@article {pmid41238601,
year = {2025},
author = {Alzarea, SI},
title = {Identification of novel neuraminidase 1 modulators as potential therapeutics for Alzheimer's disease using virtual screening and molecular dynamics simulations.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {39901},
pmid = {41238601},
issn = {2045-2322},
support = {KSRG-2024-340//King Salman Center for Disability Research/ ; },
mesh = {*Neuraminidase/antagonists & inhibitors/metabolism/chemistry ; *Alzheimer Disease/drug therapy/enzymology/metabolism ; Molecular Dynamics Simulation ; Molecular Docking Simulation ; Humans ; *Enzyme Inhibitors/pharmacology/chemistry ; Drug Evaluation, Preclinical ; },
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder caused by the accumulation of β-amyloid (Aβ) plaques and neurofibrillary tangles, resulting in neuronal dysfunction and cognitive decline. The neuraminidase isoenzyme NEU1 is a most ubiquitous mammalian enzyme, involved in various cellular mechanisms. The deficiency of NEU1 has been implicated in the pathophysiology of AD, significantly in amyloid precursor protein (APP) metabolism and Aβ clearance. Despite extensive research, no potent NEU1 modulator has been developed to regulate its activity for therapeutic intervention in AD. The present work aims to identify potential NEU1 modulators from a library of seaweed Metabolites Database through molecular docking, ADMET analysis, and molecular dynamics (MD) simulations. A library of 1,077 seaweed metabolites was screened, identifying 20 active compounds, of which 4 met Lipinski's Rule of Five criteria. ADMET profiling revealed favorable pharmacokinetic properties for BE003, BS032, and RG007, with good blood-brain barrier permeability and bioavailability. Molecular docking demonstrates that BE003, BS032, RG007, and BD039 metabolites exhibited the highest binding affinities for the NEU1 active site. Additionally, MD simulation and MM-GBSA validated the stability of the metabolite-protein complex, with BE003 demonstrating the most stable interactions. Comparative docking against a natural substrate (Neu5Ac) and a NEU1 inhibitor (17f) revealed that BE003 shares significant interaction, RMSD stability profiles with the substrate and loop conformational dynamics while differing from the inhibitor. Our findings emphasize the potential of this modulator as a novel therapeutic target against NEU1 in AD treatment. Further experimental validation and preclinical studies are needed to confirm its efficacy in modulating NEU1 activity.},
}

*Neuraminidase/antagonists & inhibitors/metabolism/chemistry
*Alzheimer Disease/drug therapy/enzymology/metabolism
Molecular Dynamics Simulation
Molecular Docking Simulation
Humans
*Enzyme Inhibitors/pharmacology/chemistry
Drug Evaluation, Preclinical

@article {pmid41238155,
year = {2025},
author = {Heath, AM and Mojabi, FS and Kraybill, EP and Beard, C and Venkataramanan, V and Cuéllar, V and Piekarski, D and McNerney, MW},
title = {Comparison of treatment schedules on cognitive effects of rTMS in the 3xTg-AD model of Alzheimer's disease.},
journal = {Experimental neurology},
volume = {},
number = {},
pages = {115551},
doi = {10.1016/j.expneurol.2025.115551},
pmid = {41238155},
issn = {1090-2430},
abstract = {Repetitive transcranial magnetic stimulation (rTMS) is a promising non-invasive therapy for improving cognition in Alzheimer's disease (AD), but the optimal treatment parameters have yet to be elucidated. One important parameter is the treatment schedule. In this study, we used an established rodent low intensity rTMS stimulation protocol to compare cognitive and biochemical effects of a intensive treatment protocol (daily for 12 days) to a distributed protocol (twice a week for six weeks) in 12-month-old 3xTg-AD mice and B6 controls. We found that both protocols improved object place memory function, but only the distributed protocol improved working memory as measured with the Y-Maze. We did not find any effect of either rTMS protocol on BDNF or amyloid pathology, although these measures correlated well with activity and cognitive performance, suggesting rTMS improvement was independent of these mechanisms. Intensive rTMS increased choline acetyltransferase-positive neurons in the anterior bed nucleus of the stria terminalis (BNST), which may be due to the function of this region in mediating cognitive and limbic circuitry. These results indicate that while both treatment protocols can improve specific aspects of recognition memory, only distributed rTMS improves working memory function, possibly due to causing less cognitive fatigue and physiological stress. Future studies should examine region specific changes relating working memory function and stress related signaling to further understand the mechanisms behind this important rTMS treatment parameter.},
}

@article {pmid41238102,
year = {2025},
author = {Long, J and Liu, S and Shi, Y and Zhang, C and Qin, L and Ai, Q},
title = {Targeting lipid metabolism in neurodegenerative diseases: From experimental to clinical.},
journal = {Metabolism: clinical and experimental},
volume = {},
number = {},
pages = {156436},
doi = {10.1016/j.metabol.2025.156436},
pmid = {41238102},
issn = {1532-8600},
abstract = {The human brain, despite accounting for only 2 % of total body weight, exhibits an exceptionally high lipid content (approximately 20 % of its mass), highlighting the critical role of lipid metabolism in maintaining neural homeostasis and function. Neurodegenerative diseases-including Alzheimer's disease (AD), Parkinson's disease (PD), stroke, Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS)-are characterized by progressive neuronal dysfunction and myelin degeneration. These conditions predominantly affect aging populations and represent a growing global health challenge. While aging remains the primary risk factor, compelling evidence now underscores the involvement of dysregulated lipid metabolism in their pathogenesis. However, the precise mechanisms linking dynamic lipid metabolic alterations to disease progression remain incompletely elucidated. This review systematically examines the multifaceted contributions of lipid metabolism to neurodegenerative processes and critically assesses emerging therapeutic strategies that target lipid pathways for the treatment of neurodegenerative disorders.},
}

@article {pmid41238077,
year = {2025},
author = {Ancy, PM and Sumithra, M},
title = {Development and optimization of flavonoid-enriched solid lipid nanoparticles of Peperomia Pellucida for enhanced brain delivery in Alzheimer's disease: A Quality by Design approach.},
journal = {Annales pharmaceutiques francaises},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.pharma.2025.11.003},
pmid = {41238077},
issn = {2772-803X},
abstract = {OBJECTIVES: The Peperomia pellucida plant exhibits notable neuroprotective potential but has low oral bioavailability in the brain. Herein, we aimed to enhance the oral bioavailability and brain distribution of Peperomia Pellucida, by formulating its flavonoid-enriched fraction into solid lipid nanoparticles as a potential therapeutic approach for Alzheimer' disease.

MATERIALS AND METHODS: Flavonoid-enriched solid lipid nanoparticles of Peperomia pellucida were formulated using an ultrasonication method. A Box-Behnken design was utilized to optimize particle size, entrapment efficiency, and burst release. The optimized formulation was identified via numerical and graphical optimization, and validated through reproducibility studies. Further characterization included scanning electron microscopy and in vivo drug release studies in rats.

RESULTS: Glycerol tripalmitate-based solid lipid nanoparticles exhibited superior entrapment efficiency and reduced burst release. The mean particle size of the solid lipid nanoparticles ranged 110-884 nm, with entrapment efficiency ranging 55-94%. Oral administration of the optimized formulation significantly improved bioavailability in rats and enhanced drug distribution in the cortex and hippocampus of the brain.

CONCLUSION: The results highlight the potential of solid lipid nanoparticles as an effective delivery system for the flavonoid-enriched fraction of Peperomia Pellucida, enhancing its therapeutic impact in the treatment of Alzheimer's disease.},
}

@article {pmid41237463,
year = {2025},
author = {Cho, E and Yi, JH and Jeon, SJ and Kim, DH and Kwon, H and Jeon, J and Kwon, KJ and Jang, DP and Moon, M and Shin, CY and Kim, DH},
title = {Increases in brain catecholamine levels counteract memory deficits and reduces Aβ deposition in 5XFAD male mice.},
journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie},
volume = {193},
number = {},
pages = {118764},
doi = {10.1016/j.biopha.2025.118764},
pmid = {41237463},
issn = {1950-6007},
abstract = {Alzheimer's disease (AD) is a degenerative brain disease that presents with neurological symptoms and memory loss, with no clear treatment. Catecholamines, including dopamine, epinephrine, and norepinephrine, can inhibit or degrade the abnormal aggregation of proteins that cause diseases; however, developing these catecholamines as medication is difficult. This study aimed to demonstrate that increasing the levels of catecholamines in the brain may help improve symptoms of AD. We tested whether an increase in catecholamines by bupropion, a dopamine and norepinephrine re-uptake inhibitor, improves the symptoms of AD. Dopamine and norepinephrine showed similar effects in inhibiting amyloid β (Aβ) aggregation and the decomposition of Aβ aggregates as curcumin, a positive control. Dopamine and norepinephrine blocked Aβ aggregates-induced abnormal hippocampal long-term potentiation. The intraperitoneal administration of bupropion increased the concentrations of dopamine and norepinephrine in the hippocampus from 1 to 6 h after administration. In the Aβ-induced memory decline model, bupropion showed a dose-dependent improvement in learning and memory. In 5XFAD mice administered bupropion for 2 months, significant improvements in memory and Aβ deposition were also found compared to vehicle-treated 5XFAD mice. These results suggest that the symptoms of AD can be improved or delayed by increasing the amount of dopamine and norepinephrine using bupropion.},
}

@article {pmid41237058,
year = {2025},
author = {Xu, F and Wang, J and Gao, P and Li, D and Liu, X},
title = {Neuroprotective Effects of Triterpenoids From Rosa laevigata Root: Identification, Molecular Docking, and In Vitro Evaluation for Alzheimer's Disease Treatment.},
journal = {Chemistry & biodiversity},
volume = {},
number = {},
pages = {e02742},
doi = {10.1002/cbdv.202502742},
pmid = {41237058},
issn = {1612-1880},
abstract = {This study investigates the neuroprotective effects of triterpenoid compounds from Rosa laevigata Michx. roots against Alzheimer's disease (AD). A total of 62 compounds were identified using ultra-performance liquid chromatography-Orbitrap-tandem mass spectrometry analysis, which included 55 triterpenoids and seven flavonoids. Among 15 isolated compounds, compound 13 demonstrated the strongest acetylcholinesterase (AChE) inhibitory activity, with an IC50 of 3.38 µmol/L, and a maximum inhibition rate of 87.20%. Compound 13 exhibited favorable and stable binding with AChE in molecular docking studies, whilst demonstrating mixed-type inhibition in enzyme kinetics. In the H2O2-induced SH-SY5Y cell model, compound 13 exhibited 84.45% viability at 25 µmol/L, surpassing Trolox's 74.16%. Research indicates that R. laevigata Michx. root triterpenes exert neuroprotective effects through AChE inhibition and antioxidant activity, with compound 13 potentially serving as a multi-target lead compound for treating AD.},
}

@article {pmid41236865,
year = {2025},
author = {Hanyu, H and Koyama, Y and Momose, T and Watanabe, S},
title = {Patient With Mild Alzheimer's Disease Homozygous for ApoE ε4 Showing Improved Cognition, No Brain Volume Loss, and Complete Amyloid Clearance After Lecanemab Treatment.},
journal = {Geriatrics & gerontology international},
volume = {},
number = {},
pages = {},
doi = {10.1111/ggi.70251},
pmid = {41236865},
issn = {1447-0594},
}

@article {pmid41236362,
year = {2025},
author = {Zide, BS and Barker, MS and Silverman, HE and Manoochehri, M and Fremont, R and Stein, C and Kunicki, ZJ and Lee, S and Devanand, DP and Huey, ED},
title = {Feasibility and tolerability of low-dose lithium for the treatment of agitation and abnormal motor behaviors in Frontotemporal Dementia.},
journal = {International review of psychiatry (Abingdon, England)},
volume = {},
number = {},
pages = {1-11},
doi = {10.1080/09540261.2025.2572365},
pmid = {41236362},
issn = {1369-1627},
abstract = {Agitation and abnormal motor behaviors are common, distressing symptoms of Frontotemporal Dementia (FTD). While these symptoms currently lack efficacious and safe pharmacological treatments, case reports in FTD and a clinical trial in Alzheimer's disease suggest that patients may benefit from lithium treatment. We designed a randomized, double-blind, placebo-controlled, 12-week clinical trial to evaluate low-dose lithium for the treatment of agitation and abnormal motor behaviors in FTD. However, the trial did not meet its recruitment target (n = 60). This report assesses the trial's feasibility and tolerability using recruitment, study completion, and safety metrics. Sixteen adults with FTD (median age 59.5 years; 69% female) were enrolled from 2017 to 2021. Fourteen participants (88%) completed the trial. The majority of participants on lithium were taking the maximum daily dose by Week 12 (600 mg), had median (interquartile range) final serum lithium levels of 0.42 (0.37-0.57), and reported minimal side effects, including drowsiness, diarrhea, constipation and insomnia. Preliminary data from intended efficacy outcomes showed no median pre-post changes between treatment groups. Low-dose lithium is feasible and well-tolerated in an FTD population. Further systematic study of lithium and its efficacy to treat agitation and abnormal motor behaviors in FTD is warranted.},
}

@article {pmid41235150,
year = {2025},
author = {Nigdelioglu Dolanbay, S},
title = {Monoterpene-rich essential oil from Artemisia santonicum L. exerts neuroprotective effects in Aβ-induced SH-SY5Y cells: Modulation of tau pathology, neuroinflammation, oxidative stress, and synaptic-metabolic pathways.},
journal = {Toxicology research},
volume = {14},
number = {6},
pages = {tfaf155},
pmid = {41235150},
issn = {2045-452X},
abstract = {Understanding the complex biological mechanisms of ad requires innovative treatment approaches for this disease. In this context, natural compounds, especially monoterpenes, attract attention with their potential for biological activity. In this study, the therapeutic potential of monoterpene rich essential oil obtained from Artemisia santonicum L. for the treatment of ad was comprehensively evaluated. GC-MS analysis showed that the major monoterpenes were limonene, camphor, pinene, terpineol, and carvone in essential oil obtained from A. santonicum L. Possible common targets of monoterpenes with ad were predicted and their PPI networks were analyzed. Furthermore, gene set enrichment analysis was applied to understand the functional roles of these possible common targets and their relationships with biological pathways. Molecular docking studies revealed the binding affinities and interaction abilities of monoterpenes with the predicted possible common targets. The monoterpene rich essential oil obtained from A. santonicum L. used in our study provides a neuroprotective effect by targeting the pathological mechanisms of ad. We designed in vitro experiments to elucidate the mechanism of the mentioned neuroprotective effect. Within the scope of the study, neuroprotective effect analyses were performed to evaluate cell viability rates and in vitro AChE enzyme activity, while the ELISA method was used to determine phosphorylated tau levels and to assess neuroinflammatory responses. In addition, apoptosis levels, MMP changes and intracellular ROS accumulation were examined by flow cytometry analyses. These comprehensive analyses aimed to reveal the molecular mechanisms of the neuroprotective effect of monoterpene rich essential oil obtained from A. santonicum L. and to shed light on its potential therapeutic applications in ad.},
}

@article {pmid41235113,
year = {2025},
author = {Zampieri, TT and Higa, GSV and Borges, FS and Viana, FJC and Cruvinel, E and Bentivoglio, LE and Lugao, AB and Ulrich, H and Britto, LR and Katti, KV and Chesne, AM and de Pasquale, R},
title = {Exposure to β-hydroxybutyrate reduces the operating set point and increases excitability in hippocampal circuitry of healthy mice.},
journal = {Frontiers in pharmacology},
volume = {16},
number = {},
pages = {1557612},
pmid = {41235113},
issn = {1663-9812},
abstract = {The ketogenic diet is a therapeutic strategy applied to reduce brain hyperexcitability in conditions such as epilepsy, Parkinson's and Alzheimer's disease, migraines, and autism. This diet reduces circulating glucose levels and increases ketone bodies, with β-hydroxybutyrate (BHB) being one of the leading promoters of the beneficial effects. BHB was previously reported as a mediator of cognitive restoration and memory formation. Herein, we investigate the effect of exogenous BHB on hippocampal neuronal excitability and synaptic plasticity mechanisms, regardless of the pathological or neurodegenerative conditions. Electrophysiological experiments were conducted to explore both passive and active neuronal properties, including action potential firing and spontaneous and evoked postsynaptic responses. Electrical stimulation along the CA3-CA1 pathway enabled the assessment of both short- and long-term synaptic plasticity, as well as the mechanisms mediated by AMPA and NMDA receptors. Experiments were conducted in hippocampal slices treated with 3-β-hydroxybutyrate glycerides (DHB) and niacin (HCAR2 agonist). Although DHB incubation did not alter passive membrane properties, it significantly increased neuronal excitability, reflected in an elevated firing rate upon depolarizing stimulation and enhanced spontaneous excitatory postsynaptic currents in CA1 pyramidal neurons, which were dependent on synaptic inputs. DHB treatment led to a reduction in long-term potentiation (LTP) in CA1 neurons, suggesting a metaplastic effect independent of NMDA receptor activation. Importantly, these DHB-induced neuronal alterations were found to be independent of HCAR2 receptor activation, supporting the involvement of distinct intracellular pathways and long-term modulatory mechanisms. Our findings indicate that DHB exerts a modulatory effect on hippocampal neural activity by enhancing excitability and concurrently promoting a compensatory reduction in LTP, suggesting a homeostatic balancing mechanism.},
}

@article {pmid41234939,
year = {2025},
author = {Wang, R and Peng, S and Zhu, J and Xu, Y and Wang, M and Zhang, L and Qiu, Y and Hou, D and Wang, Q and Liu, R},
title = {Innovations in Alzheimer's disease diagnostic technologies: clinical prospects of novel biomarkers, multimodal integration, and non-invasive detection.},
journal = {Frontiers in neurology},
volume = {16},
number = {},
pages = {1651708},
pmid = {41234939},
issn = {1664-2295},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the deposition of β-amyloid (Aβ) plaques and the formation of neurofibrillary tangles composed of hyperphosphorylated tau protein, ultimately leading to cognitive decline and neuronal loss. Current diagnostic methods, including clinical evaluations, neuroimaging examinations, and cerebrospinal fluid biomarker testing, face challenges such as insufficient sensitivity and specificity, as well as operational complexity. In recent years, significant advancements have been made in diagnostic technologies, with the emergence of new biomarkers and detection methods, including blood-based Aβ and tau protein detection, ocular biomarker testing, and non-invasive screening through urine or breath analysis. These innovative developments, combined with multimodal diagnostic technologies that integrate imaging, genomics, and proteomics, have opened new possibilities for the early diagnosis and precise staging of Alzheimer's disease. Furthermore, advancements in microfluidic chips and biosensor technologies have enhanced the capability for rapid, efficient, and cost-effective diagnosis. As research continues to evolve, the gradual application of these advanced technologies in clinical practice is expected to revolutionize the management of Alzheimer's disease, facilitating early intervention and the formulation of individualized treatment strategies.},
}

@article {pmid41234220,
year = {2025},
author = {Fujishiro, H and Kawakami, I and Oshima, K and Torii, Y and Arafuka, S and Iritani, S and Ikeda, K},
title = {Systematized delusions in a patient with covert hepatic encephalopathy: A clinicopathological insight into prodromal dementia with Lewy bodies.},
journal = {PCN reports : psychiatry and clinical neurosciences},
volume = {4},
number = {4},
pages = {e70247},
pmid = {41234220},
issn = {2769-2558},
abstract = {BACKGROUND: Late-onset psychosis is an early clinical manifestation of psychiatric-onset prodromal dementia with Lewy bodies (DLB); however, its underlying neuropathology remains poorly understood. Clinicopathological correlations are often limited by the gap between symptom onset and the autopsy.

CASE PRESENTATION: A 66-year-old man with autopsy-confirmed DLB presented with persistent systematized delusions. After treatment for liver cirrhosis during hospitalization, the patient's physical symptoms improved; however, persecutory delusions developed. The patient was clinically diagnosed with covert hepatic encephalopathy (HE). The delusions were atypical for covert HE, suspecting delusional disorder. His systematized delusions persisted for 3 months until his death, without the development of cognitive decline or Parkinsonism during his lifetime. An autopsy revealed an early transitional type of Lewy body disease with minimal Alzheimer's type II astrocytes indicative of HE. Severe neuronal loss was observed in the locus coeruleus (LC), while the substantia nigra (SN) and nucleus basalis of Meynert (nbM) were preserved. Abundant alpha-synuclein-positive structures were identified in the LC, periaqueductal gray matter, nbM, amygdala, and thalamus, with sparse involvement of the SN, neocortex, peripheral autonomic nervous system, including the heart and gastrointestinal tract.

CONCLUSION: Selective Lewy body involvement, sparing the SN and neocortex, may explain the isolated psychiatric symptoms in the absence of Parkinsonism or dementia. Systemic conditions such as covert HE may have contributed to the emergence of persistent delusions. This case highlights the need for multidisciplinary approaches that integrate psychosomatic assessments with neuropathological investigations to evaluate late-onset psychosis.},
}

@article {pmid41233409,
year = {2025},
author = {Lai, Y and Zhao, H},
title = {Therapeutic efficacy of rehmannioside A on 5×FAD mice in Alzheimer's disease.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {39825},
pmid = {41233409},
issn = {2045-2322},
mesh = {Animals ; *Alzheimer Disease/drug therapy/pathology/metabolism ; Mice ; Oxidative Stress/drug effects ; Disease Models, Animal ; *Neuroprotective Agents/pharmacology/therapeutic use ; Hippocampus/drug effects/metabolism/pathology ; Male ; *Saponins/pharmacology/therapeutic use ; Amyloid beta-Peptides/metabolism ; Memory/drug effects ; Mice, Transgenic ; Plaque, Amyloid/drug therapy/pathology ; Drugs, Chinese Herbal ; },
abstract = {Alzheimer's disease (AD), characterized by Aβ plaques and cognitive decline, remains a significant therapeutic challenge due to limited efficacy of current pharmacotherapies, while Rehmannioside A (ReA) has shown promising neuroprotective effects against neurodegenerative diseases. This research focuses on investigating the therapeutic effects of ReA on 5×FAD mice, emphasizing its potential application in AD treatment. The 5×FAD mice were divided into experimental groups and treated with ReA at varied dosages or donepezil for a twelve-week continuous treatment period. A series of evaluation methods, including behavioral tests, histopathological analysis, Western blotting, and measurement of oxidative and inflammatory markers, were implemented. The findings demonstrated that optimal ReA doses significantly improved learning, memory, and cognitive functions in 5×FAD mice, reduced Aβ plaque accumulation in the hippocampus, decreased microglial cell counts, increased PSD 95 and synapsin-1 protein expression, mitigated oxidative stress and inflammation, and showed no harmful effects on liver or kidney function. ReA's diverse biological activities suggest its potential in reducing neural damage. More extensive studies are needed to fully understand its molecular mechanisms in AD, which could lead to the development of innovative and effective treatments for this severe neurodegenerative condition.},
}

Animals
*Alzheimer Disease/drug therapy/pathology/metabolism
Mice
Oxidative Stress/drug effects
Disease Models, Animal
*Neuroprotective Agents/pharmacology/therapeutic use
Hippocampus/drug effects/metabolism/pathology
Male
*Saponins/pharmacology/therapeutic use
Amyloid beta-Peptides/metabolism
Memory/drug effects
Mice, Transgenic
Plaque, Amyloid/drug therapy/pathology
Drugs, Chinese Herbal

@article {pmid41233403,
year = {2025},
author = {Kovač, V and Huntosova, V and Fedorova, V and Georgiou, N and Lai, JZ and Chien, FC and Chen, SJ and Dolenec, F and Siposova, K},
title = {Unraveling the structure-activity relationships of organometallic ferrocene-pyrazole and ferrocene-pyrimidine curcumin analogues in amyloid-β aggregation and glioblastoma treatment.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {39867},
pmid = {41233403},
issn = {2045-2322},
support = {HRZZ-IP-2020-02-9162//Hrvatska Zaklada za Znanost/ ; No. 09-I02-03-V01-00021//NextGenerationEU/ ; SAS-NSTC-JRP-2024-03_SUPRA-SIGHT//Slovenská Akadémia Vied/ ; 2/0034/22//Vedecká Grantová Agentúra MŠVVaŠ SR a SAV/ ; No.101007642; PhytoApp//European Union's Horizon 2020 Research and Innovation programme/ ; },
mesh = {Humans ; *Ferrous Compounds/chemistry/pharmacology ; *Glioblastoma/drug therapy/metabolism/pathology ; *Metallocenes/chemistry/pharmacology ; *Curcumin/pharmacology/chemistry/analogs & derivatives ; *Amyloid beta-Peptides/metabolism/chemistry ; *Pyrazoles/chemistry/pharmacology ; *Pyrimidines/chemistry/pharmacology ; Structure-Activity Relationship ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Apoptosis/drug effects ; Protein Aggregates/drug effects ; Cell Survival/drug effects ; *Protein Aggregation, Pathological/drug therapy/metabolism ; },
abstract = {Neurodegenerative and oncological disorders, such as Alzheimer's disease (AD) and glioblastoma (GBM), are major global health challenges. Recent evidence indicates shared molecular mechanisms between these diseases, including dysregulated oxidative stress, mitochondrial dysfunction, and protein aggregation. We hypothesized that ferrocene-containing curcumin derivatives could exert dual-functional effects by simultaneously modulating amyloid-β (Aβ) aggregation and inhibiting glioblastoma cell proliferation. This study explores organometallic ferrocene compounds linked to four pyrazole and two pyrimidine analogues of curcumin with different substituents for their effects on amyloid-β-peptide (Aβ) aggregation and glioblastoma. To test this, pyrazole (FcPy-Cur-H, FcPy-Cur-COPh, FcPy-Cur-COFc, FcPy-Cur-Me) and pyrimidine (FcPyn-Cur-O, FcPyn-Cur-S) analogues were synthesized and evaluated. Thioflavin T fluorescence, atomic force microscopy, and single-molecule localization microscopy revealed structure-dependent inhibition of Aβ fibrillogenesis, with FcPyn-Cur-O, FcPyn-Cur-S, and FcPy-Cur-H showing the strongest anti-amyloidogenic activity. Concurrently, these derivatives reduced U87MG glioblastoma cell viability in a dose-dependent manner, inducing apoptotic features, mitochondrial disruption, and α-tubulin destabilization. Our results demonstrate that specific structural modifications of ferrocene-curcumin analogues enhance their dual anti-amyloidogenic and anticancer activities, highlighting the therapeutic potential of multifunctional compounds. This study provides a conceptual advance by combining neurodegenerative and oncological targets within a single chemical framework, offering a promising strategy for the development of multitargeted therapeutics for complex brain disorders.},
}

