shared structural features.},
}

@article {pmid41155541,
year = {2025},
author = {Perez, DM},
title = {α1A-Adrenergic Receptor as a Target for Neurocognition: Cautionary Tale from Nicergoline and Quinazoline Non-Selective Blockers.},
journal = {Pharmaceuticals (Basel, Switzerland)},
volume = {18},
number = {10},
pages = {},
doi = {10.3390/ph18101425},
pmid = {41155541},
issn = {1424-8247},
support = {RO1AG066627/GF/NIH HHS/United States ; },
abstract = {Decades ago, previous studies that used non-selective ergot derivatives suggested that blockage of the α1A-adrenergic receptor mildly increased cognition through increased blood flow to the brain due to vasodilation and, thus, could be used as a treatment for dementia. However, further studies indicated that nicergoline was non-specific and hit many different targets. Today, a similar scenario is developing with the use of non-selective α1-AR antagonists of the quinazoline class, referred to as "osins", as potential treatments for COVID-19/SARS, post-traumatic stress disorder, cancer, and neurodegenerative disorders, such as Parkinson's, Alzheimer's, and amyotrophic lateral sclerosis. While there is extensive evidence of neuroprotection from many clinical trials, the mechanism of action of quinazolines is often not α1-AR-mediated but keyed to its glycolysis-enhancing effects through activation of the enzyme phosphoglycerate kinase 1 (PGK1). These studies have incorrectly labeled the α1A-adrenergic receptor as an "old target" to treat Alzheimer's and other neurocognitive diseases, hampering drug development. This review will summarize these and other studies to indicate that activation, not blockage, of norepinephrine's actions, through α1A-AR, mediates cognitive, memory, and neuroprotective functions that may reverse the progression of neurocognitive diseases.},
}

@article {pmid41155525,
year = {2025},
author = {Lin, GB and Liu, HH and Kuo, YY and Chen, YM and Hsu, FT and Wang, YW and Kung, Y and Ching, C and Chao, CY},
title = {Thermal Cycling Stimulation via Nasal Inhalation Attenuates Aβ25-35-Induced Cognitive Deficits in C57BL/6 Mice.},
journal = {International journal of molecular sciences},
volume = {26},
number = {20},
pages = {},
doi = {10.3390/ijms262010236},
pmid = {41155525},
issn = {1422-0067},
support = {NSTC 113-2112-M-002-024//National Science and Technology Council/ ; NSTC 112-2112-M-002-033//National Science and Technology Council/ ; MOST 110-2112-M-002-004//Ministry of Science and Technology/ ; },
mesh = {Animals ; *Amyloid beta-Peptides/metabolism/toxicity ; Mice ; Mice, Inbred C57BL ; *Cognitive Dysfunction/therapy/metabolism/chemically induced ; Male ; *Peptide Fragments/toxicity ; Hippocampus/metabolism ; Disease Models, Animal ; Alzheimer Disease/therapy/metabolism ; *Hyperthermia, Induced/methods ; Administration, Inhalation ; Maze Learning ; },
abstract = {Alzheimer's disease (AD) remains a significant public health challenge, with current treatments limited partly due to the difficulty of delivering therapeutics across the blood-brain barrier (BBB). The nose-to-brain (N-2-B) pathway offers a promising alternative to circumvent the BBB, but no drugs have yet been clinically applied via this route for AD. Mild stress is thought to activate intrinsic protective mechanisms against neurodegeneration, but traditional methods lack specificity and practicality. To address this, we propose the inhalation of mildly heated air as thermal stimulation, which utilizes the N-2-B pathway to induce mild stress and stimulate cerebral activity. This study employs thermal cycling-hyperthermia (TC-HT) in developing thermal cycling-stimulation via nasal inhalation (TCSNI), providing cyclic stimulation to maintain pathway activity while minimizing thermal injury. In C57BL/6 mice, TCSNI showed no adverse olfactory effects. In β-amyloid (Aβ)-treated mice, TCSNI significantly enhanced cognitive performance in Y-maze and novel object recognition (NOR) assessments, suggesting cognitive improvement. Mice hippocampal protein analyses indicated a reduction in Aβ accumulation, alongside increased expression of heat shock protein 70 (HSP70), insulin-degrading enzyme (IDE), and phosphorylated Akt (p-Akt). These results suggest that N-2-B-delivered TCSNI effectively modulates protein expression and enhances cognitive function, highlighting its potential for further exploration in AD treatment.},
}

Animals
*Amyloid beta-Peptides/metabolism/toxicity
Mice
Mice, Inbred C57BL
*Cognitive Dysfunction/therapy/metabolism/chemically induced
Male
*Peptide Fragments/toxicity
Hippocampus/metabolism
Disease Models, Animal
Alzheimer Disease/therapy/metabolism
*Hyperthermia, Induced/methods
Administration, Inhalation
Maze Learning

@article {pmid41155356,
year = {2025},
author = {Trifonova, EA and Pashchenko, AA and Ivanov, RA and Kochetov, AV and Lashin, SA},
title = {Genetic and Pathogenic Overlaps Between Autism Spectrum Disorder and Alzheimer's Disease: Evolutionary Features and Opportunities for Drug Repurposing.},
journal = {International journal of molecular sciences},
volume = {26},
number = {20},
pages = {},
doi = {10.3390/ijms262010066},
pmid = {41155356},
issn = {1422-0067},
mesh = {*Autism Spectrum Disorder/genetics/drug therapy ; Humans ; *Alzheimer Disease/genetics/drug therapy/metabolism ; *Drug Repositioning ; Gene Regulatory Networks ; TOR Serine-Threonine Kinases/metabolism/genetics ; Genetic Predisposition to Disease ; Evolution, Molecular ; Signal Transduction ; },
abstract = {Autism spectrum disorder (ASD) and Alzheimer's disease (AD) are neurodevelopmental and neurodegenerative disorders, respectively. While exome sequencing is routinely employed during the early stages of ASD diagnosis, it rarely influences therapeutic strategies. To address this gap, we have reconstructed and analyzed the gene networks linking autism spectrum disorders, Alzheimer's disease, and mTOR signaling. In addition, we have performed a phylostratigraphic analysis that reveals similarities and differences in the evolution of both ASD and Alzheimer's disease predisposition genes. We have shown that almost half of the genes predisposing to autism and two-fifths of the genes predisposing to Alzheimer's disease are directly related to the mTOR signaling pathway. Analysis of Phylostratigraphic Age Index (PAI) value distributions revealed a significant enrichment of evolutionarily ancient genes in both ASD- and AD-related gene sets. When studying the distribution of ASD predisposition genes by Divergence Index (DI) values, a significant enrichment with genes having extremely low DI = 0 has been found. Such low DI values indicate that most likely these genes are under stabilizing selection. Using the ANDVisio tool, both pharmacological and natural mTOR regulators with potential for ASD treatment were selected, such as propofol, dexamethasone, celecoxib, statins, berberine, resveratrol, quercetin, myricetin, mio-inositol, and several amino acids.},
}

*Autism Spectrum Disorder/genetics/drug therapy
Humans
*Alzheimer Disease/genetics/drug therapy/metabolism
*Drug Repositioning
Gene Regulatory Networks
TOR Serine-Threonine Kinases/metabolism/genetics
Genetic Predisposition to Disease
Evolution, Molecular
Signal Transduction

@article {pmid41155218,
year = {2025},
author = {Lee, J and Lee, E and Kwon, H and Moon, S and Bae, HJ and Hwang, JH and Cho, GH and Kong, H and Park, MH and Kim, SK and Kim, DH and Jung, JW},
title = {Synaptic Plasticity-Enhancing and Cognitive-Improving Effects of Standardized Ethanol Extract of Perilla frutescens var. acuta in a Scopolamine-Induced Mouse Model.},
journal = {International journal of molecular sciences},
volume = {26},
number = {20},
pages = {},
doi = {10.3390/ijms26209925},
pmid = {41155218},
issn = {1422-0067},
support = {S3400191//Ministry of SMEs and Startups/ ; },
mesh = {Animals ; Scopolamine/toxicity ; Mice ; Male ; *Plant Extracts/pharmacology/chemistry ; *Perilla frutescens/chemistry ; *Neuronal Plasticity/drug effects ; Disease Models, Animal ; Mice, Inbred ICR ; Hippocampus/drug effects/metabolism ; Long-Term Potentiation/drug effects ; Ethanol/chemistry ; *Cognition/drug effects ; Receptors, N-Methyl-D-Aspartate/metabolism ; *Cognitive Dysfunction/drug therapy/chemically induced ; Maze Learning/drug effects ; },
abstract = {In our previous study, we demonstrated that a standardized ethanol extract of Perilla frutescens var. acuta (PE) alleviates memory deficits in an Alzheimer's disease mouse model by inhibiting amyloid β (Aβ) aggregation and promoting its disaggregation. However, the extent to which PE exerts additional cognitive benefits independent of Aβ pathology remained unclear. Here, we aimed to evaluate the effects of PE on synaptic plasticity and learning and memory functions. Male ICR mice were used, and cognitive impairment was induced by scopolamine administration. PE was orally administered at doses determined from previous studies, and cognitive performance was assessed using the passive avoidance, Y-maze, and Morris water maze tests. In parallel, hippocampal slices were employed to examine the effects of PE on synaptic plasticity. PE (100 and 300 μg/mL) significantly enhanced long-term potentiation (LTP) in a concentration-dependent manner without altering basal synaptic transmission. This facilitation of LTP was blocked by scopolamine (1 μM), a muscarinic acetylcholine receptor (mAChR) antagonist, and IEM-1460 (50 μM), a calcium-permeable α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (CP-AMPAR) inhibitor, indicating the involvement of mAChR and CP-AMPAR pathways. In vivo, PE (100, 250, and 500 mg/kg) treatment improved memory performance across all behavioral tasks and upregulated hippocampal synaptic proteins including GluN2B, PSD-95, and CaMKII. Collectively, these results demonstrate that PE ameliorates scopolamine (1 mg/kg)-induced cognitive impairment by enhancing synaptic plasticity, likely through modulation of mAChR, CP-AMPAR, and NMDA receptor signaling. These findings highlight the therapeutic potential of PE for memory deficits associated with cholinergic dysfunction.},
}

Animals
Scopolamine/toxicity
Mice
Male
*Plant Extracts/pharmacology/chemistry
*Perilla frutescens/chemistry
*Neuronal Plasticity/drug effects
Disease Models, Animal
Mice, Inbred ICR
Hippocampus/drug effects/metabolism
Long-Term Potentiation/drug effects
Ethanol/chemistry
*Cognition/drug effects
Receptors, N-Methyl-D-Aspartate/metabolism
*Cognitive Dysfunction/drug therapy/chemically induced
Maze Learning/drug effects

@article {pmid41155192,
year = {2025},
author = {Kowalczyk, T and Muskała, M and Piekarski, J and Kowalski, M and Staszewski, M and Konuklugil, B and Rijo, P and Sitarek, P},
title = {Therapeutic Promise and Biotechnological Prospects of Dendroaspis polylepis Venom Proteins: Mambalgins, Fasciculins, and Dendrotoxins.},
journal = {International journal of molecular sciences},
volume = {26},
number = {20},
pages = {},
doi = {10.3390/ijms26209895},
pmid = {41155192},
issn = {1422-0067},
mesh = {Humans ; Animals ; *Snake Venoms/chemistry/therapeutic use/pharmacology ; *Neurotoxins/therapeutic use/pharmacology/chemistry ; Neoplasms/drug therapy ; Biotechnology/methods ; },
abstract = {Animal toxins contain various bioactive peptides and proteins which have evolved to interact in specific ways. As such, they are a good starting point for developing new drugs and vaccines. This paper examines three natural neurotoxins derived from the black mamba (Dendroaspis polylepis), which show significant pharmacological potential: mambalgins, fasciculins and dendrotoxins. All three may be of value in the treatment of pain, cancer and neurodegenerative disease. Mambalgins provide similar pain relief to opioids but without the risk of addiction; they act by selectively blocking acid-sensitive ion channels (ASICs), especially ASIC1a. Thanks to this inhibitory activity they also demonstrate selective activity against glioblastoma, melanoma and leukemia cells as innovative anticancer drugs. Fasciculins are very strong inhibitors of acetylcholinesterase (AChE) and hence offer promise in multi-target drugs and as treatments for treating Alzheimer's disease. Dendrotoxins such as DTX-K and DTX-I are able to modulate neuronal excitability and synaptic transmission by blocking voltage-gated potassium channels (Kv1.1, Kv1.2, Kv1.6); both have been shown to be effective against cancer cells, and to influence the cardiovascular, immune, and digestive systems. Recent advances in recombinant biotechnology and protein engineering have allowed their safe production with increased therapeutic value. The review examines the translational potential of D. polylepis venom proteins and highlights the need for additional preclinical research on bioactive molecules of toxin origin.},
}

Humans
Animals
*Snake Venoms/chemistry/therapeutic use/pharmacology
*Neurotoxins/therapeutic use/pharmacology/chemistry
Neoplasms/drug therapy
Biotechnology/methods

@article {pmid41155149,
year = {2025},
author = {Frei, M and Wirawan, R and Wein, T and Bracher, F},
title = {Lead Structure-Based Hybridization Strategy Reveals Major Potency Enhancement of SirReal-Type Sirt2 Inhibitors.},
journal = {International journal of molecular sciences},
volume = {26},
number = {20},
pages = {},
doi = {10.3390/ijms26209855},
pmid = {41155149},
issn = {1422-0067},
support = {project ID: 325871075-SFB1309//Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) with funds from SFB1309 (Chemical Biology of Epigenetic Modifications)/ ; },
mesh = {*Sirtuin 2/antagonists & inhibitors/chemistry/metabolism ; Molecular Docking Simulation ; Humans ; Structure-Activity Relationship ; *Histone Deacetylase Inhibitors/chemistry/pharmacology ; },
abstract = {Selective and potent inhibitors of the NAD[+]-dependent deacetylase Sirt2 represent a valuable epigenetic strategy for the treatment of currently incurable diseases such as Parkinson's disease, Huntington's disease, Alzheimer's disease, and multiple sclerosis. Guided by molecular docking and MM/GBSA validation studies, a lead structure-based hybridization strategy was developed, resulting in a series of very effective Sirt2 inhibitors. With RW-93, we present a highly potent and subtype selective Sirt2 inhibitor (IC50 = 16 nM), which as a next generation SirReal-type inhibitor significantly surpasses established Sirt2 inhibitors and contributes to the extension of the current SAR profile. The structural modification strategy employed in this study proved to be highly promising, resulting in the identification of the most potent low-molecular-weight Sirt2 inhibitor reported to date, providing a promising target for further medicinal chemistry-driven SAR studies.},
}

*Sirtuin 2/antagonists & inhibitors/chemistry/metabolism
Molecular Docking Simulation
Humans
Structure-Activity Relationship
*Histone Deacetylase Inhibitors/chemistry/pharmacology

@article {pmid41155106,
year = {2025},
author = {Rahman, S and Rahman, MM and Bhatt, S and Sundararajan, R and Faezipour, M},
title = {NeuroNet-AD: A Multimodal Deep Learning Framework for Multiclass Alzheimer's Disease Diagnosis.},
journal = {Bioengineering (Basel, Switzerland)},
volume = {12},
number = {10},
pages = {},
doi = {10.3390/bioengineering12101107},
pmid = {41155106},
issn = {2306-5354},
abstract = {Alzheimer's disease (AD) is the most prevalent form of dementia. This disease significantly impacts cognitive functions and daily activities. Early and accurate diagnosis of AD, including the preliminary stage of mild cognitive impairment (MCI), is critical for effective patient care and treatment development. Although advancements in deep learning (DL) and machine learning (ML) models improve diagnostic precision, the lack of large datasets limits further enhancements, necessitating the use of complementary data. Existing convolutional neural networks (CNNs) effectively process visual features but struggle to fuse multimodal data effectively for AD diagnosis. To address these challenges, we propose NeuroNet-AD, a novel multimodal CNN framework designed to enhance AD classifcation accuracy. NeuroNet-AD integrates Magnetic Resonance Imaging (MRI) images with clinical text-based metadata, including psychological test scores, demographic information, and genetic biomarkers. In NeuroNet-AD, we incorporate Convolutional Block Attention Modules (CBAMs) within the ResNet-18 backbone, enabling the model to focus on the most informative spatial and channel-wise features. We introduce an attention computation and multimodal fusion module, named Meta Guided Cross Attention (MGCA), which facilitates effective cross-modal alignment between images and meta-features through a multi-head attention mechanism. Additionally, we employ an ensemble-based feature selection strategy to identify the most discriminative features from the textual data, improving model generalization and performance. We evaluate NeuroNet-AD on the Alzheimer's Disease Neuroimaging Initiative (ADNI1) dataset using subject-level 5-fold cross-validation and a held-out test set to ensure robustness. NeuroNet-AD achieved 98.68% accuracy in multiclass classification of normal control (NC), MCI, and AD and 99.13% accuracy in the binary setting (NC vs. AD) on the ADNI dataset, outperforming state-of-the-art models. External validation on the OASIS-3 dataset further confirmed the model's generalization ability, achieving 94.10% accuracy in the multiclass setting and 98.67% accuracy in the binary setting, despite variations in demographics and acquisition protocols. Further extensive evaluation studies demonstrate the effectiveness of each component of NeuroNet-AD in improving the performance.},
}

@article {pmid41154564,
year = {2025},
author = {Wei, C and Chen, X and Sun, M and Cao, J and Liao, D and Cheng, Z and Wang, H},
title = {α-Asarone Maintains Protein Homeostasis Through SKN-1-Mediated Proteasome and Autophagy Pathways to Mitigate Aβ-Associated Toxicity in Caenorhabditis elegans.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {14},
number = {10},
pages = {},
doi = {10.3390/antiox14101255},
pmid = {41154564},
issn = {2076-3921},
support = {32370420//National Natural Science Foundation of China/ ; 31670347//National Natural Science Foundation of China/ ; 23ZR1467200//Natural Science Foundation of Shanghai/ ; },
abstract = {Acorus tatarinowii Schott (A. tatarinowii), a traditional Chinese medicine, has been widely used in the treatment of dementia, particularly AD. α-Asarone is the main active component of A. tatarinowii oil, and its neuroprotective effects and underlying molecular mechanism in AD remain unclear. In this study, we utilized different transgenic Caenorhabditis elegans (C. elegans) AD models to investigate the neuroprotective mechanism of α-asarone in vivo. Our findings revealed that α-asarone significantly ameliorated Aβ- and tau-induced phenotypic abnormalities, including deficits in chemotaxis-related learning, hyposensitivity to exogenous serotonin, and impaired neuronal integrity. Furthermore, the α-asarone treatment effectively reduced Aβ-induced oxidative stress. Mechanistically, α-asarone reduced Aβ accumulation and maintained protein homeostasis by stimulating proteasome degradation and autophagy in an SKN-1/Nrf2-dependent manner. Our study highlights the potential of α-asarone as an SKN-1/Nrf2 activator and its capability to facilitate proteostasis, supporting its therapeutic potential for AD treatment.},
}

@article {pmid41154171,
year = {2025},
author = {Zou, J and Liao, R and Zhang, W and Kuang, Z},
title = {Acupuncture Modulation of the Lung-Brain Axis in Alzheimer's Disease: Mechanisms and Therapeutic Perspectives.},
journal = {Brain sciences},
volume = {15},
number = {10},
pages = {},
doi = {10.3390/brainsci15101076},
pmid = {41154171},
issn = {2076-3425},
support = {2025A1515012049//Natural Science Foundation of Guangdong Province/ ; 20251096//the Research Project of the Traditional Chinese Medicine Bureau of Guangdong Province/ ; 2023A1515110788//Basic and Applied Basic Research Foundation of Guangdong Province/ ; },
abstract = {Alzheimer's disease (AD) is a prevalent neurodegenerative disorder characterized by progressive cognitive decline and an impaired quality of life, for which no curative treatment is currently available. Recent research indicates that chronic pulmonary conditions-including chronic obstructive pulmonary disease (COPD) and obstructive sleep apnea (OSA)-exhibit significant epidemiological associations with AD pathogenesis, suggesting that the lung-brain axis may contribute to AD development. Acupuncture, a core TCM intervention, shows promise for modulating multisystem functions and enhancing cognitive performance. This review synthesizes the current evidence regarding pulmonary diseases influencing AD through the lung-brain axis, elucidates potential mechanisms by which acupuncture may modulate pulmonary function and mitigate AD pathology, and explores future directions for lung-brain axis-targeted acupuncture interventions. Our overarching aim is to propose integrative, evidence-based strategies that combine Chinese and Western medicine for the prevention and management of AD.},
}

@article {pmid41153730,
year = {2025},
author = {Danesin, L and D'Este, G and Barresi, R and Piazzalunga, E and Di Garbo, A and Giustiniani, A and Semenza, C and Bottini, G and Oliveri, M and Burgio, F},
title = {Preliminary Evidence of Biological and Cognitive Efficacy of Prismatic Adaptation Combined with Cognitive Training on Patients with Mild Cognitive Impairment.},
journal = {Biomedicines},
volume = {13},
number = {10},
pages = {},
doi = {10.3390/biomedicines13102447},
pmid = {41153730},
issn = {2227-9059},
support = {Ricerca Corrente//Ministero della Salute/ ; },
abstract = {Background/Objectives: This study evaluated a novel rehabilitation tool that combines prismatic adaptation (PA) and cognitive training through serious games (SGs) in patients with mild cognitive impairment (MCI) due to prodromal Alzheimer's dementia or consequent to Parkinson's disease. While non-pharmacological interventions have been shown to improve cognition or delay dementia onset, their underlying neurobiological mechanisms, such as brain plasticity, remain unclear. Leveraging studies suggesting neuromodulatory effects of PA, we investigated whether the combined PA+SGs treatment could influence plasticity-related mechanisms, assessed through brain-derived neurotrophic factor (BDNF) serum levels, compared to cognitive training with only SGs and standard cognitive rehabilitation (SCR). Methods: Twenty three MCI patients were randomized into three intervention groups: PA+SGs (experimental group), SG-only (control group), and SCR (control group), completing ten treatment sessions. Patients underwent neuropsychological assessments and blood sampling pre- and post-treatment. Results: At baseline, demographic, clinical, and biological characteristics were comparable across groups. Post-treatment, though differences from control groups were not statistically significant, the PA+SGs group showed significant within-group improvements in memory, with trend-level changes also in executive function and visuospatial abilities, which, however, did not reach the significance threshold. Notably, only the PA+SGs group exhibited increased BDNF levels, which positively correlated with memory and language performance. Conclusions: Our findings suggest that combining PA with cognitive training may enhance cognitive functioning in MCI patients, yielding results comparable to SCR. Furthermore, PA appears to enhance neuroplasticity mechanisms that may support the behavioral improvements observed in cognitive training. Future research should validate these findings and further explore the relationship between cognitive impairment and its rehabilitation, while also considering the underlying neurobiological mechanisms.},
}

@article {pmid41152946,
year = {2025},
author = {Bali, ZK and Bruszt, N and Göntér, K and Hernádi, I},
title = {Differential cognitive enhancer effects of acetylcholinesterase inhibitors and memantine on age-related deficits in vigilance and sustained attention: a preclinical validation study.},
journal = {Behavioral and brain functions : BBF},
volume = {21},
number = {1},
pages = {35},
pmid = {41152946},
issn = {1744-9081},
support = {KK/492/2019//Gedeon Richter Plc., Budapest, Hungary/ ; RRF-2.3.1-21-2022-00015//National Research, Development and Innovation Office/ ; K 143816//National Research, Development, and Innovation Office of the Hungarian Government/ ; },
mesh = {Animals ; *Memantine/pharmacology ; Donepezil/pharmacology ; *Cholinesterase Inhibitors/pharmacology ; Galantamine/pharmacology ; *Attention/drug effects ; Rats ; Male ; *Nootropic Agents/pharmacology ; Psychomotor Performance/drug effects ; Reaction Time/drug effects ; *Aging/drug effects/psychology ; Cognition/drug effects ; *Arousal/drug effects ; Indans/pharmacology ; Cognitive Dysfunction/drug therapy ; },
abstract = {BACKGROUND: The psychomotor vigilance task (PVT) is a cognitive test commonly used to measure sustained attention and vigilance in humans in healthy and diseased states. Here, we aimed to utilize a recently designed rat version of the PVT to assess potential cognitive enhancer effects of various pharmacological compounds in a natural model of age-related cognitive decline. Therefore, we treated aged rats (> 28 months old) with different doses of three approved Alzheimer's disease drugs: donepezil, galantamine, and memantine.

RESULTS: Aged rats made significantly slower responses to the cue stimuli compared to young animals and fewer correct responses, mainly because of an increased number of missed trials (i.e., when the trial was not initiated by the rat). Donepezil improved the performance of aged rats by accelerating their responses at a dose of 0.03 mg/kg. However, galantamine treatment showed no beneficial effects on either reaction time or the number of correct trials. Furthermore, both donepezil (0.3 and 1.0 mg/kg) and galantamine (3.0 mg/kg) increased the reaction time and number of missed trials at high doses. Memantine did not affect the reaction time of aged rats, but it increased the number of correct responses at 0.1 and 0.3 mg/kg doses.