Humans
*Ferrous Compounds/chemistry/pharmacology
*Glioblastoma/drug therapy/metabolism/pathology
*Metallocenes/chemistry/pharmacology
*Curcumin/pharmacology/chemistry/analogs & derivatives
*Amyloid beta-Peptides/metabolism/chemistry
*Pyrazoles/chemistry/pharmacology
*Pyrimidines/chemistry/pharmacology
Structure-Activity Relationship
Cell Line, Tumor
Cell Proliferation/drug effects
Apoptosis/drug effects
Protein Aggregates/drug effects
Cell Survival/drug effects
*Protein Aggregation, Pathological/drug therapy/metabolism

@article {pmid41233387,
year = {2025},
author = {Park, JS and Kim, S and Jeong, D and Choi, JP and Jeong, H and Park, AJ and Kim, YS and Lee, J and Kim, SH},
title = {Dementia in older adults with schizophrenia: a 12-year analysis of prevalence, incidence, and treatment patterns in South Korea.},
journal = {Schizophrenia (Heidelberg, Germany)},
volume = {11},
number = {1},
pages = {134},
pmid = {41233387},
issn = {2754-6993},
abstract = {Older adults with schizophrenia face a significantly elevated risk of dementia. However, recent trends remain unclear within South Korea's rapidly aging schizophrenia population. This study aimed to quantify the burden of dementia in older schizophrenia patients by examining prevalence, incidence, dementia subtypes, pharmacologic treatment, and healthcare utilization. Using nationwide Health Insurance Review and Assessment (HIRA) data from 2010 to 2021, we identified 220,378 individuals aged ≥50 with schizophrenia. Dementia was diagnosed in 14.6% of patients, with 20.7% of cases occurring before age 60. Patients with dementia were more likely to be female and to have a higher comorbidity burden. Age-standardized all-cause dementia prevalence rose from 11.8% (2010) to 15.8% (2021) in those aged ≥50, and from 24.2% to 32.8% in those aged ≥65-exceeding estimates in the general population. In contrast, incidence declined from 3.4% to 1.7% over the same period. Alzheimer's disease (AD) was the most prevalent subtype (12.2%), followed by vascular dementia (VD, 2.4%), and frontotemporal dementia (0.5%). A lower AD/VD prevalence ratio in schizophrenia (5.3 vs. 8.6 in the general population) suggests a relatively higher burden of vascular pathology. Cognitive enhancer prescriptions increased from 62% to 77% in patients with dementia, compared to 4% to 10% in those without dementia. In 2021, those with dementia were more likely to live in nursing homes (68% vs. 56%) and had greater annual increases in psychiatric hospitalization duration (+2.30 vs. +1.11 days/year). These findings underscore growing care demands and need for integrated treatment strategies for aging schizophrenia patients with dementia.},
}

@article {pmid41233182,
year = {2025},
author = {Nakayama, H},
title = {[Brain Pathology of Cognitive Dysfunction in Aged Non-human Animals].},
journal = {Brain and nerve = Shinkei kenkyu no shinpo},
volume = {77},
number = {11},
pages = {1241-1247},
doi = {10.11477/mf.188160960770111241},
pmid = {41233182},
issn = {1881-6096},
mesh = {Animals ; *Cognitive Dysfunction/pathology ; *Brain/pathology/metabolism ; *Aging/pathology ; Humans ; Alzheimer Disease/pathology ; Cats ; Amyloid beta-Peptides/metabolism ; },
abstract = {Cognitive dysfunction, characterized by the deposition of amyloid β (Aβ), such as senile plaque (SP) and cerebral amyloid angiopathy (CAA), and phosphorylated tau are observed in several animal species, including primates, dogs, and cats, suggesting that these disorders are universal age-related phenomena in vertebrates. Additionally, argyrophilic neurofibrillary tangles positive for phosphorylated tau have been observed in primates, marine mammals, and felines. Recent findings regarding the pathology of cognitive dysfunction in aged non-human animals provide valuable information from a comparative perspective for advancing research on the pathogenesis, diagnosis, and treatment of Alzheimer's disease.},
}

Animals
*Cognitive Dysfunction/pathology
*Brain/pathology/metabolism
*Aging/pathology
Humans
Alzheimer Disease/pathology
Cats
Amyloid beta-Peptides/metabolism

@article {pmid41233181,
year = {2025},
author = {Yoshiyama, K},
title = {[Agitation].},
journal = {Brain and nerve = Shinkei kenkyu no shinpo},
volume = {77},
number = {11},
pages = {1231-1240},
doi = {10.11477/mf.188160960770111231},
pmid = {41233181},
issn = {1881-6096},
mesh = {Humans ; *Dementia/therapy/complications ; *Psychomotor Agitation/therapy/etiology ; },
abstract = {Agitation is a behavioral and psychological symptom of dementia (BPSD); however, until recently, there has been no consensus-based definition. When initiating therapeutic interventions, the type of dementia that is the cause of the BPSD must be considered and treatment must be tailored accordingly. As with other types of BPSD, non-pharmacological interventions are considered the first-line treatment for agitation, unless the symptoms present an exceptional level of urgency. Person-centered care is effective as a non-pharmacological intervention for agitation. Other examples include music therapy, animal-assisted therapy, and aromatherapy; however, these are not very effective for agitation. Useful information on non-pharmacological interventions for agitation can be obtained from the website "Ninchisho Chienowa-net," which is a web-based system that collects information on the coping strategies of caregivers for BPSD. If non-pharmacological interventions are ineffective or the symptoms are urgent, pharmacological treatment should be considered. Brexpiprazole has been approved as effective for agitation in Alzheimer's disease. For the treatment of agitation, medications other than brexpiprazole are frequently used in clinical settings and may offer some degree of efficacy.},
}

Humans
*Dementia/therapy/complications
*Psychomotor Agitation/therapy/etiology

@article {pmid41232717,
year = {2025},
author = {Castellano Candalija, A and Díez Porres, L and Notario Leo, H and Roca Martiartu, A and Mayoral Canalejas, N and Alonso Babarro, A},
title = {Prevalence and decision-making in advanced dementia.},
journal = {Revista clinica espanola},
volume = {},
number = {},
pages = {502388},
doi = {10.1016/j.rceng.2025.502388},
pmid = {41232717},
issn = {2254-8874},
abstract = {INTRODUCTION: Dementia is a chronic neurodegenerative disease with a high prevalence and economic cost. Our objective was to evaluate the prevalence of advanced dementia (AD) in patients hospitalized in the Internal Medicine service; to analyze the therapeutic and diagnostic measures implemented, the degree of adequacy of the therapeutic effort and the information of the family.

METHODOLOGY: Descriptive study that included a retrospective analysis of medical records and a telephone interview with family. Patients with GDS 6-7 dementia admitted to Internal Medicine were included, for 3 weeks in 3 different months.

RESULTS: 194 (22%) patients with dementia were included. The prevalence of admissions with AD was 11%. The median age was 87.5 years (QR 81.75-93), 65% women. 45% came from residence for the elderly. The most frequent etiology was Alzheimer's (48%). The most frequent cause of admission was infection (72%). 37% died. Regarding the measures implemented: 100% were treatment intravenous; 89% received anticoagulation; 26% received artificial nutrition; 81% received pharmacological restraint and 63% physical restraint; and 48% underwent invasive diagnostic tests. Regarding adequacy: lipid-lowering treatment was withdrawn in 19%, antidementia drugs in 23%, anticoagulation in 21%; cardiopulmonary resuscitation was not performed in 30%, adequacy of care in 34%, and 13% were assessed by Palliative Care. A telephone interview was conducted with 55 patients. 42% were not aware of any complications. Care planning was carried out in 2 patients.

CONCLUSIONS: The prevalence of admission to AD is high, and almost half of the patients come from residence for the elderly. Associated mortality is high and therapeutic adequacy and planning are very scarce.},
}

@article {pmid41232709,
year = {2025},
author = {Zhou, W and Qu, R and Luo, W and Zhang, H and Gong, L and , },
title = {Identification of cognitive brain diseases using a dual-branch siamese network on structural magnetic resonance imaging data.},
journal = {Neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuroscience.2025.11.011},
pmid = {41232709},
issn = {1873-7544},
abstract = {Early diagnosis of Alzheimer's Disease is crucial for optimizing treatment efficacy, as delayed detection often limits therapeutic outcomes. Traditional diagnostic approaches, such as cognitive assessments, PET scans, and lumbar punctures, are often invasive, costly, and less accessible. To address these limitations, we propose a Dual-Branch Siamese Network aimed at enhancing the classification accuracy of Alzheimer's Disease, Mild Cognitive Impairment, and Cognitively Normal individuals using structural MRI data. Our model integrates neuroimaging features from both Subcortical Segmentation and Cortical Parcellation, leveraging their complementary strengths to improve diagnostic precision. Experimental evaluations demonstrate that our model achieves a classification accuracy of 93% on the original dataset. To further validate the model's generalizability, we tested the trained model on a separate independent test set from the new ADNI4 database (N=191). On this independent cohort, the model achieved a robust classification accuracy of 88.48%, demonstrating its potential for real-world application. Additionally, by implementing network pruning, we reduced the model's complexity by 60% without sacrificing accuracy, thereby enhancing its feasibility for clinical use. Compared to other methods, such as convolutional neural networks and ensemble learning systems, our model demonstrates superior accuracy in multi-class classification and remains competitive in binary classification tasks. Notably, our pruned model balances accuracy with efficiency, outperforming other models in terms of computational feasibility without compromising diagnostic precision. These findings highlight the potential of our approach to facilitate early diagnosis and intervention for neurodegenerative diseases like Alzheimer's Disease.},
}

@article {pmid41232397,
year = {2025},
author = {Zuo, Y and Ding, X and Sun, Y and Wang, L and Song, Y and Zhao, Z and Liu, C},
title = {Critical nodes in precision diagnosis and treatment of Alzheimer's disease: exploration of multidimensional biomarkers and prospects for targeted intervention.},
journal = {Journal of the neurological sciences},
volume = {479},
number = {},
pages = {123734},
doi = {10.1016/j.jns.2025.123734},
pmid = {41232397},
issn = {1878-5883},
abstract = {Alzheimer' s disease (AD), characterized by cognitive decline and progressive neurodegeneration, remains a major clinical and scientific challenge due to its complex pathophysiology and marked heterogeneity. Important signs of the disease, like the buildup of β-amyloid, changes in Tau proteins, inflammation in the brain, and problems with mitochondria, form the basis for developing targeted treatments. This review summarizes recent advances in the identification of therapeutic targets and multi-dimensional biomarkers, such as liquid, imaging, and multi-omics-based markers. These biomarkers hold potential for early diagnosis, disease subtyping, and therapeutic response monitoring. We suggest that combining biomarkers and treatment targets could be a key approach to improving personalized care for AD.},
}

@article {pmid41232357,
year = {2025},
author = {Castillo-Moral, Á and Tchoumtchoua, J and Leonard, K and Del Bas, JM and Ortega, N and Escoté, X and Teichenné, J},
title = {Neuroprotective effects of polyphenol-rich extracts obtained from agricultural by-products in an induced cognitive decline model of zebrafish larvae and in human neurons.},
journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie},
volume = {193},
number = {},
pages = {118776},
doi = {10.1016/j.biopha.2025.118776},
pmid = {41232357},
issn = {1950-6007},
abstract = {Neurodegenerative diseases are closely associated with chronic neuroinflammation and oxidative stress, which contribute to progressive neuronal dysfunction and cell death. Due to their antioxidant and anti-inflammatory properties, polyphenols have gained attention as potential neuroprotective agents. Agricultural by-products represent a promising and sustainable source of polyphenols, yet their neuroprotective value remains underexplored. In this study, we evaluated four polyphenol-rich extracts derived from red onion peels (ROPE), olive pruning (OPE), vineyard pruning (VPE) and chicory leaves (CLE), obtained by subcritical water extraction. Their effects were tested in two complementary models of neurodegeneration: in vitro human neurons (SH-SY5Y cells) exposed to D-galactose and a basic cognitive decline model of zebrafish larvae exposed to aluminium chloride (AlCl3). All extracts exhibited anti-inflammatory effects in vitro, significantly reducing IL-1β and IL-8 mRNA expression, at doses ranging 12.5-50 μg/mL in cell medium. In the zebrafish model, treatment with 100 μg/mL ROPE or VPE in medium restored the normal sensorimotor pattern in the Dark-Light-Dark test, while ROPE treatment additionally rescued basal startle responses and enhanced habituation indexes, even surpassing healthy control larvae. Overall, these results highlight the potential of polyphenol-rich agri-food extracts, particularly ROPE, as neuroprotective and cognitive-enhancing compounds and support their further investigation as natural and sustainable interventions to slow or prevent neurodegenerative processes.},
}

@article {pmid41230868,
year = {2025},
author = {Cavagnero, PS and Sánchez, Y and Fell, B and Ramírez Molina, O and Gavilán, J and Polo, EA and Fuentealba, J and Gutierrez, M and Jiménez, CA and López, JJ},
title = {Neuroprotective Activity of 3-((6-(Phenylethynyl)pyridin-3-yl)oxy)quinuclidine: A Potential Ligand for the Treatment of Alzheimer's Disease.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.5c00527},
pmid = {41230868},
issn = {1948-7193},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder marked by the accumulation of β-amyloid (Aβ) peptides, which disrupt neuronal homeostasis through their neurotoxic effects. Aβ aggregates interfere with synaptic function by interacting with nicotinic acetylcholine receptors (nAChRs), particularly the α7 subtype, thereby impairing cholinergic signaling, which is crucial for cognition and memory. Pharmacological advancements have identified Positive Allosteric Modulators (PAMs) as promising therapeutic agents to counteract Aβ neurotoxicity. PAMs enhance nAChR activity by binding to allosteric sites, thereby reducing Aβ-induced neurotoxicity without competing with acetylcholine. This study evaluates 3-((6-(phenylethynyl)pyridine-3-yl)oxy)quinuclidine (EQ-04), a novel PAM with high selectivity for the α7 nAChR subtype, demonstrating neuroprotective potential. In vitro analyses using PC-12 cells evaluated the cytotoxic and neuroprotective properties of EQ-04. Cytotoxicity assays confirmed EQ-04's safety, showing no adverse effects on cell viability across concentrations. EQ-04 significantly enhanced cell viability by 37% at 1 nM against Aβ toxicity and inhibited Aβ aggregation. These findings highlight the potential of EQ-04 as a neuroprotective agent for Alzheimer's disease (AD) therapy, warranting further investigation into its pharmacokinetics and in vivo efficacy.},
}

@article {pmid41230514,
year = {2025},
author = {Wang, X and Liu, Y and Fan, S and Zhao, H and Sun, C and Liu, L and Wang, X and Zou, L},
title = {Combined 64-channel EEG and PET evaluation of lecanemab efficacy: Two case reports.},
journal = {Journal of Alzheimer's disease reports},
volume = {9},
number = {},
pages = {25424823251395615},
pmid = {41230514},
issn = {2542-4823},
abstract = {Lecanemab, an anti-amyloid-β (Aβ) monoclonal antibody, has shown potential in slowing Alzheimer's disease (AD) progression. We report divergent responses in two AD patients with similar backgrounds following lecanemab treatment. Subject 1 showed worsened daily functioning, increased Aβ/tau deposition, and elevated electroencephalogram (EEG) slow/fast wave ratios (>30%) in right fronto-occipital regions (Fp2/F8/O1). Subject 2 improved cognitively, with modest Aβ reduction, marked tau suppression, and mixed EEG frontal declines (F3/F7/O1/Pz) and parietal/occipital gains (P3/P4/T3/T6). EEG alterations corresponded with positron emission tomography findings, suggesting its potential for therapeutic monitoring. Multimodal analysis revealed region-specific lecanemab effects, supporting EEG's role in evaluating treatment efficacy.},
}

@article {pmid41230033,
year = {2025},
author = {Oviedo, DC and Haughbrook, R and Culjat, C and Ramirez Surmeier, L and Tratner, AE and Carreira, MB and Villarreal, AE and Harmon, SL and Batista, OI and Meng, Z and Millender, E and Xavier Hall, CD and Britton, GB},
title = {Ethical disclosure of biomarkers for Alzheimer risk in Latin American participants.},
journal = {Frontiers in dementia},
volume = {4},
number = {},
pages = {1672075},
pmid = {41230033},
issn = {2813-3919},
abstract = {INTRODUCTION: In recent years, the disclosure of Alzheimer's disease (AD) biomarkers has become increasingly common, offering critical insights into disease risk and progression. However, in low-resource settings, where healthcare access, provider training, and patient support are often limited, disclosing AD biomarkers presents unique ethical, logistical, and psychological challenges.

OBJECTIVE: This perspective explores the implications of AD biomarker disclosure in these settings, highlighting the potential risks of patient distress, misinformation, and inadequate follow-up care. For this purpose, we conducted a review of available literature, peer-reviewed studies, regional reports, and policy documents addressing AD in Latin America. Our literature search prioritized diagnostic advances, biomarker disclosure, treatment access, and health system challenges, providing a focused evidence base to frame the discussion of regional gaps and opportunities.

DISCUSSION: We discuss strategies to support responsible disclosure practices, including culturally sensitive participant education, enhanced provider training, and policy adaptations to improve accessibility and support systems. Ultimately, we advocate for a careful, context-specific approach to AD biomarker disclosure that prioritizes patient well-being and equity in low-resource environments.},
}

@article {pmid41229208,
year = {2025},
author = {Bosire, EN and Kamau, LW and Kiio, C and Blackmon, K and Taylor, ON and Shah, J and Sokhi, D and Mbugua, S and Meier, I and Hooker, J and Narayan, V and Merali, Z and Udeh-Momoh, C},
title = {Community perceptions and willingness to donate biospecimen for Alzheimer's disease research in Nairobi, Kenya.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251389227},
doi = {10.1177/13872877251389227},
pmid = {41229208},
issn = {1875-8908},
abstract = {BackgroundBiomarkers play a critical role in understanding disease mechanisms and advancing diagnostic and treatment options for Alzheimer's disease and related dementias (AD/ADRD). However, in many African countries, biomarker research is limited by insufficient knowledge, infrastructure, funding, and trained personnel.ObjectiveThis study explored community perceptions and willingness to donate biospecimens for AD/ADRD research in Kenya.MethodsEight focus group discussions were conducted in the informal settlements of Mathare and Kibera in Nairobi, Kenya, stratified by age and gender (n = 81). Data were transcribed verbatim and thematically analyzed using QSR Nvivo 14.ResultsParticipants generally expressed a positive attitude toward brain health research and donating biospecimens. Willingness to participate was influenced by altruism, perceived benefits, and improved understanding of AD/ADRD. Non-invasive samples such as saliva, blood, and stool were widely accepted due to perceptions of safety and familiarity. However, several barriers were identified, including cultural beliefs (e.g., fear of witchcraft linked to donating hair), religious beliefs, fear of invasive procedures (spinal taps), and low awareness about biospecimen research. To address these barriers, participants recommended community sensitization, inclusive and transparent research processes, clear communication of benefits, involvement of family members in consenting, and assurance of safety measures for managing potential risks.ConclusionsCommunity willingness to donate biospecimens for AD/ADRD research in Kenya is shaped by a complex interplay of cultural, ethical, and practical considerations. Culturally sensitive, community-driven approaches are essential to enhance participation in AD/ADRD biomarker research in Kenya and similar low-resource settings.},
}

@article {pmid41229078,
year = {2025},
author = {Zhang, N and Liu, Y and Guan, Y},
title = {Piceatannol ameliorates the memory ability and cognitive behavior in Alzheimer's disease mice.},
journal = {Neurological research},
volume = {},
number = {},
pages = {1-10},
doi = {10.1080/01616412.2025.2581245},
pmid = {41229078},
issn = {1743-1328},
abstract = {OBJECTIVE: To investigate the effects of different doses of Piceatannol (PIC) on oxidative stress and cognitive function in a mouse model of Alzheimer's disease (AD).

METHODS: Firstly, a mouse model was established by inducing 70 days with D-gal and AlCl3. Sixty male mice are randomly divided into a normal control group (Control), an AD group (AD Model), positive control group (treated with donepezil), an AD model+low-dose group (PIC-L) receiving low-dose piceatannol treatment, an AD model+medium-dose group (PIC-M) receiving medium-dose piceatannol treatment, and an AD model+high-dose group (PIC-H) receiving high-dose piceatannol treatment, with 10 mice in each group. After 35 days of establishing an AD mouse model, different doses of piceatannol are continuously applied for treatment.

RESULTS: After 2 days of treatment, the AD Model had a longer escape latency than the Control. The escape latency time of PIC-L, PIC-M, and PIC-H was below AD Model, (p < 0.05). After treatment for 4d and 5d, the escape latency time of PIC-L, PIC-M, and PIC-H was below the AD Model, and the PIC-H group was even lower, with statistical significance (p < 0.05). PIC-L, PIC-M, and PIC-H crossed the platform more frequently than the AD Model, (p < 0.05). The SOD and GSH-Px levels in AD Model were below the Control, (p < 0.05). The MDA of AD Model exceeded the Control, (p < 0.05). The SOD, and GSH-Px in PIC-L, PIC-M, PIC-H exceeded the AD Model, (p < 0.05).

CONCLUSION: PIC significantly improved memory and cognition in AD mice, elevated serum SOD and GSH-Px, lowered MDA, and attenuated oxidative tissue injury with minimal organ toxicity.},
}

@article {pmid41228597,
year = {2025},
author = {Gomes, ACC and Almeida, A and Freire, CSR and Ferreira, BL},
title = {Chitosan (Nano)formulations as Therapeutic Tools for Neurodegenerative Diseases: A Comprehensive Review.},
journal = {Polymers},
volume = {17},
number = {21},
pages = {},
pmid = {41228597},
issn = {2073-4360},
support = {UIDB/50011/2020 (DOI 10.54499/UIDB/50011/2020)//FCT/MCTES (PIDDAC)/ ; UIDP/50011/2020 (DOI 10.54499/UIDP/50011/2020)//FCT/MCTES (PIDDAC)/ ; LA/P/0006/2020 (DOI 10.54499/LA/P/0006/2020)//FCT/MCTES (PIDDAC)/ ; (UIDP/50017/2020+UIDB/50017/2020+LA/P/0094/2020)//FCT/MCTES (PIDDAC)/ ; 2022.10449.BD (https://doi.org/10.54499/2022.10449.BD)//Fundação para a Ciência e Tecnologia/ ; DOI 10.54499/ND/00464/2017/CP1459/CT0033//Fundação para a Ciência e Tecnologia/ ; DOI: 10.54499/DL57/2016/CP1482/CT0019//National funds (OE), through FCT/ ; },
abstract = {According to the World Health Organization, Alzheimer's disease and other forms of dementia were the seventh leading cause of death in 2021. The prevalence of these disorders is predictable to increase with life expectancy, and their control is hampered by several factors, including late diagnosis due to the lack of specific biomarkers and the absence of disease-modifying treatments, as currently available therapies can only lighten some of the symptoms. Nanotechnology could be the key to overcoming some of the limitations associated with neurodegenerative diseases, as nanomaterials have excellent properties compared to their bulk counterparts and can be used as drug delivery systems, diagnostic tools and platforms for tissue regeneration. Chitosan is a biopolymer with numerous properties that impart it with great potential for biomedical applications, in particular its ability to cross the blood-brain barrier and its versatility in nanoscale design. In this context, the aim of this review is to provide an in-depth analysis of the latest developments and future opportunities for chitosan (nano)formulations for the treatment and management of neurodegenerative diseases.},
}

@article {pmid41228523,
year = {2025},
author = {Liu, Y and Dong, Y and Cao, Z and Ji, Y and Cheng, X and Zheng, X},
title = {The Multi-Dimensional Action Map of Resveratrol Against Alzheimer's Disease: Mechanism Integration and Treatment Strategy Optimization.},
journal = {Nutrients},
volume = {17},
number = {21},
pages = {},
doi = {10.3390/nu17213451},
pmid = {41228523},
issn = {2072-6643},
support = {//the Youth Talent Cultivation Fund Project of Dalian Medical University./ ; },
mesh = {*Resveratrol/pharmacology/therapeutic use ; *Alzheimer Disease/drug therapy/metabolism ; Humans ; Oxidative Stress/drug effects ; *Antioxidants/pharmacology/therapeutic use ; *Neuroprotective Agents/pharmacology/therapeutic use ; Animals ; Plaque, Amyloid/drug therapy ; Energy Metabolism/drug effects ; Mitochondria/drug effects/metabolism ; Neurofibrillary Tangles/drug effects/metabolism ; },
abstract = {Alzheimer's disease (AD) represents a prevalent neurodegenerative disorder marked by a gradual decline in cognitive and behavioral functions. Despite advancements in elucidating several potential mechanisms underlying the pathogenesis of AD, there remains a limitation in effective supplements or medications for its intervention. Resveratrol, a natural antioxidant, has emerged as a significant player in the treatment of AD. This article reviews the role of resveratrol in four key aspects: amyloid plaque deposition and neurofibrillary tangles, inflammatory response and oxidative stress, energy metabolism and mitochondrial homeostasis, and neuroprotection and regeneration. Furthermore, we also explore treatment strategies to enhance the therapeutic effect of resveratrol.},
}

*Resveratrol/pharmacology/therapeutic use
*Alzheimer Disease/drug therapy/metabolism
Humans
Oxidative Stress/drug effects
*Antioxidants/pharmacology/therapeutic use
*Neuroprotective Agents/pharmacology/therapeutic use
Animals
Plaque, Amyloid/drug therapy
Energy Metabolism/drug effects
Mitochondria/drug effects/metabolism
Neurofibrillary Tangles/drug effects/metabolism

@article {pmid41228437,
year = {2025},
author = {Kim, G and Lee, HG and Kwon, S},
title = {Current Utilization and Research Status of the Herbal Medicine Guibi-Tang and Its Variants for Cognitive Impairment: A Scoping Review.},
journal = {Nutrients},
volume = {17},
number = {21},
pages = {},
doi = {10.3390/nu17213365},
pmid = {41228437},
issn = {2072-6643},
support = {RS-2022-KH127675//Korea Health Industry Development Institute/Republic of Korea ; },
mesh = {Humans ; *Cognitive Dysfunction/drug therapy ; *Drugs, Chinese Herbal/therapeutic use/adverse effects ; Aged ; Cognition/drug effects ; Middle Aged ; },
abstract = {Background/Objectives: Guibi-tang (GBT) and its variant Kami-guibi-tang (KGBT) are traditional East Asian multi-herb formulas prescribed for memory loss, insomnia, and fatigue. Preclinical data suggest multimodal neuroprotective actions, including cholinergic signaling modulation and activation of the cAMP response element-binding protein (CREB)/extracellular signal-regulated kinase (ERK) pathway; however, clinical evidence for cognitive disorders remains scattered. This scoping review aimed to map the breadth, design characteristics, efficacy signals, and safety profile of GBT and KGBT across the full spectrum of cognitive impairment. Methods: Following the Arksey-O'Malley framework and PRISMA-ScR guidelines, seven databases were searched (MEDLINE, Embase, Cochrane Library, China National Knowledge Infrastructure, ScienceON, Scopus, Citation Information by the National Institute of Informatics) from inception to 31 January 2025, for human studies evaluating GBT or KGBT in subjective cognitive decline, mild cognitive impairment (MCI), dementia, or post-stroke cognitive impairment (PSCI). Two reviewers independently screened, extracted, and charted data on study design, participants, interventions, outcomes, and adverse events. Results: Fifteen studies met the inclusion criteria-nine randomized controlled trials, one crossover trial, and five observational reports-enrolling 555 participants (age range, 59-87 years). All were conducted in the Republic of Korea, Japan, or China. GBT or KGBT, given as monotherapy or adjunctive therapy for 4 weeks to 9 months, produced modest but consistent improvements in global cognition (Mini-Mental State Examination/Montreal Cognitive Assessment), memory domains, activities of daily living, and neuropsychiatric symptoms across MCI, Alzheimer's disease, and PSCI cohorts. Reported adverse event rates were comparable to or lower than those of placebo, usual care, or conventional drugs, and no serious treatment-related toxicity was identified. Conclusions: Current evidence-although limited by small sample sizes, heterogeneous formulations, short follow-up durations, and regional concentration-indicates that GBT and KGBT are well tolerated and confer clinically meaningful cognitive and functional benefits. Standardized, multicenter, placebo-controlled trials with biomarker end points are warranted to confirm long-term efficacy, clarify mechanisms, and guide integrative clinical use.},
}

Humans
*Cognitive Dysfunction/drug therapy
*Drugs, Chinese Herbal/therapeutic use/adverse effects
Aged
Cognition/drug effects
Middle Aged

@article {pmid41227390,
year = {2025},
author = {Habib, SA and Kamal, MM and Aly, MH and Ghaiad, HR and Rizk, SM and Banks, WA and Erickson, MA},
title = {Streptozotocin Causes Blood-Brain Barrier and Astrocytic Dysfunction In Vitro.},
journal = {Cells},
volume = {14},
number = {21},
pages = {},
doi = {10.3390/cells14211745},
pmid = {41227390},
issn = {2073-4409},
support = {ACOS Research Fund//VA Puget Sound Health Care System/ ; Graduate Scholarship//United States Agency for International Development/ ; },
mesh = {*Blood-Brain Barrier/drug effects/pathology/metabolism ; *Astrocytes/drug effects/pathology/metabolism ; Humans ; *Streptozocin/pharmacology/toxicity ; Endothelial Cells/drug effects/metabolism/pathology ; Induced Pluripotent Stem Cells/drug effects/metabolism ; Glucose Transporter Type 1/metabolism ; Cells, Cultured ; },
abstract = {Streptozotocin (STZ) is an alkylating agent that has neurotoxic effects when injected into the cerebral ventricles (ICV) and also models many other features of Alzheimer's disease. However, the mechanisms of STZ neurotoxicity are not well understood. In this study, we hypothesized that some of the neurotoxic effects of STZ could be due to direct activities on brain endothelial cells and astrocytes, which are key in forming and supporting the functions of the blood-brain barrier (BBB), respectively. To test this hypothesis, we characterized the changes induced by STZ either in cultures of human-induced pluripotent stem cell (iPSC)-derived brain endothelial-like cells (iBECs), which form an in vitro BBB model, or in primary human astrocytes. We found that STZ at a dosage of 5 mM caused a delayed reduction in the transendothelial electrical resistance (TEER) of iBECs at 7-11 days post-treatment, indicating induction of BBB leakage. Additionally, we observed significant increases in albumin leakage across the monolayer, altered iBEC morphology, and reductions in tight junction proteins, suggesting that STZ causes BBB disruption. We further found that the BBB glucose transporter GLUT-1 was reduced in iBECs, as was the total number of iBECs. In astrocytes, the 5 mM dose of STZ reduced the GFAP signal and total number of cells, suggesting that STZ has anti-proliferative and/or toxic effects on astrocytes. Together, these data support that STZ's neurotoxic effects could be due, in part, to its direct toxic activities on brain endothelial cells and astrocytes.},
}

*Blood-Brain Barrier/drug effects/pathology/metabolism
*Astrocytes/drug effects/pathology/metabolism
Humans
*Streptozocin/pharmacology/toxicity
Endothelial Cells/drug effects/metabolism/pathology
Induced Pluripotent Stem Cells/drug effects/metabolism
Glucose Transporter Type 1/metabolism
Cells, Cultured

@article {pmid41226838,
year = {2025},
author = {Zhao, Y and Wang, Z and Xi, E and Yang, F and Gao, N},
title = {Hydrophobic Drug Delivery Platforms Based on Covalent Organic Frameworks for Combined Treatment of Alzheimer's Disease.},
journal = {International journal of molecular sciences},
volume = {26},
number = {21},
pages = {},
doi = {10.3390/ijms262110803},
pmid = {41226838},
issn = {1422-0067},
support = {2022YFB3805902//the National Key R&D Program of China/ ; 22077118//National Natural Science Foundation of China/ ; B18012//the "111" project/ ; 20210101353JC//the National Natural Science Foundation of Jilin Province/ ; },
mesh = {*Alzheimer Disease/drug therapy ; Animals ; *Curcumin/chemistry/administration & dosage/pharmacology/therapeutic use ; Hydrophobic and Hydrophilic Interactions ; Mice ; *Drug Delivery Systems/methods ; *Metal-Organic Frameworks/chemistry ; *Drug Carriers/chemistry ; Humans ; Disease Models, Animal ; },
abstract = {Alzheimer's disease (AD) is a complex neurodegenerative disease. The pathogenesis of AD remains incompletely understood. It is characterized by a variety of neuropathological changes, including neuroinflammation, neuronal loss and synaptic damage. Multiple pathological changes make achieving good therapeutic effects with a single drug treatment difficult, and using multiple drugs for combination therapy is currently the most effective method. Currently, the mainstay drugs used for AD treatment are hydrophobic drugs, such as curcumin, donepezil, and resveratrol. Because hydrophobic drugs cannot dissolve in bodily fluids and often aggregate or precipitate, their efficacy is greatly reduced. Therefore, there is an urgent need for a drug carrier that can effectively load and continuously release drugs. However, currently, there are few drug carriers that can achieve efficient co-loading of multiple hydrophobic drugs. Therefore, three of two-dimensional imine covalent organic frameworks (COFs) with different monomers were synthesized through rational design and screening. These three synthesized COFs are simultaneously loaded with curcumin (CUR) and benzofurazan (BZ) to achieve combined therapy. The results indicate that among this series of synthesized COFs, the COF synthesized from 4,4',4″-(1,3,5-Triazine-2,4,6-triyl) trianiline and benzene-1,3,5-tricarboxaldehyde (COF-TB) exhibits optimal hydrophobic drug-loading capacity, enabling effective co-loading of CUR and BZ (BC@COF-TB). After treatment with BC@COF-TB, the cognitive function of 5×FAD mice was significantly improved. The COF platform provides a new way to deliver hydrophobic drugs for AD treatment.},
}

*Alzheimer Disease/drug therapy
Animals
*Curcumin/chemistry/administration & dosage/pharmacology/therapeutic use
Hydrophobic and Hydrophilic Interactions
Mice
*Drug Delivery Systems/methods
*Metal-Organic Frameworks/chemistry
*Drug Carriers/chemistry
Humans
Disease Models, Animal

@article {pmid41226821,
year = {2025},
author = {Paszternák, A and Varga, K and Gyöngyössy, R and Tarnóczi, K and Sikur, N and Szökő, É and Tábi, T},
title = {Resveratrol Analogs Ameliorate Mitochondrial Impairment and Insulin Resistance in a Streptozotocin-Induced In Vitro Model of Alzheimer's Disease.},
journal = {International journal of molecular sciences},
volume = {26},
number = {21},
pages = {},
doi = {10.3390/ijms262110787},
pmid = {41226821},
issn = {1422-0067},
support = {2024-2.1.1-EKÖP-2024-0004 (203)//National Research, Development and Innovation Office/ ; EFOP-3.6.3.-VEKOP-16-2017-00009//National Research, Development and Innovation Office/ ; },
mesh = {*Resveratrol/pharmacology/analogs & derivatives ; *Insulin Resistance ; Humans ; *Alzheimer Disease/metabolism/drug therapy/chemically induced/pathology ; *Mitochondria/drug effects/metabolism/pathology ; Streptozocin/toxicity ; Cell Line, Tumor ; *Neuroprotective Agents/pharmacology/chemistry ; Autophagy/drug effects ; Oxidative Stress/drug effects ; Stilbenes/pharmacology/chemistry ; Antioxidants/pharmacology ; },
abstract = {Alzheimer's disease (AD) is characterized by mitochondrial dysfunction, oxidative stress, insulin resistance, and aberrant protein aggregation. Neurodegeneration model with neuronal insulin resistance was induced in SH-SY5Y human neuroblastoma cells by streptozotocin (STZ). We evaluated the neuroprotective effects of resveratrol (RZV) and three structural analogs: oxyresveratrol (OXI), monomethyl resveratrol (MONO), and trimethyl resveratrol (TRI). Mitochondrial function, plasma membrane integrity, oxidative stress) and autophagy were studied by fluorescent assays. Phosphorylated GSK3 levels were measured by ELISA as an indicator of insulin sensitivity. TRI exhibited significant mitochondrial protective effects and strongly induced autophagy. OXI demonstrated excellent antioxidant activity but showed no detectable mitochondrial protective or autophagy-inducing effects. RZV and MONO exhibited moderate antioxidant effects along with strong insulin-sensitizing and autophagy-inducing properties. Insulin sensitivity was most potently restored by RZV (IC50 = 54 pM) and MONO (IC50 = 50 pM), whereas TRI (IC50 = 160 pM) was less potent, and OXI (IC50 = 97 pM) showed moderate potency. Our findings suggest that the neuroprotective effects of resveratrol analogs significantly depend on their molecular structure and that they exert their beneficial effects through distinct mechanisms. This research may contribute to the development of novel, multi-target compounds for the treatment of neurodegenerative diseases.},
}

*Resveratrol/pharmacology/analogs & derivatives
*Insulin Resistance
Humans
*Alzheimer Disease/metabolism/drug therapy/chemically induced/pathology
*Mitochondria/drug effects/metabolism/pathology
Streptozocin/toxicity
Cell Line, Tumor
*Neuroprotective Agents/pharmacology/chemistry
Autophagy/drug effects
Oxidative Stress/drug effects
Stilbenes/pharmacology/chemistry
Antioxidants/pharmacology

@article {pmid41226793,
year = {2025},
author = {Machowska, M and Leszek, J and Rączy-Krzemianowska, M and Tomasiewicz, B and Hurkacz, M and Rąpała, M and Piechota, J and Głowacka, K and Wiela-Hojeńska, A},
title = {ABC Transporters, APOE, CYP46A1, and LRP1 Gene Polymorphisms as Markers of Dementia Development in Patients with Hyperlipidemia.},
journal = {International journal of molecular sciences},
volume = {26},
number = {21},
pages = {},
doi = {10.3390/ijms262110759},
pmid = {41226793},
issn = {1422-0067},
support = {RPDS.01.02.01-02-0002/20//Regional Operational Programme of the Lower Silesian Voivodeship 2014-2020, co-financed by the European Union, European Regional Development Fund/ ; },
mesh = {Humans ; *Hyperlipidemias/genetics/complications ; Male ; Female ; *Apolipoproteins E/genetics ; *Dementia/genetics/etiology ; Aged ; *Polymorphism, Single Nucleotide ; *ATP Binding Cassette Transporter 1/genetics ; Genetic Predisposition to Disease ; *Low Density Lipoprotein Receptor-Related Protein-1/genetics ; Genotype ; Middle Aged ; Alleles ; Gene Frequency ; Biomarkers ; Alzheimer Disease/genetics ; Aged, 80 and over ; *ATP-Binding Cassette Transporters/genetics ; Case-Control Studies ; },
abstract = {In an aging society, solving problems associated with the diagnosis and treatment of dementia-related diseases represents a serious challenge. The aim of the study was to evaluate the possibility of applying molecular biology methods to test polymorphisms recognized in the global literature as potentially useful in assessing the risk of developing dementia in a group of patients with hyperlipidemia. A sample of 203 patients: 109 diagnosed with both dementia and hyperlipidemia, 94 with hyperlipidemia, and 101 individuals as an allele frequency control group-were genotyped. Additional data about cognitive decline and neuropsychological assessment were collected. Among all the studied polymorphisms, the frequency of the ABCA1 rs2230806 polymorphism differed between the analyzed groups. The GG genotype (p = 0.0002, RR = 3.22, CI = 1.63 ÷ 6.37) and the G allele (p = 0.0007, RR = 1.53, CI = 1.19 ÷ 1.97) were more frequent in patients diagnosed with dementia, specifically in those with Alzheimer's disease. Furthermore, the GG genotype was more common in individuals with a shorter disease duration and lower scores on the Montreal Cognitive Assessment (MoCA) scale, and consequently, with greater cognitive function deficits during early stages of the diagnostic process. ABCA1 rs2230806 genotyping is a potential marker for the early identification of dementia risk in patients with hyperlipidemia, which supports the validity of exploring options for incorporating diagnostics based on molecular biology methods.},
}

Humans
*Hyperlipidemias/genetics/complications
Male
Female
*Apolipoproteins E/genetics
*Dementia/genetics/etiology
Aged
*Polymorphism, Single Nucleotide
*ATP Binding Cassette Transporter 1/genetics
Genetic Predisposition to Disease
*Low Density Lipoprotein Receptor-Related Protein-1/genetics
Genotype
Middle Aged
Alleles
Gene Frequency
Biomarkers
Alzheimer Disease/genetics
Aged, 80 and over
*ATP-Binding Cassette Transporters/genetics
Case-Control Studies

@article {pmid41226707,
year = {2025},
author = {Hale, HK and Elias, KM and Ho, S and Kwakye, GF},
title = {Methylene Blue Attenuates 3-Nitropropionic Acid-Induced Oxidative Stress and Mitochondrial Dysfunction in Striatal Cells: Therapeutic Implications in Huntington's Disease Neuropathology.},
journal = {International journal of molecular sciences},
volume = {26},
number = {21},
pages = {},
doi = {10.3390/ijms262110672},
pmid = {41226707},
issn = {1422-0067},
support = {Research and Professional Development Portfolio//Oberlin College Arts and Sciences Dean's Office (GFK)/ ; Endowed Professor Research Portfolio//Robert W. & Eleanor H. Biggs Endowed Professor of Neuroscience (GFK)/ ; },
mesh = {*Oxidative Stress/drug effects ; *Huntington Disease/drug therapy/metabolism/pathology ; *Nitro Compounds/toxicity ; *Propionates/toxicity ; *Methylene Blue/pharmacology ; *Mitochondria/drug effects/metabolism/pathology ; Animals ; *Corpus Striatum/drug effects/metabolism/pathology ; Humans ; Reactive Oxygen Species/metabolism ; *Neuroprotective Agents/pharmacology ; Huntingtin Protein/genetics/metabolism ; Cell Survival/drug effects ; Membrane Potential, Mitochondrial/drug effects ; Mice ; },
abstract = {There are no disease-modifying treatments available for Huntington's disease (HD), a neurodegenerative disease caused by a genetic mutation in the Huntingtin gene. Previous research suggests that disruptions in the bioenergetics of the mitochondria and increased oxidative stress are potential inducers of HD. Therapies that enhance antioxidant pathways intend to target and attenuate the overproduction of reactive oxygen species associated with mitochondrial dysfunction. We have investigated the effect of Methylene Blue (MB) as a potential therapy for HD. MB is a small molecule demonstrated to exhibit neuroprotective effects in other neurodegenerative disease models, including Parkinson's and Alzheimer's, by attenuating the oxidative stress pathways implicated in their pathophysiology. We used an established striatal cell model of HD expressing wild-type (STHdh[Q7/Q7]) or mutant (STHdh[Q111/Q111]) HTT and a chemical inducer of HD, 3-Nitropropionic acid (3-NPA), to determine the HD-specific mechanisms regulated by 3 h of MB pre-treatment. Upon 24 h of exposure to 3-NPA, mutant HD cells exhibited a significant concentration-dependent decrease in cell survival and a concomitant increase in cell death compared to wild-type, confirming that 3-NPA exacerbates mutant HTT neurotoxicity. Examination of mitochondrial membrane potential and mitochondrial function in the striatal cells by JC-1 and ATP assays, respectively, revealed MB mediated neuroprotection against 3-NPA-induced reduction in mitochondrial activity. Immunoblotting analysis revealed that MB restores baseline expression of oxidative-stress-related proteins, including HO1 and p62, in both wild-type and mutant cells exposed to 3-NPA. Our findings establish a novel neuroprotective role of MB in both genetic and pharmacological models of HD, suggesting that MB might be a promising therapeutic candidate for altering the underlying pathophysiology of HD by improving mitochondrial function.},
}

*Oxidative Stress/drug effects
*Huntington Disease/drug therapy/metabolism/pathology
*Nitro Compounds/toxicity
*Propionates/toxicity
*Methylene Blue/pharmacology
*Mitochondria/drug effects/metabolism/pathology
Animals
*Corpus Striatum/drug effects/metabolism/pathology
Humans
Reactive Oxygen Species/metabolism
*Neuroprotective Agents/pharmacology
Huntingtin Protein/genetics/metabolism
Cell Survival/drug effects
Membrane Potential, Mitochondrial/drug effects
Mice

@article {pmid41226670,
year = {2025},
author = {Bayo Jimenez, MT and Rivas-García, L and Sánchez-González, C and Grosso, G and Lipari, V and Vera-Ramírez, L and Battino, M and Giampieri, F and Quiles, JL and Forbes-Hernández, TY},
title = {Natural Products in Alzheimer's Disease: A Systematic Review of Clinical Trials and Underlying Molecular Mechanisms.},
journal = {International journal of molecular sciences},
volume = {26},
number = {21},
pages = {},
doi = {10.3390/ijms262110631},
pmid = {41226670},
issn = {1422-0067},
support = {PID2019-106778RB-I00//MCIN/AEI/10.13039/501100011033 FEDER "Una manera de hacer Europa/ ; Visiting Scholars 2022//Universidad de Granada/ ; },
mesh = {*Alzheimer Disease/drug therapy/metabolism ; Humans ; *Biological Products/therapeutic use/pharmacology ; Clinical Trials as Topic ; *Plant Extracts/therapeutic use/pharmacology ; Cognitive Dysfunction/drug therapy ; *Neuroprotective Agents/therapeutic use/pharmacology ; Aged ; },
abstract = {This systematic review included 31 clinical trial articles examining the effects of natural compounds on Alzheimer's disease (AD) and mild cognitive impairment (MCI), involving 3582 participants aged 50-90. Treatment durations ranged from 8 weeks to 2 years, with an average of 12.5 months. Notably, 11 studies focused on herbal extracts highlighting their prominence in current research. These extracts showed potential cognitive and neuroprotective benefits, although results varied across compounds and study designs. Other natural compounds-including flavonoids, polyphenols, omega-3 fatty acids, Aloe vera, Spirulina, and citrus phytochemicals-may provide cognitive and neuroprotective benefits, with ginseng and Ginkgo biloba combinations also showing promise. Curcumin and Melissa officinalis had limited effects, resveratrol showed mixed outcomes with some side effects, and matcha green tea may improve cognition and sleep quality. Despite generally favorable results, the studies varied considerably in design and quality; nonetheless, herbal extracts represent a prominent category of natural interventions in AD and MCI, underscoring the need for further large-scale, high-quality clinical trials to confirm their therapeutic potential.},
}

*Alzheimer Disease/drug therapy/metabolism
Humans
*Biological Products/therapeutic use/pharmacology
Clinical Trials as Topic
*Plant Extracts/therapeutic use/pharmacology
Cognitive Dysfunction/drug therapy
*Neuroprotective Agents/therapeutic use/pharmacology
Aged

@article {pmid41226604,
year = {2025},
author = {Hu, C and Lin, M and Wang, C and Zhang, S},
title = {Current Understanding of Protein Aggregation in Neurodegenerative Diseases.},
journal = {International journal of molecular sciences},
volume = {26},
number = {21},
pages = {},
doi = {10.3390/ijms262110568},
pmid = {41226604},
issn = {1422-0067},
support = {32170784, 32170707//National Natural Science Foundation of China/ ; },
mesh = {Humans ; *Neurodegenerative Diseases/metabolism/therapy/pathology ; Animals ; *Protein Aggregates ; *Protein Aggregation, Pathological/metabolism ; Autophagy ; Protein Folding ; },
abstract = {Protein aggregates are central to the pathogenesis of neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. This comprehensive review explores the mechanisms of protein misfolding and aggregation, their prion-like propagation, and the critical role of oligomeric species in neurotoxicity. It further examines cellular clearance pathways, including the ubiquitin-proteasome system and autophagy, alongside the regulatory functions of molecular chaperones. The review also covers advanced diagnostic imaging and biomarker techniques, as well as emerging therapeutic strategies such as pharmacological agents, gene therapy, and immunotherapy. Controversies regarding the toxicity of aggregates and future directions, including novel degradation technologies and targeted therapeutic approaches, are discussed. By integrating current knowledge, this review aims to provide a broad yet detailed overview of the field, highlighting both established concepts and promising avenues for research and treatment.},
}

Humans
*Neurodegenerative Diseases/metabolism/therapy/pathology
Animals
*Protein Aggregates
*Protein Aggregation, Pathological/metabolism
Autophagy
Protein Folding