CONCLUSIONS: Here, we showed that PVT is suitable for addressing pharmacological effects on various cognitive domains in a single behavioral paradigm. Our findings also indicate that different cognitive enhancer compounds (even when their targets are thought to be the same) may differentially influence distinct cognitive domains and modulate task performance.},
}

Animals
*Memantine/pharmacology
Donepezil/pharmacology
*Cholinesterase Inhibitors/pharmacology
Galantamine/pharmacology
*Attention/drug effects
Rats
Male
*Nootropic Agents/pharmacology
Psychomotor Performance/drug effects
Reaction Time/drug effects
*Aging/drug effects/psychology
Cognition/drug effects
*Arousal/drug effects
Indans/pharmacology
Cognitive Dysfunction/drug therapy

@article {pmid41152341,
year = {2025},
author = {Fujii, K and Koshidaka, Y and Yanagibashi, Y and Adachi, M and Matsuo, M and Kimura, K and Saito, T and Saido, TC and Takao, K},
title = {Ovariectomy attenuates phenotypes related to Alzheimer's disease in a preclinical mouse model and in C57BL/6 J mice.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {36995},
pmid = {41152341},
issn = {2045-2322},
support = {22H04922//Japan Society for the Promotion of Science/ ; },
mesh = {Animals ; *Alzheimer Disease/metabolism/genetics/pathology/physiopathology ; *Ovariectomy ; Disease Models, Animal ; Female ; Mice ; Mice, Inbred C57BL ; Phenotype ; Amyloid beta-Protein Precursor/genetics/metabolism ; Mice, Transgenic ; Behavior, Animal ; Mutation ; Amyloid beta-Peptides/metabolism ; Fear ; Anxiety ; Gene Knock-In Techniques ; Memory ; },
abstract = {Women are at higher risk for Alzheimer's disease (AD) than men and hormonal changes during perimenopause are considered a risk factor. The relationship between ovarian hormones and AD has been explored using AD animal models, especially through ovariectomy (OVX) in established AD models. The link between early-stage AD and ovarian hormones, however, remains unclear, largely due to the lack of suitable animal models. Appropriate models for studying early-stage AD pathology, treatment, and prevention are critically needed. The App knock-in mouse model, which carries a single amyloid precursor protein (App) gene mutation, effectively reproduces early amyloid AD pathology. To elucidate the relationship between ovarian hormone deficiency and the behavioral phenotypes of a preclinical AD model, we applied a comprehensive behavioral test battery to this mouse model with bilateral OVX. The App mutation reduced anxiety-like behavior and impaired performance in the fear memory task. OVX restored the anxiety-like behavior of the App mutation mice to a level comparable to that in wild-type (WT) mice. Furthermore, OVX enhanced performance in a fear memory task in both genotypes and reduced amyloid-β staining in WT mice. Together, these findings suggest that OVX attenuates AD-related phenotypes in a preclinical AD model and in C57BL/6 J WT mice.},
}

Animals
*Alzheimer Disease/metabolism/genetics/pathology/physiopathology
*Ovariectomy
Disease Models, Animal
Female
Mice
Mice, Inbred C57BL
Phenotype
Amyloid beta-Protein Precursor/genetics/metabolism
Mice, Transgenic
Behavior, Animal
Mutation
Amyloid beta-Peptides/metabolism
Fear
Anxiety
Gene Knock-In Techniques
Memory

@article {pmid41152189,
year = {2025},
author = {Snyder, A and Samra, K and Wu, T and Russell, LL and Farren, J and Crook, J and Haselhuhn, T and Porter, K and Szabo, M and Duckett, A and Lin, F and Danielian, L and Traynor, BJ and Scholz, SW and Boeve, BF and Rosen, HJ and Rohrer, JD and Kwan, JY},
title = {Integrating a motor domain enhances disease severity scales in an FTD-ALS spectrum cohort.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {10},
pages = {e70786},
doi = {10.1002/alz.70786},
pmid = {41152189},
issn = {1552-5279},
support = {U01AG045390//The National Institute on Aging/ ; U54NS092089//The National Institute on Aging/ ; U19AG063911//The National Institute on Aging/ ; //The Intramural Research Program of the National Institutes of Health/ ; /NS/NINDS NIH HHS/United States ; },
mesh = {Humans ; Male ; *Severity of Illness Index ; Female ; *Frontotemporal Dementia/diagnosis/physiopathology ; Middle Aged ; *Amyotrophic Lateral Sclerosis/diagnosis/physiopathology ; Aged ; Longitudinal Studies ; Cohort Studies ; Neuropsychological Tests ; },
abstract = {INTRODUCTION: The Genetic Frontotemporal Initiative (GENFI) and Advancing Research and Treatment in Frontotemporal Lobar Degeneration (ARTFL)-Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (LEFFTDS) Longitudinal Frontotemporal Lobar Degeneration Study (ALLFTD) consortia developed Clinical Dementia Rating (CDR)-derived scales with a motor domain to overcome systematic underestimation of disease severity by the CDR. We calculated disease severity scores using these scales in a mixed neurodegenerative cohort and correlated them with objective motor measures.

METHODS: The CDR plus National Alzheimer's Coordinating Center (NACC) Frontotemporal Lobar Degeneration (FTLD), CDR + NACC FTLD-M (Motor), and Multidomain Impairment Rating (MIR) scores and motor measures were determined and correlated in 242 participants.

RESULTS: Both CDR + NACC FTLD-M and MIR showed increased disease severity scores and correlated with motor measures. These findings were held in 81 amyotrophic lateral sclerosis (ALS) participants and correlated with the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale. Including a motor domain required fewer study participants in a simulated clinical trial sample size calculation.

DISCUSSION: With a motor domain, CDR + NACC FTLD-M and MIR improve disease severity classification and correlate with quantitative motor assessments. This addition more fully captures the extent of symptoms across the FTD-ALS spectrum and improves clinical trial efficiency.

HIGHLIGHTS: CDR + NACC FTLD-M and MIR strongly correlate with objective motor measures. The enhanced scales improve disease severity classification in FTD and ALS. Greater clinical trial efficiency is achieved using these enhanced scales.},
}

Humans
Male
*Severity of Illness Index
Female
*Frontotemporal Dementia/diagnosis/physiopathology
Middle Aged
*Amyotrophic Lateral Sclerosis/diagnosis/physiopathology
Aged
Longitudinal Studies
Cohort Studies
Neuropsychological Tests

@article {pmid41151846,
year = {2025},
author = {Kuzuya, A and Ohara, T and Akamatsu, N},
title = {Pathogenesis of comorbid epilepsy in Alzheimer's disease and use of perampanel, an ampa receptor inhibitor.},
journal = {Expert review of neurotherapeutics},
volume = {},
number = {},
pages = {},
doi = {10.1080/14737175.2025.2581758},
pmid = {41151846},
issn = {1744-8360},
abstract = {INTRODUCTION: Alzheimer's disease (AD) and epilepsy frequently co-occur and are risk factors for each other's onset. In patients with AD-comorbid epilepsy, seizure control with appropriate anti-seizure medications (ASMs) is crucial, yet no established treatment guidelines exist. Recent studies indicate that α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors (AMPARs) are involved in the pathogenesis of both diseases. Perampanel, an AMPAR antagonist, has been approved as an ASM.

AREAS COVERED: This review explains the relationship between AD and epilepsy and discusses the involvement of AMPARs. Furthermore, it focuses on and presents opinions regarding the role of AMPAR inhibitors in the treatment of AD-comorbid epilepsy. The authors searched clinical studies that were published and identifiable in PubMed and Scopus (Jan 2015-Dec 2024) including the terms 'Alzheimer's disease,' or 'dementia,' with 'epilepsy' or 'seizure'.

EXPERT OPINION: Considering the hypothesis that AD and epilepsy are linked, creating a cycle that progresses both diseases via AMPARs, AMPAR inhibition may have beneficial effects in treatment of epilepsy in AD. Although evidence is limited, studies of perampanel have demonstrated symptomatic improvement in patients with AD-comorbid epilepsy. Perampanel may be particularly useful for specific subgroups of patients with AD-comorbid epilepsy, such as those with myoclonus, sleep disturbances, or poor medication adherence.},
}

@article {pmid41151285,
year = {2025},
author = {Song, J and Ding, X and Li, M and Xin, Y and Lu, Y and Yang, X and Lu, X},
title = {N[6]-methyladenosine reader YTHDF1 mediates neuronal apoptosis induced by aluminum via m[6]A/Bcl-2 manner.},
journal = {Ecotoxicology and environmental safety},
volume = {306},
number = {},
pages = {119270},
doi = {10.1016/j.ecoenv.2025.119270},
pmid = {41151285},
issn = {1090-2414},
abstract = {Aluminum (Al) has emerged as a pervasive environmental and industrial risk factor for cognitive impairment and neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease. Nowadays, N6-methyladenosine (m[6]A) modification mechanism contributing to aluminum toxicity is gradually gaining attention. m[6]A modification determines the fate of RNA through m[6]A "readers". Novel findings indicate that YTH N6-methyladenosine RNA binding protein 1 (YTHDF1, a kind of "readers") participates in various pathological processes induced by some toxic chemicals. Here, we investigated the function of YTHDF1 in neuronal apoptosis induced by aluminum and explored the molecular mechanisms. We first observed the YTHDF1 expression both in vivo and in vitro neuronal apoptosis model induced by aluminum, as well as the reversal effect of YTHDF1 overexpression by lentivirus transfection in vitro. Further, we explored Bcl-2 as a target gene of YTHDF1 and probed their m[6]A modification manner and molecular mechanism using RIP assay, Me-RIP assay, and Actinomycin D (ActD) assay. Finally, we examined the regulatory role of YTHDF1/m[6]A/Bcl-2 axis in aluminum neurotoxicity in vitro and in vivo. Functionally, Al(mal)3 treatment decreased YTHDF1 expression, which negatively regulates apoptosis via m[6]A modification manner. Mechanistically, Bcl-2 acted as the target of YTHDF1, and YTHDF1 regulated Bcl-2 by enhancing its mRNA stability. Collectively, Al(mal)3 treatment inhibited the YTHDF1/m[6]A/Bcl-2 axis, thereby promoting neuronal apoptosis and subsequent cognitive impairment. This study provides a novel protective strategy against aluminum toxicity.},
}

@article {pmid41151129,
year = {2025},
author = {Yang, F and Guo, Q and Chen, M and Wang, W and Chen, X and Zhang, S and Bian, H and Li, J and Jiao, Z and Wang, Q and Xiong, W and Huang, YY and Liu, Y and Xu, C and Huang, L},
title = {Discovery of novel 2,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridine-7-one derivatives as PDE2 inhibitors with Alzheimer's disease therapeutic potential.},
journal = {European journal of medicinal chemistry},
volume = {302},
number = {Pt 1},
pages = {118302},
doi = {10.1016/j.ejmech.2025.118302},
pmid = {41151129},
issn = {1768-3254},
abstract = {Phosphodiesterase 2 (PDE2), a dual-substrate cyclic nucleotide hydrolase, represents a potential therapeutic target for cognitive impairment. This study aims to develop 2,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridine-7-one-based PDE2 inhibitors with favorable drug-like properties for the treatment of Alzheimer's disease. Through scaffold hopping and cocrystal structure analysis, compound 14c was identified as an effective PDE2 inhibitor (IC50 = 0.6 μM, aqueous solubility = 60.36 μg/mL). Moreover, 14c demonstrated favorable hepatic microsomal stability, pharmacokinetic properties (t1/2 = 4.4 h, F% = 95.66 %) and promising safety both in vitro and in vivo. In the OKA-induced AD mice models, administration of 14c significantly improved memory deficits and cognitive impairment. Molecular mechanism studies revealed that the neuroprotective effects of 14c were mediated through the PKA/CREB/BDNF signaling pathway. Collectively, these findings represent significant advances in developing PDE2 inhibitors with favorable drug-like properties and establish a solid foundation for their therapeutic application in AD.},
}

@article {pmid41149051,
year = {2025},
author = {Valdez Gayosso, N and Omaña Covarrubias, A and Nez Castro, AT and López Pontigo, L and Acuña Gurrola, MDR and Pimentel Pérez, BM},
title = {The Effect of Bacteria Modulation with Probiotic Consumption in Neurodegeneration During Aging: A Narrative Review of the Literature.},
journal = {Diseases (Basel, Switzerland)},
volume = {13},
number = {10},
pages = {},
doi = {10.3390/diseases13100317},
pmid = {41149051},
issn = {2079-9721},
support = {NA//Universidad Autónoma del Estado de Hidalgo/ ; },
abstract = {Aging is the result of the accumulation of a great variety of molecular and cellular damage over time. During aging, the brain undergoes changes and diseases such as depression, dementia, anxiety, Alzheimer's, delirium, behavioral disorders and aggression, and prolonged mourning, among others, appear. The gut-brain axis suggests that the gut and the brain have a bidirectional communication, so it is important to maintain proper intestinal health to strengthen the neurological changes of this age group. The intestinal microbiota is a dynamic and highly complex ecosystem of microorganisms residing in the gastrointestinal tract. The bidirectional and dynamic communication between the homeostatic systems, such as the endocrine and immune systems, as well as the nervous system, allow us to face problems associated with several diseases. Probiotics are defined as non-pathogenic live microorganisms that provide beneficial effects to the organism and participate in the prevention and treatment of diseases, which is the reason why it is important to promote interventions that keep intestinal microbiota in eubiosis (microbiota balance). The concentration and balance of the intestinal microbiota depend on several conditions, such as diet, antibiotic consumption, and lifestyle, to mentioned a few. However, interventions with probiotics have shown improvements in both cognitive function and processes that promote neurodegeneration. It is such that the research has been directed on designing strategies that improve not only oral bioavailability but also intestinal adhesion and retention, to clarify the frequency and dosage that should be consumed.},
}

@article {pmid41148458,
year = {2025},
author = {Goel, F and Kumar, D and Singh, P and Rai, SN and Yadav, DK},
title = {Molecular crosstalk between miRNAs and lncRNAs in neurodegenerative disease pathways.},
journal = {Molecular biology reports},
volume = {53},
number = {1},
pages = {16},
pmid = {41148458},
issn = {1573-4978},
mesh = {Humans ; *RNA, Long Noncoding/genetics/metabolism ; *MicroRNAs/genetics/metabolism ; *Neurodegenerative Diseases/genetics/metabolism/therapy ; Gene Expression Regulation ; Animals ; Signal Transduction ; Gene Regulatory Networks ; },
abstract = {Neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and Amyotrophic Lateral Sclerosis (ALS), are characterized by progressive neuronal degeneration and dysfunction. Of recent interest, a series of studies have been targeting the role of non-coding RNAs, particularly miRNAs and lncRNAs, in regulating gene expression and influencing cellular pathways that may play a critical role in the pathogenesis of these diseases. miRNAs regulate many biological processes by degrading or repressing the translation of target mRNAs, whereas lncRNAs act as scaffolds, sponges, and guides to control gene expression and cellular activities. Both miRNAs and lncRNAs participate in neurodegenerative mechanisms such as protein aggregation, inflammation, oxidative stress, and neuroinflammation. While targeting miRNAs and lncRNAs holds promise for potential therapeutic benefits, problems persist with their efficient delivery, specificity, and off-target effects. New techniques like viral vectors, lipid nanoparticles, and CRISPR-based gene editing will further enhance the development of therapies based on miRNA and lncRNA. Moreover, their interaction with regulatory networks may present new avenues toward understanding disease mechanisms and guiding therapeutic design. This review covers the role of miRNAs and lncRNAs in neurodegenerative disorders, their therapeutic potential, challenges, and future directions in ncRNA-based treatment approaches.},
}

Humans
*RNA, Long Noncoding/genetics/metabolism
*MicroRNAs/genetics/metabolism
*Neurodegenerative Diseases/genetics/metabolism/therapy
Gene Expression Regulation
Animals
Signal Transduction
Gene Regulatory Networks

@article {pmid41147168,
year = {2025},
author = {Hu, D and Li, X and Li, Y and Zhang, Q and Dai, Y and Teng, X and Hou, H and Li, J},
title = {A Drug Screening Targeting Upregulation of Syk Gene Identifies Neochlorogenic Acid and L-Arabinitol Capable of Inducing the M2 Phenotype of Microglia in Alzheimer's Disease.},
journal = {Chembiochem : a European journal of chemical biology},
volume = {},
number = {},
pages = {e202500515},
doi = {10.1002/cbic.202500515},
pmid = {41147168},
issn = {1439-7633},
support = {2023000CA0050//Beijing Life Science Academy Initiative Scientific Research Program/ ; 2024100CA0080//Beijing Life Science Academy Initiative Scientific Research Program/ ; 2024101RPIA02//Beijing Life Science Academy Initiative Scientific Research Program/ ; 2024501QPIC05//Beijing Life Science Academy Initiative Scientific Research Program/ ; },
abstract = {Despite numerous therapeutic attempts of Alzheimer's disease (AD), treatment options remain limited. Targeting microglia (MG) polarization from M1 to M2 is considered a promising approach, yet no drug specifically modulating this transition has been identified. The spleen tyrosine kinase (Syk) has emerged as a potential therapeutic target due to its role in regulating AD risk genes and promoting Amyloid-β (Aβ) clearance. Herein, a microglial reporter gene screening model targeting Syk is developed and two small molecules, neochlorogenic acid (NCGA) and L-arabinitol (L-Ara), that can upregulate Syk gene expression, leading to the activation of MG M2 phenotype, are identified. Furthermore, these compounds markedly enhance the capacity of MG to migrate toward Aβ and phagocytose Aβ. However, when Syk expression is silenced using shRNA, the ability of these small molecules to induce the MG M2 phenotype and promote Aβ phagocytosis by MG is substantially attenuated. These findings offer new insights into AD therapy development.},
}

@article {pmid41145342,
year = {2025},
author = {Dickson, SP and Mallinckrodt, C and Burstein, AH and Nisenbaum, L and Fillit, HM and Zhang, C and Hendrix, SB},
title = {The impact of recent approvals on future alzheimer's disease clinical development: Statistical considerations for combination trials.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {},
number = {},
pages = {100391},
doi = {10.1016/j.tjpad.2025.100391},
pmid = {41145342},
issn = {2426-0266},
abstract = {BACKGROUND: A new era of Alzheimer's disease (AD) research is beginning with multiple approved anti-amyloid monoclonal antibodies (mABs). These drugs are currently not widely used, but may be soon, especially at clinical trial sites. Putative disease-modifying therapies (DMTs) may alter the progression rate, potentially reducing our ability to detect effects on top of mABs. Co-administration of amyloid-targeted agents may diminish benefit (antagonism, due to the overlapping mechanism of action); alternatively, complementary treatment mechanisms may increase benefit (synergy).

METHOD: We consider several clinical trial design scenarios: a 2-arm trial added-on to a mAB, a 2-arm combination compared to double placebo, and a 4-arm full factorial trial. We calculate the required sample sizes for the shortest practical study for secondary prevention (prevention of AD clinical diagnosis in biomarker positive individuals, 2-year study), early AD (18-months), and mild-to-moderate AD (1-year). We consider additivity, antagonism, and synergy.

RESULT: The expected interaction between investigational and mAB treatment can have a large effect on power and study design. Antagonistic treatment effects often require double the sample size of synergistic effects. The 4-arm scenario required ∼10-fold increase compared to a 2-arm combination study.

CONCLUSION: Studies evaluating investigational therapies as add-on to mABs are complex, and their cost will depend on the interaction between treatments. An inescapable fact in add-on trials is the slower progression of the control arm; and it is difficult to further slow already slow progression. Treatments that are likely to work better with amyloid removal will be easier to study due to their complementary MOA. Symptomatic treatments may require fewer additional subjects than disease-modifying treatments since they are less affected by the presence or absence of mABs.},
}

@article {pmid41145339,
year = {2025},
author = {Ballard, C and Sultana, J and Doherty, P and Williams, G and Corbett, A},
title = {Identifying synergistic combinations of repurposed treatments for Alzheimer's Disease.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {},
number = {},
pages = {100329},
doi = {10.1016/j.tjpad.2025.100329},
pmid = {41145339},
issn = {2426-0266},
abstract = {There is considerable opportunity to fast-track novel treatments for Alzheimer's Disease (AD) through repurposing of existing licensed medications as a way of complementing ongoing drug discovery efforts. Given the complex interplay between AD neuropathological mechanisms, there is also a strong rationale that treatment benefits may be enhanced by examining combinations of treatments to identify potential synergies that would address multiple disease-modifying mechanisms. A Delphi consensus programme combined with a pragmatic analysis of primary care data has identified a series of individual and combined therapies that warrant further investigation in pre-clinical and clinical trials. These include treatments which target well-established neurodegeneration pathways and more explorative agents, including hormonal and anti-infective agents, which align to emerging hypotheses relating to endocrine and immune pathways in AD. Whilst caution is critical when considering combined therapy due to the risks of interaction and polypharmacy, this study provides valuable indications of potential synergistic drug pairs that warrant further investigation.},
}

@article {pmid41145338,
year = {2025},
author = {Cummings, J and Burstein, AH and Fillit, H},
title = {Add-on combination therapy with monoclonal antibodies: Implications for drug development.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {},
number = {},
pages = {100359},
doi = {10.1016/j.tjpad.2025.100359},
pmid = {41145338},
issn = {2426-0266},
abstract = {Three anti-amyloid monoclonal antibodies (MABs) including aducanumab, lecanemab, and donanemab have been approved by the FDA and lecanemab and donanemab are available in the US market and a variety of other national markets. The increasing use of anti-amyloid MABs to treat early AD will require that development of novel agents occur as add-on treatment to MABs. There is limited experience with add-on therapy to anti-amyloid agents. In most cases, it is prudent to initiate novel agents after at least six-months exposure to the MAB at the highest dose. Agents with extensive data on pharmacokinetics and pharmacodynamics and well-known safety may employ alternative approaches. Anti-amyloid MABs have different mechanisms of action, titration, and side effect profiles suggesting that add-on trials include only one type of MAB if possible. Demonstration of clinical benefit with add-on therapy will require showing additional slowing beyond that provided by the anti-amyloid MAB. Anti-amyloid therapies have profound effects on biomarkers including amyloid positron emission tomography and plasma p-tau and plasma GFAP measures. Definition of the biomarker profile of a novel agent prior to initiation of add-on therapies, inclusion of target engagement biomarkers specific to the novel intervention, assessment of biomarkers not known to be affected by anti-amyloid MABs, and interrogation of the magnitude, timing, and trajectory of biomarker change in the add-on context compared to monotherapy with MABs will provide insight into the biological impact of the novel therapy on AD. Patient convenience in terms of formulation and timing of add-on therapies will be important to successful clinical implementation. Add-on therapies are an important step in addressing the complexity of AD and optimizing patient outcomes.},
}

@article {pmid41145337,
year = {2025},
author = {Cummings, JL and Burstein, AH and Fillit, H},
title = {Alzheimer Combination Therapies: Overview and Scenarios.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {},
number = {},
pages = {100328},
doi = {10.1016/j.tjpad.2025.100328},
pmid = {41145337},
issn = {2426-0266},
abstract = {Progress in understanding the complexity of Alzheimer's disease informs the search for combination therapies that can successfully prevent or substantially slow the progression of the disease. Anti-amyloid monoclonal antibodies are the first approved disease targeted therapies; they slow disease progression by approximately 30 %. Building on these agents in add-on therapies is one avenue to designing combination treatments. Development of combination drugs consisting of two or more novel interventions is an alternate pathway for combination treatment development. Combination therapies can involve small molecule drugs, biological agents, devices, stem cells, gene therapies, lifestyle interventions, or cognitive training. Nonclinical assessment of drug combinations may involve animal models or new approach methodologies such as induced pluripotent stem cells or organoids. Phase 1 trials are required to characterize each member of a novel combination. Phase 2 trials may use a 2-by-2 factorial design comparing each drug to placebo and the drug combination. In Phase 3, comparison of the novel combination to standard of care may be sufficient or more complex designs may be required. Targets for combination therapies beyond amyloid-related processes include tau abnormalities, inflammation, neurodegeneration, and co-pathologies such as alpha-synuclein and TDP-43. The choice of combination therapies will depend on the strength of the information regarding the target, biomarkers to guide clinical trials, and a candidate agent with the appropriate mechanism of action. Computational strategies based on network analysis of disease and drugs, validation in non-clinical models, and use of real-world data may facilitate prioritization of candidates for combination treatments.},
}

@article {pmid41144509,
year = {2025},
author = {Morden, NE and Chyn, D and Meara, E},
title = {Falls and Fractures Among Medicare Beneficiaries Concurrently Receiving Anti-Dementia Drugs and Potentially Risky Medications.},
journal = {Medical care},
volume = {},
number = {},
pages = {},
doi = {10.1097/MLR.0000000000002229},
pmid = {41144509},
issn = {1537-1948},
abstract = {BACKGROUND: Patients with Alzheimer disease and related dementias (ADRD) face risks from medications labeled "potentially inappropriate in older adults" (risky); concurrent receipt of anti-dementia drugs may amplify risk. We studied adverse events among older adults concurrently receiving anti-dementia and risky medications.

METHODS: Using 2016-2019 administrative data from a random 40% sample of fee-for-service Medicare beneficiaries receiving anti-dementia medications (acetylcholinesterase inhibitors (AChEI) and/or memantine), we identified days with concurrent receipt of select, risky medications (benzodiazepines, sedative hypnotics, opioids). We measured diagnosed falls, hip fractures, and deaths among person-days with anti-dementia drug receipt comparing person-days with versus without concurrent risky drug receipt. We stratified regression analyses on long-term care (LTC) residence.

RESULTS: We studied 633,528 beneficiaries; 64.3% were women, 33.7% met LTC residence criteria. Mean (SD) age was 80.9 (7.6) years. Each beneficiary contributed a mean (SD) of 551.7 (449.2) anti-dementia drug receipt days. Overall, 4.5% of person-days involved receipt of AChEI plus benzodiazepines; 3.8% involved AChEI plus an opioid. Falls, the most common outcome, affected 22.5% of our beneficiaries. Concurrent receipt of AChEI and opioids was associated with the greatest fall risk increase. Among community-dwelling beneficiaries, AChEI and opioid receipt (vs. AChEI alone) was associated with a hazard ratio for falls of 2.25 (95% CI: 2.19, 2.32); among LTC residents the corresponding hazard ratio was 1.46 (95% CI: 1.42, 1.51).