@article {pmid41226584,
year = {2025},
author = {Costea, D and Dobrin, N and Tataru, CI and Toader, C and Șerban, M and Covache-Busuioc, RA and Munteanu, O and Diaconescu, IB},
title = {The Glymphatic-Venous Axis in Brain Clearance Failure: Aquaporin-4 Dysfunction, Biomarker Imaging, and Precision Therapeutic Frontiers.},
journal = {International journal of molecular sciences},
volume = {26},
number = {21},
pages = {},
doi = {10.3390/ijms262110546},
pmid = {41226584},
issn = {1422-0067},
mesh = {Humans ; *Glymphatic System/metabolism/diagnostic imaging ; *Aquaporin 4/metabolism ; Biomarkers/metabolism ; Animals ; *Brain/metabolism/diagnostic imaging/blood supply ; *Neurodegenerative Diseases/metabolism/therapy/diagnostic imaging ; Precision Medicine ; },
abstract = {The identification of brain clearance failure as a precursor to a large variety of neurodegenerative diseases has shifted fluid dynamics from a secondary to a tertiary target of brain health. The identification of the glymphatic system, detailing cerebrospinal fluid entry along perivascular spaces and exit via perivenous and meningeal lymphatic pathways, provided a challenge to previous diffusion models and established aquaporin-4-dependent astroglial polarity as a governing principle of solute transport. Multiple lines of evidence now support a coupled glymphatic-venous axis, wherein vasomotion, venous outflow, and lymphatic drainage are functionally interrelated. Failure of any axis will cascade and affect the entire axis, linking venous congestion, aquaporin-4 disassembly, and meningeal lymphatic failure to protein aggregation, neuroinflammation, edema, and intracranial hypertension. Specific lines of evidence from diffusion tensor imaging along vascular spaces, clearance MRI, and multi-omic biomarkers can provide a measure of transport. Therapeutic strategies are rapidly advancing from experimental strategies to translational approval, including behavioral optimization, closed-loop sleep stimulation, vascular and lymphatic therapies, focused ultrasound, pharmacological polarity recoupling, and regenerative bioengineering. Novel computational approaches, such as digital twin dynamic modeling and adaptive trial designs, suggest that clearance measures may serve as endpoints to be approved by the FDA. This review is intended to bridge relevant mechanistic and translational reviews, focusing on impaired clearance as an exploitable systems defect rather than an incapacitating secondary effect. Improving our understanding of the glymphatic-venous axis Injury may lead to future target strategies that advance cognitive resilience, alleviate disease burden, and improve quality of life. By clarifying the glymphatic-venous axis, we provide a mechanistic link between impaired interstitial clearance and the pathological accumulation of amyloid-β, tau, and α-synuclein in neurodegenerative diseases. The repair of aquaporin-4 polarity, venous compliance, and lymphatic drainage might therefore open new avenues for the diagnosis and treatment of Alzheimer's and Parkinson's disease, supplying both biomarkers of disease progression and new targets for early intervention. These translational implications not only locate clearance failure as an epiphenomenon of neurodegeneration but, more importantly, as a modifiable driver of the course of neurodegeneration.},
}

Humans
*Glymphatic System/metabolism/diagnostic imaging
*Aquaporin 4/metabolism
Biomarkers/metabolism
Animals
*Brain/metabolism/diagnostic imaging/blood supply
*Neurodegenerative Diseases/metabolism/therapy/diagnostic imaging
Precision Medicine

@article {pmid41226231,
year = {2025},
author = {Ananda, SH and Kuragano, M and Tokuraku, K},
title = {Elucidation of the Neuroprotective Effects of Astaxanthin Against Amyloid β Toxicity in the SH-SY5Y Human Neuroblastoma Cell Line.},
journal = {Molecules (Basel, Switzerland)},
volume = {30},
number = {21},
pages = {},
pmid = {41226231},
issn = {1420-3049},
support = {SUNBOR GRANT//Suntory Foundation for Life Sciences/ ; JPMJPF2213//Japan Science and Technology Agency/ ; JP24K08627//JSPS KAKENHI/ ; },
mesh = {Humans ; Xanthophylls/pharmacology/chemistry ; *Amyloid beta-Peptides/metabolism/toxicity ; *Neuroprotective Agents/pharmacology ; Cell Line, Tumor ; *Neuroblastoma/metabolism/pathology/drug therapy ; Apoptosis/drug effects ; Cell Movement/drug effects ; Cell Survival/drug effects ; Alzheimer Disease/drug therapy/metabolism ; },
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder characterized by memory loss and cognitive decline, primarily due to amyloid β (Aβ) aggregation in the brain. Astaxanthin (AxN), a xanthophyll carotenoid derived from Haematococcus pluvialis, possesses antioxidant and neuroprotective properties. This study investigated the neuroprotective effects of AxN against Aβ aggregation in human neuroblastoma SH-SY5Y cells. Initially, AxN inhibited Aβ aggregation in DMEM/F12 culture medium but not in PBS, suggesting a medium-dependent effect. Using quantum dot nanoprobes, Aβ aggregation was visualized in the presence of SH-SY5Y cells. AxN treatment (0.032-20 µM) significantly reduced Aβ aggregation and accumulation on SH-SY5Y cells. AxN also prevented Aβ-induced early apoptotic cell death but was less effective against late necrosis. Furthermore, a wound-healing assay showed that AxN restored the impaired cell motility caused by Aβ aggregation. Thioflavin T staining confirmed the reduction in Aβ fibril formation around the cells following AxN treatment. In conclusion, our study suggests that AxN prevents Aβ aggregation and accumulation on the cell surface, thereby restoring cell motility and preventing early apoptosis in neuronal cells.},
}

Humans
Xanthophylls/pharmacology/chemistry
*Amyloid beta-Peptides/metabolism/toxicity
*Neuroprotective Agents/pharmacology
Cell Line, Tumor
*Neuroblastoma/metabolism/pathology/drug therapy
Apoptosis/drug effects
Cell Movement/drug effects
Cell Survival/drug effects
Alzheimer Disease/drug therapy/metabolism

@article {pmid41226137,
year = {2025},
author = {Guaya, D and Espinoza, LC and Jaramillo-Fierro, X and Gualotuña Campoverde, D and Sosa, L and Calpena, AC},
title = {Zinc-Modified Mordenite Zeolite as a Molecular Carrier for Donepezil: A Framework for Drug Delivery Applications.},
journal = {Molecules (Basel, Switzerland)},
volume = {30},
number = {21},
pages = {},
pmid = {41226137},
issn = {1420-3049},
support = {PROY_INV_QU_2022_3585//Universidad Técnica Particular de Loja (UTPL)/ ; },
mesh = {*Zeolites/chemistry ; *Donepezil/chemistry/pharmacology/administration & dosage ; *Zinc/chemistry ; *Drug Carriers/chemistry ; *Drug Delivery Systems ; Adsorption ; Drug Liberation ; Kinetics ; Cholinesterase Inhibitors/chemistry ; Hydrogen Bonding ; },
abstract = {The development of advanced drug delivery systems is essential for improving therapeutic efficacy, particularly in the treatment of neurodegenerative disorders such as Alzheimer's disease. This study investigates zinc-modified mordenite zeolite (MR-ZN) as a novel platform for the controlled delivery of donepezil (DPZ), a cholinesterase inhibitor. Natural mordenite was modified with zinc, enhancing its surface area from 62.1 to 85.4 m[2]/g and improving its adsorption properties. Donepezil was successfully loaded at two doses (10 mg and 23 mg), achieving high loading efficiencies of 95% and 94%, respectively. Adsorption kinetics followed a pseudo-second-order model (R[2] > 0.99), indicating that chemisorption predominates through coordination between DPZ functional groups and Zn[2+] sites, while complementary physisorption via hydrogen bonding and van der Waals interactions also contributes to molecular stabilization within the zeolite framework. In vitro release studies under simulated gastrointestinal conditions demonstrated sustained and pH-responsive release profile with 80% and 82% of donepezil released after 24 h for 10 mg and 23 mg formulations, respectively. Density Functional Theory (DFT) calculations revealed favorable adsorption energy (-26.4 kJ/mol), while Bader and Electron Localization Function (ELF) analyses confirmed hydrogen bonding and electrostatic interactions without compromising the zeolite framework. These findings validate MR-ZN as structurally stable, efficient, cost-effective and biocompatible matrix for oral drug delivery. The combination of experimental data and theoretical modeling supports its potential to improve bioavailability and therapeutic performance in neurodegenerative treatment.},
}

*Zeolites/chemistry
*Donepezil/chemistry/pharmacology/administration & dosage
*Zinc/chemistry
*Drug Carriers/chemistry
*Drug Delivery Systems
Adsorption
Drug Liberation
Kinetics
Cholinesterase Inhibitors/chemistry
Hydrogen Bonding

@article {pmid41225966,
year = {2025},
author = {Hayat, MT and Allawi, YM and Alamro, W and Sultan, SM and Abadleh, A and Kang, H and Zreikat, AI},
title = {A Hybrid Convolutional Neural Network-Long Short-Term Memory (CNN-LSTM)-Attention Model Architecture for Precise Medical Image Analysis and Disease Diagnosis.},
journal = {Diagnostics (Basel, Switzerland)},
volume = {15},
number = {21},
pages = {},
pmid = {41225966},
issn = {2075-4418},
support = {PNURSP2025R829//Princess Nourah bint Abdulrahman University/ ; },
abstract = {Background: Deep learning (DL)-based medical image classification is becoming increasingly reliable, enabling physicians to make faster and more accurate decisions in diagnosis and treatment. A plethora of algorithms have been developed to classify and analyze various types of medical images. Among them, Convolutional Neural Networks (CNNs) have proven highly effective, particularly in medical image analysis and disease detection. Methods: To further enhance these capabilities, this research introduces MediVision, a hybrid DL-based model that integrates a vision backbone based on CNNs for feature extraction, capturing detailed patterns and structures essential for precise classification. These features are then processed through Long Short-Term Memory (LSTM), which identifies sequential dependencies to better recognize disease progression. An attention mechanism is then incorporated that selectively focuses on salient features detected by the LSTM, improving the model's ability to highlight critical abnormalities. Additionally, MediVision utilizes a skip connection, merging attention outputs with LSTM outputs along with Grad-CAM heatmap to visualize the most important regions of the analyzed medical image and further enhance feature representation and classification accuracy. Results: Tested on ten diverse medical image datasets (including, Alzheimer's disease, breast ultrasound, blood cell, chest X-ray, chest CT scans, diabetic retinopathy, kidney diseases, bone fracture multi-region, retinal OCT, and brain tumor), MediVision consistently achieved classification accuracies above 95%, with a peak of 98%. Conclusions: The proposed MediVision model offers a robust and effective framework for medical image classification, improving interpretability, reliability, and automated disease diagnosis. To support research reproducibility, the codes and datasets used in this study have been publicly made available through an open-access repository.},
}

@article {pmid41225766,
year = {2025},
author = {Jeon, SY and Byun, MS and Choi, HJ and Kim, YH and Gwag, CH and Oh, Y and Park, JE and Yi, D and Jung, G and Ahn, H and Sohn, BK and Jung, JH and Chang, YY and Kong, N and Choi, H and Kang, KM and Sohn, CH and Lee, DY},
title = {Eligibility for lecanemab and donanemab in Korea under Appropriate Use Recommendations.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {11},
pages = {e70875},
doi = {10.1002/alz.70875},
pmid = {41225766},
issn = {1552-5279},
support = {//New Faculty Startup Fund from Seoul National University/ ; //National Research Foundation of Korea/ ; RS-2022-00165636//Ministry of Science and ICT, South Korea/ ; 2014M3C7A1046042//Ministry of Science and ICT, South Korea/ ; //Korea Health Technology R&D Project/ ; //Korea Health Industry Development Institute/ ; HI18C0630//Ministry of Health and Welfare, Republic of Korea/ ; HI19C0149//Ministry of Health and Welfare, Republic of Korea/ ; //Korea Dementia Research Project/ ; //Korea Dementia Research Center (KDRC)/ ; //Ministry of Health & Welfare and Ministry of Science and ICT/ ; RS-2023-KH136195//Republic of Korea/ ; //Basic Science Research Program through the NRF/ ; RS-2023-00210380//Ministry of Education/ ; U01AG072177//National Institute of Aging/ ; //National Institute of AGING/ ; RS-2023-KH136195//Korea Dementia Research Center/ ; HI18C0630//Ministry of Health and Welfare/ ; HI19C0149//Ministry of Health and Welfare/ ; //Seoul National University/ ; },
mesh = {Humans ; Republic of Korea ; Male ; Female ; Magnetic Resonance Imaging ; Aged ; *Alzheimer Disease/drug therapy/diagnostic imaging ; Mental Status and Dementia Tests ; Aged, 80 and over ; Brain/diagnostic imaging ; Middle Aged ; Antibodies, Monoclonal, Humanized ; },
abstract = {INTRODUCTION: Appropriate Use Recommendations (AURs) guide real-world use of lecanemab and donanemab in early symptomatic Alzheimer's disease (AD), but their applicability to Asian populations with diverse education backgrounds remains unclear.

METHODS: Among 2726 participants who visited a Korean memory clinic, 1005 amyloid-positive participants with magnetic resonance imaging (MRI) and Clinical Dementia Rating data were included. Eligibility for lecanemab and donanemab was assessed using AUR criteria, including age, Mini-Mental State Examination (MMSE), brain MRI, apolipoprotein E genotype (for donanemab), and anticoagulant use, applying both raw and z-score-based MMSE thresholds.

RESULTS: Among 1005 amyloid-positive participants, 24.6% were eligible for lecanemab and 28.0% for donanemab (9.1% and 10.3% of the initial sample). Applying MMSE z-scores increased eligibility to 38.4% and 33.7%, respectively. Over a third of participants were excluded due to MRI findings, mainly vascular lesions associated with increased amyloid-related imaging-abnormality risks.

DISCUSSION: Incorporating demographically adjusted MMSE z-score threshold improves real-world eligibility and promotes equitable access to anti-amyloid therapies.

HIGHLIGHTS: About a fourth of A+ patients in Korea met AUR criteria for anti-amyloid therapy. Donanemab eligibility slightly exceeded lecanemab despite narrower age criteria. MMSE z-score adjustment increased eligibility in older, less-educated individuals. Over 30% of eligible patients were excluded due to ARIA-related MRI findings. Culturally adapted cognitive thresholds are essential for equitable treatment access.},
}

Humans
Republic of Korea
Male
Female
Magnetic Resonance Imaging
Aged
*Alzheimer Disease/drug therapy/diagnostic imaging
Mental Status and Dementia Tests
Aged, 80 and over
Brain/diagnostic imaging
Middle Aged
Antibodies, Monoclonal, Humanized

@article {pmid41224179,
year = {2025},
author = {Tigro, H and Moëlo, C and Pelcman, J and Paslawski, W and Chen, G and Poska, H and Shimmo, R and Svenningsson, P and Kronqvist, N and Johansson, J},
title = {Bri2 BRICHOS, a molecular chaperone-like domain that can cross brain vascular endothelial cells and deliver proteins into neurons.},
journal = {Journal of controlled release : official journal of the Controlled Release Society},
volume = {},
number = {},
pages = {114403},
doi = {10.1016/j.jconrel.2025.114403},
pmid = {41224179},
issn = {1873-4995},
abstract = {The transport of biological drugs from the bloodstream into the central nervous system is hindered by the blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier, creating a need for efficient and safe delivery systems to the brain parenchyma. Recombinant human (rh) BRICHOS, a chaperone-like domain from the protein Bri2, can access the brain after systemic injection and has shown therapeutic efficiency in Alzheimer model mice. Here, we show that rh Bri2 BRICHOS and cargo proteins fused to it are efficiently transcytosed over human BBB models made of cerebral microvascular endothelial cells and astrocytes. Moreover, intravenously injected protein fused with Bri2 BRICHOS can access the brain parenchyma of mice and enter neurons and astrocytes. Our results suggest that rh Bri2 BRICHOS can be harnessed to deliver cargo from the bloodstream into neurons.},
}

@article {pmid41224085,
year = {2025},
author = {Gharedaghi, P and Faridi, N and Wang, P and Bathaie, SZ},
title = {Natural C20 Carotenoids Protect dPC12 Cells from Aβ-Induced Cell Cycle Re-entry, Tau Phosphorylation, and Nrf2 Activation via the Akt/GSK-3β Pathway.},
journal = {Journal of ethnopharmacology},
volume = {},
number = {},
pages = {120816},
doi = {10.1016/j.jep.2025.120816},
pmid = {41224085},
issn = {1872-7573},
abstract = {Saffron has been known to improve mood and memory since ancient times. Crocin and Crocetin, bioactive C20 carotenoids, were isolated from saffron stigma and demonstrated multiple biological and pharmacological effects.

AIM OF THE STUDY: We recently demonstrated the effect of Crocin/Crocetin on apoptosis inhibition in an amyloid beta oligomer (AβO)-induced Alzheimer's disease (AD) model using neuronally differentiated PC12 (dPC12) cells. This study investigates their neuroprotective effects on the Akt/GSK-3β pathway in these cells, focusing on NRF2 activity, NQO1 expression, and Tau phosphorylation.

METHODS: dPC12 cells were exposed to AβO to mimic the AD condition. The cells were treated with Crocin/Crocetin before and after to produce preventive and therapeutic modalities. The expression of key pathway markers was evaluated using Western blot and immunocytochemistry. Flow cytometry was employed to assess cell cycle arrest and apoptosis.

RESULTS: Crocin/Crocetin significantly attenuated AβO-induced toxicity in dPC12 cells in both modalities mentioned. The named carotenoids significantly suppressed GSK3β kinase activity and reduced Tau phosphorylation (p-Thr231). Furthermore, they increased AKT phosphorylation, promoted NRF2 translocation into the nucleus, and induced NQO1 expression. These effects were observed in a time-dependent manner. Flow cytometry analyses revealed the involvement of both cell cycle arrest and apoptosis in response to AβO treatment. Crocin and Crocetin inhibited this response.

CONCLUSIONS: Collectively, Crocin/Crocetin effectively mitigated AβO-induced injury in dPC12 cells. Although Crocetin was more effective than Crocin and improved at lower concentrations, both carotenoids exhibited neuroprotective effects against AβO toxicity in preventive and therapeutic modalities via activating the Akt/GSK-3β signaling pathway.},
}

@article {pmid41224062,
year = {2025},
author = {Tiwari, P and Tiwari, S},
title = {Comparative anti-amyloidogenic potential of pristine and nitrogen doped graphene quantum dots against amyloid beta protein.},
journal = {International journal of biological macromolecules},
volume = {},
number = {},
pages = {148951},
doi = {10.1016/j.ijbiomac.2025.148951},
pmid = {41224062},
issn = {1879-0003},
abstract = {This study investigates the effect of nitrogen doping of graphene quantum dots (GQDs) upon their ability to inhibit the fibrillation of amyloid beta fragments containing 1-42 amino acids (Aβ). Misfolded aggregates of Aβ have been implicated in the pathogenesis of Alzheimer's disease, the most prevalent form of dementia. We employed spectroscopic and microscopic techniques to characterize both quantum dots. Anti-amyloidogenic potential was assessed using circular dichroism (CD) spectroscopy and the thioflavin T (ThT) binding. Atomic force microscopy (AFM) was utilized to characterize the morphological and nanomechanical properties of Aβ fibrils following treatment with the quantum dots. We observed that nitrogen doping significantly alters the absorbance and fluorescence emission profiles, likely due to an increased surface charge density induced by the incorporation of nitrogen atoms. N-GQDs exhibited superior anti-amyloidogenic activity in comparison to pristine quantum dots. This effect varied in accordance to the dose. Using the data of MTT, trypan blue exclusion, differential staining and apoptosis assays on SH-SY5Y neuroblastoma cells, we infer that adsorption of Aβ on doped quantum dots was accompanied with reduction in the stiffness of fibrils and their toxicity to the cells.},
}

@article {pmid41223445,
year = {2025},
author = {Vlachos, I},
title = {Spectral brain connectivity in dementia: Coherence, imaginary coherence and partial coherence analysis of EEG signals.},
journal = {Journal of neural engineering},
volume = {},
number = {},
pages = {},
doi = {10.1088/1741-2552/ae1ea1},
pmid = {41223445},
issn = {1741-2552},
abstract = {OBJECTIVE: As the prevalence of dementia continues to rise, the need for accurate and early diagnostic tools becomes increasingly critical. Despite diverse underlying causes, dementia types share common cognitive symptoms, making accurate diagnosis essential for effective treatment.

APPROACH: This study investigates EEG-based spectral brain connectivity in individuals with Alzheimer's disease (AD, N=36), frontotemporal dementia (FTD, N=23), and healthy controls (HC, N=29), with the dual aim of identifying condition-specific connectivity patterns and evaluating three coherence-based connectivity measures: coherence, imaginary coherence, and partial coherence. Resting-state, eyes-closed EEG data (19 channels) were analyzed, and connectivity was estimated across frequencies to assess both global and local network alterations.

MAIN RESULTS: The results indicate that dementias (both AD and FTD) are characterized by decreased connectivity in higher frequency bands and increased connectivity in lower frequencies, reflecting respectively impaired neural communication and neurodegeneration. Moreover, the severity of cognitive impairment correlates with the spatial extent and magnitude of connectivity disruptions. Notably, partial coherence-unlike coherence and imaginary coherence-effectively distinguishes between the AD and FTD groups, suggesting that direct connectivity measures may provide more discriminative information for differential diagnosis.

SIGNIFICANCE: These findings highlight the potential of EEG-based spectral connectivity analysis, particularly partial coherence, as a non-invasive tool to aid in the diagnosis and differential diagnosis of dementia subtypes, supporting early clinical decision-making.},
}

@article {pmid41223194,
year = {2025},
author = {Yoo, SS and Reddy, A and Carroll, W and Ploypradith, K},
title = {Repeated application of transcranial ultrasound maintains spatial and recognition memory in 5xFAD mice with reduction of amyloid-β burden.},
journal = {PloS one},
volume = {20},
number = {11},
pages = {e0336114},
doi = {10.1371/journal.pone.0336114},
pmid = {41223194},
issn = {1932-6203},
abstract = {Pharmacological removal of amyloid beta protofibrils has emerged as a promising therapeutic strategy to delay the onset of Alzheimer's disease (AD) symptoms. As a non-pharmacological and noninvasive alternative, transcranial application of low-intensity ultrasound through intact skull can induce convective acoustic streaming, which has been shown to enhance cerebrospinal fluid solute transport and facilitate the clearance of interstitial solutes. This has led to the development of device-based approaches aimed at removing the precursors of amyloid beta (Aβ) plaques and mitigating cognitive decline in AD. We applied non-thermal, non-cavitational ultrasound (400 kHz frequency) in a pulsed mode (75 ms pulse duration, 2 Hz repetition rate) to the hippocampal region of male 5xFAD mice for 30 minutes weekly, starting at 10 weeks of age and continuing for 15 weeks (until 6 months of age). Spatial and recognition memory performance was assessed monthly using the Y-maze spontaneous alternation (SA) and novel object recognition (NOR) tests. A control group of age-matched mice underwent the same procedures with receiving zero acoustic output. Mice subjected to transcranial ultrasound (tUS) treatment maintained both SA and NOR performance throughout the entire experimental period, whereas mice that received sham tUS exhibited a progressive decline in memory beginning at 3-4 months of age. Congo Red staining of the brain sections revealed a significant (> 40%) reduction in Aβ plaques in the sonicated group. Histological analysis confirmed that repeated ultrasound exposure did not cause any detectable tissue damage. These findings suggest that low intensity tUS may serve as a novel, noninvasive therapeutic strategy to delay the onset of AD symptoms through the reduction of Aβ burden.},
}

@article {pmid41223122,
year = {2025},
author = {Wiest, R and Radojewski, P and Lieb, JM and Psychogios, M and Benzinger, TLS and Franceschi, AM and Wanke, I and Draganski, B and Kurz, FT and Lövblad, KO},
title = {Clinical practice recommendations of the Swiss Society for Neuroradiology*: Neuroimaging standards for enrollment and disease monitoring in Anti-Amyloid Immunotherapies.},
journal = {Neuro-degenerative diseases},
volume = {},
number = {},
pages = {1-24},
doi = {10.1159/000549521},
pmid = {41223122},
issn = {1660-2862},
abstract = {INTRODUCTION: The Swiss Society for Neuroradiology (SSNR) has established clinical practice recommendations to guide the use of neuroimaging techniques in the enrollment and disease monitoring of patients undergoing anti-amyloid immunotherapies for Alzheimer's disease (AD). In Switzerland, anti-amyloid immunotherapy (AAT) has not been approved by Swissmedic ahead of this publication. This paper therefore reflects the existing international standards of care and will be updated after market clearance of AATs in Switzerland.

BACKGROUND AND RATIONALE: Neuroimaging is a key requirement to assess therapeutic responses and manage potential adverse effects, particularly amyloid-related imaging abnormalities (ARIA). The SSNR recommendations specify the appropriate use of MRI biomarkers to support therapy inclusion, routine monitoring and decision-making in case of manifestations of ARIA-E and ARIA-H during treatment.

CONCLUSIONS: This paper reviews the required image protocols and neuroimaging criteria for patient eligibility and discusses the key findings of ARIA-E and ARIA-H. These findings are required to be recognized by the practicing radiologist to ensure patient safety. The practice recommendations of the SSNR align with previous published recommendations of the American Society of Neuroradiology and the European Society of Neuroradiology. We also provide practical recommendations for workflows and candidate selection to continue or discontinue therapy.},
}

@article {pmid41221473,
year = {2025},
author = {Perez, FP and Bandeira, J and Morisaki, J and Kanakri, H and Rizkalla, M},
title = {Electromagnetic Field Stimulation Effects on Intrinsically Disordered Proteins and Their Role in Aging and Neurodegeneration.},
journal = {Journal of biomedical science and engineering},
volume = {18},
number = {10},
pages = {408-438},
pmid = {41221473},
issn = {1937-6871},
abstract = {There is increasing evidence from preclinical studies. There is growing evidence from preclinical studies in cell cultures and small organisms that exposure to Electromagnetic Fields (EMFs) produces beneficial biological effects. However, controversy persists due to the absence of a clearly defined mechanism. Classical physics, constrained by the non-ionizing nature of these exposures, cannot account for these effects, which do not involve the breaking of chemical bonds to induce conformational changes in proteins. Emerging studies suggest that these effects are mediated through quantum mechanical phenomena-specifically, quantum tunneling and particle-wave duality-acting on the water surrounding proteins at their interfaces. Furthermore, we present evidence of EMF-induced conformational changes in Intrinsically Disordered Proteins (IDPs), including beta-amyloid, tau, alpha-synuclein, and Heat Shock Factor 1 (HSF1). These findings offer a new framework for understanding EMF bioeffects and open promising avenues for research in biophysics and quantum biology. In this context, we address the challenge of reproducibility by examining how variables such as frequency, intensity, Specific Absorption Rate (SAR), and exposure time windows interact, along with how parameters like polarization, phase, pulse modulation, and scheduling influence outcomes. Experimental data identify specific RF frequencies and SAR levels that activate proteostasis and autophagy in cell cultures and small animal models, with potential applications in human treatments that remain consistent with safety thresholds established by regulatory agencies.},
}

@article {pmid41220866,
year = {2025},
author = {Kim, J and Kim, GH and Kang, K and Kim, HJ and Suh, J and Yoon, B and Cho, H and Pyun, JM and Park, YH and Choe, HK and Kim, YK and Lee, KH and Kim, JG and Yang, SJ and Baek, MJ and Chin, J and Jang, H and Moon, SY and , },
title = {Executive Summary of 2025 International Conference of the Korean Dementia Association and International Congress of the Asian Society Against Dementia (IC-KDA/ASAD 2025): A Report From the Academic Committee of the Korean Dementia Association.},
journal = {Dementia and neurocognitive disorders},
volume = {24},
number = {4},
pages = {209-232},
pmid = {41220866},
issn = {2384-0757},
abstract = {The International Conference of the Korean Dementia Association (IC-KDA) 2025 was held jointly with the 19th International Congress of the Asian Society Against Dementia (ASAD) in Seoul, South Korea (May 8-10, 2025), under the theme "Breaking Barriers of Dementia: From Research to Real-world Practice." The program opened with a Pre-Conference Symposium on "Dementia Treatment Update: Lecanemab and NPH" featuring 14 speakers, followed by the main meeting comprising 3 plenary sessions (5 speakers), 7 luncheon-symposium presentations, 16 parallel symposia (48 speakers), a special symposium (2 speakers), and 4 oral-presentation sessions (20 presenters). The congress was attended by 1,052 participants from 27 countries and included 213 poster presentations. Scientific highlights spanned the continuum from discovery to implementation: plasma and imaging biomarkers, retinal and electroencephalogram/voice-based digital biomarkers, and multimodal neuroimaging for risk stratification and outcome prediction; updates on anti-amyloid monoclonal antibodies (MABs) (lecanemab, donanemab), safety/amyloid-related imaging abnormalities management, and real-world data frameworks; mechanistic and multi-omics insights (genetics, metabolomics, epigenomics, transcriptomics); neuroinflammation and glia-mediated pathways; young-onset dementia cohorts across Asia-Pacific; vascular cognitive impairment trials and pathophysiology; neuropsychiatric symptoms and evidence-based behavioral and psychological symptoms of dementia care; lifestyle and multidomain prevention (Mediterranean-Dietary Approaches to Stop Hypertension (DASH) Intervention for Neurodegenerative Delay-based interventions); dementia-friendly communities and caregiver support; and emerging neuromodulation modalities (low-intensity ultrasound, photobiomodulation, vagus nerve stimulation). Together, the joint IC-KDA & ASAD 2025 meeting emphasized precision medicine and implementation science, bridging laboratory advances with clinical practice and health-system delivery to improve outcomes for people living with dementia and their caregivers.},
}

@article {pmid41220257,
year = {2025},
author = {Wang, HJ and Ruthirakuhan, M and Andreazza, AC and Beroncal, EL and Black, SE and Gallagher, D and Herrmann, N and Kiss, A and Verhoeff, NPLG and Lanctôt, KL},
title = {Identifying a combination of biomarkers to predict treatment response to nabilone for agitation in Alzheimer's disease - an exploratory post hoc analysis.},
journal = {Neurodegenerative disease management},
volume = {},
number = {},
pages = {1-10},
doi = {10.1080/17582024.2025.2587549},
pmid = {41220257},
issn = {1758-2032},
abstract = {BACKGROUND: To identify if a combination of blood-based biomarkers related to inflammation and oxidative stress predict treatment response to nabilone for Alzheimer's disease (AD)-associated agitation.

RESEARCH DESIGN AND METHODS: Agitation was assessed using the Cohen-Mansfield Agitation Inventory (CMAI). Serum concentrations of 13 markers were quantified. Univariable and multivariable regression were used to determine differences in CMAI change given nabilone and placebo. A model combining biomarkers with clinical predictors was also evaluated.

RESULTS: Overall, 38 participants enrolled in the original trial (76% male, mean ± SD age 87 ± 10). Nabilone was more efficacious in participants with higher IL-6, higher 8-ISO, higher 24S-OHC, and lower clusterin. Participants in the first tertile (T1) of index scores demonstrated better response to nabilone compared to placebo with a mean difference in CMAI change of -20.6 (95%CI: -30.3, -10.4). During the nabilone phase, 83% of participants in T1 were responders versus 38% in T2 + 3 (Fisher's p = .01). In the combined model, T1 showed better response to nabilone with a mean difference in CMAI change of -26.4 (95%CI: -34.0, -19.6). The proportion of responders was significantly higher in T1 (91%, n = 11) compared to T2 + 3 (32%, n = 19) (Fisher's p = .002).

CONCLUSION: A combination of biomarkers could help characterize responders and non-responders to nabilone.},
}

@article {pmid41219714,
year = {2025},
author = {Blasi, V and Isernia, S and Rossetto, F and Pagliari, C and Borgnis, F and Pirastru, A and Marzulli, M and Foglia, E and Garagiola, E and Baglio, F},
title = {Study protocol for a randomized controlled trial assessing clinical efficacy of digital cognitive rehabilitation for preclinical and mild clinical stages of alzheimer's disease continuum: the MI-RICORDO project.},
journal = {BMC psychiatry},
volume = {25},
number = {1},
pages = {1075},
pmid = {41219714},
issn = {1471-244X},
support = {FP-1321//THCS Horizon Europe Programme/ ; },
abstract = {BACKGROUND: Early or preclinical stages of AD continuum may benefit from lifestyle interventions and cognitive rehabilitation strategies that can delay or prevent progression to dementia. In this context, digital health technologies offer a disruptive potential to expand access to cognitive rehabilitation and meet the increasing demand for early interventions. This study protocol outlines a randomized controlled trial (RCT) designed to evaluate the efficacy and efficiency of a personalized, multidomain digital cognitive rehabilitation approach compared to conventional paper-and-pencil therapy. A secondary objective is to investigate the structural and functional neuroplasticity mechanisms associated with both interventions, using advanced magnetic resonance imaging techniques.

METHODS: The study presents a single-blinded (assessors) 1:1 parallel-arm RCT design involving 102 patients with Subjective Cognitive Decline, o Mild Cognitive Impairment or early-stage dementia. For the experimental intervention group (EG) the digital therapeutic RICORDO-DTx will be employed, while the control group (CG) will perform an unstructured pencil-paper stimulation program. Both interventions will last 5 weeks with 3 session/week. Outcome measures will evaluate efficacy as changes in: behavioural and cognitive abilities, patients' engagement, and structural and functional neuroplasticity mechanisms by means of Magnetic Resonance Imaging. Additional evaluation will include efficiency measures related to usability, acceptability, safety, sustainability and user experience. Patients will be evaluated at baseline (T0), after treatment (T1) and at follow up six months post baseline (T2). Data analyses will involve repeated measures ANOVA models on primary and secondary outcome measures to compare efficacy of intervention between EG and CG. Finally, efficiency measures will be reported with descriptive statistics.

CONCLUSIONS: The expected results lay on the ability of RICORDO DTx, to adapt task difficulty automatically based on patients' performance and perceived difficulty. This adaptive approach is anticipated to yield superior treatment outcomes relative to traditional pencil-and-paper exercises.

TRIAL REGISTRATION: ClinicalTrials.gov NCT07064226. Date of registration 30th July 2025.},
}

@article {pmid41219645,
year = {2025},
author = {Hoang, VD and Nguyen, HMT and Nguyen, TA and Garg, S},
title = {Pharmaceutical Formulations and Analytical Methods of Donepezil.},
journal = {AAPS PharmSciTech},
volume = {27},
number = {1},
pages = {28},
pmid = {41219645},
issn = {1530-9932},
support = {R01AG064688 (Hinton/Nguyen MPI)//the National Institute of Aging (NIA) of the National Institutes of Health (NIH)/ ; },
abstract = {Donepezil is a selective acetylcholinesterase inhibitor widely prescribed for the symptomatic treatment of Alzheimer's disease. As therapeutic needs grow and delivery systems evolve, ensuring product quality, efficacy, safety and patient compliance becomes increasingly important. Meanwhile, pharmaceutical formulation innovations can improve clinical outcomes and usability, and analytical methods help ensure accurate assessment of drug behavior and quality control. This narrative review first provides a concise overview of donepezil's physicochemical properties and synthesis, then focuses on two interrelated domains: (i) pharmaceutical formulations and (ii) analytical methodologies. The former highlights advancements in novel delivery systems-such as liposomes, nanoparticles, microneedles, nasal gels, and long-acting injectable depots-developed to enhance brain targeting, prolong drug release, and reduce systemic side effects. The latter reviews validated analytical methods for quantifying and characterizing donepezil in pharmaceutical and biological matrices, with emphasis on RP-HPLC, LC-MS/MS, chiral separations, and emerging electrochemical and spectroscopic techniques. These analytical strategies are essential for evaluating formulation performance, monitoring drug stability, and ensuring regulatory compliance. Collectively, this review underscores that progress in both formulation design and analytical science is vital to optimizing donepezil-based therapies for Alzheimer's disease management.},
}

@article {pmid41219231,
year = {2025},
author = {Mahadik, N and Paruchuri, SN and Arif, R and Coutts, AS and Barron, GA and Kong Thoo Lin, P and Chatterjee, S and Thompson, CJ},
title = {Evaluation of the toxicity and efficacy of a multi-target polymer-drug nano-polyplex in SH-SY5Y cells and Drosophila model of tauopathy.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {39454},
pmid = {41219231},
issn = {2045-2322},
support = {C23-1720928079//Royal Society of Chemistry/ ; C23-1720928079//Royal Society of Chemistry/ ; C23-1720928079//Royal Society of Chemistry/ ; C23-1720928079//Royal Society of Chemistry/ ; C23-1720928079//Royal Society of Chemistry/ ; },
abstract = {Hyperphosphorylated tau contributes to synaptic damage and neuronal dysfunction in neurodegenerative diseases such as Alzheimer's disease (AD), making it a key therapeutic target. This study evaluated the toxicity and therapeutic potential of a novel polymer-drug nano-polyplex, N5NM15, and polyacrylic acid (PAA) in Drosophila tauopathy models and undifferentiated human SH-SY5Y cells. Cellular uptake was demonstrated by N5NM15, and SH-SY5Y cell viability was significantly enhanced (45%, p ≤ 0.0001) under okadaic acid-induced stress, and total tau levels were reduced (1.43-fold, p ≤ 0.01). In comparison, PAA had a modest effect on decreasing tau phosphorylation (1.3-fold) at the pSer202/pThr205 site. Toxicity studies in Drosophila revealed that N5NM15 (3.5:1 and 44:12.5 µg/mL) and PAA (44 µg/mL) were toxic to adult flies expressing the eye-specific driver (GMR-GAL4) but were well-tolerated in flies overexpressing the pan-neuronal driver ELAV-GAL4. Furthermore, treatment with N5NM15 and PAA did not improve the ommatidial arrangement, eye bristle count, or eye length in tauopathy models. Climbing and survival assays indicated a potential mild protective effect at a lower concentration (3.5:1 µg/mL) at the early stage of the disease, but at a higher dose (44:12.5 µg/mL) was significantly toxic, in both wild-type (p ≤ 0.0001) and tauopathy models (p < 0.05). These findings highlight the need for N5NM15 and PAA dose optimisation and reformulation with non-toxic buffers to enhance therapeutic potential while minimising adverse effects in normal and Drosophila tauopathy models for AD treatment.},
}

@article {pmid41219110,
year = {2025},
author = {Rose, DK and Lyketsos, CG and Rosenberg, PB and Nowrangi, MA},
title = {Neuropsychiatric symptoms in Alzheimer's disease: Bridging mechanisms, management, and emerging innovations.},
journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics},
volume = {},
number = {},
pages = {e00788},
doi = {10.1016/j.neurot.2025.e00788},
pmid = {41219110},
issn = {1878-7479},
abstract = {Neuropsychiatric symptoms (NPS) are among the most distressing and functionally disruptive features of Alzheimer's disease (AD), affecting the vast majority of individuals across the disease continuum. These symptoms, ranging from apathy and depression to agitation and psychosis, not only worsen quality of life but also predict faster decline, earlier institutionalization, and heightened caregiver burden. Yet, despite their clinical significance, NPS remain under-recognized and undertreated. This review synthesizes current understanding of the biological underpinnings of NPS in AD, highlighting network-level dysfunction, neurotransmitter imbalances, neuroinflammation, and emerging roles for tau pathology and circadian disruption. We critically examine current treatment paradigms, noting that pharmacologic interventions offer benefit but often carry significant risks. In contrast, non-pharmacological approaches, particularly those that integrate caregiver training, environmental design, and sensory engagement, hold promise but are inconsistently applied in routine care. Emerging innovations, including neuromodulation, repurposed agents (e.g., beta-blockers, cannabinoids), and digital therapeutics such as virtual reality and AI-enabled monitoring tools, offer new therapeutic avenues. We call for a paradigm shift toward person-centered, mechanistically-informed care that aligns intervention strategies with biological drivers of NPS. Future progress hinges on inclusive clinical trials, implementation of first-line behavioral strategies, and development of biomarker-guided, precision approaches to symptom management. Effective care for NPS in AD demands integration, not substitution, of pharmacologic and non-pharmacologic strategies, grounded in a deeper understanding of both disease biology and lived patient experience.},
}

@article {pmid41219002,
year = {2026},
author = {Radhakrishna, BK and Kaladiyil, AP and Chakraborty, A and Gautam, V and Muddashetty, RS},
title = {Group 1 mGluR stimulation rescues APOE4-mediated translation defects in neurons.},
journal = {Life science alliance},
volume = {9},
number = {2},
pages = {},
doi = {10.26508/lsa.202503287},
pmid = {41219002},
issn = {2575-1077},
abstract = {The E4 isoform of apolipoprotein (APOE4) is the most recognized risk factor for Alzheimer's disease, implicated in early neurodegeneration and impaired synaptic plasticity. In neurons, exposure to APOE4 disrupts basal and NMDAR-mediated calcium signaling, further disrupting protein synthesis response. Group 1 mGluRs, a major class of glutamate receptors, also play a critical role in synaptic plasticity through activity-dependent protein synthesis. In this study, we examine neuronal protein synthesis response to mGluR stimulation in the background of APOE4 treatment. In DIV15 primary cortical neurons from Sprague-Dawley rat embryos, exposure to APOE4 induces inhibition of protein synthesis, which is rescued by stimulation of mGluRs for 5 min. mGluR stimulation also rescued the APOE4-induced reduction in synaptic activity as measured by the multi-electrode array. This mGluR-mediated rescue is driven by phosphorylation of RPS6, downstream of the mammalian target of rapamycin (mTOR) pathway as it is abolished by rapamycin treatment. This p-RPS6-driven rescue is independent of calcium-mediated translation inhibition induced by APOE4, demonstrating a specific and independent role of mTORC1 activity in maintaining mGluRs' translation capacity under APOE4 exposure. The potential of mGluR-mediated response to compensate for the effect of APOE4 suggests a dynamic mechanism for the induction of plasticity in human APOE4 carriers. This study provokes a critical need to explore the altered synaptic dynamics in the presence of APOE4 and its impact on cognition.},
}

@article {pmid41218737,
year = {2025},
author = {Ahangaran, S and Pourgholaminejad, A and Nosrati, R and Babaei, P},
title = {TLR4 Inhibition Attenuate Facilitatory Effects of JQ1 on Learning & Memory Via Polarization of Microglia, and BDNF Expression in Alzheimer's Disease Model.},
journal = {Behavioural brain research},
volume = {},
number = {},
pages = {115919},
doi = {10.1016/j.bbr.2025.115919},
pmid = {41218737},
issn = {1872-7549},
abstract = {OBJECTIVE: Neuroinflammation is a core event in the pathogenesis of Alzheimer's disease (AD), which is mediated by microglia. The present study aimed to investigate the effect of co-inhibition of Toll-like receptor (TLR4) and chromatin reader of BRD4 on cognition deficit, polarization of microglia, and Brain-derived neurotrophic factor in the hippocampus.

METHODS: Forty male Wistar rats were randomly divided into five groups: saline +saline, Aβ+saline, Aβ+JQ1(BRD4 inhibitor), Aβ+TAK242 (TLR4 inhibitor), Aβ+JQ1+TAK-2452, and received the related treatments. Then cognitive functions were assessed by passive avoidance learning (PAL) and Morris water maze (MWM) tests. Then, the polarization of microglia and BDNF level in the hippocampus, were measured using flow cytometry and western blotting, respectively.

RESULTS: Chronic intracerebroventricular administration of JQ1, either alone or in combination with TAK-242, significantly reduced escape latency and increased the time spent in the target quadrant (TTS) during the probe test of the Morris Water Maze (MWM), compared with the Aβ + saline group (p < 0.05). In contrast, TAK-242 alone prolonged escape latency and reduced TTS (p < 0.05). Moreover, JQ1 treatment markedly elevated the M2/M1 microglial polarization and the mBDNF/proBDNF ratio in the hippocampus (p < 0.05), suggesting that JQ1 promotes neuroprotective and cognitive function mechanisms in this model.

CONCLUSION: Our results indicate that JQ1 successfully improves learning and memory in the rat model of Alzheimer's disease, primarily by inducing the transcription of BDNF expression and suppressing inflammatory factors related to the M1 microglia. In contrast, co-treatment with a TLR4 inhibitor attenuate both spatial and aversive memories, probably through a decrease in BDNF expression.},
}

@article {pmid41218709,
year = {2025},
author = {Ruoff, LK and Bänfer, IWH and Liedtke, DE and China, SE and Wiltfang, J and Bayer, TA and Bock, SF and Spandau, F and Bouter, C and Beindorff, N and Bouter, Y},
title = {Long-term thiethylperazine treatment in the Tg4-42 mouse model of Alzheimer's disease mouse: Therapeutic potential vs. adverse effects.},
journal = {Pharmacology, biochemistry, and behavior},
volume = {},
number = {},
pages = {174127},
doi = {10.1016/j.pbb.2025.174127},
pmid = {41218709},
issn = {1873-5177},
abstract = {BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline and behavioral impairments. Thiethylperazine, a dopamine receptor antagonist with antiemetic and antidopaminergic properties, has been proposed as a potential therapeutic agent for AD. However, its impact on cognitive function in AD remains unclear.

AIMS: This study investigated the long-term effects of thiethylperazine on memory, anxiety-like behavior, motor function, and AD pathology in Tg4-42 mice, a model characterized by Aβ4-42 overexpression and progressive neurodegeneration. Additionally, the impact of prolonged thiethylperazine treatment on behavioral outcomes and cerebral glucose metabolism in healthy adult C57BL/6J wild-type (WT) mice were examined.

METHODS: Tg4-42 and WT mice were treated daily with 10 mg/kg thiethylperazine for 6 months, starting at 10 weeks of age. Memory, anxiety-related, and motor tests were performed at 7.5 months. Immunohistochemical analyses were conducted to quantify effects on Aβ pathology, neurogenesis, neuron number, and neuroinflammation. Additionally, [18]F-FDG-PET imaging was used to evaluate metabolic activity in WT mice following treatment.

RESULTS: Thiethylperazine improved recognition memory in Tg4-42 mice in the Novel Object Recognition test and exhibited anxiolytic properties. However, it impaired spatial learning in the Morris Water Maze (MWM), reduced locomotion, and failed to mitigate motor impairments. No effects on neuron loss or neuroinflammation were observed. In WT mice, thiethylperazine altered learning processes in the MWM, as indicated by shifts in search strategies, induced hypometabolism and increased neurogenesis.

CONCLUSION: Although thiethylperazine offers mild cognitive benefits in Tg4-42, its adverse effects on learning strategies and locomotion raise questions about its potential as a therapeutic option for AD.},
}

@article {pmid41216966,
year = {2025},
author = {Hovde, MJ and Maaser-Hecker, A and Bae, JS and Tanzi, RE},
title = {Inhibition of Acyl-CoenzymeA: Cholesterol Acyltransferase 1 promotes shedding of soluble triggering receptor on myeloid cells 2 (TREM2) and low-density lipoprotein receptor 1 (LRP1)-dependent phagocytosis of amyloid beta protein in microglia.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {11},
pages = {e70879},
doi = {10.1002/alz.70879},
pmid = {41216966},
issn = {1552-5279},
support = {//Freedom Together Fund/ ; T32 AG000222-31//Cure Alzheimer's Fund/ ; T32AG000222/AG/NIA NIH HHS/United States ; //NIH/ ; },
abstract = {INTRODUCTION: Lipid regulation is crucial role in Alzheimer's disease (AD) pathogenesis. In AD, microglia show elevated sterol O-acyltransferase 1/Acyl-coenzymeA: Choleseterol Acyltransferase 1 (SOAT1) expression, encoding Acyl-coenzymeA: Cholesterol Acyltransferase 1 (ACAT1), which produces cholesteryl esters (CEs) in lipid droplets. Inhibiting ACAT1 has been shown to reduce amyloid beta (Aβ) pathology, though the mechanism is unclear.

METHODS: We inhibited ACAT1 using avasimibe (AV) in wild-type, triggering receptor expressed on myeloid cells 2 (TREM2) knockout (KO), and low-density lipoprotein receptor related protein 1 (LRP1) KO mouse BV2 and human induced pluripotent stem cell-derived microglia and measured the impact on Aβ uptake to determine the mechanism through which the inhibition of ACAT1 enhances Aβ uptake.

RESULTS: ACAT1 inhibition increased LRP1 levels and soluble TREM2 (sTREM2) release via enhanced TREM2 cleavage by ADAM metallopeptidase domain 10/17 (ADAM10/17). KO of TREM2 or blockade of sTREM2 release prevented AV-enhanced Aβ uptake. This effect was rescued by recombinant sTREM2, but only when LRP1 was present.

DISCUSSION: ACAT1 inhibition promotes microglial Aβ uptake in a sTREM2- and LRP1-dependent manner, offering insights into novel therapeutic strategies for AD.

HIGHLIGHTS: Inhibition of ACAT1, the major enzyme that catalyzes cholesterol storage via esterification enhances microglia-mediated Aβ uptake. Increased Aβ uptake is dependent on the presence of both TREM2 and LRP1. Inhibition of ACAT1 increases cleavage of TREM2 via ADAM10/17 to release sTREM2. Treatment of microglial cells with sTREM2 rescues Aβ uptake in TREM2 KO BV2 cells. Inhibition of ACAT1 promotes Aβ uptake through increased shedding of TREM2, which enhances Aβ uptake through a LRP1-dependent mechanism.},
}

@article {pmid41216919,
year = {2025},
author = {Heikal, SA and Fawi, G and Khedr, EM and Othman, M and Moustafa, SA and Elsheikh, NG and Tawfik, HM and Elfarrash, S and Salama, S and Ali, EM and Hassanin, HI and Salama, M},
title = {The Egyptian Dementia Network (EDN): Baseline characteristics from the first dementia registry in an African Arab country.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {11},
pages = {e70770},
doi = {10.1002/alz.70770},
pmid = {41216919},
issn = {1552-5279},
support = {//100 PhDs for Africa programme/ ; //UM6P- EPFL Excellence in Africa Initiative/ ; //American University in Cairo, Research Support/ ; },
abstract = {INTRODUCTION: Dementia is a growing public health challenge in low- and middle-income countries (LMICs) like Egypt, where data are scarce. The Egyptian Dementia Network (EDN) registry addresses this gap by capturing epidemiological, clinical, and environmental data across Egypt.

METHODS: In this multicenter study, 662 participants from six governorates were enrolled using standardized tools.

RESULTS: The cohort had advanced age (mean 68.3 years), low education (65.9% illiterate), and high comorbidities including hypertension (55%) and diabetes (23%). Alzheimer's disease (62%) and vascular dementia (23%) predominated. Only 24.4% received pharmacological treatment and 2.1% psychosocial support, highlighting care gaps. Household insecticide exposure (20.4%) was notable.

DISCUSSION: EDN demonstrates the feasibility of implementing a national dementia registry in LMICs, generating baseline insights into demographic, clinical, and environmental risks. In addition, registry-linked biosamples have enabled pilot multi‑omics and exposome analyses, underscoring its potential as a scalable scientific platform for future dementia research.