CONCLUSIONS: Assessment and treatment of symptoms among people with ADRD is complex; concurrent receipt of opioids and dementia medications is uncommon but seems risky. Efforts to eliminate avoidable opioids may decrease adverse events and associated suffering in this population.},
}

@article {pmid41143926,
year = {2025},
author = {Shi, Y and Ma, H and Li, H and Wang, Y and Wang, C and Zhang, N and Luo, G and Wang, Y and Gao, X},
title = {Sennoside A alleviating cognitive impairment in APP/PS1 mice via balancing microbiome metabolism.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251389922},
doi = {10.1177/13872877251389922},
pmid = {41143926},
issn = {1875-8908},
abstract = {BackgroundThe progression of Alzheimer's disease (AD) is associated with constipation, potentially mediated by gut microbiota. Laxatives have shown potential in improving the cognitive function of AD, but the specific mechanism remains underexplored. Sennoside A (SA), a well-established laxative, is commonly used for treating constipation.ObjectiveThis work used SA as a probe to explore the therapeutic effects and potential mechanisms of laxatives on AD via the gut-brain axis.MethodsFollowing a two-month treatment, behavioral experiments were used to assess the cognitive function. The central pathologies and neuroinflammation were evaluated by histopathology and ELISA. 16S rRNA sequencing, fecal microbiota transplantation and antibiotic treatment were conducted to verify whether SA exerts anti-AD effects via gut microbiota. Further, non-targeted metabolomics coupled with Spearman correlation analysis was employed to elucidate the underlying mechanisms.ResultsSA significantly countered cognitive dysfunction and central pathological damage in APP/PS1 mice. Besides, SA ameliorated gut dysbiosis and affected the metabolic functions of the flora. Furthermore, the therapeutic effects of SA decrease with the depletion of gut microbes and could be transferred with the microbiota. Intriguingly, amino acid metabolism and aminoacyl-tRNA biosynthesis were the main metabolic pathways regulated by SA, consistent with the predicted functions of gut bacteria. Finally, correlation analysis revealed a strong correlation between gut microbes, fecal metabolites, and cognitive ability affected by SA.ConclusionsThe study investigated the efficacy and mechanisms of laxatives represented by SA for AD from the perspective of the gut-brain axis.},
}

@article {pmid41143875,
year = {2025},
author = {Saak, TM and Tervo, JP and Motter, JN and Overdevest, JB},
title = {Expanding the scope of olfactory evaluation in Alzheimer's disease and related dementias (ADRD): A narrative review of the role for odor memory and recognition in AD/ADRD.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251389113},
doi = {10.1177/13872877251389113},
pmid = {41143875},
issn = {1875-8908},
abstract = {Olfactory dysfunction (OD) is a well-characterized feature of Alzheimer's disease (AD) and is often one of the earliest functional biomarkers in the disease course. As such, olfactory evaluation shows promise as an important tool in AD screening and may provide insight into pathologic underpinnings and potential treatment pathways. The National Plan to Address Alzheimer's Disease emphasizes the importance of including Alzheimer's disease related dementias (ADRD) in research efforts, and while olfaction is also associated with ADRD, this association is relatively understudied. Additionally, there have been efforts to expand the evaluation of olfactory function to include assessments beyond key domains, such as odor threshold, odor discrimination, and odor identification, which have been the primary focus of most olfaction research in AD/ADRD. Odor recognition memory assessments have been developed primarily for their utility in identifying and stratifying individuals along the AD continuum, although a wide variety of methods have been reported in the literature. In this narrative review, we provide an overview of odor identification, odor threshold, and odor discrimination in AD/ADRD with a specific focus on providing a centralized guide detailing odor recognition memory methods and their utility in AD/ADRD.},
}

@article {pmid41143243,
year = {2025},
author = {Allué, JA and Sarasa, L and Fandos, N and Gonzalo, R and Sabido-Vera, R and Loscos, J and Romero, J and Sánchez, A and Terencio, J and Matias-Guiu, JA and Piñol-Ripoll, G and Pascual-Lucas, M},
title = {Clinical validation of a plasma-based antibody-free LC-MS method for identifying CSF amyloid positivity in mild cognitive impairment.},
journal = {Frontiers in aging neuroscience},
volume = {17},
number = {},
pages = {1681516},
pmid = {41143243},
issn = {1663-4365},
abstract = {BACKGROUND: The recent approval of monoclonal antibodies for the treatment of Alzheimer's disease (AD) in several countries has accelerated the need for affordable, simple and scalable methods to identify patients who are eligible for treatment with the new disease-modifying therapies (DMT). Blood-based biomarkers offer less invasive alternatives to established gold standards. We have clinically validated a predictive model combining plasma Aβ42/Aβ40, apolipoprotein E (APOE) genotype and age, in two independent real-world cohorts to identify brain amyloid deposition.

METHODS: We conducted a clinical validation study involving 450 patients with mild cognitive impairment (MCI) from two real-world cohorts (HCSC, Madrid, Spain and HUSM, Lleida, Spain). Plasma Aβ42/Aβ40 was measured by ABtest-MS, an antibody-free liquid chromatography-mass spectrometry method. CSF Aβ42/Aβ40 and p-tau181/Aβ42 (gold standards) were quantified with the Lumipulse[®] platform. The model was trained in the HCSC cohort and validated in the HUSM cohort. Finally, an overall analysis in the combined population was performed. A dual cutoff approach was used to classify the patients as positive or negative. Statistical analysis included bootstrap resampling and model calibration.

RESULTS: In the HCSC, HUSM, external validation and combined analysis, AUCs were 0.89 (95% confidence intervals-CI: 0.84-0.93), 0.88 (0.84-0.93), 0.88 (0.83-0.92) and 0.88 (0.84-0.91), with corresponding accuracies of 82.3, 81.6, 82.3, and 81.1%, respectively. After the combined analysis, positive and negative predictive values (PPV and NPV) were established at 87.5%, resulting in cutoff values of 0.30 and 0.67 for the likelihood of amyloid negativity and positivity, respectively, for a prevalence of 62%. Probability values lower than 0.30 indicate low probability of brain amyloid deposition, while values greater than 0.67 indicate high probability. Less than 28% of the participants fell into the intermediate zone. Additional cutoffs were derived for different prevalence values. Predictive model calibration showed excellent agreement with observed data, confirming accurate predictions (slope = 0.98, intercept = -0.01).

CONCLUSION: This predictive model has demonstrated high accuracy for the identification of brain amyloid deposition in patients with MCI. Derived cutoffs enabled over 70% reduction in invasive testing, supporting efficient and cost-effective identification of candidates for DMTs.},
}

@article {pmid41141907,
year = {2025},
author = {Blazquez-Folch, J and Limones Andrade, M and Calm, B and Auñón García, JM and Alegret, M and Muñoz, N and Cano, A and Fernández, V and García-Gutiérrez, F and De Rojas, I and García-González, P and Olivé, C and Puerta, R and Capdevila-Bayo, M and Muñoz-Morales, Á and Bayón-Buján, P and Miguel, A and Montrreal, L and Espinosa, A and Sanz-Cartagena, P and Rosende-Roca, M and Zaldua, C and Gabirondo, P and Cantero-Fortiz, Y and Gurruchaga, MJ and Tarraga, L and Boada, M and Ruiz, A and Marquié, M and Valero, S},
title = {Federated learning for cognitive impairment detection using speech data.},
journal = {Frontiers in artificial intelligence},
volume = {8},
number = {},
pages = {1662859},
pmid = {41141907},
issn = {2624-8212},
abstract = {INTRODUCTION: In Alzheimer's disease (AD) research, clinical, neuroimaging, genetic, and biomarker data are vital for advancing its understanding and treatment. However, privacy concerns and limited datasets complicate data sharing. Federated learning (FL) offers a solution by enabling collaborative research while preserving data privacy.

METHODS: This study analyzed data from patients assessed at the Memory Unit of the Ace Alzheimer Center Barcelona who completed a standardized digital speech protocol. Acoustic features extracted from these recordings were used to distinguish between cognitively unimpaired (CU) and cognitively impaired (CI) individuals. The aim was to evaluate how data heterogeneity impacted the FL model performance across three scenarios: (1) equal contributions and class ratios, (2) unequal contributions, and (3) imbalanced class ratios. In each scenario, the performance of local models trained using an MLP feed-forward neural network on institutional data was analyzed and compared to a global model created by aggregating these local models using Federated Averaging (FedAvg) and Iterative Data Aggregation (IDA).

RESULTS: The cohort included 2,239 participants: 221 CU individuals (mean age 66.8, 64.7% female) and 2,018 CI subjects, comprising 1,219 with mild cognitive impairment (mean age 74.3, 61.9% female) and 799 with mild AD dementia (mean age 80.8, 64.8% female). In scenarios 1 and 3, FL provided modest gains in accuracy and AUC. In scenario 2, FL markedly improved performance for the smaller dataset (balanced accuracy rising from 0.51 to 0.80) while preserving 0.86 accuracy in the larger dataset, highlighting scalability across heterogeneous conditions.

CONCLUSION: These findings demonstrate the potential of FL to enable collaborative modeling of speech-based biomarkers for cognitive impairment detection, even under conditions of data imbalance and institutional disparity. This work highlights FL as a scalable and privacy-preserving approach for advancing digital health research in neurodegenerative diseases.},
}

@article {pmid41141199,
year = {2025},
author = {Sorod, P and Chen, GI},
title = {Hearing All About Donepezil: Its Role in the Field of Auditory Processing.},
journal = {Cureus},
volume = {17},
number = {9},
pages = {e93143},
pmid = {41141199},
issn = {2168-8184},
abstract = {Donepezil is a central-acting acetylcholinesterase inhibitor aimed at increasing acetylcholine availability at the neuron synapses to enhance cholinergic transmission. It is often used to assist with cognitive function and is well-known as the first-line treatment for mild to severe dementia of several etiologies. However, its mechanism of action within "top-down" and "bottom-up" neurological pathways continues to be explored. This case reports on a 93-year-old woman in an ambulatory geriatrics clinic with moderate-to-severe dementia. Her significant history of hearing loss with auditory hallucination impressively responded to the initiation of donepezil. There may be potential benefits of donepezil within the peripheral pathways of neuro-cortical reorganization in the field of hearing loss and auditory processing.},
}

@article {pmid41140221,
year = {2025},
author = {Mastrostefano, A and Alborghetti, M and Tiso, D and Davinelli, S and Medoro, A and Scapagnini, G},
title = {Pleiotropic Actions of Gastrodia Elata Glucosides in the Treatment of Painful Neuropathies and CNS Disorders: Focus on Mitochondrial Dysfunction and Modulation of Ion Channels.},
journal = {Current neuropharmacology},
volume = {},
number = {},
pages = {},
doi = {10.2174/011570159X402568251002112117},
pmid = {41140221},
issn = {1875-6190},
abstract = {Glycosides contained in Gastrodia elata have consistently shown neuroprotective and antiinflammatory activity in preclinical models of neurological disorders, including peripheral neuropathies, cerebrovascular disorders, and chronic neurodegenerative disorders. In a commercial product used in Italy, gastrodin has replaced α-lipoic, the use of which is now limited by unexpected adverse effects, such as severe hypoglycemia. The clinical efficacy of gastrodin in traditional Chinese medicine has been ascribed to a plethora of mechanisms, which involve the modulation of intracellular signaling pathways and membrane ion channels. Moving from the pathophysiology of diabetic neuropathy, Alzheimer's disease, and Parkinson's disease, we now focus on what we consider a key mechanism in the action of gastrodin, i.e., the regulation of mitochondrial quality control. Gastrodin is able to enhance mitochondrial fusion and biogenesis, as shown by the induction of specific biochemical markers, such as mitofusins and mitochondrial transcription factors. This supports mitochondrial health, preventing the loss of energy production and formation of reactive oxygen species associated with disorders of the central and peripheral nervous system. In addition, gastrodin physically interacts with, and restrains the expression and activity of, voltage-sensitive ion channels and acid-sensing ion channels, which play a central role in pain transmission and nociceptive sensitization. Thus, gastrodin and other constituents of Gastrodia elata show promising potential to support first-line treatments, based on preclinical evidence in models of neurological disease.},
}

@article {pmid41140219,
year = {2025},
author = {Devi, S and Singh, AP},
title = {Novel Therapeutic Approaches to Neuroinflammation in Neurodegenerative Disorders: Aptamers as Central Nervous System Agents.},
journal = {Central nervous system agents in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118715249392444251002135338},
pmid = {41140219},
issn = {1875-6166},
abstract = {INTRODUCTION: Neurodegenerative disorders (NDDs) like Alzheimer's, Parkinson's, and multiple sclerosis all begin with neuroinflammation. Neuroinflammation targeting has recently gained attention as a potential approach to treating several diseases affecting the central nervous system. The objective of this review is to explore the potential of aptamers as innovative therapeutic agents for targeting neuroinflammation in neurodegenerative disorders, offering a novel approach to CNS treatment.

METHODS: The use of aptamers, which are single-stranded nucleic acids, in diagnostic and therapeutic contexts may one day help overcome these obstacles. Myotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, and other neurodegenerative disorders are linked to neuroinflammation. Important regulators of CNS inflammatory responses include microglia and astrocytes.

RESULTS: Neurotoxic (M1-phenotype microglia and A1-phenotype astrocytes) and neuroprotective (M2-phenotype microglia and A2-phenotype astrocytes) activation of microglia and astrocytes, respectively, is a diverse and complex process. There may be a lack of reflection of the diverse morphologies of microglia and astrocytes in this binary categorisation. In addition to the complexity of the relationships between these activated glial cells, the phenotypic distribution can vary as neurodegenerative illnesses progress.

DISCUSSION: To create effective treatments for neurodegenerative illnesses, a deeper knowledge of microglia and astrocyte functions is required. Drug efficacy, safety concerns, and pharmacokinetics are only a few of the topics covered, along with the enormous possibilities and enormous hurdles of employing aptamers as therapeutic agents.

CONCLUSION: This review highlights aptamers as a promising genetic tool for treating neuroinflammation and neurodegenerative diseases through targeted delivery to the central nervous system.},
}

@article {pmid41140213,
year = {2025},
author = {Zhao, R and Che, M and Cui, Y and Peng, J and Chen, M},
title = {The Role of Lipoprotein and Gut Microbiome in Alzheimer's Disease: A Review of Novel Findings and Potential Applications.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050407276251014113234},
pmid = {41140213},
issn = {1875-5828},
abstract = {Alzheimer's disease (AD), a progressive neurodegenerative disorder, is inadequately comprehended, with hypotheses implicating amyloid-β, tau pathology, mitochondrial dysfunction, and epigenetic factors. Recent research underscores the significance of lipoproteins and the gut microbiota in the etiology of AD. Apolipoprotein E (ApoE), particularly the E4 subtype, emerges as a key genetic risk factor, influencing oxidative stress, synaptic defects, glucose metabolism, and amyloid-β clearance. Lipoprotein receptors, such as LRP-1, also influence the integrity of the blood-brain barrier, indicating potential for therapeutic applications. Novel therapies targeting lipoproteins, such as ALZ-801 and IDOL inhibitors, show promise in preclinical and clinical trials. Concurrently, the gut microbiome's impact on AD is increasingly recognized. Dysbiosis correlates with inflammation, mitochondrial oxidative stress, impaired autophagy, and neurotransmitter imbalances. Gut-derived metabolites, including phenylalanine and isoleucine, promote Th1 cell activation and microglial dysfunction, exacerbating AD pathology. Interventions, like probiotics, GV-971, and polyphenols, demonstrate efficacy in restoring microbial balance and mitigating cognitive decline. Crucially, bidirectional interactions between lipoproteins and the gut microbiome are implicated in AD. ApoE genotypes influence gut microbial composition, while microbiota- derived short-chain fatty acids and endotoxins modulate lipid metabolism and neuroinflammation. These interactions, mediated via the gut-brain axis, highlight novel therapeutic avenues. Current FDA-approved AD drugs face limitations in efficacy and side effects, underscoring the need for innovative strategies targeting lipoprotein-gut microbiome crosstalk. Integrating insights into lipoprotein biology and gut microbiota dynamics may offer transformative potential for AD treatment, emphasizing combinatorial approaches to modulate these interconnected pathways. Further research is warranted to elucidate mechanistic links and translate preclinical findings into clinical applications.},
}

@article {pmid41140062,
year = {2025},
author = {Abdel-Lah, ES and Hamad, N and Taha, AF and Mohamed, WH and Fawy, MA and Attaai, AH and Abbas, FYA and Sherkawy, HS and Abdelwarith, A and Gamea, MG},
title = {Neuroprotective Effect of Empagliflozin/Rivastigmine in Alzheimer's Disease Rat Model: Optimization of Multifaceted Mechanism of Action.},
journal = {Drug development research},
volume = {86},
number = {7},
pages = {e70180},
doi = {10.1002/ddr.70180},
pmid = {41140062},
issn = {1098-2299},
support = {//The authors received no specific funding for this work./ ; },
mesh = {Animals ; *Rivastigmine/pharmacology/administration & dosage ; *Glucosides/pharmacology/administration & dosage/therapeutic use ; *Neuroprotective Agents/pharmacology/administration & dosage ; *Alzheimer Disease/drug therapy/chemically induced/metabolism/pathology ; Male ; *Benzhydryl Compounds/pharmacology/administration & dosage/therapeutic use ; Rats ; Disease Models, Animal ; Oxidative Stress/drug effects ; Acetylcholinesterase/metabolism ; Glucose/metabolism ; Brain/drug effects/pathology/metabolism ; Rats, Wistar ; Sodium-Glucose Transporter 2 Inhibitors/pharmacology ; tau Proteins/metabolism ; Drug Therapy, Combination ; Lipid Peroxidation/drug effects ; },
abstract = {This study assessed the neuroprotective potential of empagliflozin (EMPA) as antidiabetic drug on glucose metabolism, comparing it to rivastigmine (RIVA) as standard treatment for Alzheimer's disease (AD), and their combination. Male rats were sorted into five groups. Group I served as the control, while groups II, III, IV, and V received the scopolamine plus heavy metal mixture for AD induction. Groups III and IV were administered RIVA and EMPA, respectively, and group V received both treatments. Cognitive function was evaluated behaviorally. Subsequently, glucose levels, acetylcholinesterase, oxidative stress, and inflammatory markers were assessed. Alongside the brain histopathological changes, the expression of phosphorylated tau protein was assessed. Moreover, glycolytic enzymes and glucose transporters were assessed using PCR analysis. The findings were attributed to a notable suppressive impact of EMPA on lipid peroxidation, acetylcholinesterase, glucose levels, phosphorylated tau protein, pro-inflammatory cytokines, and neuropathological changes, while enhancing antioxidant and interleukin-10 levels. It also improves glucose metabolism. The findings suggest that EMPA may be a viable candidate for future therapeutic exploration in AD, which has a multifaceted mechanism of action encompassing anti-neuroinflammation, antioxidant stress, and enhanced glucose metabolism, as well as decreased acetylcholinesterase activity and phosphorylated tau protein levels. Interestingly, combined treatment showed a superior effect than EMPA alone.},
}

Animals
*Rivastigmine/pharmacology/administration & dosage
*Glucosides/pharmacology/administration & dosage/therapeutic use
*Neuroprotective Agents/pharmacology/administration & dosage
*Alzheimer Disease/drug therapy/chemically induced/metabolism/pathology
Male
*Benzhydryl Compounds/pharmacology/administration & dosage/therapeutic use
Rats
Disease Models, Animal
Oxidative Stress/drug effects
Acetylcholinesterase/metabolism
Glucose/metabolism
Brain/drug effects/pathology/metabolism
Rats, Wistar
Sodium-Glucose Transporter 2 Inhibitors/pharmacology
tau Proteins/metabolism
Drug Therapy, Combination
Lipid Peroxidation/drug effects

@article {pmid41139687,
year = {2025},
author = {Li, X and Singh, S and DeVries, A and Gurwitz, JH},
title = {Lecanemab Therapy Use Patterns for Alzheimer's Disease Among Early Initiators in a Large National Health Plan.},
journal = {Journal of the American Geriatrics Society},
volume = {73},
number = {10},
pages = {3203-3207},
doi = {10.1111/jgs.70010},
pmid = {41139687},
issn = {1532-5415},
support = {3R33AG057806-07S1/AG/NIA NIH HHS/United States ; K01AG073651/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *Alzheimer Disease/drug therapy ; Female ; Aged ; Male ; United States ; Medicare Part C/statistics & numerical data ; Magnetic Resonance Imaging ; *Antibodies, Monoclonal, Humanized/therapeutic use/administration & dosage ; Aged, 80 and over ; },
abstract = {BACKGROUND: Lecanemab, an anti-amyloid monoclonal antibody, has been approved for treatment of early Alzheimer's disease. However, real-world data remain limited regarding use.

METHODS: Using data from a large national health plan with primarily Medicare Advantage enrollees, we characterized demographic and clinical characteristics in the 6 months preceding the initial infusion among individuals who initiated lecanemab between 1/1/2023 and 06/30/2024. We also characterized the patterns of infusions and the timing of MRIs for safety monitoring following the initial infusion among initiators who had ≥ 3 months of follow-up. We further assessed trends in lecanemab use between 1/1/2023 and 12/31/2024.

RESULTS: Of the 195 lecanemab initiators, the average age was 74.6 (SD = 5.5) years, 62.1% were female, 87.7% were White, 4.1% were Black, 1.5% were Hispanic, and 98.5% were on a Medicare Advantage plan. Almost all initiators resided in nonrural areas (96.4%); 2.6% used anticoagulants, and 1.5% used antiplatelets. Among the 119 initiators who had ≥ 3 months of follow-up, 40 (33.6%) received 7 total infusions, the expected number of infusions based on the recommended schedule of every 2 weeks. From the initial infusion, the average number of days to the first MRI was 47.1 (SD = 15.8), and to the second MRI scan was 73.4 (SD = 12.0) days, consistent with the recommended schedule. During 2023-2024, there were 526 patients who had ever received lecanemab. The increase in new initiators was modest over 2024, with only 43 more initiators during the final (n = 137) versus the first quarter (n = 94) of 2024.

CONCLUSIONS: This study demonstrated slow uptake of lecanemab among Medicare Advantage beneficiaries. Adherence to the ideal treatment schedule was less than recommended. Early lecanemab users were not representative of the population likely eligible for treatment nationally. Further research is warranted to track longer-term trends in utilization, as well as reasons for treatment interruption or discontinuation in real-world populations.},
}

Humans
*Alzheimer Disease/drug therapy
Female
Aged
Male
United States
Medicare Part C/statistics & numerical data
Magnetic Resonance Imaging
*Antibodies, Monoclonal, Humanized/therapeutic use/administration & dosage
Aged, 80 and over

@article {pmid41139428,
year = {2025},
author = {Justo-Henriques, SI and Lemos, R and Rahmatpour, P and Silva, RCG and Carvalho, JO and Ribeiro, O},
title = {Effectiveness of Individual Cognitive Stimulation on Cognition in Mild Alzheimer's Disease: A Multicenter RCT.},
journal = {Psychogeriatrics : the official journal of the Japanese Psychogeriatric Society},
volume = {25},
number = {6},
pages = {e70109},
doi = {10.1111/psyg.70109},
pmid = {41139428},
issn = {1479-8301},
mesh = {Humans ; *Alzheimer Disease/therapy/psychology ; Female ; Male ; Aged ; *Executive Function/physiology ; Neuropsychological Tests ; Treatment Outcome ; *Cognition/physiology ; Aged, 80 and over ; *Cognitive Behavioral Therapy/methods ; Memory ; Portugal ; *Cognitive Dysfunction/therapy ; },
abstract = {BACKGROUND: Alzheimer's Disease (AD) is characterised by impairments across several neurocognitive domains, including memory and executive function. The study explored the effectiveness of a 3-month individual Cognitive Stimulation (iCS) program in older adults with mild AD.

METHODS: A multicenter randomised controlled trial was conducted with 62 Portuguese older adults with mild AD. Participants were randomly assigned to either iCS (n = 33; 53%) or treatment as usual (TAU, n = 29; 47%). Cognitive outcomes were assessed at baseline, post-intervention, and 12-week follow-up using standardised tests for global cognition, memory and executive function.

RESULTS: The iCS group showed a significant improvement in memory and executive function compared to the TAU group. The analysis of subscales revealed significant improvements in encoding and semantic memory (Memory Alteration Test) and free delayed recall (Free and Cued Selective Reminding Test). Adherence and engagement with the intervention were high.

CONCLUSIONS: A 3-month iCS program showed preliminary benefits in specific cognitive domains (memory and executive function) in older adults with mild AD, warranting further research with larger samples and longer follow-up.

TRAIL REGISTRATION: Clinicaltrials.gov ID: NCT05433493; Effect of Individual Cognitive Stimulation on Memory and Executive Function in Older Adults With Alzheimer's Disease.},
}

Humans
*Alzheimer Disease/therapy/psychology
Female
Male
Aged
*Executive Function/physiology
Neuropsychological Tests
Treatment Outcome
*Cognition/physiology
Aged, 80 and over
*Cognitive Behavioral Therapy/methods
Memory
Portugal
*Cognitive Dysfunction/therapy

@article {pmid41139132,
year = {2025},
author = {Sonwani, A and Pathak, A and Jain, K},
title = {Development and characterization of multifunctional dendrimeric nanoconjugates for delivery of rutin: in vitro characterization for potential neuroprotective application.},
journal = {Nanomedicine (London, England)},
volume = {},
number = {},
pages = {1-14},
doi = {10.1080/17435889.2025.2576463},
pmid = {41139132},
issn = {1748-6963},
abstract = {AIM: In the present research work, multifunctional dendrimeric nanoconjugates were developed, where poly(amidoamine) dendrimer generation 4.0 (G4.0) was conjugated with folic acid and N-acetyl cysteine simultaneously to deliver rutin for potential neuroprotective applications.

METHODS: G4.0 was functionalized with folic acid and N-acetyl cysteine by carbodiimide coupling chemistry, and the conjugation was confirmed using [1]H NMR and FTIR spectroscopy. Further, rutin was incorporated within the conjugate, and the rutin-loaded dendrimeric conjugate was evaluated for size, drug release, cytotoxicity, cellular uptake, and antioxidant activity.

RESULTS: The results of FTIR and [1]H NMR confirmed the conjugation of folic acid and N-acetyl cysteine over the dendrimeric surface. The particle size of NAC-FA-G4.0 was 163.4 ± 16.63 nm, which was increased to 229.76 ± 14.05 nm following the rutin incorporation. The in vitro drug release study showed an initial burst release of rutin, i.e. 44.27 ± 6.4% from dendrimeric conjugate within 4 h, followed by sustained release up to 72 h. The safety and biocompatibility of the developed nanoconjugate were confirmed by the hemolytic toxicity and cytotoxicity studies.

CONCLUSION: The developed rutin-loaded dendrimeric conjugate showed improved antioxidant activity and acetylcholinesterase inhibition, suggesting promising neuroprotection properties and hence may be further explored for the treatment of neurodegenerative diseases, including Alzheimer's disease.},
}

@article {pmid41139043,
year = {2025},
author = {Yu, C and Liu, L and Lu, Z and Chen, M and Yang, N and Li, Z and Bai, L and Li, C and Zhou, X},
title = {A new approach for treating AD: Guifu Dihuang Pills improves brain insulin resistance by promoting NrCAM to activate the EGFR/PI3K/Akt signaling pathway.},
journal = {Journal of ethnopharmacology},
volume = {},
number = {},
pages = {120642},
doi = {10.1016/j.jep.2025.120642},
pmid = {41139043},
issn = {1872-7573},
abstract = {Guifu Dihuang Pills (GFDHP), a classical Chinese herbal formula originally recorded in the Synopsis of the Golden Chamber (Jingui Yaolüe), significantly ameliorate cognitive dysfunction in patients with Alzheimer's disease (AD). However, the precise molecular mechanisms underlying its therapeutic effects, particularly those involving the regulation of cerebral insulin resistance (IR), are not yet fully elucidated.

AIM OF THE STUDY: This study systematically investigated the neuroprotective mechanism of the traditional Chinese medicine (TCM) compound GFDHP in alleviating AD by integrating RNA-seq transcriptomics, surface plasmon resonance (SPR) analysis, and bioinformatic analysis. The aim was to clarify its key targets and signaling pathways involved in the modulation of cerebral IR by in vitro and in vivo experiments.

METHODS: The chemical components of GFDHP were characterized using ultra-performance liquid chromatography quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS). An AD model with cerebral IR was established by an intracerebroventricular streptozotocin (ICV-STZ) injection. Cognitive function was assessed using the Morris water maze (MWM) test, while hippocampal damage was evaluated by histological staining. The insulin level in hippocampal tissues was quantified using enzyme-linked immunosorbent assay (ELISA). AD-related proteins were analyzed using immunohistochemistry and western blot. Integrated transcriptome sequencing, AlphaFold3 prediction, and SPR analysis confirmed the interaction between neuronal cell adhesion molecule (NrCAM) and epidermal growth factor receptor (EGFR). In vitro experiments were performed using HT22 cells treated with dexamethasone (DXM) to induce an IR model, followed by evaluation of IR and AD-related markers. Lentivirus-mediated shRNA knockdown of NrCAM was performed to systematically examine its regulatory effect on the EGFR/PI3K/Akt signaling pathway and GFDHP's therapeutic intervention.

RESULTS: GFDHP significantly attenuated ICV-STZ-induced IR and AD-related neuropathological alterations. SPR analysis further revealed that NrCAM mediated the neuroprotective effect through the specific binding to EGFR, thereby activating the downstream PI3K/Akt signaling cascade. NrCAM silencing not only exacerbated both IR and AD pathology but also suppressed the EGFR/PI3K/Akt pathway and reduced the therapeutic effect of GFDHP.

CONCLUSIONS: This study demonstrated that GFDHP alleviated IR by upregulating NrCAM expression and subsequently activating the EGFR/PI3K/Akt signaling pathway, thereby ameliorating AD. This is the first report identifying NrCAM as the key molecular target mediating the neuroprotective effect of this herbal formulation, providing a novel therapeutic strategy for AD treatment.},
}

@article {pmid41138654,
year = {2025},
author = {Ha, TY and Kim, Y and Lim, SM and Hong, Y and Chang, KA},
title = {GPR40 agonist ameliorates neurodegeneration by regulating mitochondria dysfunction and NLRP3 inflammasome in Alzheimer's disease animal models.},
journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie},
volume = {192},
number = {},
pages = {118678},
doi = {10.1016/j.biopha.2025.118678},
pmid = {41138654},
issn = {1950-6007},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by mitochondrial dysfunction and chronic neuroinflammation. G-protein coupled receptor 40 (GPR40), primarily known for its role in metabolic regulation, has recently emerged as a modulator of neuronal activity and inflammatory signaling. In this study, we investigated the therapeutic potential of the selective GPR40 agonist TUG469 in both in vitro and in vivo models of AD. Treatment with amyloid-β oligomers (AβO) induced mitochondrial dysfunction in primary hippocampal neurons, as evidenced by disrupted mitochondrial morphology and membrane potential. TUG469 treatment restored mitochondrial integrity and membrane potential. Moreover, TUG469 significantly reduced AβO-induced reactive oxygen species (ROS) production. In the 5xFAD mouse model of AD, TUG469 administration improved cognitive performance and reduced Aβ plaque burden. Furthermore, TUG469 rescued impaired autophagy flux, as demonstrated by the regulation of LC3, p62, and LAMP1 expression, and attenuated neuroinflammatory responses by inhibiting NLRP3 inflammasome activation and modulating microglial reactivity. These findings indicate that GPR40 activation mitigates mitochondrial dysfunction and neuroinflammation, thereby alleviating AD-related pathology. Our results highlight the therapeutic potential of TUG469 as a multi-target modulator for AD.},
}

@article {pmid41141948,
year = {2023},
author = {Sarko, L and Saha, K},
title = {Harnessing chimeric antigen receptor (CAR)-T cells as a potential treatment for Alzheimer's disease.},
journal = {Cell & gene therapy insights},
volume = {9},
number = {7},
pages = {1003-1010},
pmid = {41141948},
issn = {2059-7800},
abstract = {Alzheimer's disease (AD) significantly burdens global healthcare systems given limited treatment options to delay or stop disease progression. Chimeric antigen receptor (CAR) T cell therapy, an immunotherapeutic approach that has produced remarkably effective responses in cancer, offers a potential avenue for the treatment of AD. Here, we discuss three significant challenges of adapting CAR-T cell therapy for AD: (i) identifying a suitable antigen target; (ii) limited permeability of the blood-brain barrier; and (iii) long-term persistence and durability of manufactured CAR-T cell products. Potential strategies to overcome these hurdles provide an attractive opportunity to revolutionize the treatment for AD and potentially other neurodegenerative disorders.},
}

@article {pmid41138336,
year = {2025},
author = {Waheed, R and Mostafa, Z and Emad, M and Darwish, SS and Purgatorio, R and Miniero, DV and De Palma, A and Cheng, TP and Wang, TY and Chen, YC and El Kerdawy, AM and Gabr, M and Catto, M and Abadi, AH and Hwang, TL and Abdel-Halim, M},
title = {Revisiting COX-2 inhibitors for Alzheimer's disease as multitargeted ligands: Development of 4-hydrazono-pyrazolidinediones with tuned COX selectivity profile and improved cellular potency.},
journal = {European journal of medicinal chemistry},
volume = {302},
number = {Pt 1},
pages = {118261},
doi = {10.1016/j.ejmech.2025.118261},
pmid = {41138336},
issn = {1768-3254},
abstract = {Herein, we expand on our previously synthesized 4-hydrazono-pyrazolidinedione COX-2 inhibitors as multitargeted agents for Alzheimer's disease (AD). Structural modifications of the 4-phenylhydrazono group led to the identification of several highly potent COX-2 inhibitors, with compound 3 exhibiting the strongest COX-2 inhibition (IC50 = 0.07 μM), with a balanced COX-2/COX-1 profile, suggesting lower cardiovascular risk. Compounds 2 and 9 showed high potency and selectivity shift toward COX-1 and displayed strong antiplatelet activity. Several derivatives showed 4-7 times improved submicromolar cellular potency, significantly inhibiting PGE2 release in LPS-stimulated THP-1 cells. Compounds 2, 3, 7, and 9 maintained the multitarget profile and inhibited Aβ and tau aggregation. Compounds 2, 3, and 7 protected against Amyloid-beta (Aβ)- and H2O2-induced cytotoxicity, confirming their neuroprotective activity with high potential for BBB permeability demonstrated via PAMPA and MDCK-MDR1 assays. These results support the potential of multitargeted COX-2 inhibitors as AD therapeutics and suggest a re-evaluation of their role in neurodegenerative disease treatment.},
}

@article {pmid41138018,
year = {2025},
author = {Hu, L and Qi, L and Lin, Z and Zhu, J and Zhang, M},
title = {Research progress of single cell RNA sequencing in nervous system.},
journal = {Molecular biology reports},
volume = {53},
number = {1},
pages = {9},
pmid = {41138018},
issn = {1573-4978},
support = {82271747//National Natural Science Foundation of China/ ; },
mesh = {Humans ; *Single-Cell Analysis/methods ; *Sequence Analysis, RNA/methods ; *Nervous System/metabolism ; Transcriptome/genetics ; *Nervous System Diseases/genetics ; Animals ; Gene Expression Profiling/methods ; },
abstract = {Single-cell RNA sequencing (scRNA-seq) and its integration with multi-omics technologies such as epigenomics and spatial transcriptomics are revolutionizing our traditional understanding of cellular heterogeneity and the microenvironment in the nervous system. While technical reviews abound, translating multi-omics data into biological and clinical insights remains a challenge. This review comprehensively outlines the latest advancements in scRNA-seq technology and its integration with multi-omics approaches and artificial intelligence. We systematically summarize its applications across neuroscience, from unraveling neurodevelopment and evolution to deciphering the mechanisms of neurological diseases such as Alzheimer's disease, Parkinson's disease, and gliomas. By deeply resolving cell-specific expression differences in neurological disorders, scRNA-seq has enabled the discovery of novel cell subtypes and revealed intercellular regulatory mechanisms, thereby facilitating the deconstruction of disease pathogenesis and the identification of new potential therapeutic targets. Furthermore, this technology has demonstrated significant value in drug screening, efficacy evaluation, and the development of novel treatment strategies. However, scRNA-seq still faces multiple technical limitations. Future efforts should focus on reducing its application costs, addressing clinical ethical concerns, and progressively advancing the clinical translation of scRNA-seq technology.},
}

Humans
*Single-Cell Analysis/methods
*Sequence Analysis, RNA/methods
*Nervous System/metabolism
Transcriptome/genetics
*Nervous System Diseases/genetics
Animals
Gene Expression Profiling/methods

@article {pmid41137894,
year = {2025},
author = {Gu, X and Yu, SP and Jiang, MQ and Zhong, W and Sastry, A and Wei, L},
title = {Preventive Memantine Treatment at the Preclinical Stage in the Alzheimer's Disease Model of the 5xFAD Mouse.},
journal = {Neuroscience bulletin},
volume = {},
number = {},
pages = {},
pmid = {41137894},
issn = {1995-8218},
abstract = {Neuronal and NMDA receptor (NMDAR) hyperactivities are common pathophysiology in Alzheimer's disease (AD). We recently identified that the deficiency of NMDAR regulatory subunit GluN3A (NR3A) cultivated early psychological and olfactory symptoms, followed by cognitive decline and deferred endogenous amyloid/tau pathologies. NMDAR antagonist memantine (MEM) prevented AD-like progression in GluN3A knockout (KO) mice. We tested the hypothesis that AD development of the 5xFAD mouse can be antagonized by the preemptive MEM treatment. MEM (10 or 20 mg/kg per day in drinking water for 3 months) was started in wild-type (WT) and 5xFAD mice at 3 months old. In this preclinical stage, the 5xFAD mouse displayed psychological and olfactory symptoms, yet exhibited no significant cognitive deficits or Aβ42 deposition. The MEM treatment antagonized early symptoms, abated cognitive decline, and amyloid/tau pathology. Early and persistent maintenance of normal neuronal/NMDAR activities in individuals carrying AD risk factors should be considered as a preventive and a possible disease-modifying therapy.},
}

@article {pmid41137616,
year = {2025},
author = {Chan, D and de Weck, G and Jackson, BL and Suk, HJ and Milman, NP and Kitchener, E and Avalos, VSF and Quay, MJ and Aoki, K and Ruiz, E and Becker, A and Zheng, M and Philips, R and Firenze, R and Geigenmüller, U and Hammerschlag, B and Arnold, S and Kivisäkk, P and Brickhouse, M and Touroutoglou, A and Brown, EN and Boyden, ES and Dickerson, BC and Klerman, EB and Tsai, LH},
title = {Gamma sensory stimulation in mild Alzheimer's dementia: An open-label extension study.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {10},
pages = {e70792},
doi = {10.1002/alz.70792},
pmid = {41137616},
issn = {1552-5279},
support = {//Freedom Together Foundation/ ; //Robert A. and Renee E. Belfer Family Foundation/ ; //Eleanor Schwartz Charitable Foundation/ ; //The Dolby Family/ ; //Che King Leo/ ; //Amy Wong and Calvin Chin/ ; //Kathleen and Miguel Octavio/ ; //the Degroof-VM Foundation/ ; //Halis Family Foundation/ ; //Chijen Lee/ ; //Eduardo Eurnekian/ ; //Larry and Debora Hilibrand/ ; //Gary Hua and Li Chen/ ; //Ko Han Family/ ; //Lester Gimpelson/ ; //David B. Emmes/ ; //Joseph P. DiSabato and Nancy E. Sakamoto/ ; //Donald A. and Glenda G. Mattes/ ; //Alan and Susan Patricof/ ; //Carol and Gene Ludwig Family Foundation/ ; //Alex Hu and Anne Gao/ ; //Elizabeth K. and Russell L. Siegelman/ ; //Marc Haas Foundation/ ; //Dave and Mary Wargo/ ; //James D. Cook, and the Nobert H. Hardner Foundation/ ; UDIW8172//NIH Loan Repayment Program/ ; 15367//Doris Duke Clinical Scientist Development Award/ ; //Picower Clinical Fellowship/ ; UL1 TR002541/TR/NCATS NIH HHS/United States ; },
mesh = {Humans ; *Alzheimer Disease/therapy/physiopathology/diagnostic imaging ; Female ; Aged ; Electroencephalography ; Magnetic Resonance Imaging ; Neuropsychological Tests ; Male ; Biomarkers/blood ; Brain/diagnostic imaging/physiopathology ; Aged, 80 and over ; tau Proteins/blood ; *Acoustic Stimulation/methods ; *Photic Stimulation/methods ; Cognition/physiology ; Mental Status and Dementia Tests ; },
abstract = {INTRODUCTION: We evaluated the long-term effects of daily 40 Hz (gamma frequency) audiovisual stimulation on cognition and biomarkers in five patients with mild Alzheimer's disease (AD).

METHODS: Over 2 years, patients received 1-h daily stimulation. Electroencephalography (EEG) was used to assess neural entrainment; magnetic resonance imaging (MRI) measured brain volumes; actigraphy monitored activity patterns; neuropsychological tests evaluated cognition; and S-PLEX assay measured plasma pTau217.

RESULTS: No adverse events occurred over the study period. Three female patients with late-onset AD (LOAD) retained strong EEG entrainment and showed less decline in Mini-Mental State Examination (MMSE), Clinical Dementia Rating (CDR), and Functional Assessment Scale (FAS) scores compared to matched controls from National Alzheimer's Coordinating Center (NACC), Alzheimer's Disease Neuroimaging Initiative (ADNI), and Longitudinal Early-Onset Alzheimer's Disease Study (LEADS). Plasma samples were available for only two of five participants - both with LOAD - and both showed pTau217 reductions of 47% and 19%.

DISCUSSION: These findings suggest that long-term 40 Hz audiovisual stimulation is safe, feasible, and may offer cognitive and biomarker benefits in some individuals with mild AD, supporting further investigation.

ClinicalTrials.gov (NCT04055376).

HIGHLIGHTS: Five mild Alzheimer's disease (AD) patients safely used daily 40 Hz audiovisual stimulation for 2 years. Late-onset AD (LOAD) patients showed increased 40 Hz electroencephalography (EEG) power and improved cognitive scores. National Alzheimer's Coordinating Center (NACC) data enhanced early-phase analysis and support precision medicine in AD studies. Plasma pTau217 declined in 2 LOAD patients after 2 years of daily use. This small pilot is the first to link long-term 40 Hz therapy to AD biomarker change.},
}

Humans
*Alzheimer Disease/therapy/physiopathology/diagnostic imaging
Female
Aged
Electroencephalography
Magnetic Resonance Imaging
Neuropsychological Tests
Male
Biomarkers/blood
Brain/diagnostic imaging/physiopathology
Aged, 80 and over
tau Proteins/blood
*Acoustic Stimulation/methods
*Photic Stimulation/methods
Cognition/physiology
Mental Status and Dementia Tests

@article {pmid41137085,
year = {2025},
author = {Zhang, W and Song, J and Zhong, F and Yu, W and Qin, Z and Yang, Z and Liu, J and Wang, X and Chen, L and Lü, W and Xing, D and Liu, J and Huang, C and Wu, J and Liu, X and Yu, W and Lü, Y},
title = {Computerized cognitive training enhances cognitive function in Alzheimer's disease by downregulating Ruminococcus-TMAO pathway.},
journal = {Journal of translational medicine},
volume = {23},
number = {1},
pages = {1173},
pmid = {41137085},
issn = {1479-5876},
support = {2022YSZX-JSX0002CSTB//grants from Innovation Programs Led by the Academicians in Chongqing under Project/ ; cstc2022ycjh-bgzxm0184//Chongqing Talent Plan/ ; CSTC2021jscx-gksb-N0020//Jiangsu Provincial Agricultural Science and Technology Independent Innovation Fund/ ; 2021ZD0201802//STI2030-Major Projects/ ; 2018YFC2001700//National Key R&D Program of China/ ; 0201[2023]160 202412//Chongqing Medical Key Discipline and Regional Medical Key Discipline Development Project/ ; },
mesh = {Humans ; Male ; *Alzheimer Disease/microbiology/physiopathology/therapy/blood ; Female ; *Cognition/physiology ; Aged ; *Methylamines/blood/metabolism ; *Down-Regulation ; Gastrointestinal Microbiome ; Cognitive Dysfunction/physiopathology ; Cognitive Training ; },
abstract = {BACKGROUND: The microbiota-gut-brain (MGB) axis is implicated in Alzheimer's disease (AD), but evidence for interventional strategies targeting this axis remains limited.

METHODS: In a 24-week, single-blind, randomized controlled trial, 84 individuals with mild cognitive impairment (MCI) or mild AD received either computerized cognitive training (CCT) or treatment as usual (TAU). Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) was the primary outcome. We also assessed functional connectivity (fNIRS), plasma trimethylamine N-oxide (TMAO) levels, and gut microbiota at baseline and 24 weeks.

RESULTS: Seventy-four participants completed the study. The CCT group showed significant improvement in ADAS-cog scores compared to controls (Cohen's d = 1.57 by week 24). Notably, CCT also induced a distinct reorganization of prefrontal functional connectivity and significantly reduced plasma TMAO levels. Microbiome analysis revealed that CCT mitigated the expansion of Ruminococcus torques group (R.torques), which was observed in the control group. Crucially, R.torques was the only genus significantly correlated with improvements in cognition (ADAS-cog, r = 0.407), neuropsychiatric symptoms (NPI, r = 0.395), TMAO reduction (r = 0.443), and functional connectivity changes (r = 0.449).

CONCLUSION: A 24-week CCT program improves cognitive function in MCI and mild AD, potentially through downregulating the R.torques-TMAO pathway within the MGB axis. This pathway represents a promising novel target for multi-domain intervention in AD.},
}

Humans
Male
*Alzheimer Disease/microbiology/physiopathology/therapy/blood
Female
*Cognition/physiology
Aged
*Methylamines/blood/metabolism
*Down-Regulation
Gastrointestinal Microbiome
Cognitive Dysfunction/physiopathology
Cognitive Training

@article {pmid41136359,
year = {2025},
author = {Pan, X and Su, Z and Huang, Z and Chen, Y and Li, X and Zheng, X},
title = {N-acetylcysteine (NAC) ameliorates ethanol-induced oxidative stress, neuroinflammation, and cognitive dysfunction in APP/PS1 mouse model.},
journal = {Translational psychiatry},
volume = {15},
number = {1},
pages = {435},
pmid = {41136359},
issn = {2158-3188},
mesh = {Animals ; *Acetylcysteine/pharmacology ; *Ethanol/toxicity/adverse effects ; Mice ; *Oxidative Stress/drug effects ; Disease Models, Animal ; *Cognitive Dysfunction/chemically induced/drug therapy/metabolism ; *Alzheimer Disease/drug therapy/metabolism ; *Neuroinflammatory Diseases/chemically induced/drug therapy ; Mice, Transgenic ; Male ; Microglia/drug effects ; *Antioxidants/pharmacology ; Brain-Derived Neurotrophic Factor/metabolism/drug effects ; Amyloid beta-Peptides/metabolism ; NLR Family, Pyrin Domain-Containing 3 Protein/metabolism/drug effects ; Disks Large Homolog 4 Protein/metabolism/drug effects ; Amyloid beta-Protein Precursor/genetics ; },
abstract = {Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder that predominantly affects the elderly, leading to a progressive decline in cognitive function. Accumulating evidence suggests that many environmental and dietary factors, especially chronic ethanol exposure, aggravate the risk of this disease. However, its precise influence on AD has not yet been clarified. Here, we show that ethanol exposure caused earlier and severer cognitive behavioral impairments, more beta amyloid (Aβ) depositions, microglia activation, decreased total antioxidant capacity (T-AOC). Moreover, inflammatory mediators, such as Nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) and Tumor necrosis factor-alpha (TNF-α) increased, while pivotal proteins involved in dendritic and synaptic development, such as Synaptophysin (SYP), postsynaptic density protein 95 (PSD95) and brain-derived neurotrophic factor (BDNF) decreased in APP/PS1 mice. N-acetylcysteine (NAC), a well-known antioxidant, could attenuate cognitive behavioral impairments and neuroinflammatory damage by restoring inflammatory and neurodevelopmental mediators. In general, our study uncovered that chronic ethanol exposure may exacerbate AD progress at the pathological and molecular levels and NAC may act as a potential drug for the treatment of AD patients with chronic ethanol exposure.},
}

Animals
*Acetylcysteine/pharmacology
*Ethanol/toxicity/adverse effects
Mice
*Oxidative Stress/drug effects
Disease Models, Animal
*Cognitive Dysfunction/chemically induced/drug therapy/metabolism
*Alzheimer Disease/drug therapy/metabolism
*Neuroinflammatory Diseases/chemically induced/drug therapy
Mice, Transgenic
Male
Microglia/drug effects
*Antioxidants/pharmacology
Brain-Derived Neurotrophic Factor/metabolism/drug effects
Amyloid beta-Peptides/metabolism
NLR Family, Pyrin Domain-Containing 3 Protein/metabolism/drug effects
Disks Large Homolog 4 Protein/metabolism/drug effects
Amyloid beta-Protein Precursor/genetics

@article {pmid41135777,
year = {2025},
author = {Zhang, S and Fan, Z and Ji, D},
title = {Advances in eye-brain axis: anatomy, immunity, and association with visual dysfunction.},
journal = {Ageing research reviews},
volume = {},
number = {},
pages = {102925},
doi = {10.1016/j.arr.2025.102925},
pmid = {41135777},
issn = {1872-9649},
abstract = {The "eye-brain axis" refers to the dynamic system of interactions between the eyes and the brain, collectively encompassing the visual signal transmission and integration pathways. The eyes and the brain exhibit structural and functional synergy, and visual dysfunction not only impairs information processing within the eye but also induces structural and functional remodeling of the central nervous system (CNS) via the eye-brain axis. For instance, the effects of glaucoma on the visual cortex are manifested as reduced blood perfusion and decreased efficiency of mitochondrial adenosine triphosphate (ATP) synthesis. Moreover, the eye can serve as an important window and biomarker for the early diagnosis and intervention of neurodegenerative diseases of the CNS. Relevant research findings include the parallelism of beta amyloid (Aβ) and phosphorylated Tau (p-Tau) between the retina and Alzheimer's disease (AD), glaucomatous neurodegeneration with AD-like features, and the role of vascular endothelial growth factor C (VEGF-C) expression along the eye-brain lymphatic pathway in regulating intraocular pressure (IOP) and correcting macular edema. Therefore, eye-brain axis research provides novel perspectives for understanding the pathophysiological mechanisms underlying visual dysfunction and related disorders, while simultaneously supporting the development of cross-organ neuroprotective strategies. This review explores the anatomical foundations, immune regulation, and bidirectional interactions of the eye-brain axis, and evaluates its relevance to the diagnosis and treatment of visual dysfunction and degenerative diseases of the CNS.},
}

@article {pmid41135742,
year = {2025},
author = {Hu, T and Xi, J and Xie, N and Zhang, X and Huang, N and Cheng, Y},
title = {Multi-Omics Analysis Reveals the Protective Role of Transcriptional Enhancer Factor and the Pathogenic Mechanism of Monocytes in Parkinson's Disease.},
journal = {Brain research bulletin},
volume = {},
number = {},
pages = {111594},
doi = {10.1016/j.brainresbull.2025.111594},
pmid = {41135742},
issn = {1873-2747},
abstract = {Parkinson's disease (PD) is a multifactorial neurodegenerative disorder whose pathogenic mechanisms remain incompletely elucidated. This study aimed to systematically identify key regulatory factors involved in PD at the genetic, cellular, and molecular levels. Using univariate Mendelian randomization (UVMR), we identified plasma proteins and genes associated with Alzheimer's disease (AD), PD, and amyotrophic lateral sclerosis (ALS), and validated their causal relationships through colocalization analysis. Cross-validation across multi-omics datasets revealed transcriptional enhancer factor (TEF) as a protective factor for PD, whereas increased counts of CD14[+]CD16[+] monocytes were identified as a risk factor. Single-cell analysis and multivariate Mendelian randomization (MVMR) further suggested potential mediating roles of these factors in PD pathogenesis. In vitro experiments demonstrated that TEF overexpression significantly enhanced the resistance of neuroblastoma cells to rotenone-induced damage, inhibited apoptosis, and preserved tyrosine hydroxylase (TH) expression. In vivo, TEF notably improved motor coordination and exploratory behavior in PD mouse models. Collectively, these findings suggest that TEF may exert neuroprotective effects by modulating immune and neuronal pathways, offering a novel therapeutic target for the prevention and treatment of Parkinson's disease.},
}