HIGHLIGHTS: Established Egypt's first national, multicenter dementia registry. Aimed to characterize dementia profiles and care gaps across diverse regions. Identified late-stage diagnosis and limited access to dementia interventions. Uncovered unique environmental risk factors relevant to the Egyptian context. Provides a foundation for policy, research, and improved dementia care in Egypt.},
}

@article {pmid41216806,
year = {2025},
author = {Oveisgharan, S and Yu, L and Wang, Y and Yang, J and Vialle, R and Lopes, KP and Tasaki, S and Young-Pearse, TL and De Jager, PL and Petyuk, VA and Schneider, JA and Seyfried, NT and Bennett, DA},
title = {Amyloid beta binding partners in the brain tissue of older adults.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {11},
pages = {e70882},
doi = {10.1002/alz.70882},
pmid = {41216806},
issn = {1552-5279},
support = {P30AG10161/NH/NIH HHS/United States ; P30AG72975/NH/NIH HHS/United States ; R01AG17917. R01AG015819/NH/NIH HHS/United States ; U01AG072572/NH/NIH HHS/United States ; U01AG046152/NH/NIH HHS/United States ; R01AG088643/NH/NIH HHS/United States ; R01AG088643/AG/NIA NIH HHS/United States ; },
abstract = {INTRODUCTION: The mechanism linking extracellular amyloid beta (Aβ) with intraneuronal tau tangles, pathological hallmarks of Alzheimer's disease (AD), is not understood; it was tested in the current study through Aβ binding partners.

METHODS: Data were from decedents of community-based clinical-pathological studies. Of 52 Aβ binding partners, suggested by non-human studies, levels of 34 together with total Aβ protein were quantified in the dorsolateral prefrontal cortex. Post mortem pathological assessment immunohistochemically quantified Aβ load and tau tangle density.

RESULTS: The strongest mediations between Aβ and tau tangles were observed for Ras-related C3 botulinum toxin substrate 1 (RAC1) and sodium/potassium-transporting ATPase subunit alpha-3 (ATP1A3), which collectively mediated 10.1% of the association between Aβ and tau tangles. In contrast, Aβ mediated >70% of the associations of matrix proteins with tau tangles.

DISCUSSION: Identification of Aβ binding partners that mediate the association between Aβ and tau tangles may provide new targets for AD treatment.

HIGHLIGHTS: RAC1 linked Aβ with tau tangles. ATP1A3 linked Aβ with tau. RAC1 and ATP1A3 collectively mediated 10.1% of the association between Aβ and tau. Aβ mediated >70% of the associations of matrix proteins, such as APOE, with tau.},
}

@article {pmid41216805,
year = {2025},
author = {Lopergolo, D and Gasparini, D and Bianchi, S and Pucci, B and Tripodi, D and Leoni, V and Chincarini, A and Sestini, S and Zetterberg, H and De Stefano, N and Mignarri, A},
title = {Miglustat in Alzheimer's Disease Associated With Heterozygous NPC1 Mutation: Exploratory Case Series and Preliminary Findings.},
journal = {European journal of neurology},
volume = {32},
number = {11},
pages = {e70419},
doi = {10.1111/ene.70419},
pmid = {41216805},
issn = {1468-1331},
support = {2023-00356//Swedish Research Council/ ; 2022-01018//Swedish Research Council/ ; 2019-02397//Swedish Research Council/ ; 101053962//European Union's Horizon Europe research and innovation programme/ ; #ALFGBG-71320//Swedish State Support for Clinical Research/ ; 201809-2016862//Alzheimer Drug Discovery Foundation (ADDF), USA/ ; ADSF-21-831376-C//AD Strategic Fund and the Alzheimer's Association/ ; ADSF-21-831381-C//AD Strategic Fund and the Alzheimer's Association/ ; ADSF-21-831377-C//AD Strategic Fund and the Alzheimer's Association/ ; ADSF-24-1284328-C//AD Strategic Fund and the Alzheimer's Association/ ; 22HLT07//European Partnership on Metrology/ ; //Bluefield Project/ ; //Cure Alzheimer's Fund/ ; //Olav Thon Foundation/ ; //Erling-Persson Family Foundation/ ; },
abstract = {INTRODUCTION: Several studies have previously demonstrated an increased risk of dementia and brain amyloid deposition in individuals with heterozygous NPC1 mutations. Moreover, in a recent study, we identified the first family with autosomal dominant late-onset Alzheimer's disease (AD) caused by a heterozygous NPC1 mutation. Unfortunately, there are currently no effective treatments available for this condition. Miglustat, which impacts the metabolism of oxysterols, has been shown to exert an anti-amyloidogenic effect in a human cellular model of AD.

METHODS: In our exploratory uncontrolled study, three patients from the previously published family were orally treated with miglustat for 12 months. They underwent monthly clinical evaluations and routine blood tests. Additionally, neuropsychological evaluations, brain amyloid-PET imaging, and biochemical analyses on plasma and CSF were performed.

RESULTS: All three patients achieved clinical stability, showed a sustained reduction in serum oxysterol levels, and experienced a marked decrease in brain amyloid burden.

DISCUSSION: Based on our preliminary observations and hypothesis-generating findings, along with the growing evidence suggesting AD as a lipid disorder, miglustat should be further tested in a larger cohort of heterozygous NPC1 mutated patients and probably evaluated as a potential disease-modifying treatment for AD.},
}

@article {pmid41216328,
year = {2025},
author = {Mohammadi, S and Zarei, S},
title = {Predicting Alzheimer's disease from environmental risk factors: An fMRI-based functional connectivity and advanced machine learning approach.},
journal = {Journal of environmental health science & engineering},
volume = {23},
number = {2},
pages = {39},
pmid = {41216328},
issn = {2052-336X},
abstract = {Alzheimer's disease (AD) is a prevalent and severe neurodegenerative disorder influenced by both genetic and environmental factors-such as air pollution, toxic elements, pesticides, and infectious agents. In recent years, machine learning techniques have become essential in biomedical research, advancing fields like drug delivery and medical imaging through predictive modeling and pattern recognition. Functional connectivity derived from functional magnetic resonance imaging (fMRI) serves as a promising noninvasive biomarker for AD by mapping the brain's connectome and revealing neural network disruptions. In this study, we employed the Robust Multitask Feature Extraction Method to evaluate six supervised machine learning algorithms logistic regression, naïve Bayes, support vector machine, random forest, XGBoost, and CatBoostmfor AD diagnosis. A dataset of 140 fMRI images from an equal number of AD patients and healthy individuals (mean age 67.3 ± 6.7 years) was analyzed. The XGBoost algorithm demonstrated exceptional performance, achieving an accuracy of 98.2%, a recall of 96.6%, perfect precision (100%), an F1-Score of 98.2%, and a Matthews correlation coefficient of 0.96 effectively minimizing false positives and negatives. Although CatBoost and Random Forest also yielded robust results, logistic regression and naïve Bayes showed lower reliability. Overall, XGBoost emerges as a robust solution for the early and precise prediction of Alzheimer's disease, carrying significant implications for proactive patient care and treatment strategies. Beyond these findings, emerging research is exploring multimodal imaging techniques-such as PET and EEG and deeper neural network architectures to further enhance early diagnostic accuracy and treatment personalization in AD.},
}

@article {pmid41215663,
year = {2025},
author = {Guo, Z and Ni, H and Lu, Y and Cui, Z and Wang, Y and Zhu, Z and Wei, X and Xia, C and Xu, M and Du, L and Yang, Y and Shu, S and Wang, K and Wang, Z and Shan, C and Wang, D},
title = {TNEA Regulates Hippocampal Oscillation by Improving Inhibitory Synaptic Plasticity to Ameliorates Cognitive Impairment in Alzheimer's Disease.},
journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
volume = {},
number = {},
pages = {e10885},
doi = {10.1002/advs.202510885},
pmid = {41215663},
issn = {2198-3844},
support = {62127810//National Natural Science Foundation of China/ ; 82272612//National Natural Science Foundation of China/ ; 82374581//National Natural Science Foundation of China/ ; 21DZ2271000//Shanghai Key Laboratory of Health Identification and Assessment/ ; YC-2023-0604//Pudong New Area of Highland Discipline development program/ ; PWRq2023-36//Pudong New Area Outstanding Young Medical Professionals Training Program/ ; YC-2024-0104//Pudong Traditional Chinese Medicine Standardization & Capacity Building Project/ ; },
abstract = {Three-needle electroacupuncture (TNEA) has demonstrated efficacy in improving cognitive function in both Alzheimer's disease (AD) model animals and patients, although its underlying mechanism remains unclear. Here this work investigates the potential connection between cognitive-enhancing effect and TNEA in 5×familial Alzheimer disease（5xFAD) mice model, a model characterized by Amyloid-beta (Aβ) pathology. This work finds alterations in gamma/theta oscillations and deficits in inhibitory monosynaptic transmission in the hippocampal CA1 region of AD. Parvalbumin-positive (PV[+]) interneurons are crucial for generating gamma oscillations and modulating theta oscillation, thereby maintaining the excitation-inhibition (E/I) balance in local neural circuits. In 5xFAD mice, TNEA modulated PV[+] interneuron function, enhancing gamma oscillations during quiescent states. Furthermore, during the novel object recognition test (NORT), TNEA increased theta oscillation power by strengthening presynaptic inhibitory interneurons involved in monosynaptic connections. Collectively, these findings suggest TNEA is a viable minimally invasive treatment approach for AD.},
}

@article {pmid41215623,
year = {2025},
author = {Li, LL and Wang, RZ and Wang, Z and Hu, H and Xu, W and Zhu, L and Sun, Y and Chen, KL and Chen, SF and He, XY and Yuan, MY and Huang, YY and Liu, X and Liu, P and Ye, QY and Wang, J and Ju, ZZ and Zhang, W and Hu, B and Guo, Y and Cao, XY and Li, YX and Zuo, CT and Cheng, W and Jiang, T and Tan, L and Chen, XC and Zhao, QH and Cui, M and Peng, GP and Xin, JW and Yu, JT},
title = {Safety and short-term outcomes of lecanemab for Alzheimer's disease in China: a multicentre study.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awaf427},
pmid = {41215623},
issn = {1460-2156},
abstract = {Lecanemab is a newly approved monoclonal antibody targeting amyloid plaques for the treatment of early Alzheimer's disease. This study aimed to evaluate the safety and short-term biomarkers and cognition changes of lecanemab in Chinese clinical practice. This multicenter real-world study involved patients receiving lecanemab treatment across seven hospitals in China. Patients underwent comprehensive assessments before treatment. Lecanemab was administered via intravenous infusion every 2 weeks. Treatment-related symptoms were monitored through self-report, and amyloid-related imaging abnormalities were assessed via magnetic resonance imaging. Amyloid and tau biomarker changes were measured using positron emission tomography imaging or plasma testing. Follow-up cognitive assessments were evaluated after 6 months of treatment. Short-term outcomes were analyzed using linear mixed-effect models, without an untreated control group. A total of 407 patients who received at least one lecanemab infusion were involved in this study, with a mean follow-up time of 5.6±3.39 months. The mean age was 68.08 years, with 67.57% of patients being female. Of the participants, 56.51% were APOE ε4 carriers, and 83.19% were at biological stage C. During the study period, 22.22% of the patients experienced treatment-related symptoms, and 12.15% developed at least one amyloid-related imaging abnormality. Only four symptomatic and seven severe amyloid-related imaging abnormality cases were reported. APOE ε4 status was not related to adverse events in the Chinese population. Patients with a higher number of microhemorrhages at baseline were more likely to develop adverse events. No significant differences in adverse events were observed between the moderate Alzheimer's disease dementia group and the mild cognitive impairment group. By the end of the research period, 9.38% of the patients withdrew from lecanemab. After 6 months of treatment, favourable short-term outcomes in biomarkers and stable cognitive function were observed. This study demonstrates that lecanemab treatment is feasible and well-tolerated among the Chinese population, with lower rates of adverse events and favourable short-term outcomes observed. Administration of lecanemab in moderate AD dementia population was relatively safe and further studies are warranted.},
}

@article {pmid41213497,
year = {2025},
author = {Hu, K and Li, C and Liu, Y and Pan, C and Xie, P and Wen, L and Xu, H and Tang, Y and Zheng, P and Huang, Y},
title = {Arabinoxylan ameliorates memory deficits and amyloid pathology in male 5 × FAD mice via modulation of gut microbiota structure.},
journal = {Neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuroscience.2025.11.010},
pmid = {41213497},
issn = {1873-7544},
abstract = {Alzheimer's disease (AD), a prevalent neurodegenerative disorder, is primarily characterized by β-amyloid (Aβ) deposition. Current therapies alleviate symptoms but lack agents capable of modifying disease progression. Meanwhile, cross-regional studies indicate that AD patients exhibit disrupted gut microbiota composition, which is closely associated with cerebral molecular dysregulation. Building on this gut-brain connection, this study aimed to attenuate AD progression by targeting gut microbiota through microbially metabolized carbohydrates. Specifically, using 5 × FAD mice modeling AD pathology, we conducted 16S rRNA sequencing, targeted metabolomics of microbiota-derived metabolites, and bulk RNA sequencing experiments to investigate gut-brain axis alterations. Our results show that AD mice exhibited gut dysbiosis, depletion of short chain fatty acids (SCFAs), and transcriptomic dysregulation in the hippocampus, particularly affecting aging and synaptic plasticity-related genes. Dietary intervention with arabinoxylan significantly increased SCFAs-producing bacteria (Oscillospiraceae and Eubacterium_coprostanoligenes_group), elevated butyric acid, and thereby reversed expression levels of these aging and synaptic plasticity-related genes. Mechanistically, arabinoxylan alleviated AD-like symptoms by modulating the microbiota-gut-brain (MGB) axis; this beneficial effect occurred through enrichment of probiotic bacteria that produce SCFAs to regulate hippocampal synaptic plasticity genes. Collectively, this work proposes arabinoxylan as a novel prebiotic strategy and identifies candidate therapeutic targets for AD treatment.},
}

@article {pmid41213496,
year = {2025},
author = {Abdulkhaliq, AA and Alasiri, G and Almoghrabi, YM and Kim, B and Khan, J and Ajoolabady, A and Ren, J and Tuomilehto, J and Borai, A and Pratico, D},
title = {Role of TREM2 in neuroinflammation.},
journal = {Experimental neurology},
volume = {},
number = {},
pages = {115547},
doi = {10.1016/j.expneurol.2025.115547},
pmid = {41213496},
issn = {1090-2430},
abstract = {Triggering receptor expressed on myeloid cells 2 (TREM2) is cell surface transmembrane receptor of the TREM family, predominantly expressed on microglia within the central nervous system (CNS). Accumulating evidence has highlighted a critical role for microglial TREM2 in modulating inflammatory signaling pathways, thereby influencing the course of neuroinflammation - a central pathological hallmark of various neurodegenerative and CNS disorders. In this review, we aim to elucidate the molecular mechanisms by which TREM2 regulates neuroinflammatory processes, with a particular focus on the most recent advances in the field. A deeper understanding of TREM2-mediated signaling may uncover novel therapeutic targets and pathways with significant translational potential for treatment of CNS diseases.},
}

@article {pmid41213450,
year = {2025},
author = {Huang, Y and Han, M and Fu, Y and Wang, G and Kong, L and Mo, J and Cao, D and Chu, Z and Li, W},
title = {HY-021068 improves neuronal ferroptosis by activating Nrf2 signaling in APP/PS1 Mice and Aβ1-42-induced HT22 cells.},
journal = {European journal of pharmacology},
volume = {},
number = {},
pages = {178349},
doi = {10.1016/j.ejphar.2025.178349},
pmid = {41213450},
issn = {1879-0712},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder with an unclear pathogenesis and no effective treatment methods. HY-021068 (HY), a novel class I drug, exhibits significant neuroprotective properties in ischemic brain injury. Recent studies suggest that neuronal ferroptosis may be a critical contributor to the onset and progression of AD. However, it is still unclear whether HY treatment has protective effects on AD by inhibiting ferroptosis. In this study, APP/PS1 double transgenic mice were used to investigate the effect and mechanism of HY in AD. In vitro, HT22 cells were stimulated with Amyloid β1-42 (Aβ1-42) (5 μM) to elucidate the therapeutic effect of HY and its potential mechanism. The present study indicated that HY treatment significantly improved cognitive dysfunction, enhanced synaptic integrity by upregulating PSD95 and Synapsin I, and reduced Aβ plaque load, APP, beta-secretase 1 (BACE1) expression, and Tau hyperphosphorylation. Furthermore, HY increased glutathione peroxidase 4 (Gpx4) and Cystine/glutamate transporter (xCT) levels, while reduced DMT1 and transferrin receptor expression, eventually inhibiting neuronal ferroptosis. Mechanistically, HY decreased reactive oxygen species (ROS) accumulation and activated the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway by elevating Nrf2, haem oxygenase 1 (HO1), and NAD(P)H quinone oxidoreductase 1 (NQO1) expression. The in vitro study also suggested that the Nrf2 inhibitor ML385 markedly diminished the protective effects of HY, while the Nrf2 activator dimethyl fumarate (DMF) resulted in a significant enhancement of HY's therapeutic effects in Aβ1-42-induced HT22 cells. Molecular docking and cellular thermal shift assay showed that HY had an interaction with Nrf2. These results suggested that HY could ameliorate AD-related cognitive decline and neuronal ferroptosis through activating Nrf2 pathway, positioning it as a promising therapeutic strategy for AD.},
}

@article {pmid41213069,
year = {2025},
author = {Lin, Y and Zhao, H and Meng, D and Wang, M},
title = {The Role of T Cells in Alzheimer's Disease.},
journal = {Critical reviews in immunology},
volume = {45},
number = {6},
pages = {53-67},
doi = {10.1615/CritRevImmunol.2025061107},
pmid = {41213069},
issn = {1040-8401},
abstract = {Alzheimer's disease (AD) is a global neurodegenerative disorder characterized by progressive cognitive decline. Its core pathology involves neurofibrillary tangles mediated by hyperphosphorylated tau protein and senile plaques formed by extracellular deposits of β-amyloid. As the global incidence of AD continues to rise, human health faces a serious threat. However, the complexity of its pathogenesis poses significant challenges to current prevention and treatment strategies. Recent studies reveal that T cells, as key components of the adaptive immune system, exhibit abnormalities in both quantity and function within the brains of AD patients. They infiltrate brain parenchyma through multiple pathways-including the blood-brain barrier, choroid plexus, and meningeal lymphatics-and are deeply involved in AD pathology. In this review, we first introduce recent discoveries in the pathogenesis of AD, including tau protein, β-amyloid plaques, and neuroinflammation. We then describe the immune mechanisms and infiltration pathways of T cells in AD. Finally, we focus on the mechanisms by which different T cell subtypes contribute to brain damage in AD, aiming to provide a theoretical foundation for developing AD therapies guided by neuroimmune homeostasis.},
}

@article {pmid41212646,
year = {2025},
author = {Song, W and Fang, M and Geng, Z and Pang, X and Yang, C and Chen, M and Song, B and Hu, C and Hu, Y and Hu, W and Zhou, S and Yan, Y and Wu, X and Wang, K},
title = {Mechanistic study of Alzheimer's disease with behavioral and psychological symptoms based on electroencephalography microstates.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251393715},
doi = {10.1177/13872877251393715},
pmid = {41212646},
issn = {1875-8908},
abstract = {BackgroundBehavioral and psychological symptoms of dementia (BPSD) are common in Alzheimer's disease (AD), yet their mechanisms remain unclear.ObjectiveWe aim to explore the possible neurophysiological mechanisms of BPSD using high temporal resolution electroencephalography (EEG) microstate technology, laying the foundation for clinical evaluation and subsequent treatment.MethodsWe enrolled 52 AD patients (25 with BPSD, 27 without) and 29 age- and gender-matched healthy controls (HC). All participants underwent various neuropsychological assessments and resting-state EEG recordings. Resting-state EEG data were analyzed employing microstate analysis techniques, with a focus on four key microstate parameters: duration, occurrence, coverage, and transition probability. Inter-group comparisons were performed using post-hoc tests, with statistical significance determined through False Discovery Rate (FDR) correction. Furthermore, the correlations between the indicators and neuropsychological assessment scores were analyzed.ResultsCompared to the HC and non-BPSD groups, the BPSD group showed an increase in the transition rate from microstate A to microstate C. Compared to the HC group, the BPSD group showed an extension in the duration of microstate A and a decrease in the frequency of microstate D. Compared to the HC group, the non-BPSD group showed prolonged durations (A, B, mean) and reduced occurrences (C, D, mean).The partial correlation analysis with years of education as a covariate showed that in the BPSD group, the duration of microstate A was correlated with the severity of the Neuropsychiatric Inventory (NPI) and the Hamilton Anxiety Scale (HAMA).ConclusionsAD with and without BPSD exhibits different altered brain dynamics.},
}

@article {pmid41212436,
year = {2025},
author = {Vizuete, AFK and Moreira, AP and Zin, LEF and de Oliveira Marques, C and Pacheco, RF and Leal, MB and Menezes, L and Gonçalves, CA},
title = {Neuroprotective Roles of Metformin in a Streptozotocin-Induced Dementia Model in Rats.},
journal = {Neurotoxicity research},
volume = {43},
number = {6},
pages = {48},
pmid = {41212436},
issn = {1476-3524},
abstract = {Alzheimer's disease (AD) is the leading cause of dementia in humans, with high social and economic costs. AD is predominantly a sporadic disorder, and its risk increases with age and in individuals with type 2 diabetes mellitus (T2DM). Metformin is considered the first line drug for treatment of T2DM and has a plethora of effects in the peripheral and nervous system. However, the neuroprotective mechanism of action of this drug is still under debate. In order to assess the effects of metformin in dementia, we investigated the optimal time to start metformin treatment in animals that were submitted to intracerebroventricular (ICV) administration of streptozotocin (STZ) (3 mg/kg) to induce a sporadic AD-like rodent model of dementia. We used two protocols of metformin administration: early metformin (50 mg/Kg/daily) treatment (2 days after STZ model induction, lasting 28 days) and late metformin (50 mg/Kg/daily) treatment (20 weeks after STZ model induction, lasting 28 days). Both time points improved cognitive behavior in STZ rats, as evaluated by the novel object recognition and Morris's water maze tasks. Moreover, both treatments reduced neuroinflammatory parameters, such as TLR4, RAGE, TNF-α and NF-κB protein expression, induced in STZ animals. Metformin downregulated the methylglyoxal/RAGE/NOX‑2 signaling pathway by restoring glyoxalase 1 activity and GSH levels, which are impaired in the STZ-induced dementia model. Our data contribute to understanding the neuroprotective role of metformin, particularly in conditions involving insulin resistance, such as diabetic encephalopathy and AD.},
}

@article {pmid41212353,
year = {2025},
author = {Shademan, B and Yousefi, H and Sharafkhani, R and Nourazarian, A},
title = {LPS-Induced Neuroinflammation Disrupts Brain-Derived Neurotrophic Factor and Kinase Pathways in Alzheimer's Disease Cell Models.},
journal = {Cellular and molecular neurobiology},
volume = {45},
number = {1},
pages = {102},
pmid = {41212353},
issn = {1573-6830},
support = {(IR.KHOY.REC.1402.030//Khoy University of Medical Sciences/ ; },
abstract = {Alzheimer's disease (AD) leads to a progressive loss of cognitive abilities and memory. A critical factor now recognized as driving AD pathology is neuroinflammation-inflammation occurring in the nervous system, which contributes to neuronal harm and communication breakdowns. our research investigated the specific effects of neuroinflammation on neuronal signaling pathways. In this study, we primarily employed the SH-SY5Y neuroblastoma cell line as an in vitro neuronal model to investigate inflammatory responses relevant to AD etiology, alongside supplementary observations in primary neurons and 3D spheroids for comparative analysis. Our analysis focused on modifications of key molecules, including the neuroprotective protein Brain-Derived Neurotrophic Factor (BDNF), pro-inflammatory cytokines such as IL-6 and TNF-α, and crucial regulatory kinases. Our results demonstrated that LPS treatment dramatically lowered the vitality and decreased BDNF levels in the SH-SY5Y cells. Furthermore, we observed a considerable elevation in the pro-inflammatory cytokines IL-6 and TNF-α, coupled with elevated levels of COX-2 and iNOS. Gene expression data validated that LPS treatment altered the expression of essential signaling kinases (Protein Kinase A (PKA), Protein Kinase B (AKT), and Mitogen-Activated Protein Kinase (MAPK)). Our first comparative analysis revealed that 3D spheroid cultures may elicit more pronounced inflammatory responses than standard 2D cultures; nevertheless, our detailed investigation primarily focused on the SH-SY5Y model. This study revealed that LPS-induced neuroinflammation affects neuronal signaling in vitro, thereby revealing a relationship between inflammation and neuronal dysfunction in cellular models of neuroinflammation. These findings highlight pathways that may be relevant to AD pathophysiology; however, further in vivo studies are necessary to demonstrate their translational relevance to humans.},
}

@article {pmid41211282,
year = {2025},
author = {Olaolorun, F and Howes, MR and Elufioye, T and Odeku, OA and Olopade, J and Chazot, P},
title = {Iron chelation as a therapeutic target in vanadium neurotoxicity and Parkinson's disease: role of medicinal plants.},
journal = {Frontiers in neurology},
volume = {16},
number = {},
pages = {1667943},
pmid = {41211282},
issn = {1664-2295},
abstract = {Bioprospecting plant natural products has yielded significant success in the development of symptomatic treatment of neurodegenerative diseases, including the two most common, Alzheimer's and Parkinson's diseases (PD). Dysregulation of iron has been strongly implicated in the pathophysiology of these serious intractable diseases. A series of Nigerian endemic plants' methanolic extracts were explored using a Ferrozine binding iron chelation assay. This identified Spondias purpurea L. (SP) leaves as a potential therapeutic candidate and this was determined by evaluation of oxidative stress in 6-hydroxydopamine (6-OHDA)-exposed monoamine cell culture and Drosophila models of PD and vanadium neurotoxicity. SP treatment protected CAD cells against 6-OHDA toxicity and improved survival in PINK-1 mutant flies, though it had little effect on motor deficits. Furthermore, SP treatment reduced the vanadium-induced reactive oxygen species, and notably, staggered SP treatment significantly extended lifespan in vanadium-treated flies. Overall, Spondias purpurea L. leaf methanolic extract exhibited iron-chelating, antioxidant, neuroprotective, and life-extending properties, relevant to Parkinson's disease and vanadium-induced toxicity.},
}

@article {pmid41211099,
year = {2025},
author = {Viani, A and Custo, A and d'Angremont, E and Garibotto, V and Frisoni, GB and Gutman, BA and Lorenzi, M},
title = {Disease Progression Modeling and Stratification for detecting sub-trajectories in the natural history of pathologies: Application to Alzheimer's disease trajectory modeling.},
journal = {Imaging neuroscience (Cambridge, Mass.)},
volume = {3},
number = {},
pages = {},
pmid = {41211099},
issn = {2837-6056},
abstract = {Quantifying the progression of degenerative diseases remains crucial for early diagnosis, prevention, and treatment. However, accurately modeling disease biomarker evolution is hindered by substantial variability in disease trajectories among individuals, driven by demographic, genetic, and lifestyle factors. This variability gives rise to heterogeneous phenotypic manifestations, underscoring the need for stratification based on underlying disease subtypes. Recent advances have shown promise in unsupervised stratification of disease trajectories. Yet, current approaches face significant challenges related to robustness, biomarker specificity, interpretability, and temporal resolution of clustering results. To address these challenges, we introduce Disease Progression Modeling and Stratification (DPMoSt), a new probabilistic model designed to optimize clusters of continuous trajectories along a long-term disease time axis. This approach allows for the determination of subtype-specific biomarkers, improving the accuracy of patient stratification and generalization on external cohorts. We demonstrate DPMoSt on both synthetic and real-world data for the modeling of Alzheimer's disease (AD) evolution. In the synthetic experiments, DPMoSt shows high accuracy in reconstructing trajectory subtypes and identifying the biomarkers' specificity for the clustering problem. Our experiments in the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset demonstrate the ability of DPMoSt to identify AD subtypes associated with accelerated cognitive decline and higher prevalence of the APOE4 variants. This result was validated on the external memory clinic cohort of the Geneva University Hospitals, confirming the association between cognitive decline and APOE4 in the pathological subtype. These results highlight the robustness of DPMoSt as well as its potential for broader applicability, offering a powerful tool for studying disease progression and subtype differentiation across diverse populations.},
}

@article {pmid41209367,
year = {2025},
author = {Xie, Z and Hu, J and Stallings-Smith, S and Kulshreshtha, A and Hong, YR},
title = {Rural-urban differences in modifiable dementia risk factors among U.S. populations aged 45 years or older.},
journal = {Journal of Alzheimer's disease reports},
volume = {9},
number = {},
pages = {25424823251395318},
pmid = {41209367},
issn = {2542-4823},
abstract = {BACKGROUND: Alzheimer's disease and related dementias (ADRD) have become a significant public health concern, and the burden is disproportionately concentrated in rural areas.