@article {pmid41134994,
year = {2025},
author = {Mullins, CA and Gannaban, RB and Kramer, A and Shah, H and Haque, ZF and Ramezan, M and Dehghani, F and Palaniyappan, AK and Bowers, F and MohanKumar, SM and MohanKumar, PS and Shin, AC},
title = {Early branched-chain amino acid reduction delays the onset of cognitive decline in a mouse model of Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251389236},
doi = {10.1177/13872877251389236},
pmid = {41134994},
issn = {1875-8908},
abstract = {BackgroundMany Alzheimer's disease (AD) treatments focus on a single variable of AD that have yet demonstrated clinically meaningful and perceived benefits by the patients. We recently showed that lowering plasma branched-chain amino acids (BCAAs) can deliver multiple pro-neuronal effects in APP/PS1 and 5xFAD mouse models.ObjectiveThe main aim was to determine the optimal point in time for the disease-modifying effects of BCAA reduction during AD development.Methods12-month-old, cognitively impaired male WT and APP/PS1 mice were injected with either vehicle or BCAA-lowering compound BT2 (40 mg/kg/day ip) for 30 days. To test if early BT2 during AD progression would have long-lasting beneficial effects, 2-month-old, cognitively intact male 5xFAD mice were treated with BT2 after which they were left alone for a month.ResultsPlasma BCAAs were reduced in BT2-treated APP/PS1 mice. Despite Aβ42 reduction, BT2 did not modify proteins or genes related to AD-related pathology, dendritic density and neurotransmitters in the cortex and hippocampus, or alleviate cognitive deficit. In another experiment, BT2-treated 5xFAD mice had lower plasma BCAAs. Importantly, early BT2, even after treatment cessation for a month, was able to effectively delay cognitive impairment which was associated with a complete restoration of cortical neurotransmitters. These results were observed without any changes in pathology markers in the brain.ConclusionsOur findings suggest that BT2-induced BCAA reduction is a novel strategy to delay AD progression possibly through enhanced neurotransmission. The efficacy is time-dependent such that treating with BT2 before the onset of AD can successfully rescue cognitive function.},
}

@article {pmid41134991,
year = {2025},
author = {Tseng, P},
title = {Does weak gamma entrainment still work? Rethinking the comfort-efficacy trade-off in 40 Hz sensory stimulation.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251389153},
doi = {10.1177/13872877251389153},
pmid = {41134991},
issn = {1875-8908},
abstract = {As 40 Hz sensory stimulation gains attention as a potential treatment for Alzheimer's disease, comfort-focused designs such as invisible spectral flicker and multi-luminaire are increasingly used to promote long-term compliance. However, these systems often produce significantly weaker electroencephalographic entrainment than traditional stroboscopic lights. It is therefore important to question the common assumption that any level of entrainment is sufficient, and consider the possibility of nonlinear or threshold-based mechanisms that may require a minimum entrainment strength for therapeutic effects. The field needs to empirically test the relationship between entrainment strength and outcome, to ensure efficacy is not compromised for comfort.},
}

@article {pmid41134085,
year = {2025},
author = {Xu, YJ and Wu, T and Lo, LT and Ko, CC and Wang, X and Ma, CHE},
title = {Microglial Deletion of Hrh4 Alleviates Alzheimer's Disease Pathologies by Enhancing Microglial Phagocytosis of Amyloid-β and Tau.},
journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
volume = {},
number = {},
pages = {e05421},
doi = {10.1002/advs.202505421},
pmid = {41134085},
issn = {2198-3844},
support = {ITS/099/23FP//Innovation and Technology Commission of the Hong Kong Special Administrative Region (HKSAR) Government/ ; R1005-24F//Research Grant Council of the HKSAR Government/ ; CityU11100424//Research Grant Council of the HKSAR Government/ ; 08193956//Health and Medical Research Fund, Food and Health Bureau, HKSAR Government/ ; 32400807//National Natural Science Foundation of China/ ; },
abstract = {Amyloid-beta (Aβ) and hyperphosphorylated tau (p-tau) aggregation are hallmark pathogenic events in Alzheimer's disease (AD). Microglial clearance of these toxic aggregates is essential, yet the underlying mechanisms remain poorly understood. This study demonstrates that low-dose ionizing radiation (LDIR) provides protection against Aβ toxicity in vitro and rescues cognitive deficits in sporadic, young, and aged familial AD mouse models, including reductions in Aβ plaque, tauopathy, and microgliosis, while promoting microglial phagocytosis in aged 3xTg-AD mice. Transcriptomic analysis identifies VUF6002, a histamine H4 receptor (H4R) antagonist, which mimics the beneficial effects of LDIR by promoting microglial activity. VUF6002 treatment restores cognitive function in aged 3xTg-AD and APPswe/PSEN1dE9 mice and significantly increases Aβ and p-tau clearance by resident microglia. Mechanistically, deletion of Hrh4 in microglia, but not in neurons, reverses cognitive deficits and mitigates key AD pathogenesis by activating the cAMP/TGF-β1/Smad3 pathway. These beneficial effects are completely abolished by inhibition of TGF-β receptor 1 signaling, which is also downregulated in AD patients. Collectively, these findings reveal a H4R/cAMP/TGF-β1/Smad3 signaling axis involved in microglial phagocytosis and cognitive function, serving as a novel therapeutic target for AD.},
}

@article {pmid41133841,
year = {2025},
author = {Yao, L and Ni, J and Wei, M and Li, T and Li, F and Wang, T and Xiao, W and Shi, J and Tian, J},
title = {Recent Advances in the Application of Artificial Intelligence in Alzheimer's Disease.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050410489250930175402},
pmid = {41133841},
issn = {1875-5828},
abstract = {Artificial intelligence (AI) refers to a system that can simulate and execute the processes of human thinking and learning, and make informed decisions. Fueled by the development of AI, the quality and effectiveness of medical work have gained momentum. AI technology plays an increasingly important role in healthcare, exhibiting substantial potential in clinical practice and decision-making processes. In Alzheimer's disease (AD), where early diagnosis and treatment remain challenging due to clinical heterogeneity and insidious progression, AI could offer excellent solutions. AI models can integrate multi-modal data to identify pre-symptomatic biomarkers and stratify high-risk cohorts, improving diagnostic accuracy, assisting with personalizing treatment and care. Furthermore, AI can accelerate drug discovery and development through drug-target identification and predictive modeling of compound efficacy. However, data quality, supervision, transparency, privacy, and ethical concerns need to be addressed. By identifying and retrieving studies for the systematic review, this article provides a comprehensive overview of current progress and related AI applications in AD.},
}

@article {pmid41133228,
year = {2025},
author = {Wang, S and Shi, Y and Xin, R and Kang, H and Xiong, H and Ren, J},
title = {Exploring the role of insulin resistance in bridging the metabolic syndrome and Alzheimer's disease-a review of mechanistic studies.},
journal = {Frontiers in endocrinology},
volume = {16},
number = {},
pages = {1614006},
pmid = {41133228},
issn = {1664-2392},
mesh = {*Insulin Resistance/physiology ; Humans ; *Alzheimer Disease/metabolism/pathology/etiology ; *Metabolic Syndrome/metabolism/pathology ; Animals ; Oxidative Stress ; Renin-Angiotensin System ; },
abstract = {The association between metabolic syndrome (MetS) and Alzheimer's disease (AD) has attracted widespread attention; nevertheless, the precise mechanism of action between the two is not yet fully elucidated. This review systematically explores the complex mechanisms of insulin resistance (IR) in MetS and AD. We first detail the intrinsic mechanisms of insulin resistance and emphasize its central role in the pathophysiology of MetS. Further, we reveal the underlying mechanisms by which insulin resistance in turn triggers AD through a multidimensional pathway that promotes the accumulation of pathological products, induces blood-brain barrier dysfunction, impairs neuroplasticity, induces neuroinflammatory responses, aberrantly activates the renin-angiotensin-aldosterone system, and exacerbates oxidative stress. In addition, we summarize potential strategies for targeting IR in AD treatment and demonstrate the promising prospects for improving insulin resistance in promoting cognitive recovery. This study offers a novel theoretical framework for elucidating the intricate relationship between MetS and AD. Furthermore, it provides a scientific foundation for the formulation of preventive and therapeutic strategies for metabolic and neurodegenerative diseases.},
}

*Insulin Resistance/physiology
Humans
*Alzheimer Disease/metabolism/pathology/etiology
*Metabolic Syndrome/metabolism/pathology
Animals
Oxidative Stress
Renin-Angiotensin System

@article {pmid41132583,
year = {2025},
author = {Zou, Z and Lei, D and Wang, X and Yin, Y and Li, H and Di, X and Li, X},
title = {Crocin Ameliorates Cognitive Impairment and Pathological Changes in Alzheimer's Disease Model Mice by Regulating Gut Microbiota.},
journal = {Food science & nutrition},
volume = {13},
number = {10},
pages = {e71117},
pmid = {41132583},
issn = {2048-7177},
abstract = {Alzheimer's disease (AD), a primary cause of dementia, places a significant strain on both patients and society due to the absence of effective treatments. Recent research suggests that the gut microbiota may play a role in the development of AD. Crocin, a compound derived from traditional medicine, has demonstrated potential in alleviating neurological disorders and influencing gut microbiota, yet its specific mechanisms in AD remain unclear. In this study, we administered Crocin or saline to 5xFAD mice and wild-type controls. We discovered that Crocin treatment led to notable improvements in cognitive function, as measured by the Morris water maze test, reduced beta-amyloid (Aβ) accumulation, and decreased neuroinflammation, as indicated by reduced microglial and astrocyte activation. Metagenomic sequencing revealed a significant increase in the gut microbiota diversity, specifically the abundance of Firmicutes, Verrucomicrobiota, and Akkermansia. Additionally, Crocin enhanced intestinal barrier function by upregulating tight junction proteins and Secretory immunoglobulin A, while improving the structure of the jejunal mucosa. These results suggest that Crocin may alleviate cognitive deficits and neuropathological changes in 5xFAD mice, possibly through modulation of the gut microbiota and strengthening the gut barrier, presenting it as a promising therapeutic approach for AD.},
}

@article {pmid41132573,
year = {2025},
author = {Sriramcharan, P and Ahmed, SS and Natarajan, J and Kumar, RR and Antony, J and Kumar, AP and Anjali, PB and Ganganagappa, N and Shah, RM and Madar, IH},
title = {Cerium oxide nanoparticles synthesized via green route exhibit neuroprotective effects in Alzheimer's-induced Albino Wistar rats.},
journal = {3 Biotech},
volume = {15},
number = {11},
pages = {398},
pmid = {41132573},
issn = {2190-572X},
abstract = {UNLABELLED: Green synthesis of cerium oxide nanoparticles emerges as a feasible therapeutic strategy for disorders like Alzheimer's to determine its antioxidant and cytotoxicity in the in vitro environment, following in vivo studies, safety and effectiveness were confirmed. This approach has gained increased reliability compared to physical and chemical methods due to its non-toxic and environmentally friendly nature. The synthesized nanoparticles are then characterized using Fourier transform infrared spectrometry (FTIR), particle size, scanning electron microscopy (SEM), X-ray diffraction (XRD), and Raman spectroscopy. Design optimization was applied to the selected variables to get the best-fit values of the experiment. FTIR spectroscopy revealed amide, carboxyl, and ester groups in the cerium oxide particles produced by Candida albicans, indicating their significance in nanoparticle stabilization. The particle size and zeta potential of cerium oxide nanoparticles were found to be 152 nm and - 15 mV, respectively. Various antioxidant studies, such as 2, 2-Diphenyl-2-Picryl Hydrazyl (DPPH), 2,2'-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid (ABTS), anti-lipid peroxidation, and catalase, were conducted, revealing that synthesized nanoparticles had high antioxidant activity. SEM images produced high-quality, evenly distributed images. Cerium oxide nanoparticles effectively inhibited SK-N-SH human neuroblastoma cells, with an IC50 value of 65 µg/ml. An in vivo study was performed using an amyloid-beta-induced intracerebroventricular rat model. The finding demonstrates the induction of AD in rats led to spatial memory impairments, whereas the treatment with cerium oxide nanoparticles suggests a significant improvement in neuroprotective effect. This outcome was validated through Morris water maze behavioral assessment and histopathological analysis. The results indicated that the synthesized cerium oxide nanoparticles, optimizing using the Box-Behnken design, resulted in strong antioxidant and cytotoxic activities (65%).

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13205-025-04563-4.},
}

@article {pmid41131967,
year = {2025},
author = {Javed, A and Mandal, P and Khan, I and Singh, A and Akhtar, J and Maheshwari, S and Prajapati, BG},
title = {Liposomal Drug Delivery for Neurological Disorders: Advances and Challenges.},
journal = {Central nervous system agents in medicinal chemistry},
volume = {25},
number = {3},
pages = {245-260},
pmid = {41131967},
issn = {1875-6166},
mesh = {Humans ; *Liposomes/chemistry/administration & dosage/metabolism ; *Drug Delivery Systems/methods/trends ; *Nervous System Diseases/drug therapy/metabolism ; Animals ; Blood-Brain Barrier/drug effects/metabolism ; *Neuroprotective Agents/administration & dosage ; },
abstract = {Liposomal drug delivery methods are becoming increasingly viable options for improving treatment outcomes for neurological illnesses. These systems provide a flexible framework for the formulation of medications intended for delivery to the brain, protecting the medication from enzymatic breakdown and enhancing its bioavailability. To maximize liposome-drug interactions and improve brain-targeted delivery efficiency, a variety of formulation strategies are used, such as surface modification and remote loading. By utilizing various pathways to cross the blood- -brain barrier (BBB), such as passive diffusion and receptor-mediated transcytosis, liposomes facilitate the effective transport of therapeutic drugs to the brain parenchyma. Liposomal formulations show potential for targeted drug delivery, reducing off-target effects, and improving treatment efficacy in neurological conditions like Parkinson's disease, Alzheimer's disease, stroke, multiple sclerosis, and brain cancers. For instance, in Parkinson's disease, liposomal delivery of neuroprotective agents can help maintain dopamine levels and protect dopaminergic neurons. In Alzheimer's disease, liposomes can be engineered to deliver drugs that reduce amyloid-beta plaques or tau tangles. For brain cancer, liposomal chemotherapy can target tumor cells more precisely while minimizing damage to surrounding healthy tissue. In stroke, liposomal delivery of neuroprotective agents can reduce the extent of brain damage, while in multiple sclerosis, liposomes can be used to deliver drugs that modulate the immune response. However, the clinical translation of liposomal drug delivery systems for brain diseases faces challenges related to scalability, stability, and immunogenicity, in addition to regulatory barriers. Scalability issues arise from the complex manufacturing processes required to produce liposomes consistently on a large scale. Stability concerns involve maintaining the integrity of liposomes during storage and after administration. Immunogenicity can be a problem if the liposomes trigger an unwanted immune response, potentially reducing their effectiveness or causing adverse effects. To overcome these obstacles, multidisciplinary cooperation is essential. Collaboration among materials scientists, pharmacologists, neurologists, and regulatory experts can drive the development of more robust liposomal formulations. Continuous research is needed to refine liposome designs, such as by optimizing lipid composition, surface charge, and size to improve stability and targeting capabilities. Advanced techniques like PEGylation (coating liposomes with polyethylene glycol) can help reduce immunogenicity and extend circulation time in the bloodstream. Despite these challenges, liposomal methods present intriguing prospects for transforming medication administration to the brain and offering effective treatments for neurological illnesses. The development of more sophisticated liposomal technologies, combined with a deeper understanding of their mechanisms of action, could lead to significant breakthroughs in the treatment of neurological disorders. For example, research into ligand- targeted liposomes, which use specific molecules to bind to receptors on the BBB, holds promise for enhancing delivery specificity and efficiency. To fully realize the therapeutic promise of these novel drug delivery systems, further advancements in liposomal technologies and a deeper understanding of their mechanisms are necessary. This includes not only technical improvements but also comprehensive preclinical and clinical studies to evaluate safety, efficacy, and long-term effects. As our knowledge expands and technology progresses, liposomal drug delivery could become a cornerstone of neurological disease treatment, providing new hope for patients with previously intractable conditions.},
}

Humans
*Liposomes/chemistry/administration & dosage/metabolism
*Drug Delivery Systems/methods/trends
*Nervous System Diseases/drug therapy/metabolism
Animals
Blood-Brain Barrier/drug effects/metabolism
*Neuroprotective Agents/administration & dosage

@article {pmid41131557,
year = {2025},
author = {Buchanan, RA and Kramer, AT and Calipari, ES and Bowman, AB and Nobis, WP and Harrison, FE},
title = {Differential impact of manganese on glutamate clearance, electroencephalography, and sleep in Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {10},
pages = {e70821},
doi = {10.1002/alz.70821},
pmid = {41131557},
issn = {1552-5279},
support = {DK135073/DK/NIDDK NIH HHS/United States ; DK020593/DK/NIDDK NIH HHS/United States ; //FEH and ABB/ ; T32 ES007028/ES/NIEHS NIH HHS/United States ; P50 HD103537/HD/NICHD NIH HHS/United States ; HD103537//Eunice Kennedy Shriver National Institute of Child Health and Human Development/ ; R01 ES031401/ES/NIEHS NIH HHS/United States ; R01 ES035518/ES/NIEHS NIH HHS/United States ; ES007028/ES/NIEHS NIH HHS/United States ; },
mesh = {Animals ; *Alzheimer Disease/metabolism/physiopathology ; *Manganese/toxicity/metabolism/pharmacology ; Electroencephalography ; *Glutamic Acid/metabolism ; Mice ; Mice, Transgenic ; Disease Models, Animal ; *Sleep/drug effects ; Amyloid beta-Protein Precursor/genetics ; Presenilin-1/genetics ; Male ; *Brain/drug effects/metabolism ; Mice, Inbred C57BL ; },
abstract = {INTRODUCTION: Underlying glutamate dysregulation in Alzheimer's disease can be worsened by environmental factors like manganese (Mn) exposure. This study examined how excess Mn affects glutamatergic signaling and neurotransmission in a beta-amyloid mouse model.

METHODS: APP/PSEN1 and control mice were exposed to systemic Mn subcutaneously. Gene expression, glutamate clearance dynamics, electroencephalography (EEG) activity, and sleep architecture were analyzed using quantitative polymerase chain reaction (qPCR), Western blot, ex vivo hippocampal slices, and EEG recordings.

RESULTS: Mn exposure elevated brain Mn levels and altered glutamate dynamics in both WT and APP/PSEN1 mice. Wild-type (WT) mice showed faster glutamate clearance, increased spiking, disrupted sleep, and brain wave changes. APP/PSEN1 mice exhibited slower glutamate clearance, altered gene expression, increased glial fibrillary acidic protein (GFAP), and changes in non-rapid eye movement (NREM) delta and rapid eye movement (REM) alpha power.

DISCUSSION: Mn exposure altered glutamate clearance and brain activity, particularly in WT mice. APP/PSEN1 mice showed impaired clearance, limited gene expression changes, and altered EEG patterns, suggesting distinct or pre-existing compensatory mechanisms.

HIGHLIGHTS: Manganese exposure significantly alters glutamate clearance dynamics differentially in wild-type and APP/PSEN1 mouse models of Alzheimer's disease. Acute manganese treatment disrupts sleep architecture, evidenced by changes in electroencephalography (EEG) patterns and vigilance states. APP/PSEN1 mice exhibit slower glutamate clearance and altered gene expression compared to wild-type mice following manganese exposure. Distinct brain wave frequency shifts were observed in response to manganese treatment, particularly affecting delta, theta, and alpha rhythms. Findings suggest a potential exacerbation of excitatory/inhibitory imbalances due to environmental manganese exposure in Alzheimer's pathology.},
}

Animals
*Alzheimer Disease/metabolism/physiopathology
*Manganese/toxicity/metabolism/pharmacology
Electroencephalography
*Glutamic Acid/metabolism
Mice
Mice, Transgenic
Disease Models, Animal
*Sleep/drug effects
Amyloid beta-Protein Precursor/genetics
Presenilin-1/genetics
Male
*Brain/drug effects/metabolism
Mice, Inbred C57BL

@article {pmid41129981,
year = {2025},
author = {Wang, B and Chang, Y and Shen, L and Ma, Y and Zhang, Z and Du, J and Wang, Y and Li, Y and Zhao, F and Wang, J and Pang, X and Fan, W and Du, L and Yan, L},
title = {Multifunctional near-infrared fluorescent probe for imaging of hydrogen peroxide and photodynamic therapy of amyloid-β aggregation in Alzheimer's disease.},
journal = {Talanta},
volume = {298},
number = {Pt B},
pages = {129009},
doi = {10.1016/j.talanta.2025.129009},
pmid = {41129981},
issn = {1873-3573},
abstract = {Photodynamic therapy (PDT) has shown significant potential in eliminating amyloid-β (Aβ) aggregates, the characteristic pathological marker of Alzheimer's disease (AD). However, traditional photosensitizers have limitations such as off-target oxidation and single functionality, which severely hinder their specificity and therapeutic efficiency in clearing Aβ plaques. Given the complexity of AD's pathological mechanisms, the development of novel photosensitizers with both targeting ability and multifunctionality has become an urgent priority. In this study, a H2O2-responsive near-infrared (NIR) fluorescent probe ENBS-P was designed and synthesized. By integrating the dual functions of H2O2 visualization and precise photodynamic therapy, it has achieved efficient application in both in vitro and in vivo models. ENBS-P could be specifically activated by H2O2 to release ENBS, resulting in a significant enhancement of fluorescence signal at 720 nm (λex = 640 nm), thus realizing highly sensitive in situ detection of H2O2 (LOD = 0.2 μM). In addition, benefiting from a more efficient intersystem crossing (ISC) process from S1 to T1, the therapeutic molecule ENBS, generated after the specific activation of ENBS-P by H2O2, could produce superoxide radical anions (O2[-•], Type I photoreaction) under NIR light excitation. Importantly, through imaging-guided PDT, it could effectively inhibit the aberrant aggregation of Aβ42 and promote the dissociation of formed aggregates. This study overcomes the limitations of traditional photosensitizers by providing an innovative "diagnosis-treatment" integrated strategy for the early diagnosis and therapy of AD, holding significant promise for advancing precision medicine in AD.},
}

@article {pmid41129661,
year = {2025},
author = {Wu, CS and Huang, WL and Wang, SH and Wu, MS and Chen, KS and Cheng, SH and Chiu, YM},
title = {Association Between Autoimmune Diseases, Treatments, and Dementia Risk: A Population-Based Case-Control Study From Taiwan.},
journal = {The Journal of clinical psychiatry},
volume = {86},
number = {4},
pages = {},
doi = {10.4088/JCP.25m15774},
pmid = {41129661},
issn = {1555-2101},
mesh = {Humans ; Taiwan/epidemiology ; Female ; Male ; *Autoimmune Diseases/epidemiology/drug therapy/complications ; *Dementia/epidemiology/etiology ; Middle Aged ; Aged ; Case-Control Studies ; Comorbidity ; Prevalence ; Aged, 80 and over ; Risk Factors ; Immunosuppressive Agents/therapeutic use ; },
abstract = {Objectives: This study aimed to assess the risk of dementia associated with specific autoimmune diseases and the impact of related pharmacologic treatments. Methods: Patients 55 years or older diagnosed with dementia by neurologists or psychiatrists between 2010 and 2021 were identified using claims data from Taiwan's National Health Insurance program. We examined 22 autoimmune diseases for their associations with dementia, controlling for age, gender, urbanization level, and comorbidities. Results: Dementia prevalence was higher among individuals with autoimmune diseases (10.5% in cases vs. 8.7% in comparisons). Thirteen autoimmune diseases were linked with an elevated dementia risk, particularly Behçet disease, multiple sclerosis, and systemic lupus erythematosus. Associations with vascular dementia were stronger than with Alzheimer disease. Although overall dementia risk was higher in women, no significant sex differences were observed for specific autoimmune diseases. Nonsteroidal anti-inflammatory drugs and corticosteroids did not significantly alter dementia risk among individuals with autoimmune diseases; however, immunosuppressants were associated with a reduced risk when used for more than 180 days. Conclusions: Certain autoimmune diseases are significantly associated with an increased risk of dementia, particularly vascular dementia, highlighting the distinct role of inflammation. Effective prevention or treatment of autoimmune diseases may reduce dementia incidence by 0.8%. While immunosuppressants show potential for risk reduction, further prospective studies are needed to confirm this effect.},
}

Humans
Taiwan/epidemiology
Female
Male
*Autoimmune Diseases/epidemiology/drug therapy/complications
*Dementia/epidemiology/etiology
Middle Aged
Aged
Case-Control Studies
Comorbidity
Prevalence
Aged, 80 and over
Risk Factors
Immunosuppressive Agents/therapeutic use

@article {pmid41128826,
year = {2025},
author = {Hoveizi, E and Bijavi, G and Parsa, H},
title = {Advancing Cell Therapy to Enhance Passive Avoidance Memory: Integrative Approaches Combining Neural-Like Cells and Rosmarinic Acid Through Behavioral, Molecular, and Histological Analyses.},
journal = {Neurochemical research},
volume = {50},
number = {6},
pages = {334},
pmid = {41128826},
issn = {1573-6903},
mesh = {Animals ; Rosmarinic Acid ; *Depsides/pharmacology/therapeutic use ; *Cinnamates/pharmacology/therapeutic use ; Male ; *Alzheimer Disease/therapy/metabolism/pathology ; Rats ; *Avoidance Learning/physiology/drug effects ; *Cell- and Tissue-Based Therapy/methods ; *Memory/physiology/drug effects ; Mesenchymal Stem Cells/cytology ; Rats, Sprague-Dawley ; *Neurons/drug effects/metabolism ; Cell Differentiation/physiology/drug effects ; Dental Pulp/cytology ; Oxidative Stress/drug effects ; },
abstract = {Alzheimer's disease (AD) is characterized by progressive neurodegeneration, synaptic dysfunction, and cognitive decline. Regenerative strategies aim to replace lost neurons and modulate the inflammatory milieu to restore neural networks. This study examined the effects of neural-like cells (NLCs) derived from dental pulp mesenchymal stem cells (DPSCs) on a chitosan scaffold using rosmarinic acid (RA) in AD rats. In this study, DPSCs were extracted from teeth, characterized and differentiated, induced an AD model by destroying the Meynert nucleus, conducted passive avoidance tests, analyzed histology and immunohistochemistry, and measured inflammatory and oxidative stress markers. The extraction and differentiation of DPSCs were successful. Differentiated DPSCs into neural progenitors showed increased expression of Tuj-1, Map2, Nestin, and NF (RT-PCR, p < 0.001). Behavioral tests confirmed the AD model after seven days, and histology showed neuronal loss and gliosis following Meynert destruction. Histomorphology revealed improved brain tissue and significantly increased choline acetyltransferase (ChAT) expression in the treatment groups. Notable behavioral improvements were observed in the Y‑maze and shuttle box for treated rats compared with the AD group. Biochemical analyses showed a significant decrease in inflammatory markers IL‑1β, IL‑6, and TNF‑α, along with increases in superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPX) in the RA-treated groups. The results provide reliable evidence that DPSCs, in combination with RA, exert a promising therapeutic effect and represent a meaningful advance toward the clinical application of combination therapies for patients with AD.},
}

Animals
Rosmarinic Acid
*Depsides/pharmacology/therapeutic use
*Cinnamates/pharmacology/therapeutic use
Male
*Alzheimer Disease/therapy/metabolism/pathology
Rats
*Avoidance Learning/physiology/drug effects
*Cell- and Tissue-Based Therapy/methods
*Memory/physiology/drug effects
Mesenchymal Stem Cells/cytology
Rats, Sprague-Dawley
*Neurons/drug effects/metabolism
Cell Differentiation/physiology/drug effects
Dental Pulp/cytology
Oxidative Stress/drug effects

@article {pmid41127243,
year = {2025},
author = {Li, G and Li, S and Zhou, W},
title = {Kynurenine pathway: a possible new mechanism for exercise in the prevention and treatment of Alzheimer's disease.},
journal = {Frontiers in aging neuroscience},
volume = {17},
number = {},
pages = {1617690},
pmid = {41127243},
issn = {1663-4365},
abstract = {Alzheimer's disease (AD) is the most common neurodegenerative disease in clinical practice. The kynurenine pathway (KP) is a potential intersection of factors associated with the development of AD (central nervous inflammation, glutamate excitotoxicity, and tau phosphorylation, among others). Pharmacological modulators targeting KP enzymes, such as inhibitors or agonists, and their major neuroprotective metabolites are beneficial in alleviating AD progression. Exercise significantly improves AD symptoms and also impacts KP pharmacokinetics. Promoting the production of neuroprotective active metabolites by KP may be one of the central mechanisms by which exercise improves AD symptoms. This article reviews the possible role of KP in AD neurodegeneration and AD exercise prevention and treatment.},
}

@article {pmid41126950,
year = {2025},
author = {Frost, B and Kolb, H and Algeciras-Schimnich, A and Betthauser, TJ and DeVos, S and Edelmayer, RM and Elwood, F and Fleisher, AS and Henley, D and Horie, K and Hyman, B and Kreisl, WC and Kulic, L and Leuzy, A and Palma, JA and Parmentier-Batteur, S and Patru, MM and Rabinovici, GD and Reyderman, L and Sperling, RA and Van Der Geyten, S and Wildsmith, KR and Mahinrad, S and Carrillo, MC and Weber, CJ},
title = {Tau biology, biomarkers, and therapeutics.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {11},
number = {4},
pages = {e70165},
pmid = {41126950},
issn = {2352-8737},
abstract = {UNLABELLED: As Alzheimer's disease (AD) research advances, tau has emerged as both a critical biomarker and a promising therapeutic target, central to understanding disease mechanisms, tracking progression, and guiding treatment development. The Fall 2024 Alzheimer's Association Research Roundtable convened experts from academia, industry, National Institutes of Health (NIH), and the United States Food and Drug Administration (FDA) to explore current progress and future directions in tau-centered diagnostics and therapeutics. Discussions addressed the integration of tau biomarkers into the 2024 Revised Diagnostic Criteria for AD, updates to amyloid and tau positron emission tomography (PET) imaging, and modeling of biomarker trajectories. Presenters highlighted tau-targeting therapeutics including antisense oligonucleotides, monoclonal antibodies, and small molecules, alongside innovations in drug delivery. The interplay between anti-amyloid and anti-tau therapies and strategic design of combination trials were key themes. Regulatory insights facilitated discussions on drug approval pathways. The meeting highlighted the rapid evolution of tau research and emphasized opportunities to improve diagnostics, trial design, and treatment strategies in AD.

HIGHLIGHTS: The Alzheimer's Association Research Roundtable (AARR) convened leaders from industry, academia, and government, to explore current progress and future directions in tau-centered diagnostics and therapeutics.Tau has emerged as both a critical biomarker and a promising therapeutic target, central to understanding disease mechanisms, tracking progression, and guiding treatment development.Discussions addressed the integration of tau biomarkers into the 2024 revised diagnostic criteria for AD, updates to amyloid and tau PET imaging, modeling of biomarker trajectories, tau-targeting therapeutics, and interplay between anti-amyloid and anti-tau therapies and strategic design of combination trials.},
}

@article {pmid41126823,
year = {2025},
author = {Atkinson, J and Dokiburra, A and Groover, H and Godbout, JP and Segal, BM and Zhang, Y},
title = {Targeting senescent microglia in progressive multiple sclerosis: a geroscience-informed approach.},
journal = {Frontiers in immunology},
volume = {16},
number = {},
pages = {1681724},
pmid = {41126823},
issn = {1664-3224},
mesh = {Animals ; *Microglia/drug effects/pathology/metabolism/immunology ; Mice ; *Encephalomyelitis, Autoimmune, Experimental/drug therapy/immunology/pathology ; *Cellular Senescence/drug effects ; Humans ; *Multiple Sclerosis/drug therapy/pathology ; *Senotherapeutics/pharmacology/therapeutic use ; Female ; Disease Models, Animal ; Senescence-Associated Secretory Phenotype/drug effects ; *Multiple Sclerosis, Chronic Progressive/drug therapy/pathology ; Mice, Inbred C57BL ; },
abstract = {Multiple sclerosis (MS) is a neuroinflammatory and neurodegenerative disorder of the central nervous system (CNS). Age is the strongest predictor of disease phenotype, with the majority of older adults transitioning to a progressive form marked by irreversible neurological decline. This clinical progression is associated with smoldering, CNS-compartmentalized inflammation and neurodegeneration, for which there are currently no effective disease-modifying therapies. Cellular senescence, characterized by the secretion of pro-inflammatory mediators collectively known as the senescence-associated secretory phenotype (SASP), increases with age and contributes to tissue injury. In MS, neuroinflammation can further promote cellular senescence, creating a self-reinforcing cycle of damage. Senescent microglia have been identified within MS lesions, where their SASP may impair remyelination and exacerbate neurodegeneration. Senolytic agents selectively target and eliminate senescent cells by disrupting anti-apoptotic pathways. In experimental autoimmune encephalomyelitis (EAE), a widely used model of MS, senolytic treatment reduces senescent microglia burden and attenuates disease severity in an age- and drug-dependent manner. Specifically, here we show that middle-aged mice (40-44 weeks) with EAE exhibit improved clinical outcomes and survival following treatment with either dasatinib plus quercetin (D+Q) or navitoclax. Early-phase clinical trials of senolytics in age-related diseases have demonstrated functional benefits, including improved gait speed in idiopathic pulmonary fibrosis and CNS penetrance in Alzheimer's disease. Translating senolytic therapy to MS will require careful selection of CNS-penetrant and well-tolerated agents, identification of appropriate patient populations, and deployment of responsive biomarkers. Senolytic therapy represents a promising geroscience-based strategy to meet the urgent therapeutic need in progressive MS.},
}

Animals
*Microglia/drug effects/pathology/metabolism/immunology
Mice
*Encephalomyelitis, Autoimmune, Experimental/drug therapy/immunology/pathology
*Cellular Senescence/drug effects
Humans
*Multiple Sclerosis/drug therapy/pathology
*Senotherapeutics/pharmacology/therapeutic use
Female
Disease Models, Animal
Senescence-Associated Secretory Phenotype/drug effects
*Multiple Sclerosis, Chronic Progressive/drug therapy/pathology
Mice, Inbred C57BL

@article {pmid41126448,
year = {2025},
author = {Biel, D and Steward, A and Dewenter, A and Dehsarvi, A and Zhu, Z and Roemer-Cassiano, SN and Frontzkowski, L and Hirsch, F and Palleis, C and Höglinger, G and Brendel, M and Franzmeier, N and , },
title = {A systematic comparison of ATN biomarkers for monitoring longitudinal cognitive changes in Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {10},
pages = {e70783},
doi = {10.1002/alz.70783},
pmid = {41126448},
issn = {1552-5279},
support = {EXC2145SyNergy-ID390857198//Munich Cluster for Systems Neurology/ ; AARG-22-973496/ALZ/Alzheimer's Association/United States ; },
mesh = {Humans ; *Alzheimer Disease/diagnostic imaging ; *Biomarkers/blood ; *tau Proteins/blood ; Positron-Emission Tomography ; Male ; Female ; Longitudinal Studies ; Aged ; Magnetic Resonance Imaging ; Amyloid beta-Peptides ; Aged, 80 and over ; *Cognitive Dysfunction/diagnostic imaging ; Brain/diagnostic imaging/pathology ; Cognition ; },
abstract = {INTRODUCTION: With anti-amyloid beta (Aβ) therapies approved for Alzheimer's disease (AD), surrogate biomarkers are needed to monitor clinical treatment efficacy. Therefore, we systematically compared longitudinal changes in A/T/N biomarkers (amyloid-positron emission tomography [PET], tau-PET, plasma phosphorylated tau at threonine 217 [p-tau217], and magnetic resonance imaging) for tracking cognitive changes.

METHODS: We analyzed longitudinal biomarker and cognitive change rates from the Alzheimer's Disease Neuroimaging Initiative (N = 141) and Anti-Amyloid Treatment in Asymptomatic Alzheimer's (A4) and Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) (N = 151), estimated using linear mixed models. Using linear models, we tested biomarker changes as predictors of cognitive changes, comparing predictive strengths across biomarkers using bootstrapping.

RESULTS: Tau-PET, plasma p-tau217, and cortical thickness changes accurately tracked change rates in Mini-Mental State Examination, Alzheimer's Disease Assessment Scale-Cognitive Subscale 13-item version, Clinical Dementia Rating-Sum of Boxes, and Preclinial Alzheimer Cognitive Composite scores. In contrast, amyloid-PET change rates were not linked to cognitive changes.

DISCUSSION: Plasma p-tau217 offers a cost-effective AD-specific alternative to tau-PET and could potentially be implemented for monitoring cognitive changes in AD trials, while amyloid-PET lacks utility. Cortical thickness changes accurately track cognitive changes but may be confounded by pseudo-atrophy in anti-Aβ treatments.

HIGHLIGHTS: Longitudinal changes in tau-PET, plasma p-tau217, cortical thickness - but not amyloid-PET - effectively track cognitive decline. Cortical thickness may be confounded by pseudo-atrophy in anti-Aβ trials. Plasma p-tau217 is a robust and cost-effective alternative to tau-PET as an AD-specific surrogate biomarker for monitoring cognitive changes.},
}

Humans
*Alzheimer Disease/diagnostic imaging
*Biomarkers/blood
*tau Proteins/blood
Positron-Emission Tomography
Male
Female
Longitudinal Studies
Aged
Magnetic Resonance Imaging
Amyloid beta-Peptides
Aged, 80 and over
*Cognitive Dysfunction/diagnostic imaging
Brain/diagnostic imaging/pathology
Cognition

@article {pmid41126430,
year = {2025},
author = {Alhawarri, MB},
title = {Hypothesis-Driven Insights and Clinical Trial Updates in Alzheimer's Disease Pathogenesis.},
journal = {CNS & neurological disorders drug targets},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118715273387383250924031644},
pmid = {41126430},
issn = {1996-3181},
abstract = {BACKGROUND: Alzheimer's disease (AD) is the primary cause of dementia and a significant threat to healthy aging. The prevalence of AD and other non-communicable diseases (NCDs) is significantly influenced by the progressive decline in physiological functions that is associated with aging.

METHODS: This review summarizes the results of drug interventions for AD that have been conducted in the past five years, with a particular emphasis on Phase I, Phase III, and Phase IV clinical trials. Systematic investigations of clinical trial registries and databases were employed to identify clinical trials. A total of 106 Phase I, 52 Phase III, and 13 Phase IV trials were considered, excluding studies on devices, biologics, and diagnostic tests.

RESULTS: This review summarizes a wide range of therapy approaches aimed at different facets of AD pathogenesis, including amyloid-beta aggregation, tau protein dysfunction, neuroinflammation, synapse loss, and metabolic dysregulation. AD's complex nature highlights the need for multi-target treatment strategies, which may encompass combination therapies and innovative targets that show potential in addressing the complex pathogenesis of AD.

DISCUSSION: Current clinical studies demonstrate a variety of therapies aimed at various pathogenic processes of AD. Progress in therapeutic discovery, including synthetic molecules and bioactive natural materials, suggests potential strategies for successful AD treatment. The efficacy of natural products as therapeutic agents is especially significant because of their multi-target effects.

CONCLUSION: Effective strategies to prevent the progression of AD require a thorough comprehension of its complex pathophysiology. Current clinical studies are essential for discovering viable chemicals and treatment strategies to combat this multifactorial neurodegenerative disorder, AD.},
}

@article {pmid41125269,
year = {2025},
author = {Lin, DE and Gunaga, S and Mowbray, FI and Isaacs, ED and Markwalter, D and George, N and Hay, AE and Manfredi, R and Westlake, E and Akhter, M and Bowman, JK and Rebollo-Lee, N and Gacioch, B and Ginsburg, AD and Brooten, JK and Pajka, S and Selman, K and Bain, P and Davis, JJ and Liu, S and Ouchi, K},
title = {Emergency department-initiated palliative care screening among older adults: a systematic review and meta-analysis protocol.},
journal = {BMJ open},
volume = {15},
number = {10},
pages = {e095894},
doi = {10.1136/bmjopen-2024-095894},
pmid = {41125269},
issn = {2044-6055},
mesh = {Humans ; *Palliative Care/methods ; Systematic Reviews as Topic ; *Emergency Service, Hospital ; Aged ; Meta-Analysis as Topic ; Quality of Life ; Research Design ; Length of Stay/statistics & numerical data ; *Mass Screening/methods ; Hospitalization/statistics & numerical data ; },
abstract = {INTRODUCTION: The rapidly growing population of older adults (individuals aged 65 years and older) presents a new set of challenges for healthcare providers in the emergency department (ED), given the prevalence of severe and life-threatening conditions among this group, such as chronic cancer, Alzheimer's disease/dementia and congestive heart failure. ED encounters often represent a critical point in an older patient's trajectory of care and can thus be an important opportunity for various interventions such as palliative care consultation. Therefore, identifying those who will benefit most from palliative care is of high importance, especially in determining the course of future treatment. Thus, we aim to conduct a systematic review assessing the efficacy of palliative care screening in the ED by assessing inpatient length of stay as the primary outcome and quality of life, percentage of hospitalisation and cost of care as secondary outcomes.

METHODS: This study will use Ovid MEDLINE, Embase, EBSCO CINAHL, Web of Science and Cochrane as databases. The study population comprises adults aged 60 years and older, with no focus on any specific clinical specialty or disease. Patients who have not received palliative care screening will serve as the comparator. Only studies with an applicable comparator will be considered. Studies published from 1 January 2000 to 1 July 2025 will be included.All articles will be reviewed independently and in duplicate, and every author will participate in the review, data abstraction and conflict resolution process.

ETHICS AND DISSEMINATION: Ethical approval is not required as it is a protocol for a systematic review. Findings will be disseminated through peer-reviewed publications and conference presentations.

PROSPERO REGISTRATION NUMBER: CRD42024562389.},
}

Humans
*Palliative Care/methods
Systematic Reviews as Topic
*Emergency Service, Hospital
Aged
Meta-Analysis as Topic
Quality of Life
Research Design
Length of Stay/statistics & numerical data
*Mass Screening/methods
Hospitalization/statistics & numerical data

@article {pmid41124320,
year = {2025},
author = {Li, C and Feng, L and Li, M and Dai, C},
title = {Research progress on the regulation of Nrf2/HO-1 signaling pathway by traditional Chinese medicine in the treatment of Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251389011},
doi = {10.1177/13872877251389011},
pmid = {41124320},
issn = {1875-8908},
abstract = {Alzheimer's disease (AD) is a common neurodegenerative disorder with a complex pathogenesis. Oxidative stress, neuroinflammation and apoptosis play key roles in the occurrence and development of AD. The Nrf2/HO-1 signaling pathway, as an important endogenous antioxidant stress pathway in cells, is of great significance in combating oxidative damage and neurodegeneration. In recent years, an increasing number of studies have shown that traditional Chinese medicine can exert therapeutic effects on AD by regulating the Nrf2/HO-1 signaling pathway. This article aims to review the research progress of traditional Chinese medicine in regulating the Nrf2/HO-1 signaling pathway for the treatment of AD, providing new ideas and strategies for the treatment of AD.},
}

@article {pmid41124311,
year = {2025},
author = {Sosa Pérez, S and Urrutia Amable, N and Viada González, CE and Lorenzo-Luaces, P and Sánchez Valdés, L and Crombet Ramos, T and León Monzón, K and Rodríguez Obaya, TJ and Pérez Ruiz, L},
title = {NeuroEPO plus (NeuralCIM[®]) in Alzheimer's disease: Post-trial observational follow-up study.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251386885},
doi = {10.1177/13872877251386885},
pmid = {41124311},
issn = {1875-8908},
abstract = {BackgroundNeuroEPO plus is a recombinant erythropoietin with a sialic acid content like that produced by astrocytes, lacking the hematopoietic activity of conventional erythropoietin.ObjectiveTo evaluate the efficacy and safety of treatment with neuroEPO plus.MethodsIt was a post-trial observational follow-up study with four groups, NE: subjects who continued treatment with neuroEPO plus after trial, PB-NE: subjects who received a placebo during the trial and then receive neuroEPO plus, NE-CTRL: subjects who received neuroEPO plus during the trial and then interrupted treatment and CTRL: subjects who were never treated. NeuroEPO plus was administrated three times a week nasally. The primary outcome was changed from baseline in the score on the11-item cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-Cog11) at 96 weeks. Secondary outcomes included Global Deterioration Scale, Montreal Cognitive Assessment, Neuropsychiatric Inventory, and Lawton Instrumental Activities of Daily Living Scale.ResultsThe adjusted median change from baseline in the ADAS-Cog11 score at 96 weeks was -6.0 in NE group and 11.0 in the CTRL group (difference, 21.0; 95% confidence interval [CI], 14.6-27.4; p = 0.000), -1.0 in the PB-NE (difference, 15.4; 95% CI, 9.0-21.8; p = 0.000) and 4.0 in the NE-CTRL (difference, 8.3; 95% CI, 1.4-15.2; p = 0.011). The results for secondary outcomes showed statistically significant differences.ConclusionsSubjects who continued or started treatment with neuroEPO plus stabilized or slowed down the progression of the disease. These results and the method of drug administration, make neuroEPO plus an attractive option to consider for Alzheimer's disease patients.},
}

@article {pmid41124234,
year = {2025},
author = {Sun, Y and Jiang, X and Yi, X and Wang, C and Zhang, X and Shen, R and Yang, A and Kou, X},
title = {Novel Biochanin A Carbamate Derivatives as Multifunctional Anti-Alzheimer's Disease Metal Chelators: Design, Synthesis, and Activity Evaluation.},
journal = {Chemistry & biodiversity},
volume = {},
number = {},
pages = {e01827},
doi = {10.1002/cbdv.202501827},
pmid = {41124234},
issn = {1612-1880},
abstract = {Considerable evidence suggests that metal ions play crucial roles in Alzheimer's disease (AD) progression, spurring the development of metal-involved therapeutic strategies. In this study, biochanin A, a bioactive ingredient derived fromTrifolium pratense L. (a traditional Chinese medicine [TCM]), was identified as a lead compound for the rational design of multifunctional metal chelators. A series of biochanin A derivatives (compounds a-e) was synthesized through a one-step carbamate introduction reaction. Their drug-likeness and pharmacokinetic profiles were assessed using an online prediction server. The bioactivities, including metal ion chelation, β-amyloid aggregation regulation, reactive oxygen species elimination, cholinesterase inhibition, and neurocytotoxicity were evaluated. The results indicated that compounds (a-e) possessed favorable pharmacokinetic profiles and potential as multifunctional metal chelators with minimal neurocytotoxicity, with compound d emerging as a particularly promising candidate. These findings may provide meaningful information for developing novel multifunctional metal chelators for AD treatment and innovative drugs derived from TCM.},
}

@article {pmid41123015,
year = {2025},
author = {Ebbert, KA and Chen, R and Culibrk, RA and Yeisley, DJ and Hahn, MS},
title = {Rapamycin and Suramin Effects on TNF-⍺-Mediated Mast Cell and Brain Microvascular Endothelial Cell Dysfunction.},
journal = {Biotechnology and bioengineering},
volume = {},
number = {},
pages = {},
doi = {10.1002/bit.70082},
pmid = {41123015},
issn = {1097-0290},
support = {//This study was supported, in part, by the National Institute of Health R03AG067140 and R03AG067970 to M.S.H./ ; },
abstract = {Chronic blood-brain barrier (BBB) disruption due to impaired function of brain microvascular endothelial cells (BMECs) is commonly observed in neuroinflammatory and neurodegenerative conditions. Current treatment approaches are generally limited in their capacity to reduce this dysfunction, with the Akt/mTOR/GSK pathway modulator rapamycin showing recent promise in ameliorating neuroinflammatory BBB dysfunction. Understanding the role of early, cellular level BMEC dysfunction, particularly in the context of interplay with immune cells involved in neuroinflammation, such as mast cells (MCs), is important for identifying targets for therapeutic intervention related to BBB disruption. In the present work, we investigate primary human BMECs and human MC line HMC-1.2 dysfunction in response to inflammatory insult with TNF-α and paracrine interactions, with an emphasis on the Akt/mTOR/GSK pathway-an upstream regulator of angiogenesis and MC activation-and associated extracellular and intracellular cytokine production and oxidative stress. We further compare alterations in BMEC-MC paracrine inflammatory crosstalk in response to Akt/mTOR/GSK pathway modulator suramin (100 µM) relative to rapamycin (250 nM). In monoculture, TNF-α stimulation significantly increased oxidative stress-assessed through measuring PGE2-extracellularly in BMECs. Similarly, proangiogenic and pro-inflammatory cytokine and chemokine secretion was increased in both TNF-α stimulated BMEC and MC monocultures. Additionally, TNF-α stimulation increased BMEC levels of the Akt/mTOR/GSK pathway intermediates p-p70S6K and p-RPS6 and MC levels of p-GSK3α and p-GSK3β. Coculture of TNF-α stimulated BMECs and MCs resulted in a modest increase in extracellular PGE2, and effects on extracellular cytokine/chemokine levels were primarily limited to increases in pro-inflammatory CCL2, CCL3 and CCL5 relative to TNF-α-stimulated BMEC monoculture. In contrast, the levels of intracellular cytokines in MCs increased 2-100 fold with TNF-α-stimulated coculture, concomitant with a decrease in MC p-p70S6K levels. Rapamycin treatment of TNF-⍺-stimulated cocultures resulted a modest increase in extracellular PGE2 as well as decreases in extracellular chemokines CCL2 and CCL3. In contrast, suramin treatment significantly decreased extracellular PGE2, GM-CSF, CCL2, and CCL5 while markedly increasing the BBB-stabilizing PDGF-BB. However, suramin also increased intracellular BMEC levels of multiple pro-inflammatory cytokines. Neither rapamycin nor suramin improved the intracellular inflammatory profile of cocultured MCs, indicating that MC activation had not been resolved by either treatment.},
}

@article {pmid41122827,
year = {2025},
author = {Tang, S and Wu, Y and Wang, R and Li, Y and Li, J and Peng, Y and Liu, S and Men, L and Hou, Z and Liu, Z and Liu, Z},
title = {Revealing the Formula Pattern of Congming Decoction by Ultra-High-Performance Liquid Chromatography Coupled With Quadrupole-Orbitrap Mass Spectrometry From the Perspective of Chemical Constituents, In Vitro, and In Vivo Properties.},
journal = {Journal of separation science},
volume = {48},
number = {10},
pages = {e70306},
doi = {10.1002/jssc.70306},
pmid = {41122827},
issn = {1615-9314},
support = {82274062//National Natural Science Foundation of China/ ; 20240602085RC//Department of Science and Technology of Jilin Province/ ; 20220101289JC//Natural Science Foundation of Jilin Province/ ; },
mesh = {Chromatography, High Pressure Liquid ; Animals ; *Drugs, Chinese Herbal/chemistry/analysis/pharmacokinetics/metabolism ; Rats ; Mass Spectrometry ; Rats, Sprague-Dawley ; Male ; Medicine, Chinese Traditional ; },
abstract = {The Congming decoction (CMD) is a classic traditional Chinese medicine formula, composed of Poria cocos (Schw.) Wolf, Polygalae Radix, and Acori Tatarinowii Rhizoma. The material basis for the rationality of CMD's compatibility remains unclear in both in vitro and in vivo studies. The relationship between its components and therapeutic efficacy still presents a research gap. Therefore, this study aims to reveal the co-extraction dissolution patterns, metabolic regularity in vitro, and absorption and distribution characteristics in vivo of CMD, thereby exploring the scientific connotation of formulation. Utilizing ultra-high-performance liquid chromatography coupled with quadrupole-orbitrap mass spectrometry technology, a total of 183 constituents were identified in CMD, with 72 recognized as differential compounds before and after combination, suggesting that co-boiling enhances the solubility of active ingredients. In vitro intestinal microbiota results indicated that combination reduced metabolism rates, allowing for greater absorption as the prototype. In vivo analysis identified 62 constituents within rat plasma and tissues; comparing content differences among groups found that the combinations regulate hepatic metabolism and enhance distribution of effective components, potentially serving as a significant material basis for treating Alzheimer's disease (AD). Furthermore, a targeted network pharmacology strategy was established to explore the mechanism of CMD in treating AD. This study clarified the chemical composition, metabolic patterns in vitro, and distribution rules in vivo regarding CMD, and also compared variations before and after composition. It provided new insights into the rationality of CMD's compatibility in the treatment of AD from multiple dimensions and levels.},
}

Chromatography, High Pressure Liquid
Animals
*Drugs, Chinese Herbal/chemistry/analysis/pharmacokinetics/metabolism
Rats
Mass Spectrometry
Rats, Sprague-Dawley
Male
Medicine, Chinese Traditional

@article {pmid41122812,
year = {2025},
author = {Dodge, HH and Chen, L and Wu, CY and Cutter, G and Bowman, GL and Feldman, HH and Arnold, SE},
title = {Seeking optimal repeated fluid biomarker assessments to enhance precision and statistical power in clinical trials: SLIM method.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {10},
pages = {e70787},
doi = {10.1002/alz.70787},
pmid = {41122812},
issn = {1552-5279},
support = {//the Epstein Family Collaboration of Powder for Pennies/ ; P30AG062421/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *Biomarkers/blood/cerebrospinal fluid ; *Alzheimer Disease/blood/cerebrospinal fluid ; *Clinical Trials as Topic/methods ; *Research Design ; Computer Simulation ; },
abstract = {INTRODUCTION: Plasma biomarkers are increasingly used as surrogate outcomes in clinical trials for Alzheimer's disease and related dementias (ADRD) due to their non-invasive nature. In early-phase trials designed to evaluate mechanisms of action and biological efficacy, assessing pre-post changes in plasma biomarkers within the same individuals - using a single-arm placebo lead-in design - offers a potentially cost-effective alternative to parallel-group designs by minimizing between-subject variability. However, plasma biomarkers are also subject to within-individual variability, which can obscure true treatment effects.