OBJECTIVE: To examine rural-urban differences in the prevalence of modifiable dementia risk factors and their treatment among U.S. adults aged 45 years and older, and to investigate how these disparities vary by age group and geographic region.

METHODS: This cross-sectional study analyzed nationally representative data from the 2023 National Health Interview Survey in 2025. Prevalence of 11 modifiable dementia risk factors (hypertension, high cholesterol, diabetes, obesity, hearing loss, visual impairment, traumatic brain injury, low education, depression, social isolation, smoking) and 7 corresponding treatments were assessed via self-report. Adjusted rate ratios (aRR) were estimated using robust Poisson regression models.

RESULTS: The study population consisted of 16,981 individuals (mean age: 62.4, 51.6% female, 68.7% non-Hispanic White, 15.5% in rural areas). Rural residents had significantly higher prevalence of hypertension (aRR, 1.11; 95% CI, 1.06-1.17), obesity (aRR, 1.22; 95% CI, 1.15-1.30), diabetes (aRR, 1.29; 95% CI, 1.15-1.45), and hearing loss (aRR, 1.22; 95% CI, 1.12-1.34) compared to urban residents. Disparities were most significant among adults aged 45-64 years and in South/Midwest regions. Treatment rates for cardiometabolic conditions were high (>85%) and similar across regions, but treatment for sensory/behavioral risk factors remained low.

CONCLUSIONS: Rural U.S. adults face higher burden of modifiable dementia risk factors, particularly cardiometabolic and sensory impairments. Targeted public health strategies are needed to address structural inequities and improve dementia prevention in rural communities.},
}

@article {pmid41208730,
year = {2025},
author = {Ke, J and Ding, J and Xu, Y and Yu, C and Hong, Y and Li, S and Meng, T and Ping, Y and Yuan, H and Hu, F},
title = {Engineering microglial exosome-mediated microRNA-124-3p delivery for Alzheimer's disease combinational therapy.},
journal = {Biomaterials science},
volume = {},
number = {},
pages = {},
doi = {10.1039/d5bm01080b},
pmid = {41208730},
issn = {2047-4849},
abstract = {Currently, single-target therapy and difficulty in brain drug delivery gravely impede the treatment of Alzheimer's disease (AD). The promising development of microRNA-124-3p (miR-124-3p) serves as a possibility for multiple therapeutic approaches for AD. However, the effective delivery of miR-124-3p to AD-affected brain regions remains a major challenge, primarily due to the blood-brain barrier (BBB) and the inherent instability of therapeutic miR-124-3p. Herein, we engineered miR-124-3p-enriched microglial exosomes (Exo-124-3p) as a biomimetic nanomedicine for the multifunctional treatment of AD. Exo-124-3p can traverse the BBB and facilitate activated-microglia targeting. Subsequently, the on-demand release of miR-124-3p from Exo-124-3p decreased the aggregation of β-amyloid (Aβ) plaques, attenuated the activation of microglia/astrocytes, and exhibited a valuable neuroprotective effect, thereby remolding the AD focal microenvironment. Notably, the in vivo results demonstrated that Exo-124-3p significantly improved the cognitive function in an AD mouse model. Mechanistically, it was elucidated that Exo-124-3p can bind to the 3'UTR region of MEKK3, ultimately inhibiting the MEKK3/NF-κB signaling pathway, thereby ameliorating AD neuroinflammation. Consequently, this study not only provides a promising therapeutic approach for AD combinational therapy, but also advances the development of miRNA delivery in other brain diseases.},
}

@article {pmid41208522,
year = {2025},
author = {Wrigley, S and Huynh, ALH and Amadoru, S and Zeimer, H and Tan, I and Woodward, M and Braitberg, G and Yates, PA},
title = {Monoclonal Antibody Therapies in Alzheimer's Disease: A Guide for Emergency Physicians.},
journal = {Emergency medicine Australasia : EMA},
volume = {37},
number = {6},
pages = {e70167},
doi = {10.1111/1742-6723.70167},
pmid = {41208522},
issn = {1742-6723},
abstract = {Whilst the advent of novel disease-modifying medications for Alzheimer's disease represents potential benefit for patients and caregivers, they may be associated with adverse events that present important considerations for emergency and primary care. This article seeks to highlight some of the challenges Emergency Departments may encounter in relation to clinical presentations of people being treated with novel anti-amyloid monoclonal antibodies in the Australian context. Given the potential for harm if not recognised and managed appropriately, it is imperative that emergency clinicians are aware of possible treatment-related adverse events and have access to appropriate decision-making support and resources.},
}

@article {pmid41208074,
year = {2025},
author = {Gupta, RA and Rajni, and Shah, K and Dewangan, HK},
title = {Review on Molecular Targeting, Pharmacological Action, and Advanced Biopharmaceutical Aspects for the Management of Alzheimer's Disease.},
journal = {Current pharmaceutical design},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113816128387875250805042824},
pmid = {41208074},
issn = {1873-4286},
abstract = {Alzheimer's disease (AD) is an ongoing progressive neurodegenerative disorder that predominantly affects elderly individuals. A systematic literature search was conducted using electronic databases such as PubMed, Scopus, Web of Science, and Google Scholar. Peer-reviewed articles, clinical trial reports, and experimental studies published in English within the last 15 years were considered. The keywords used for the search included "Alzheimer's disease," "amyloid-beta," "tau protein," "neuroinflammation," "immunotherapy," "drug repurposing," and "experimental treatment strategies." It is the most common form of dementia, ultimately leading to death in advanced stages. Recent advances in AD have featured the expected role of antiamyloid, anti-tau, and anti-inflammatory therapies. Nonetheless, these treatments are still in various stages of preclinical and clinical trials. Moreover, drug repurposing is another promising avenue to identify effective therapeutic alternatives for Alzheimer's disease. This review highlights the underlying pathophysiological mechanisms of AD along with the limits of existing treatments. It also includes two methodologies, specifically; active immunotherapy and passive immunotherapy. Active immunotherapy tactics include the administration of antigens to stimulate antibody production. Additionally, this study discusses several experimental drugs and novel pharmaceutical approaches for AD.},
}

@article {pmid41206815,
year = {2025},
author = {Tian, S and Liu, Y and Hu, H and Li, S},
title = {Tau Liquid-Liquid Phase Separation in Alzheimer's Disease: Mechanisms, Pathogenesis, and Therapeutic Implications.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {18},
pmid = {41206815},
issn = {1559-1182},
support = {U24A20806//National Natural Science Foundation of China/ ; 82404605//National Natural Science Foundation of China/ ; U23A20510//National Natural Science Foundation of China/ ; BX20220048//National Postdoctoral Program For Innovative Talents/ ; 2022MD723713//China Postdoctoral Science Foundation/ ; },
abstract = {Tau protein undergoes liquid-liquid phase separation (LLPS), forming dynamic condensates that act as intermediates in the transition to neurofibrillary tangles in Alzheimer's disease (AD). This review highlights tau's dynamic and reversible LLPS behavior, an underexplored aspect of tau's role, particularly as an early pathogenic driver in AD. We summarize the molecular mechanisms and regulatory factors governing tau LLPS, with a focus on its physiological functions in microtubule stability, synaptic activity, and cellular stress responses. Additionally, we discuss how metal ions, RNA, and neurodegenerative cofactors influence tau's phase behavior in a cell-type-specific manner. Emerging strategies targeting tau LLPS-such as nanobodies, AAV-based delivery, engineered degradation platforms, and CRISPR tools-show promise for early, reversible intervention. We also explore the potential of LLPS-informed biomarkers for diagnosing and monitoring disease progression. Overall, LLPS provides a dynamic, targetable framework linking early AD pathogenesis with therapeutic innovation, opening opportunities for earlier intervention and more effective treatment strategies.},
}

@article {pmid41206776,
year = {2025},
author = {Mulet I Piera, X and Del Campo-Montoya, R and Cuadrado-Tejedor, M and Garcia-Osta, A and Garbayo, E and Blanco-Prieto, MJ},
title = {Intranasal delivery of lipid-based nanoparticles for the treatment of neurodegenerative diseases: advances, challenges and future perspectives.},
journal = {Expert opinion on drug delivery},
volume = {},
number = {},
pages = {},
doi = {10.1080/17425247.2025.2587903},
pmid = {41206776},
issn = {1744-7593},
abstract = {INTRODUCTION: Neurodegenerative diseases such as Parkinson's or Alzheimer's disease urgently require new therapeutic approaches. Despite significant efforts, no disease-modifying therapies targeting specific molecular pathways have demonstrated consistent clinical efficacy. This challenge has shifted attention toward drug delivery strategies that improve bioavailability, targeting, and patient accessibility. Intranasal delivery has emerged as a promising, noninvasive approach that bypasses the blood-brain barrier, and improves patient compliance. Lipid-based systems, especially following the success of COVID-19 vaccines, have gained attention as versatile platforms for delivering RNAs and other therapeutic molecules. Their ability to encapsulate diverse payloads and tunable composition makes them ideal candidates for targeting neurodegenerative disorders via the intranasal route.

AREAS COVERED: This review discusses recent advances in intranasal delivery for the treatment of neurodegenerative disorders, with emphasis on lipid-based nanoparticle formulations. It addresses formulation challenges such as stability, targeting efficiency, and compatibility with nasal physiology, and outlines key design parameters affecting brain delivery. Future directions are explored to advance formulation development and clinical translation.

EXPERT OPINION: Intranasal lipid-based drug delivery represents a promising strategy to bypass the blood-brain barrier in neurogenerative disorder treatment. Although regulatory gaps and the absence of long-term safety evaluation, intranasal administration offers clear advantages for CNS targeting underscoring strong potential for future clinical translation.},
}

@article {pmid41205639,
year = {2025},
author = {Bhosale, S and Chakor, R and Lohidasan, S and Sivakkumar, S and Arulmozhi, S},
title = {Neuroprotective and Nootropic Effects of a Standardised Siddha Polyherbal Formulation, Bhiramiyadhi Bhavanai Choornam, Against β-Amyloid-Induced Neurodegeneration.},
journal = {Journal of ethnopharmacology},
volume = {},
number = {},
pages = {120850},
doi = {10.1016/j.jep.2025.120850},
pmid = {41205639},
issn = {1872-7573},
abstract = {Bhiramiyadhi bhavanai choornam (BBC) is a traditional Siddha polyherbal formulation composed of 15 medicinal plants. The classical text claims that regular intake of BBC strengthens cognitive function, improves memory, boosts morale, enhances longevity, and promotes overall physical vitality Aim of the study: The present investigation focused on standardising Bhiramiyadhi bhavanai choornam and assessing its neuroprotective effect against β-amyloid-induced neurodegeneration in Wistar rats.

MATERIALS AND METHODS: Standardisation of BBC was carried out following AYUSH guidelines. A validated HPTLC method was developed for the marker compounds ascorbic acid, gallic acid, quercetin, piperine, and asiaticoside. Experimental neurodegeneration was induced by intracerebroventricular administration of Aβ1-42 in male Wistar rats. The effects of BBC were evaluated using behavioural paradigms, such as the Morris water maze, locomotor activity, social recognition, and novel object recognition tests. Biochemical assessments included acetylcholinesterase activity, brain-derived neurotrophic factor (BDNF), oxidative stress and antioxidant indices, and inflammatory cytokines. Brain histopathology was performed to assess neuronal architecture and the deposition of amyloid plaques.

RESULTS: and discussion: The HPTLC method developed provided accurate and reliable chemical profiling of BBC. Treatment with BBC significantly improved cognitive and memory performance in Aβ1-42-treated rats. It enhanced brain BDNF levels, improved antioxidant defence mechanism, reduced acetylcholinesterase activity, and suppressed oxidative stress and inflammatory cytokines. Histological studies further confirmed its protective effect by attenuating neuronal damage and plaque formation.

CONCLUSION: A validated HPTLC method was developed for the standardisation of BBC. Pharmacological findings indicate its strong neuroprotective and nootropic activities, highlighting its potential for Alzheimer's disease and related neuro disorders.},
}

@article {pmid41205178,
year = {2025},
author = {Royo Marco, A and Bruch, KR and Cowan, MN and Dill, JG and Moore, KA and Bolte, AC and Lukens, JR},
title = {Therapeutic VEGFC treatment provides protection against traumatic-brain-injury-driven tauopathy pathogenesis.},
journal = {Cell reports},
volume = {44},
number = {11},
pages = {116521},
doi = {10.1016/j.celrep.2025.116521},
pmid = {41205178},
issn = {2211-1247},
abstract = {Traumatic brain injury (TBI) increases one's risk of developing Alzheimer's disease and tauopathy. Yet, the mechanisms linking TBI to neurodegenerative disease remain poorly defined. Mounting recent evidence indicates that defects in brain lymphatic drainage contribute to multiple neurodegenerative diseases. Here, we investigated whether promoting brain lymphatic drainage recuperation following TBI via treatment with the lymphangiogenic factor vessel endothelial growth factor C (VEGFC) mitigates the ability of TBI to exacerbate tauopathy. In this study, we show that a single mild TBI leads to worsened neuropathology, brain macrophage activation, and neurodegeneration in the PS19 mouse model of tauopathy. Moreover, we find that viral-vector-based delivery of VEGFC into the meningeal compartment 24 h post-TBI ameliorates tau-mediated neurodegenerative disease pathogenesis. Findings from these studies offer new insights into how TBI leads to the development of tauopathy later in life and suggest that VEGFC-based treatments might offer a therapeutic strategy to limit tauopathy after sustaining a head injury.},
}

@article {pmid41205008,
year = {2025},
author = {Jana, K and Ghosh, S and Parua, P and Debnath, B and Halder, J and Sahoo, RK and Rai, VK and Pradhan, D and Dash, P and Das, C and Kar, B and Ghosh, G and Rath, G},
title = {Insights into the Versatile Role of Extracellular Vesicles in the Treatment of CNS Disorders.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {14},
pmid = {41205008},
issn = {1559-1182},
mesh = {Humans ; *Extracellular Vesicles/metabolism ; Animals ; *Central Nervous System Diseases/therapy/metabolism ; Drug Delivery Systems/methods ; Blood-Brain Barrier/metabolism ; },
abstract = {E xtracellular vesicles (EVs) are lipid bilayer-enclosed nanocarriers composed primarily of phospholipids and membrane proteins. They are released by cells into the surrounding extracellular environment and vary in size, composition, and biogenesis pathways. Beyond their natural role in intercellular communication, mediating the transfer of proteins, lipids, and nucleic acids (like mRNA and miRNA) between cells, EVs have emerged as a highly versatile and promising therapeutic platform for a range of challenging disorders, particularly those affecting the central nervous system (CNS) and various cancers. The CNS presents unique therapeutic challenges, notably the formidable blood-brain barrier (BBB), which restricts the entry of most conventional drugs. EVs, however, possess an inherent capacity to traverse this barrier, either naturally or through engineered modifications. This characteristic positions them as ideal nanocarriers for delivering therapeutic payloads such as neurotrophic factors, gene therapy constructs, or anti-inflammatory agents directly to target neural cells for conditions like Alzheimer's disease, Parkinson's disease, stroke recovery, multiple sclerosis, and even glioblastoma. Their biocompatibility and low immunogenicity further reduce systemic side effects, making them a safer alternative to synthetic delivery systems. This review outlines recent progress in extraction techniques using EVs for treating neurological disorders. It covers clinical applications in neurodegenerative, infectious diseases, inflammatory, genetic, and oncological diseases and highlights current limitations and considerations for advancing future research in this evolving field.},
}

Humans
*Extracellular Vesicles/metabolism
Animals
*Central Nervous System Diseases/therapy/metabolism
Drug Delivery Systems/methods
Blood-Brain Barrier/metabolism

@article {pmid41204969,
year = {2025},
author = {Phuong, HT and Tomas, RF and Akmese, C and Mijares, A and Gerstin, IM and Guo, S and Bell, LR and Ellwood, R and Yegorova, S and Ng, SK and Massey, G and Phillips, J and Melloni, A and Pletnikova, O and Lou, X and Clark, HB and Troncoso, JC and Hyman, BT and Prokop, S and Ranum, LPW and Nguyen, L},
title = {PolyGR-containing aggregates link with pathology and clinical features of Alzheimer's disease.},
journal = {Acta neuropathologica},
volume = {150},
number = {1},
pages = {49},
pmid = {41204969},
issn = {1432-0533},
mesh = {Humans ; *Alzheimer Disease/pathology/metabolism ; Male ; Female ; Aged ; Aged, 80 and over ; *Brain/pathology/metabolism ; tau Proteins/metabolism ; Plaque, Amyloid/pathology/metabolism ; Middle Aged ; Amyloid beta-Peptides/metabolism ; Protein Aggregates ; *Protein Aggregation, Pathological/pathology/metabolism ; Neurofibrillary Tangles/pathology/metabolism ; },
abstract = {Alzheimer's disease is the most common form of dementia; however, its molecular mechanisms are not fully understood. We recently identified polymeric glycine-arginine-containing (polyGR+) aggregates as a novel type of proteinopathy in AD autopsy brains. Here, we performed a comprehensive analysis to study if polyGR+ aggregates are associated with AD neuropathological changes (ADNC) and clinical features of AD cases. We show polyGR+ aggregates are detected in ~ 60% of AD postmortem brains from three AD cohorts but not age-similar controls or disease controls with primary age-related tauopathy (PART). A subtype of polyGR+ aggregates with a clustered-punctate morphology that is positive for the markers of dystrophic neurites is associated with earlier onset and shortened survival in AD cases. Increased levels of Aβ plaques and phosphorylated tau (pTau) tangles are detected in the hippocampus of AD autopsy brains with high levels of polyGR+ aggregates compared to AD autopsy brains with minimal polyGR+ staining. In addition to ADNC, a subset of polyGR+ aggregates coexists with limbic-predominant age-related TDP-43 encephalopathy neuropathological changes (LATE-NC) or Lewy body pathology (LBP). Hippocampal polyGR+ aggregate levels are ~ 3.8- and ~ 3.71-fold higher in late-onset AD cases who experienced stroke or high blood pressure, respectively. In SH-SY5Y cells, hydrogen peroxide treatment which mimics oxidative stress leads to increased levels of polyGR+ proteins produced by the CASP8 GGGAGA repeat expansion, which was recently shown to associate with increased AD risk. In addition, we show the accumulation of pTau induced by CASP8 polyGR+ protein aggregates is elevated upon hydrogen peroxide treatment. In summary, our results demonstrate polyGR+ aggregates are a frequent and understudied type of proteinopathy in AD autopsy brains and that polyGR proteinopathy is associated with ADNC.},
}

Humans
*Alzheimer Disease/pathology/metabolism
Male
Female
Aged
Aged, 80 and over
*Brain/pathology/metabolism
tau Proteins/metabolism
Plaque, Amyloid/pathology/metabolism
Middle Aged
Amyloid beta-Peptides/metabolism
Protein Aggregates
*Protein Aggregation, Pathological/pathology/metabolism
Neurofibrillary Tangles/pathology/metabolism

@article {pmid41204210,
year = {2025},
author = {Afxenti, S and Zachariou, M and Athieniti, E and Lambrianides, A and Pantzaris, M and Spyrou, GM},
title = {Integrating imaging and omics for enhanced subtyping of mild cognitive impairment associated with Alzheimer's disease.},
journal = {Journal of translational medicine},
volume = {23},
number = {1},
pages = {1240},
pmid = {41204210},
issn = {1479-5876},
support = {This research was supported by the Muscular Dystrophy Association Cyprus/Telethon Cyprus.//This research was supported by the Muscular Dystrophy Association Cyprus/Telethon Cyprus./ ; },
mesh = {Humans ; *Cognitive Dysfunction/diagnostic imaging/complications/classification ; *Alzheimer Disease/diagnostic imaging/complications/cerebrospinal fluid ; Male ; *Neuroimaging ; Female ; Aged ; Magnetic Resonance Imaging ; *Proteomics ; Biomarkers/metabolism ; Cluster Analysis ; },
abstract = {BACKGROUND: Mild Cognitive Impairment (MCI), considered the prodromal stage of Alzheimer's disease (AD), is a heterogeneous condition characterised by mild but measurable cognitive decline. However, not all individuals with MCI follow the same trajectory-some remain stable, while others progress rapidly to AD. Understanding variation in clinical, molecular, and imaging features is crucial for reducing disease heterogeneity, improving prognosis, and developing targeted interventions. This study aims to increase MCI subtyping resolution by generating enriched individual-level profiles through the integration of imaging and omics data, facilitating precision medicine approaches for AD prevention and treatment.

METHODS: We used data from the Alzheimer's Disease Neuroimaging Initiative (ADNI), including structural MRI, CSF peptidomics/proteomics, and clinical indices. Using a multi-modal integration and clustering framework, we identified distinct MCI subgroups, characterised by clinical and neuropsychological scores, AD biomarkers, biological pathway enrichments, and imaging patterns. We further employed supervised multi-modal integration and correlation analyses to explore the links between imaging, peptidomic/proteomic and clinical features within each subgroup. Additionally, we labelled individuals by future conversion to AD and analysed longitudinal cognitive function (CDRSB and MMSE scores). Finally, we performed in silico drug repurposing to identify candidate drugs targeting each subgroup's molecular profile.

RESULTS: (1) Multi-modal integration revealed two distinct MCI subgroups. (2) The Resilient Neuronal Hyperplasticity subgroup was characterised by elevated markers of neuronal plasticity, minimal brain atrophy and cortical thinning, better clinical scores, and upregulated peptide/protein markers associated with less severe structural changes. In contrast, the Vulnerable Neurodegenerative subgroup exhibited AD-like disturbances, pronounced atrophy and cortical thinning, primarily affecting executive functions, and downregulation of peptide/protein markers linked to significant structural changes. (3) Future conversion analysis revealed the second subgroup predominantly comprised fast converters, while the first predominantly consisted of stable individuals. (4) Longitudinal cognitive analysis showed a more pronounced decline in the second subgroup compared to the first. (5) Drug repurposing identified both shared and subgroup-specific candidate compounds aligned with the underlying pathologies.