METHODS: One strategy to address this limitation is to collect repeated measures during each study period. This approach can improve measurement precision, enhance the signal-to-noise ratio, and increase statistical power, even with modest sample sizes.

RESULTS: We propose an innovative early-phase trial design, Single-arm Lead-In with Multiple measures (SLIM), which incorporates repeated biomarker assessments over a short follow-up period.

DISCUSSION: Using simulation studies, we demonstrate that the SLIM design can substantially reduce required sample sizes.

HIGHLIGHTS: SLIM involves repeated biomarker assessments during both the lead-in and post-treatment periods. It minimizes between-subject variability and improves the precision of within-subject estimates. It is well suited for early-phase, short-duration trials. It is not suitable for cognitive tests or other outcomes prone to practice or placebo effects. SLIM design can be an alternative to the traditional parallel design by reducing required sample sizes, thereby lowering the recruitment burden.},
}

Humans
*Biomarkers/blood/cerebrospinal fluid
*Alzheimer Disease/blood/cerebrospinal fluid
*Clinical Trials as Topic/methods
*Research Design
Computer Simulation

@article {pmid41122803,
year = {2025},
author = {Chaunsali, L and Li, J and Fleischel, E and Prim, CE and Kasprzak, I and Jiang, S and Hou, S and Escalante, M and Cope, EC and Olsen, ML and Tewari, BP and Sontheimer, H},
title = {Degradation of perineuronal nets in hippocampal CA2 explains the loss of social cognition memory in Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {10},
pages = {e70813},
doi = {10.1002/alz.70813},
pmid = {41122803},
issn = {1552-5279},
support = {R01AG065836/NH/NIH HHS/United States ; R01NS036692/NH/NIH HHS/United States ; R01NS123069/NH/NIH HHS/United States ; },
mesh = {Animals ; *Alzheimer Disease/metabolism/pathology/psychology/genetics ; Mice ; Disease Models, Animal ; *CA2 Region, Hippocampal/metabolism/pathology ; *Extracellular Matrix/metabolism ; Mice, Transgenic ; Matrix Metalloproteinases/metabolism ; *Social Behavior ; *Memory Disorders ; },
abstract = {INTRODUCTION: Loss of social cognition memory impairs Alzheimer's disease (AD) patients to recognize family members, friends, and caregivers. We investigate the role of perineuronal nets (PNNs), specialized coats of extracellular matrix around hippocampal CA2 neurons in AD-associated social memory impairments.

METHODS: We utilized 5XFAD mouse model of AD and employed immunohistochemistry, microscopy, bulk RNA-sequencing, animal behavior, gene-knockout, and drug-treatment approaches.

RESULTS: AD mice showed profound disruption of CA2 PNNs with concomitant impairment of social cognition memory. Genetic or enzymatic CA2 PNN disruption in wild-type mice mimicked these impairments. Transcriptomic analysis shows upregulation of PNN-cleaving matrix metalloproteinases (MMP) in AD mice causing disequilibrium of PNN synthesis and remodeling. Chronic inhibition of MMPs retains CA2 PNN and delays social memory impairments in 5XFAD mice.

DISCUSSION: AD-associated social memory impairments are caused by loss of CA2 PNNs. Inhibition of PNN proteolysis by MMPs preserves social memory, suggesting PNN as a promising therapeutic target.

HIGHLIGHTS: Perineuronal nets (PNNs) are disrupted in the CA2 area of the hippocampus in 5XFAD Alzheimer's disease (AD) mice at 6 months of age and beyond. Social memory deficits in 5XFAD mice coincide with the disruption of CA2 PNNs and PNN loss alone is sufficient to cause loss of social memory. Bulk RNA sequencing of hippocampal CA2 tissue reveals alterations in PNN remodeling enzymes. Inhibition of matrix metalloproteinase (MMP) activity with GM6001 prevents PNN disruption and protects against social memory deficits in the 5XFAD AD mouse model.},
}

Animals
*Alzheimer Disease/metabolism/pathology/psychology/genetics
Mice
Disease Models, Animal
*CA2 Region, Hippocampal/metabolism/pathology
*Extracellular Matrix/metabolism
Mice, Transgenic
Matrix Metalloproteinases/metabolism
*Social Behavior
*Memory Disorders

@article {pmid41122453,
year = {2025},
author = {Jangid, K and Devi, B and Dahiya, R and Mishra, J and Kumar, V and Bhatti, JS and Thareja, S and Kumar, V},
title = {Investigation of the multifunctional profile of dihydroquinazoline derivatives as potential therapeutics for Alzheimer's disease.},
journal = {RSC medicinal chemistry},
volume = {},
number = {},
pages = {},
pmid = {41122453},
issn = {2632-8682},
abstract = {Multitarget directed ligands represent an innovative strategy in the management of Alzheimer's disease (AD) by addressing its multifactorial etiology. These agents are designed to simultaneously modulate multiple key targets involved in the disease progression, offering a holistic approach for the effective treatment of AD. The current work presents the synthesis and evaluation of novel dihydroquinazoline-based multitargeting agents for the management of Alzheimer's disease. Most of the compounds showed good selectivity for AChE and MAO-B, and two compounds, viz.K2V-9 and K2V-12, emerged as potent inhibitors against both the targets. Compound K2V-9 displayed IC50 values of 1.72 ± 0.01 μM and 0.950 ± 0.52 μM against AChE and MAO-B, respectively. Compound K2V-12 showed IC50 values of 1.10 ± 0.078 μM and 1.68 ± 0.25 μM against AChE and MAO-B, respectively. Moreover, amyloid β self-aggregation inhibition studies were performed, where K2V-9 and K2V-12 showed percentage inhibitions of 37.34% and 48.10%, respectively, after 48 h. Both compounds were found to be non-toxic and neuroprotective and showed the capability of reducing the ROS levels in SHSY-5Y cells. Reversibility and kinetic studies of these lead compounds showed that both molecules produced reversible and mixed-type of inhibition against the targeted enzymes. In the docking and molecular dynamics simulation studies, K2V-9 and K2V-12 were found to be well accommodated in the active cavity with good thermodynamic stability.},
}

@article {pmid41122344,
year = {2025},
author = {Casey, CS and Patel, N and Vasileva-Metodiev, SZ and Cotton, S and Walker, C and Nilforooshan, R},
title = {Real-world diagnosis and management of mild cognitive impairment and Alzheimer's disease dementia in the United Kingdom.},
journal = {Journal of Alzheimer's disease reports},
volume = {9},
number = {},
pages = {25424823251370708},
pmid = {41122344},
issn = {2542-4823},
abstract = {BACKGROUND: Timely diagnosis of Alzheimer's disease (AD) remains challenging in the United Kingdom and improvements are needed with the introduction of new therapies.

OBJECTIVE: To examine the United Kingdom diagnostic and current treatment journey for people with mild cognitive impairment (MCI) and AD dementia to identify future opportunities for new treatments.

METHODS: Physician-reported data were drawn from the Adelphi Real World Dementia Disease Specific Programme™, a cross-sectional survey of physicians treating patients with MCI or AD dementia in the United Kingdom between 2022 and 2024. Analyses were descriptive.

RESULTS: Physicians (n = 109) reported data for 717 patients with MCI or AD dementia (including 264 with MCI or mild dementia). Overall median (interquartile range) time from symptom onset to first consultation was 26.0 (9.1-52.9) weeks. Time from consultation to diagnosis, for patients not diagnosed at initial consultation, was 15.2 (5.1-21.0) weeks for patients who first consulted and were diagnosed by a general practitioner and 21.9 (12.6-39.0) weeks for those who consulted a general practitioner and were diagnosed by a specialist. Few patients (4.9%) had a biomarker-confirmed diagnosis. Delays due to waiting for specialist referrals and diagnostic tests were reported for 57.6% and 26.9% of patients, respectively. Acetylcholinesterase inhibitors were the most common first-line treatment (82.0%).

CONCLUSIONS: Our data highlighted delays in AD diagnosis and potential areas for United Kingdom health system improvement. Expediting timely diagnosis through increased public awareness, expanded biomarker use and addressing disparities in services is crucial to maximize access to emerging new therapies.},
}

@article {pmid41121478,
year = {2025},
author = {Hsieh, CY and Chuang, CH and Gomez, MC and Tayo, LL and Huang, SM and Tsai, PW},
title = {Computational Analysis and in vitro Verification Insights into Quercetin's Suppression of Neuroinflammation in BV-2 Microglia through NF-κB Pathway Inhibition.},
journal = {Current medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0109298673395813250901012530},
pmid = {41121478},
issn = {1875-533X},
abstract = {INTRODUCTION: Neuroinflammation, primarily mediated by activated microglia, is a significant contributor to neurodegenerative diseases, such as Alzheimer's and Parkinson's disease. Quercetin (QCT), a dietary flavonoid, has demonstrated anti-inflammatory and neuroprotective properties; however, the detailed molecular mechanisms behind these effects remain unclear. This study aimed to investigate the anti-inflammatory actions of QCT, particularly focusing on its potential to suppress the activation of microglia and subsequent neuroinflammation.

METHODS: BV-2 microglial cells were stimulated with lipopolysaccharide (LPS) to induce an inflammatory response and were subsequently treated with various concentrations of QCT. Cell viability was assessed using the MTT assay. Levels of pro-inflammatory cytokines (IL-6, TNF- α) and nitric oxide (NO) were quantified through ELISA and Griess reaction methods, respectively. Western blot analysis was conducted to examine inducible nitric oxide synthase (i- NOS), NF-κB, IκBα, and phosphorylated IκBα protein expressions. In silico approaches, including protein-protein interaction (PPI) network analysis and molecular docking, were employed to explore potential molecular mechanisms involving NF-κB signaling pathways.

RESULTS: Treatment with QCT significantly reduced the secretion of IL-6 (96%) and TNF-α (87%), as well as NO production (42%), in a dose-dependent manner. Western blot results demonstrated a marked reduction in iNOS expression and inhibition of NF-κB activation through reduced phosphorylation of IκBα following QCT treatment. Molecular docking indicated a strong binding affinity between QCT and IKKβ, suggesting inhibition of the NF-κB pathway.

DISCUSSION: The findings indicated QCT to exert potent anti-inflammatory effects in LPS-stimulated BV-2 cells by modulating key proteins involved in the NF-κB signaling pathway. Specifically, the docking results implied QCT's direct interaction with the catalytic subunit IKKβ, inhibiting IκBα phosphorylation and subsequent NF-κB activation. The results have been found to be consistent with previous literature, reinforcing QCT's role in reducing neuroinflammation through specific molecular targets and pathways. Further in vivo studies are necessary to validate the findings.

CONCLUSION: Quercetin effectively suppressed neuroinflammation in microglial cells through inhibition of the NF-κB signaling pathway, reducing levels of critical pro-inflammatory mediators. The outcomes have highlighted the potential of quercetin as a preventive nutraceutical for neurodegenerative diseases, necessitating future in vivo investigations to confirm its therapeutic efficacy.},
}

@article {pmid41121098,
year = {2025},
author = {Afolayan, O and Nwaogu, V and Idowu, O and Dosumu, O},
title = {Differential oxido-reductive activities of aged garlic extract and S-allyl-cysteine in genetically modified Drosophila model of Alzheimer's disease.},
journal = {BMC complementary medicine and therapies},
volume = {25},
number = {1},
pages = {392},
pmid = {41121098},
issn = {2662-7671},
abstract = {Alzheimer’s disease (AD) is a progressive neurodegenerative disorder frequently associated with ageing. It is characterised by the loss of neurons in the hippocampus and cortex, leading to declines in cognitive function and memory. Recent research has spotlighted Aged Garlic Extract (AGE) and its bioactive component, S-allyl-cysteine (SAC), as promising candidates for the treatment of AD due to their potent antioxidant, anti-inflammatory, and neuroprotective properties. These features help mitigate oxidative stress and neuronal damage associated with the disease. The present study aimed to evaluate the neuroprotective effects of AGE and SAC using a Drosophila melanogaster (Drosophila) model of Alzheimer’s disease. The Drosophila (UAS-Aβ > Elav-GAL4) were reared on a diet supplemented with varying concentrations of AGE (10 µL, 20 µL, and 40 µL) and SAC (at doses of 25, 50, and 75 mg/kg). Key parameters measured included larval motility, negative geotaxis, and oxidative stress markers. The AD models exhibited reduced motor abilities, decreased antioxidant levels, increased oxidative stress, and elevated acetylcholinesterase (AChE) activity. However, treatment with different concentrations of AGE and SAC significantly improved locomotor function and modulated redox activities, along with a reduction in AChE activity. This study highlights the neuroprotective potential of AGE and its active component, SAC, in the Drosophila AD model, indicating that the beneficial effects of AGE are primarily attributed to SAC.},
}

@article {pmid41120520,
year = {2025},
author = {Rahman, MO and Ahmed, SS and Alqahtani, AS and Rehman, MT and Sultana, N and Bouhrim, M and Ali, MA and Lee, J},
title = {Identification of stigmasterol derived AChE inhibitors for Alzheimer's disease using high throughput virtual screening and molecular dynamics simulations.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {36676},
pmid = {41120520},
issn = {2045-2322},
support = {ORF-2025-132//King Saud University/ ; },
mesh = {*Stigmasterol/chemistry/analogs & derivatives/pharmacology ; *Cholinesterase Inhibitors/chemistry/pharmacology/therapeutic use ; Molecular Dynamics Simulation ; *Alzheimer Disease/drug therapy ; Humans ; High-Throughput Screening Assays ; Molecular Docking Simulation ; *Acetylcholinesterase/metabolism/chemistry ; Neuroprotective Agents/chemistry ; },
abstract = {Alzheimer's disease (AD), a progressive neurodegenerative disorder, poses a significant global health burden due to its intricate pathology and the absence of curative treatments. Current therapies primarily offer symptomatic relief, often with limited efficacy and complications, thereby underscoring the urgent need for innovative, safer, and more effective interventions. Stigmasterol, a plant-derived phytosterol, has demonstrated neuroprotective properties, including anti-inflammatory and antioxidant effects, which positions this sterol as a compelling candidate for further investigation in AD treatment. In this investigation, high-throughput virtual screening of 972 stigmasterol analogs (SAs) was conducted to identify potential acetylcholinesterase (AChE) inhibitors, followed by ADMET filtering, molecular dynamics (MD) simulations, MM/GBSA free binding energy estimations, and DFT calculations. Three lead compounds, including SA4 (-10.9 kcal/mol), SA12 (-10.6 kcal/mol), and SA15 (-10.5 kcal/mol), demonstrated superior binding affinities compared to stigmasterol (-9.6 kcal/mol) and the control drug donepezil (-8.6 kcal/mol). Docking interaction analysis revealed strong binding by hydrogen bonds and hydrophobic interactions, whereas pharmacokinetic, pharmacodynamic, and toxicity assessments confirmed the favorable characteristics of these compounds. MD simulations (200 ns) demonstrated the structural compactness of the compounds, which was further supported by principal component analysis and Gibbs free energy landscape experiments. MM/GBSA identified SA4 as the most potent analog (-82.21 kcal/mol), followed by SA15 (-80.40 kcal/mol) and SA12 (-69.72 kcal/mol). A DFT-based molecular reactivity analysis revealed decreased reactivity and increased kinetic stability of the lead candidates in their transition from free to bound states. These findings provide insights into the therapeutic potential of stigmasterol analogs as AChE inhibitors, thus offering the groundwork for in vivo and in vitro validation for advancing AD treatment.},
}

*Stigmasterol/chemistry/analogs & derivatives/pharmacology
*Cholinesterase Inhibitors/chemistry/pharmacology/therapeutic use
Molecular Dynamics Simulation
*Alzheimer Disease/drug therapy
Humans
High-Throughput Screening Assays
Molecular Docking Simulation
*Acetylcholinesterase/metabolism/chemistry
Neuroprotective Agents/chemistry

@article {pmid41120130,
year = {2025},
author = {Marziliano, A and Babar, H and Patel, P and Gieniusz, M and Mongelli, J and Burns, E and Applebaum, AJ and Pessin, H and Breitbart, W and Sinvani, L and Perissinotto, C and Diefenbach, MA},
title = {The adaptation of meaning centered psychotherapy to develop RELOAD-C: a web-based tool to reduce loneliness in caregivers of persons with Alzheimer's disease and related dementias.},
journal = {Translational behavioral medicine},
volume = {15},
number = {1},
pages = {},
doi = {10.1093/tbm/ibaf059},
pmid = {41120130},
issn = {1613-9860},
support = {K01AG076888//National Institute on Aging (NIA) of the National Institutes of Health (NIH)/ ; },
mesh = {Humans ; *Caregivers/psychology ; *Alzheimer Disease/psychology/nursing ; *Psychotherapy/methods ; Male ; Female ; *Loneliness/psychology ; *Dementia/nursing/psychology ; Middle Aged ; Internet ; Aged ; Internet-Based Intervention ; },
abstract = {BACKGROUND: More than 60% of caregivers of persons with Alzheimer's disease and related dementias (AD/ADRD) are lonely. Meaning and purpose in life is associated with reduced feelings of loneliness, but has not yet been systematically fostered among caregivers of patients with AD/ADRD. Adapting meaning-centered psychotherapy (MCP), an evidence-based treatment for increasing meaning and purpose in life in cancer caregivers, might decrease loneliness in the dementia caregiver population.

PURPOSE: The purpose of this manuscript is to report on the development, usability, and acceptability testing of REducing LOneliness in Alzeheimer's Disease-Care Partners (RELOAD-C), a web-based platform that features six brief videos and aims to reduce loneliness in caregivers of patients with dementia through introducing major concepts and principles adapted from meaning centered psychotherapy.

METHOD: Within 12 months, RELOAD-C was developed through two rounds of one-on-one interviews with 15 dementia caregivers to obtain feedback on video scripts, recording of videos, and placement of videos and written content (e.g. thought exercises) on the website. Following this, RELOAD-C underwent rigorous usability and acceptability testing by another 16 dementia caregivers.

RESULTS: Quantitative assessments show that RELOAD-C is deemed usable by caregivers (mean = 1.69 on system usability scale, where possible range is 1-5 and lower scores indicate more favorable views of the website; and more than 90% of the usability sample correctly engaged in ≥8 of 10 discreet tasks). Qualitative data indicate acceptability of the intervention with feedback such as "love that the videos are clear and load fast."

CONCLUSIONS: RELOAD-C is a web-based intervention focused on reducing loneliness in dementia caregivers. It contains six therapist-narrated videos and written content, reinforcing MCP principles. It is currently undergoing pilot testing in preparation for a large-scale randomized controlled clinical trial evaluating its efficacy in reducing loneliness in dementia caregivers.},
}

Humans
*Caregivers/psychology
*Alzheimer Disease/psychology/nursing
*Psychotherapy/methods
Male
Female
*Loneliness/psychology
*Dementia/nursing/psychology
Middle Aged
Internet
Aged
Internet-Based Intervention

@article {pmid41118083,
year = {2025},
author = {Kopi, TA and Shanehbandpour-Tabari, F and Arani, RM and Ataie, A and Pouramir, M and Khaleghzadeh-Ahangar, H},
title = {Piperine Prevents Scopolamine-Induced Cognitive Impairment via its Antioxidant and Anti-Inflammatory Roles; Suggesting Potential Modulation of Necroptosis-Related Genes Including MLKL and TNF-α.},
journal = {Journal of molecular neuroscience : MN},
volume = {75},
number = {4},
pages = {142},
pmid = {41118083},
issn = {1559-1166},
support = {724133561//Babol University of Medical Science/ ; },
mesh = {Animals ; *Benzodioxoles/pharmacology/therapeutic use ; *Piperidines/pharmacology/therapeutic use ; Male ; *Alkaloids/pharmacology/therapeutic use ; *Polyunsaturated Alkamides/pharmacology/therapeutic use ; Rats, Wistar ; Rats ; Tumor Necrosis Factor-alpha/genetics/metabolism ; *Cognitive Dysfunction/prevention & control/drug therapy/metabolism/chemically induced ; Necroptosis ; Hippocampus/metabolism/drug effects ; *Antioxidants/pharmacology/therapeutic use ; Scopolamine/toxicity ; *Neuroprotective Agents/pharmacology/therapeutic use ; *Anti-Inflammatory Agents/pharmacology/therapeutic use ; Protein Kinases/genetics/metabolism ; NF-E2-Related Factor 2/genetics/metabolism ; Heme Oxygenase-1/genetics/metabolism ; Caspase 8/genetics/metabolism ; },
abstract = {Alzheimer's disease (AD) is the leading cause of dementia, characterized by cognitive decline and neurodegeneration. Given the limitations of current treatments, research has turned to natural substances such as piperine, which is known for its neuroprotective properties. This study investigates the effects of piperine on cognitive function and genes associated with oxidative stress, inflammation, and necroptosis-related genes in a rat model of cognitive impairment. Fifty adult male Wistar rats were used, divided into five groups: an intact group, a control group (vehicle solution followed by scopolamine), and three experimental groups receiving piperine (5, 10, and 20 mg/kg) followed by scopolamine during the training period. Behavioral assessment was conducted using the Morris Water Maze (MWM) test. Hippocampal tissue was collected after euthanasia for gene expression analysis of Nrf2, HO‑1, TNF‑α, Fas, TRAIL, MLKL, and Caspase‑8. Spatial learning and memory improved significantly in piperine-treated groups, with no impact on swimming velocity, indicating cognitive enhancement without affecting motor functions in the scopolamine-induced cognitive impairment model. Piperine pretreatment prevented oxidative stress and inflammation, as evidenced by the restoration of Nrf2, HO-1, and Caspase-8 and the reduction of TNF-α, Fas, TRAIL, and MLKL expression levels. These findings suggest that piperine has antioxidative, anti‑inflammatory, and cognitive‑enhancing effects, with particular effects possibly on necroptosis, and could be a valuable addition to the current AD treatment paradigm, warranting further investigation in clinical trials.},
}

Animals
*Benzodioxoles/pharmacology/therapeutic use
*Piperidines/pharmacology/therapeutic use
Male
*Alkaloids/pharmacology/therapeutic use
*Polyunsaturated Alkamides/pharmacology/therapeutic use
Rats, Wistar
Rats
Tumor Necrosis Factor-alpha/genetics/metabolism
*Cognitive Dysfunction/prevention & control/drug therapy/metabolism/chemically induced
Necroptosis
Hippocampus/metabolism/drug effects
*Antioxidants/pharmacology/therapeutic use
Scopolamine/toxicity
*Neuroprotective Agents/pharmacology/therapeutic use
*Anti-Inflammatory Agents/pharmacology/therapeutic use
Protein Kinases/genetics/metabolism
NF-E2-Related Factor 2/genetics/metabolism
Heme Oxygenase-1/genetics/metabolism
Caspase 8/genetics/metabolism

@article {pmid41118046,
year = {2025},
author = {Aswinanand, B and Palani, KN and Santhanam, SD and Ramamurthy, K and Palaniappan, S and Arasu, MV and Guru, A and Muthuramamoorthy, M and Kumaradoss, KM and Arockiaraj, J},
title = {Pyrimidine Derivative, (E)-N-[4-(4-Chlorophenyl)-6-(4-Methylphenyl)Pyrimidin-2-yl]-1-(Furan-2-yl)Methanimine, Named BN5 Ameliorates Cognitive Dysfunction and Regulates esr1 and esr2b Expression in Female In Vivo Zebrafish Alzheimer Model.},
journal = {Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology},
volume = {20},
number = {1},
pages = {94},
pmid = {41118046},
issn = {1557-1904},
mesh = {Animals ; Female ; Zebrafish ; *Pyrimidines/pharmacology/therapeutic use ; *Alzheimer Disease/drug therapy/metabolism/genetics ; *Cognitive Dysfunction/drug therapy/metabolism ; *Estrogen Receptor alpha/biosynthesis/genetics ; *Estrogen Receptor beta/biosynthesis/genetics ; Disease Models, Animal ; *Furans/pharmacology/therapeutic use ; *Imines/pharmacology/therapeutic use ; },
abstract = {Alzheimer's disease (AD) is the most common form of dementia, characterized by a progressive decline in cognitive functions. It is more prevalent in women, especially after menopause, likely due to factors like longer life expectancy and hormonal changes. Current therapies focus on cholinesterase inhibitors, but recent studies suggest that pyrimidine derivatives hold promise as multi-target agents targeting complex mechanisms of AD. This study evaluated the potential of a pyrimidine derivative, (E)-N-[4-(4-chlorophenyl)-6-(4-methylphenyl)pyrimidin-2-yl]-1-(furan-2-yl)methanimine (named BN5), in a scopolamine (SCO)-induced female zebrafish model. SCO induces cognitive dysfunction mimicking AD conditions. BN5, particularly at a 60 µM concentration, significantly improved AD-related parameters, including anxiety, memory, shoaling, and social behaviour in vivo. Biochemical analyses supported these findings, as BN5 reversed SCO-induced changes in acetylcholinesterase (AChE) activity and oxidative stress markers, such as superoxide dismutase (SOD), catalase (CAT), glutathione (GSH), glutathione peroxidase (GPx), malondialdehyde (MDA), and γ-Aminobutyric acid (GABA) levels. Additionally, BN5 demonstrated positive regulation of neurotransmitter-related genes such as appb, bdnf, mbpa, and il-1β, essential for neural function and cognitive processes. It also upregulated estrogen receptor genes esr1 and esr2b, which have neuroprotective roles but are often downregulated in postmenopausal women due to hormonal changes. These results highlight the therapeutic potential of BN5, as it alleviates cognitive impairments through Aβ aggregation inhibition and addresses the decline in estrogen receptor activity, providing a targeted treatment option particularly beneficial for females, who are at greater risk of developing AD.},
}

Animals
Female
Zebrafish
*Pyrimidines/pharmacology/therapeutic use
*Alzheimer Disease/drug therapy/metabolism/genetics
*Cognitive Dysfunction/drug therapy/metabolism
*Estrogen Receptor alpha/biosynthesis/genetics
*Estrogen Receptor beta/biosynthesis/genetics
Disease Models, Animal
*Furans/pharmacology/therapeutic use
*Imines/pharmacology/therapeutic use

@article {pmid41117350,
year = {2025},
author = {Khachaturian, Z},
title = {History of Alzheimer's Disease Research Centers: From inception in 1984 to evolution beyond 2025.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {10},
pages = {e70778},
doi = {10.1002/alz.70778},
pmid = {41117350},
issn = {1552-5279},
support = {1975-1982/AG/NIA NIH HHS/United States ; 1983-1991/AG/NIA NIH HHS/United States ; 1978-1995/AG/NIA NIH HHS/United States ; },
mesh = {*Alzheimer Disease/history/therapy ; Humans ; History, 20th Century ; United States ; *Biomedical Research/history ; History, 21st Century ; },
abstract = {This paper reviews the history of the so-called Alzheimer Movement in the United States, the origins of the Alzheimer's Disease Research Centers (ADRC) program, and their critical role in shaping the National Plan to Address Alzheimer's Disease by 2035. The long narration unfolds in three parts: (1) Beginnings, (2) Accomplishments, and (3) Charting the Next Step. HIGHLIGHTS: This paper reviews the history of the Alzheimer movement in the United States, the origins of the ADRC program, and the centers' critical role in shaping the National Plan to Address Alzheimer's Disease by 2035. The long narration unfolds in three parts: (1) Beginnings: Establishing a Foothold, (2) Accomplishments: Key Achievements and Future Lessons, and (3) Charting the Next Step: Rethinking the ADRC's role after 2035. This perspective offers a high-level view of the scientific landscape during the inception of programmatic research in aging and dementia. The story covers the significant challenges involved in starting such an undertaking. It recounts the rationale, intent, achievements, and structure of the ADRCs. The narrative focuses on the politics of science that shaped programs like the ADRC and NACC, particularly through earmarked funding. It explains why the program prioritized the creation of infrastructure and building capacity for longitudinal clinical studies. The discussion of future directions will (1) explain the reasoning for reformulating the mission and structure of the ADRC's concept to accommodate a comprehensive range of emerging needs and (2) explore the role of the re-engineered centers as a catalyst to promote and maintain brain health to prevent cognitive impairments. It will suggest some possible options to restructure some current centers into comprehensive regional centers as instruments to deal with new challenges.},
}

*Alzheimer Disease/history/therapy
Humans
History, 20th Century
United States
*Biomedical Research/history
History, 21st Century

@article {pmid41116989,
year = {2025},
author = {Lei, L and Mei, SY and Lü, Y and Huang, GQ and Lü, PR and Liu, Q and Zhang, N},
title = {[Effect of moxibustion on synaptic plasticity in mice with Alzheimer's disease based on the CaMKⅡ/RyR3 pathway].},
journal = {Zhen ci yan jiu = Acupuncture research},
volume = {50},
number = {10},
pages = {1161-1168},
doi = {10.13702/j.1000-0607.20240673},
pmid = {41116989},
issn = {1000-0607},
mesh = {Animals ; *Alzheimer Disease/therapy/genetics/metabolism/physiopathology/enzymology/psychology ; *Moxibustion ; Mice ; *Neuronal Plasticity ; *Calcium-Calmodulin-Dependent Protein Kinase Type 2/metabolism/genetics ; Male ; Mice, Inbred C57BL ; Humans ; *Ryanodine Receptor Calcium Release Channel/metabolism/genetics ; Acupuncture Points ; Hippocampus/metabolism ; Female ; },
abstract = {OBJECTIVES: To explore the mechanism by which moxibustion promotes synaptic plasticity of hippocampal neurons and improves learning and memory in mice with Alzheimer's disease (AD) based on the calmodulin-dependent protein kinase Ⅱ (CaMKⅡ)/ryanodine receptor (RyR)3 pathway.

METHODS: Forty APP/PS1 mice were randomly divided into the model (n=15), moxibustion (n=25) groups, and 15 C57BL/6J mice served as the blank control group. The mice in the moxibustion group were given moxibustion at the "Baihui"(GV20) and "Yongquan"(KI1) acupoints, 30 minutes each time, once a day. A course of treatment lasted for 5 days, and there were a total of 4 courses of treatment. Ten mice from the moxibustion group were randomly selected as the moxibustion+inhibitor group, and were intraperitoneally injected with the CaMKⅡ protein inhibitor KN-93 (2 mg/100 g) one day before sample collection on the basis of moxibustion. After the treatment, the shuttle box test was used to evaluate the learning and memory ability of the mice. Transmission electron microscopy was used to detect the changes in the ultrastructure of synapses in the CA1 region of the hippocampus. Western blot was used to detect the expression levels of β-amyloid protein (Aβ) and CaMKⅡ protein in the hippocampus of the mice. Immunofluorescence staining was used to detect the positive expression of CaMKⅡ in the hippocampus and the co-expression of RyR3/PSD95.

RESULTS: Compared with the blank control group, the number of active avoidance responses, the protein expression and positive expression of CaMKⅡ in the hippocampus, and the percentage of the co-expression area of RyR3/PSD95 of the mice in the model group were decreased (P<0.01, P<0.05), and the number of synaptic vesicles in the CA1 region of the hippocampus was decreased;while the expression of Aβ protein in the hippocampus was increased (P<0.01). Compared with the model group, the number of active avoidance responses, the protein expression and positive expression of CaMKⅡ in the hippocampus, and the co-expression area percentage of RyR3/PSD95 of the mice in the moxibustion group were increased significantly (P<0.01), and the number of synaptic vesicles in the CA1 region of the hippocampus was increased;while the expression of Aβ protein was decreased (P<0.05). Compared with the moxibustion group, the number of active avoidance, the positive expression of CaMKⅡ and the co-expression area percentage of RyR3/PSD95 in the moxibustion+inhibitor group were decreased (P<0.01), and the number of synaptic vesicles in the CA1 region of the hippocampus was decreased.

CONCLUSIONS: Moxibustion can improve the learning and memory ability of AD model mice, and its mechanism may be related to up-regulating the expression of CaMKⅡ, activating the endoplasmic reticulum RyR3 channel, inducing the release of Ca[2+], and then promoting neuronal synaptic plasticity.},
}

Animals
*Alzheimer Disease/therapy/genetics/metabolism/physiopathology/enzymology/psychology
*Moxibustion
Mice
*Neuronal Plasticity
*Calcium-Calmodulin-Dependent Protein Kinase Type 2/metabolism/genetics
Male
Mice, Inbred C57BL
Humans
*Ryanodine Receptor Calcium Release Channel/metabolism/genetics
Acupuncture Points
Hippocampus/metabolism
Female

@article {pmid41114448,
year = {2025},
author = {Sato, K and Niimi, Y and Ihara, R and Iwata, A and Nemoto, K and Arai, T and Higashi, S and Igarashi, A and Kasuga, K and Akiyama, H and Awata, S and Ikeda, M and Iwatsubo, T},
title = {Real-world lecanemab adoption in Japan 1 year after launch: Insights from 311 specialists on infrastructure and reimbursement barriers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {10},
pages = {e70652},
pmid = {41114448},
issn = {1552-5279},
support = {JPMH23CA2008//MHLW Health Labour Sciences Research Grant/ ; 24GB1001//MHLW Health Labour Sciences Research Grant/ ; JP24K10653//JSPS KAKENHI/ ; JP25K19014//JSPS KAKENHI/ ; JP23dk0207048//AMED Research and Development Grants for Dementia/ ; JP24dk0207054//AMED Research and Development Grants for Dementia/ ; JP24dk0207068//AMED Research and Development Grants for Dementia/ ; //Japan Agency for Medical Research and Development/ ; },
mesh = {Humans ; Japan ; *Alzheimer Disease/drug therapy ; Surveys and Questionnaires ; Male ; *Insurance, Health, Reimbursement ; Female ; },
abstract = {INTRODUCTION: Lecanemab was approved for early Alzheimer's disease in Japan, with ≈ 6000 patients treated in the first year post approval. This study explores real-world practices, challenges, and potential solutions.

METHODS: We conducted an anonymized online survey of clinical specialists authorized to prescribe lecanemab, obtaining responses from 311 specialists who collectively treated 3259 patients with lecanemab.

RESULTS: A majority of respondents (79%) reported wait times of ≤ 3 months from first consultation to initial infusion. One fourth reported tight outpatient space and staffing and significantly lower capacity of treatment than anticipated. Safety concerns were limited, with amyloid imaging-related abnormality-related interruptions in 3.5%. More than half highly supported additional reimbursement for infusion-related services and insurance coverage for apolipoprotein E (APOE) testing.

DISCUSSION: Early access to lecanemab appears feasible, yet infrastructure and financial hurdles remain. Dedicated reimbursement and insurance coverage for APOE testing may be essential for ensuring safer, more accessible, and sustainable use of this therapy in Japan.

HIGHLIGHTS: Results from an online survey of 311 Japanese specialists prescribing lecanemab in its first year are reported. Majority of wait times from first consultation to initial infusion were 1 to 3 months. Tight affordability of infusion space and staffing was reported by one quarter. Establishing additional medical fee for infusion management was highly expected. Reimbursement of apolipoprotein E test in Japanese health insurance system was also demanded.},
}

Humans
Japan
*Alzheimer Disease/drug therapy
Surveys and Questionnaires
Male
*Insurance, Health, Reimbursement
Female

@article {pmid41113923,
year = {2025},
author = {Shine, S and Chandrapragasam, V},
title = {Acetylcholinesterase inhibitory potency of Lactobacillus plantarum fermentation extracts, and antioxidant scavenging effects against LPS-induced nitric oxide production in PC12 cell lines.},
journal = {3 Biotech},
volume = {15},
number = {11},
pages = {393},
pmid = {41113923},
issn = {2190-572X},
abstract = {Nutrient optimization of Lactobacillus plantarum MTCC 1325 with cinnamon (40 µg/mL) and pantothenic acid (4 µg/mL) resulted in a chloroform extract of Media D that exhibited a strong activity profile relevant to the therapeutic approach to Alzheimer's disease. Across 20-100 µg/mL extracts were non-cytotoxic to undifferentiated PC12 cells. Chloroform extract of Media D showed potent radical scavenging [IC50(superoxide) = 41.7 ± 2.1 µg/mL, IC50(NO) = 33.4 ± 1.1 µg/mL], high total phenolics (68.6 ± 1.1 mg GAE/g), and acetylcholinesterase inhibition [IC50 = 33.2 ± 4.2 µg/mL, galantamine (standard) = 22.5 ± 3.2 µg/mL]. Pre-treatment with chloroform extract of Media D reduced LPS-induced cytotoxicity [IC50 = 32.6 ± 3.6 µg/mL] and lowered nitrite accumulation up to 1.69-fold versus LPS. GC-MS of the active fraction resolved six constituents, consistent with lipid and aromatic metabolites. Together, these results support a nutrient-first media design strategy, demonstrating that selective modulation of media composition under fixed incubation parameters can enrich L. plantarum culture-derived metabolites with antioxidants, anti-inflammatory, and AChE inhibitory activities related to the medical management of AD. This is a preliminary in vitro study using one strain and a single-cell model, Extract were crude and tested with modest replication, and library matched GC-MS identification. Mechanistic markers were not quantified, and in vivo validation is warranted.},
}

@article {pmid41111974,
year = {2025},
author = {Woo, HG and Park, MS and Park, JY and Chun, H and Song, TJ},
title = {Association of hemorrhoidal disease with dementia risk: a nationwide cohort study.},
journal = {Frontiers in neurology},
volume = {16},
number = {},
pages = {1655944},
pmid = {41111974},
issn = {1664-2295},
abstract = {INTRODUCTION: Research on the association between hemorrhoidal diseases (HDs) and dementia is limited. We explored this relationship in a population-based longitudinal cohort and proposed that individuals with HD may experience a higher incidence of dementia.

METHODS: Our study included 381,031 participants drawn from results from the South Korean health-screening cohort database, between 2005 and 2010. HD was identified based on at least two claims using the International Classification of Diseases, Tenth Revision (ICD-10) code I84. We used propensity score matching (PSM) to categorize the participants into two groups based on the presence or treatment of HD. The primary outcome was the incidence of all-cause dementia as determined by two or more claims with ICD-10 codes (F00-03, G30, and G31). Secondary outcomes included the occurrence of Alzheimer's (F00 or G30) and vascular dementia (F01).

RESULTS: Over a median follow-up period of 15.49 years (interquartile range: 12.21-18.77 years), the cumulative incidence of all-cause dementia was 80,488 cases (22.47%). Multivariate analysis showed that the group with HD consistently had a higher incidence of all-cause dementia than the group without HD after PSM (hazard ratio [HR], 1.243; 95% confidence interval [CI], 1.199-1.288). Participants who underwent surgical procedures or treatment for HD revealed a significantly lower incidence of all-cause dementia after PSM (HR, 0.925; 95% CI, 0.872-0.981).

DISCUSSION: This study revealed a significantly higher incidence of all-cause dementia among participants with hemorrhoidal disease, suggesting that while hemorrhoidal disease may not directly cause dementia, it may serve as a marker of an underlying systemic condition that increases dementia risk.},
}

@article {pmid41111606,
year = {2025},
author = {Wu, X and Zhang, R and Chen, W and Mei, Y and Hu, Q and Lan, W and Zhang, Y and Ye, Z and Huang, C and Zhu, B},
title = {Preoperative perivascular space burden predicts treatment response to deep cervical lymphovenous anastomosis in Alzheimer's disease: A pilot study.},
journal = {Journal of Alzheimer's disease reports},
volume = {9},
number = {},
pages = {25424823251387366},
pmid = {41111606},
issn = {2542-4823},
abstract = {BACKGROUND: Deep cervical lymphovenous anastomosis (DLVA) shows promise for Alzheimer's disease (AD) treatment, but patient selection criteria remain undefined. Perivascular spaces (PVS) may predict glymphatic enhancement potential.

OBJECTIVE: To investigate whether preoperative magnetic resonance imaging (MRI) measures of PVS burden can predict treatment response to DLVA in AD patients and explore potential mechanisms through longitudinal glymphatic function assessment.

METHODS: Retrospective analysis of 10 AD patients undergoing DLVA. Preoperative T1-weighted MRI quantified PVS volumes using Frangi filtering. Treatment response was assessed at one month using Mini-Mental State Examination/Montreal Cognitive Assessment improvements ≥2 points.

RESULTS: Total PVS volume demonstrated perfect predictive accuracy for treatment response (AUC = 1.000) with an optimal cut-off of 5150 mm³ (sensitivity 100%, specificity 100%). White matter PVS volume also showed strong predictive performance (AUC = 0.875, cut-off 3630 mm³, sensitivity 75%, specificity 100%). The improved group had significantly higher preoperative PVS volumes (total PVS: p = 0.012, Cohen's d = 2.631; white matter PVS: p = 0.050, Cohen's d = 1.689). Preliminary longitudinal analysis revealed divergent Analysis Along the Perivascular Space (ALPS) index changes: the improved group showed mean increase (+0.0276), while the non-improved group demonstrated decrease (-0.0252).

CONCLUSIONS: Preoperative PVS burden serves as a powerful predictor of DLVA response, with higher volumes indicating sufficient anatomical reserve for therapeutic benefit. These findings establish PVS volume as clinically actionable biomarkers for precision patient selection in glymphatic-targeted AD interventions.},
}

@article {pmid41110764,
year = {2025},
author = {Tagad, A and Galatage, ST and Hankuntimath, N and Hugar, S and Raikar, SR and Patil, VP and Arehalli, SM},
title = {Neuroprotective Potential of Green-Synthesized Silver Nanoparticles from Psidium guajava in a Scopolamine-Induced Rat Model of Alzheimer's Disease.},
journal = {Annales pharmaceutiques francaises},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.pharma.2025.10.006},
pmid = {41110764},
issn = {2772-803X},
abstract = {Alzheimer's disease (AD) is a chronic neurodegenerative condition marked by progressive memory decline and cognitive dysfunction, and oxidative stress, with no definitive cure currently available. The present study aimed to develop a plant-based nanotherapeutic approach for AD by synthesizing silver nanoparticles (AgNPs) using the ethanolic leaf extract of Psidium guajava (PG) via a green synthesis method. Formation of PG-AgNPs was confirmed by a characteristic surface plasmon resonance (SPR) peak observed in UV-Visible spectroscopy and a visible colour change to dark brown. The synthesized nanoparticles exhibited a mean particle size of 107 ± 4 nm, a polydispersity index (PDI) of 0.364 ± 0.08, and a zeta potential of -30.7 ± 2.3 mV, indicating good colloidal stability. Energy-dispersive X-ray diffraction (E-XRD) confirmed the crystalline nature and elemental composition of silver. In a scopolamine-induced rat model of AD, treatment with PG-AgNPs significantly improved cognitive performance. Rats treated with PG-AgNPs showed a statistically significant increase (p < 0.001) in spontaneous alternation behaviour, prolonged step-through latency in the passive avoidance test (p < 0.001), and a significant reduction in escape latency time in the Morris Water Maze test (p < 0.001) compared to the disease control group. Biochemical analyses revealed that PG-AgNPs significantly reduced lipid peroxidation (LPO) levels (p < 0.001) and significantly increased catalase (CAT) activity (p < 0.001), indicating strong antioxidant potential. In conclusion, Psidium guajava leaf extract and its green-synthesized silver nanoparticles demonstrated statistically significant neuroprotective, antioxidant, and cognitive-enhancing effects, supporting their potential as a novel therapeutic strategy for the treatment of Alzheimer's disease. Further research is needed to explore and conform their clinical applicability.},
}

@article {pmid41110751,
year = {2025},
author = {Wang, Y and Deng, L and Wang, L and Liu, W},
title = {Schisandrin B combined with vitamin D inhibits NLRP3 inflammasome to improve cognitive dysfunction and Alzheimer's disease.},
journal = {European journal of pharmacology},
volume = {},
number = {},
pages = {178268},
doi = {10.1016/j.ejphar.2025.178268},
pmid = {41110751},
issn = {1879-0712},
abstract = {PURPOSE: This study investigates the therapeutic effects of Schisandrin B (Sch B) combined with vitamin D (VD) on cognitive dysfunction and Alzheimer's disease (AD)-like pathology in aged rats induced by a high-fat and high-sugar (HFHS) diet, with a focus on the inhibition of NLRP3 inflammasome activation as a potential mechanism.

METHODS: Eighteen-week-old male Sprague-Dawley rats were randomly assigned to five groups: Control, HFHS, HFHS+Sch B, HFHS+VD, and HFHS+Sch B+VD. After 20 weeks of treatment, metabolic parameters (body weight, fasting blood glucose, insulin resistance, lipid profiles), inflammatory markers, and hippocampal protein expression were assessed. Cognitive function was evaluated using the Morris water maze, novel object recognition, open field, and elevated plus maze tests.

RESULTS: Combined Sch B and VD markedly attenuated body weight gain, fasting blood glucose, fasting serum insulin, and homeostatic model assessment of insulin resistance (HOMA-IR), while improving lipid profiles (TG, TC, LDL-C). Behavioral tests revealed significant improvements in spatial learning, memory, and object recognition (p < 0.01), with combined therapy outperforming monotherapy. Additionally, the combination downregulated hippocampal NLRP3 inflammasome components (ASC, cleaved caspase-1, IL-1β, IL-18) and reduced pro-inflammatory cytokines (IL-1β, IL-6, TNF-α).

CONCLUSION: In this HFHS diet-induced aging rat model, Sch B combined with VD improved cognitive performance and reduced AD-like lesions, likely via inhibition of NLRP3 inflammasome-mediated neuroinflammation. These findings provide mechanistic insights and support further preclinical evaluation of this combination as a potential strategy for AD prevention and intervention.},
}

@article {pmid41110688,
year = {2025},
author = {Qin, RZ and Peng, SY and Huang, ZX and Zhang, BF and Tang, RN and Zhao, YC and Jiang, FS and Xu, XH and Pan, JL and Li, MY},
title = {Coelonin, an active component extract from Bletilla striata (Thunb.) Reichb.f., alleviates lipopolysaccharide-induced acute lung injury by increasing the expression of non-coding RNA Gm27505 and inhibiting the M1 polarization of macrophages caused by inflammatory responses.},
journal = {The international journal of biochemistry & cell biology},
volume = {},
number = {},
pages = {106871},
doi = {10.1016/j.biocel.2025.106871},
pmid = {41110688},
issn = {1878-5875},
abstract = {Coelonin is a dihydrophenanthrene compound derived from the traditional Chinese medicine Bletilla striata (Thunb.) Reichb.f., which exhibits significant anti-inflammatory activity and effectively inhibits lipopolysaccharide (LPS)-induced inflammatory responses in RAW264.7 cells. Although previous studies have demonstrated the protective effect of Bletilla striata against LPS-induced acute lung injury (ALI), the potential protective role and underlying molecular mechanisms of its major active component, Coelonin, in ALI remain unclear. In this study, an LPS-induced mouse ALI model was established to systematically evaluate the protective effects of Coelonin on ALI. Furthermore, transcriptomic analysis was utilized to investigate the anti-inflammatory mechanisms mediated by Coelonin through the regulation of non-coding RNA (ncRNA)-associated inflammatory pathways. The results indicated that Coelonin significantly ameliorated LPS-induced pathological damage in lung tissues and markedly reduced the levels of inflammatory markers in bronchoalveolar lavage fluid (BALF). In vitro experiments using the murine alveolar macrophages (MH-S) cell line further confirmed the anti-inflammatory activity of Coelonin. Transcriptome analysis revealed that Coelonin markedly upregulates the expression of the ncRNA Gm27505, which was previously found to be downregulated in a mouse model of Alzheimer's disease. To date, there have been no reports on the biological functions of Gm27505. Bioinformatics analysis and real-time quantitative fluorescence PCR (qPCR) confirmed that this ncRNA is primarily localized within the nucleus. Overexpression of Gm27505 in MH-S cells significantly downregulated the expression of inflammation-related genes such as Il6, Tnfα, Il27, and Ccl3 induced by LPS stimulation. Moreover, overexpression of Gm27505 promoted macrophage polarization toward the M2 phenotype while suppressing M1 polarization. These findings suggest that the ncRNA Gm27505 plays an important biological role and is critically involved in the regulation of inflammatory responses. Coelonin may alleviate LPS-induced ALI in mice by up-regulating Gm27505 expression and modulating macrophage polarization. Therefore, Gm27505 may represent a potential target for the prevention and treatment of ALI, providing new research directions for future therapeutic strategies against related diseases.},
}

@article {pmid41110565,
year = {2025},
author = {Lv, H and Liu, Y and Yang, X and Xu, X and Zhou, J and Yu, W},
title = {Research progress on the role of oxidative stress in the pathogenesis of vascular dementia and its treatment.},
journal = {Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association},
volume = {},
number = {},
pages = {108475},
doi = {10.1016/j.jstrokecerebrovasdis.2025.108475},
pmid = {41110565},
issn = {1532-8511},
abstract = {BACKGROUND: Vascular dementia (VaD) is the second most common type of dementia after Alzheimer's disease, imposing a substantial burden on global health. Accumulating evidence indicates that oxidative stress, characterized by an imbalance between reactive oxygen species (ROS) production and antioxidant defense, plays a pivotal role in the pathogenesis of VaD.

OBJECTIVE: This review aims to summarize the latest research progress on the involvement of oxidative stress in the pathogenesis of VaD and explore emerging therapeutic strategies targeting oxidative stress.

RESULTS: Oxidative stress is deeply involved in multiple pathological processes of VaD. Its root cause lies in chronic cerebral hypoperfusion (CCH), which leads to mitochondrial dysfunction and excessive ROS production. Such oxidative damage exacerbates blood-brain barrier (BBB) disruption, neuroinflammation, and neuronal apoptosis, ultimately resulting in cognitive decline. Key molecular mechanisms include the activation of NADPH oxidase, impairment of the Nrf2 antioxidant pathway, and dysregulation of SIRT1. Therapeutic strategies have evolved from traditional antioxidants (e.g., α-lipoic acid) to novel approaches, including targeting the Nrf2/HO-1 pathway (e.g., using saffron-rich GJ-4 extract), regulating mitochondrial function, utilizing natural compounds (e.g., resveratrol acting via SIRT1 activation), and non-pharmacological interventions such as acupuncture. These strategies alleviate oxidative stress through multi-target mechanisms and have demonstrated significant efficacy.

CONCLUSION: The central role of oxidative stress in VaD provides new targets for treatment, but a shift from single-target antioxidant therapy to multi-level intervention is required. Future research should focus on developing targeted antioxidant therapies, exploring combination treatment regimens, and validating biomarkers applicable for early detection and therapeutic efficacy assessment.},
}