CONCLUSIONS: This study delineates two MCI subgroups, using multi-modal integration, offering insights into disease heterogeneity and laying the foundation for precision medicine and AI-driven strategies in MCI and AD research and clinical care.},
}

Humans
*Cognitive Dysfunction/diagnostic imaging/complications/classification
*Alzheimer Disease/diagnostic imaging/complications/cerebrospinal fluid
Male
*Neuroimaging
Female
Aged
Magnetic Resonance Imaging
*Proteomics
Biomarkers/metabolism
Cluster Analysis

@article {pmid41203507,
year = {2025},
author = {Zhang, YP and Kedia, S and Klenerman, D},
title = {Rethinking neurodegeneration through a co-proteinopathy lens.},
journal = {Trends in neurosciences},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.tins.2025.10.006},
pmid = {41203507},
issn = {1878-108X},
abstract = {Neurodegenerative diseases have long been considered distinct proteinopathies: amyloid-β and tau in Alzheimer's disease, α-synuclein in Parkinson's disease, and TDP-43 in amyotrophic lateral sclerosis. This single-protein paradigm has guided therapeutic development for decades; yet clinical outcomes remain modest. Mounting evidence, however, reveals that protein aggregates rarely occur in isolation; instead, they coexist, colocalise, and modulate each other's pathogenicity. Here, we propose a co-proteinopathy framework that views neurodegeneration as an interactive network of misfolded proteins rather than as isolated disorders. Adopting this framework demands multiplexed quantification of protein aggregates and disease models that better reflect the biological complexity of human neurodegeneration. The co-proteinopathy perspective offers a more realistic foundation for next-generation approaches to neurodegeneration research and treatment.},
}

@article {pmid41202963,
year = {2025},
author = {Padhy, DS and Dhanve, P and Chaturvedi, K and Banerjee, S},
title = {Ambroxol rescues cognitive impairment by ameliorating oxidative stress and autophagic dysfunction in the streptozotocin-induced Alzheimer's disease model.},
journal = {European journal of pharmacology},
volume = {},
number = {},
pages = {178334},
doi = {10.1016/j.ejphar.2025.178334},
pmid = {41202963},
issn = {1879-0712},
abstract = {Alzheimer's disease (AD) is the most prevalent neurodegenerative disease, contributing to the majority of dementia cases worldwide. Due to its multifaceted and complex pathogenesis, drugs that completely halt the disease progression are still elusive. Several reports suggest that repurposing a clinically approved drug could be an excellent strategy to tackle this devastating disease. Ambroxol, a US-FDA and EMA-approved generic mucolytic drug, possess ameliorative action on various neurological ailments. However, its role as a disease-modifying drug targeting AD is yet to be studied. In this study, we elucidate the therapeutic potential of ambroxol in the streptozotocin (STZ)-induced AD model by assessing the behavioural, biochemical, and histological parameters. Intracerebroventricular (ICV) administration of STZ (3 mg/kg) was performed to mimic the AD pathology in rats. Ambroxol was administered (p.o.) at doses of 500 and 1000 mg/kg for three weeks. On day 21, behavioural tests, including the Y-maze test, novel object recognition test, and passive avoidance test, were performed to assess memory function. Subsequently, the animals were euthanised and the hippocampus was collected for biochemical, molecular and histological analysis. Three weeks of ambroxol treatment improved the cognitive performance in ICV-STZ-treated rats. Ambroxol treatment reduces oxidative stress by upregulating heme oxygenase-1 (HO-1) and lowering inducible nitric oxide synthase (iNOS) levels in the hippocampus of diseased rats. It also attenuates inflammatory and autophagic dysfunction, facilitating the clearance of amyloid beta (Aβ) aggregates in the hippocampus of ICV-STZ rats. The findings of this study suggest that ambroxol could be a viable repurposed drug candidate for AD treatment.},
}

@article {pmid41202483,
year = {2025},
author = {Yuan, C and Li, L and Lin, HY and Aubry, AV and Parise, LF and Morel, C and Chen, F and Wong, J and Russo, SJ and Wang, J},
title = {Targeting neuronal activity and neuroinflammation for the treatment of Alzheimer's disease in a mouse model.},
journal = {Neurobiology of aging},
volume = {157},
number = {},
pages = {111-118},
doi = {10.1016/j.neurobiolaging.2025.10.006},
pmid = {41202483},
issn = {1558-1497},
abstract = {Alzheimer's disease (AD) is characterized by progressive cognitive decline driven by complex pathological processes, including tau hyperphosphorylation (p-Tau), amyloid-beta (Aβ) accumulation, and neuroinflammation. In this study, we investigated the effects of two bioactive compounds, dihydrocaffeic acid (DHCA) and malvidin-glucoside (Mal-gluc), targeting inflammation and neuronal activity, respectively, on cognitive function and AD pathology in a mouse model of AD. Our results demonstrate that chronic DHCA/Mal-gluc treatment significantly improves recognition memory in 3xTg-AD mice without reducing p-Tau or Aβ burden. Employing a newly developed whole-brain cFOS and IBA-1 mapping technique, we found that this combination treatment enhances neuronal activity and promotes microglial homeostasis across multiple brain regions in 3xTg-AD mice. These findings underscore the potential of restoring neuronal function and immune homeostasis as a therapeutic approach for AD. Future study will explore the underlying mechanisms and evaluate whether DHCA/Mal-gluc, combined with currently approved Aβ monoclonal therapy, can synergistically prevent or delay AD onset and progression.},
}

@article {pmid41202479,
year = {2025},
author = {Samsami, S and Parvar, MD and Mehralitabar, H and Dehghanbanadaki, N and Naderi-Manesh, H},
title = {In silico investigation of CNS-11 as a potential inhibitor of Aβ42 aggregation and its protofibril disassembly.},
journal = {Biochemical and biophysical research communications},
volume = {790},
number = {},
pages = {152899},
doi = {10.1016/j.bbrc.2025.152899},
pmid = {41202479},
issn = {1090-2104},
abstract = {Amyloidogenic peptide aggregation and fibril formation are key components in neurodegenerative diseases such as Alzheimer's disease (AD). One effective strategy for treating these conditions involves preventing amyloid peptide aggregation by using interfering agents, such as small molecules, at the onset of amyloid peptide assembly. Another approach could involve destabilizing the formed fibrils using small molecules as well. In this study, we utilized both all-atom and coarse-grained molecular dynamics (MD) simulation methods to investigate the aggregation mechanistic details of amyloid-β42 (Aβ42) peptides, the impact of CNS-11 (a small molecule inhibitor with proven Tau fibrils decomposing agent) on this Aβ42 aggregation, and the destabilization effect of CNS-11 on an Aβ42 fiber section, alongside the Aβ42 fiber section itself. Our results demonstrated that Aβ42 monomers in the free state strongly tend to dimerize and form beta-sheets by integrating the hydrophobic sections of the Aβ42 peptides. Still, as CNS-11 was added to the system, the ligand formed a hydrophobic core composed of CNS-11 and Aβ42 peptides surrounding this core, resulting in an amorphous and significantly disordered structure. Additionally, CNS-11 could interact with the Aβ42 pre-formed fiber section, partially destabilizing it through interactions with the buried hydrophobic core. Moreover, simulating the Aβ42 fiber section revealed that the N-terminal region of these peptide aggregates is naturally flexible and capable of becoming disorganized even without the addition of external disrupting agents. This study provides comprehensive insights into the molecular-level mechanisms underlying the dual effects of CNS-11 on amyloid beta aggregation and fibril degradation. This study can provide a computational framework with the potential to be applied to various small molecules, exploring their potential in the prevention and treatment of Alzheimer's disease.},
}

@article {pmid41201547,
year = {2025},
author = {Akkaya, EC and Ilgin, R and Adil, H and Çelik, A},
title = {Magnesium L-Threonate Reduces Hippocampal Amyloid-β Load without Cognitive Improvement in a PTU-induced Hypothyroidism Model in Young Rats.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {8},
pmid = {41201547},
issn = {1559-1182},
support = {TSA-2024-565//Usak University Research Foundation/ ; },
mesh = {Animals ; *Hippocampus/metabolism/drug effects/pathology ; *Amyloid beta-Peptides/metabolism ; *Hypothyroidism/chemically induced/drug therapy/metabolism ; *Cognition/drug effects ; Disease Models, Animal ; Male ; Rats ; Rats, Wistar ; Brain-Derived Neurotrophic Factor/metabolism ; Maze Learning/drug effects ; },
abstract = {The brain is among the most critical target organs for thyroid hormones. Therefore, both congenital and acquired hypothyroidism can have significant neuropsychiatric consequences. Learning and memory problems, concentration disorders, and some psychiatric disorders such as depression can be observed in diseases causing acquired hypothyroidism. Although thyroid hormone therapy is the standard treatment, it does not always fully reverse these neuropsychiatric complications. Several studies have demonstrated the positive effects of magnesium L-threonate (MgT) supplementation on cognitive functions. Research suggests that MgT may help alleviate cognitive deficits, particularly in neurodegenerative conditions like Alzheimer's disease, where it has been associated with improvements in memory and reductions in hippocampal amyloid-β accumulation. However, there is limited data on the effect of MgT supplementation on hypothyroid conditions in the brain. The purpose of this study was to evaluate the effects of MgT supplementation on cognitive functions in hypothyroid rats. We report that while MgT supplementation did not significantly improve cognitive performance in behavioral tasks or inflammatory markers in hypothyroid rats, it did increase hippocampal BDNF levels in euthyroid animals and reduced hippocampal amyloid-β load under both euthyroid and hypothyroid conditions. The reduction in amyloid beta load under hypothyroid conditions suggests that MgT may exert partial therapeutic effects even in the absence of thyroid hormone replacement. These findings highlight the need for further studies to evaluate the therapeutic potential of MgT, particularly in combination with thyroid hormone replacement.},
}

Animals
*Hippocampus/metabolism/drug effects/pathology
*Amyloid beta-Peptides/metabolism
*Hypothyroidism/chemically induced/drug therapy/metabolism
*Cognition/drug effects
Disease Models, Animal
Male
Rats
Rats, Wistar
Brain-Derived Neurotrophic Factor/metabolism
Maze Learning/drug effects

@article {pmid41200978,
year = {2025},
author = {Zhang, Y and Fan, J and Nan, S and Pan, J and Guo, W and Zhang, Y},
title = {Rubiadin Alleviates Alzheimer's Disease Pathology via NF-κB Pathway Regulation.},
journal = {Journal of integrative neuroscience},
volume = {24},
number = {10},
pages = {33497},
doi = {10.31083/JIN33497},
pmid = {41200978},
issn = {0219-6352},
support = {20210101293JC//Natural Science Foundation of Jilin Province/ ; },
mesh = {Animals ; *Alzheimer Disease/drug therapy/metabolism/pathology ; Mice ; *NF-kappa B/metabolism/drug effects ; Disease Models, Animal ; *Neuroprotective Agents/pharmacology/administration & dosage ; *Signal Transduction/drug effects ; Mice, Transgenic ; Male ; Amyloid beta-Peptides/metabolism ; Plaque, Amyloid/metabolism/drug therapy ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is a severe neurodegenerative disorder that impacts the global impact on the population. Nevertheless, the intricate nature of its pathogenesis has posed significant challenges to drug discovery in this field. This study aimed to verify the therapeutic potential of rubiadin (RB) on AD through both in vivo and in vitro experiments, thereby facilitating translational research for the advancement of AD treatment.

METHODS: We investigated the neuroprotective effects of RB on AD using both in vivo and in vitro models. Immunohistochemistry and western blot analysis were employed to evaluate inflammatory factors and the Nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway in Mo/HuAPP695swe (APP)/PS1-dE9 (PS1) mice and N2a cells.

RESULTS: RB enhanced the memory performance of APP/PS1 mice in various tests, including the Morris water maze, step-down and step-through passive avoidance tasks, and novel object recognition. RB reduced the accumulation of Amyloid-beta (Aβ) plaques, as shown by immunohistochemical analysis. It also decreased the expression levels of pro-inflammatory cytokines interleukin (IL)-1β, IL-6, and tumor necrosis factor-alpha (TNF-α), while increasing the release of IL-4. Additionally, RB inhibited the NF-κB pathway, as demonstrated by western blot. Moreover, a cell viability test showed that RB protected N2a cells against toxicity caused by Aβ1-42 through a cell viability test. Western blot analysis revealed that neuroinflammation and the NF-κB pathway were inhibited by RB treatment in Aβ1-42-induced N2a cells. Accordingly, RB suppressed the nuclear translocation of NF-κB in Aβ1-42-induced N2a cells.

CONCLUSIONS: Our results provide experimental evidence supporting the preclinical research and future clinical applications of RB, thereby facilitating the development of new drugs for AD clinical therapy.},
}

Animals
*Alzheimer Disease/drug therapy/metabolism/pathology
Mice
*NF-kappa B/metabolism/drug effects
Disease Models, Animal
*Neuroprotective Agents/pharmacology/administration & dosage
*Signal Transduction/drug effects
Mice, Transgenic
Male
Amyloid beta-Peptides/metabolism
Plaque, Amyloid/metabolism/drug therapy

@article {pmid41200903,
year = {2025},
author = {Chockchowwat, W and Hannongbua, S and Saparpakorn, P},
title = {Role of triterpenoid derivatives from Centella asiatica as quantum chemical calculations.},
journal = {Journal of biomolecular structure & dynamics},
volume = {},
number = {},
pages = {1-17},
doi = {10.1080/07391102.2025.2578225},
pmid = {41200903},
issn = {1538-0254},
abstract = {To date, the treatment for Alzheimer's disease (AD) has focused on the cholinergic hypothesis, particularly through the inhibition of acetylcholinesterase (AChE). Asiatic acid, madecassic acid, asiaticoside, and madecassoside, which are triterpenoid derivatives from Centella asiatica, have previously been reported to exhibit the AChE inhibitory activity. This study aimed to investigate their binding modes and to determine efficient computational methods for analyzing their interactions with AChE. Molecular dynamics simulations demonstrated that most of their equilibrated structures remained within the AChE binding site. Principal component analysis and free energy landscape (FEL) confirmed their stability of the binding. Among the evaluated methods, the MM-(ALPB)SA binding energies, when combined with ligand surface binding efficiency index, showed the best correlation with experimental binding free energy. Density functional theory (DFT) calculations revealed the common key interaction between triterpenoids and AChE, including hydrogen bonds (Tyr124, Arg296, Tyr337, and Tyr341), H-π (Tyr341) and van der Waals (Trp86) interactions. Additionally, pharmacokinetics and drug-likeness predictions indicated that madecassic acid and asiatic acid are promising candidates for drug development. This study highlights the potential of triterpenoid derivatives in AChE inhibition and provides valuable insights into their binding efficiency, which could contribute to future drug discovery targeting Alzheimer's disease.},
}

@article {pmid41200863,
year = {2025},
author = {Wang, C and Shao, X and Cao, X and Fan, T and Li, Z and Wang, K and Li, M and Wang, X and Guan, P and Hu, X},
title = {Silver-functionalized carbon dots regulate amyloid aggregation and microbial infection.},
journal = {Nanoscale},
volume = {},
number = {},
pages = {},
doi = {10.1039/d5nr03379a},
pmid = {41200863},
issn = {2040-3372},
abstract = {Amyloid accumulation and microbial infections are major risk factors for Alzheimer's disease (AD). However, most of the current drugs are limited to single-target therapeutic strategies against amyloid or microbial infections, resulting in poor clinical treatment effects. Herein, we propose a novel multi-targeted strategy that can achieve multiple effects of inhibition of amyloid aggregation, depolymerization of mature amyloid fibrils, and anti-microbial infection. Experiments conducted in vitro have shown that silver-functionalized carbon dots (Ag@TACDs), at concentrations as low as 10 μg mL[-1], significantly impact the misfolding of Aβ42 and the depolymerization of Aβ42 fibrils. Moreover, Ag@TACDs exhibit outstanding ability to resist bacterial infections. At the same time, Ag@TACDs have good biocompatibility, enhance cell activity, and alleviate the cytotoxicity caused by Aβ42 oligomers. Our approach provides an effective strategy for the design of multi-target inhibitors for Alzheimer's disease.},
}

@article {pmid41199875,
year = {2025},
author = {Chande, K and Nirmal, R and Varpe, N and Doke, R and Vinchurkar, K and Singh, S},
title = {Alkaloid's undiscovered neuroprotective potential: a multi-target strategy to fight against neurodegenerative illnesses.},
journal = {3 Biotech},
volume = {15},
number = {12},
pages = {409},
pmid = {41199875},
issn = {2190-572X},
abstract = {Neurodegeneration (ND) refers to the progressive decline of neurons, leading to Alzheimer's disease, Parkinson's disease, multiple sclerosis, and Huntington's disease. These conditions are marked by gradual neuronal loss and cognitive impairment, with limited treatment options currently available. The available strategies only provide symptomatic relief and having more side effects, however none of them able to halt the disease progression, so there is strong need to develop alternative therapeutic strategies with no or less toxicity. Alkaloids, a class of naturally occurring compounds, exhibit diverse biological activities, including antioxidant and neuroprotection. Emerging research suggests that these molecules can influence key signaling pathways associated with neurodegeneration, potentially offering therapeutic benefits. By targeting multiple aspects of disease progression and modulating neuroinflammatory responses, alkaloids interact with critical molecular components such as transcription factors, receptors, and enzymes essential for neuronal survival and homeostasis. This review underscores the therapeutic potential of alkaloids in ND treatment and emphasizes the need for further research to explore their clinical applications. Future studies should aim to identify neuroprotective alkaloids, elucidate their mechanisms of action, and assess their effectiveness in treating neurodegenerative diseases. A deeper understanding of their interactions with key disease pathways is crucial for the development of effective therapeutic strategies.},
}

@article {pmid41199470,
year = {2025},
author = {Shao, Y and Liu, L and Zhu, S and Zhu, Z and Wang, P and Biswal, BB and Lin, H},
title = {Fornix Mediates Information Propagation in Brain Networks Following DLPFC-Targeted rTMS in Alzheimer's Disease: A Randomized Controlled Trial.},
journal = {CNS neuroscience & therapeutics},
volume = {31},
number = {11},
pages = {e70630},
doi = {10.1111/cns.70630},
pmid = {41199470},
issn = {1755-5949},
support = {CFH2022-2-2014//Capital's Funds for Health Improvement and Research/ ; 2022YFC2402205//National Key R&D Program of China/ ; 51977205//National Natural Science Foundation of China/ ; NSFC62401106//National Natural Science Foundation of China/ ; NSFC62171101//National Natural Science Foundation of China/ ; NSFC-AF 82211530041//NSFC Projects of International Cooperation and Exchanges/ ; 2024NSFSC1661//Sichuan Science and Technology Program/ ; },
mesh = {Humans ; *Alzheimer Disease/therapy/diagnostic imaging/physiopathology ; Male ; Female ; *Transcranial Magnetic Stimulation/methods ; Aged ; *Fornix, Brain/diagnostic imaging/physiopathology/physiology ; *Dorsolateral Prefrontal Cortex/diagnostic imaging/physiopathology/physiology ; Diffusion Tensor Imaging ; Middle Aged ; *Nerve Net/diagnostic imaging/physiopathology ; White Matter ; Aged, 80 and over ; Neural Pathways ; },
abstract = {AIMS: Repetitive transcranial magnetic stimulation (rTMS) could improve the clinical manifestations in Alzheimer's disease (AD), but its impact on deep brain tissue related to memory remains unclear. This study explored whether rTMS targeting cortical gray matter could regulate the white matter (WM) and exert modulatory effects on the network through WM bundles.

METHODS: Seventy-three AD patients underwent 14-day rTMS over the left dorsolateral prefrontal cortex (44 real, 25 sham). Granger causality analysis assessed changes in effective connectivity (EC) between the fornix and whole-brain voxels. Furthermore, the effects of rTMS treatment on fiber tracking parameters were analyzed.

RESULTS: After rTMS therapy, patients with AD showed increased EC based on fornix in the real-stimulation group. Functional network projections indicated that these clusters belonged to the frontoparietal network, the somatomotor network, as well as three white matter networks. Additionally, increased EC associated with fornix exhibited lateralization on the right side. Diffusion tensor imaging results showed no significant differences after the 14-day rTMS treatment.

CONCLUSION: In conclusion, a 14-day rTMS treatment in AD could regulate fornical function by increasing cortical-fornix EC, indicating neuroplasticity changes in response to therapy.

TRIAL REGISTRATION: Chinese Clinical Trial Registry (https://www.chictr.org.cn/index.html; ChiCTR2200062564).},
}

Humans
*Alzheimer Disease/therapy/diagnostic imaging/physiopathology
Male
Female
*Transcranial Magnetic Stimulation/methods
Aged
*Fornix, Brain/diagnostic imaging/physiopathology/physiology
*Dorsolateral Prefrontal Cortex/diagnostic imaging/physiopathology/physiology
Diffusion Tensor Imaging
Middle Aged
*Nerve Net/diagnostic imaging/physiopathology
White Matter
Aged, 80 and over
Neural Pathways

@article {pmid41198610,
year = {2025},
author = {Pirraglia, E and Osorio, RS and Glodzik, L and Ashebir, Y and Shao, Y},
title = {Subtypes of multiple-etiology dementias and the heterogeneous impact of APOE variants.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {11},
pages = {e70872},
doi = {10.1002/alz.70872},
pmid = {41198610},
issn = {1552-5279},
support = {U01OH012486//Centers for Disease Control and Prevention (CDC)/ ; U24 AG072122/NH/NIH HHS/United States ; R01NS104364/NH/NIH HHS/United States ; R01HL111724/NH/NIH HHS/United States ; P01 AG060882/AG/NIA NIH HHS/United States ; P30 AG066512/AG/NIA NIH HHS/United States ; P30AG062429/AG/NIA NIH HHS/United States ; P30AG066468/AG/NIA NIH HHS/United States ; P30AG062421/AG/NIA NIH HHS/United States ; P30AG066509/AG/NIA NIH HHS/United States ; P30AG066514/AG/NIA NIH HHS/United States ; P30AG066530/AG/NIA NIH HHS/United States ; P30AG066507/AG/NIA NIH HHS/United States ; P30AG066444/AG/NIA NIH HHS/United States ; P30AG066518/AG/NIA NIH HHS/United States ; P30AG066462/AG/NIA NIH HHS/United States ; P30AG072979/AG/NIA NIH HHS/United States ; P30AG072972/AG/NIA NIH HHS/United States ; P30AG072976/AG/NIA NIH HHS/United States ; P30AG072975/AG/NIA NIH HHS/United States ; P30AG072978/AG/NIA NIH HHS/United States ; P30AG072977/AG/NIA NIH HHS/United States ; P30AG066519/AG/NIA NIH HHS/United States ; P30AG062677/AG/NIA NIH HHS/United States ; P30AG079280/AG/NIA NIH HHS/United States ; P30AG062422/AG/NIA NIH HHS/United States ; P30AG066511/AG/NIA NIH HHS/United States ; P30AG072946/AG/NIA NIH HHS/United States ; P30AG062715/AG/NIA NIH HHS/United States ; P30AG072973/AG/NIA NIH HHS/United States ; P30AG066506/AG/NIA NIH HHS/United States ; P30AG066508/AG/NIA NIH HHS/United States ; P30AG066515/AG/NIA NIH HHS/United States ; P30AG072947/AG/NIA NIH HHS/United States ; P30AG072931/AG/NIA NIH HHS/United States ; P30AG066546/AG/NIA NIH HHS/United States ; P20AG068024/AG/NIA NIH HHS/United States ; P20AG068053/AG/NIA NIH HHS/United States ; P20AG068077/AG/NIA NIH HHS/United States ; P20AG068082/AG/NIA NIH HHS/United States ; P30AG072958/AG/NIA NIH HHS/United States ; P30AG072959/AG/NIA NIH HHS/United States ; R01AG056031/AG/NIA NIH HHS/United States ; R01AG056531/AG/NIA NIH HHS/United States ; R01AG067523/AG/NIA NIH HHS/United States ; R01AG066870/AG/NIA NIH HHS/United States ; R21AG067549/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; Male ; Female ; *Dementia/genetics/mortality/pathology/classification ; *Apolipoproteins E/genetics ; *Alzheimer Disease/pathology/genetics/mortality ; Aged ; Aged, 80 and over ; Autopsy ; *Apolipoprotein E4/genetics ; Brain/pathology ; Mixed Dementias ; },
abstract = {INTRODUCTION: Multiple-etiology dementias (MEDs) are frequently identified at autopsy but often missed in clinical diagnosis, limiting the efficiency of dementia research and treatment. This study aimed to characterize subtypes of MEDs, evaluate clinical underdiagnosis, and assess the heterogeneous impact of apolipoprotein E (APOE) variants on mortality across MED subtypes.

METHODS: Data from the National Alzheimer's Coordinating Center (NACC) repository, which includes standardized clinical and autopsy assessments, were analyzed using competing risks survival models.

RESULTS: Pure Alzheimer's disease (AD) neuropathology was rare, whereas mixed neuropathologies were common and frequently misdiagnosed as AD alone. APOE ε4 decreased mortality risk in decedents without AD neuropathology and increased mortality in decedents with mixed AD neuropathology, but not in those with AD alone. APOE ε2 increased mortality in decedents having vascular neuropathology with cerebral amyloid angiopathy.

DISCUSSION: Heterogeneity in MEDs remains substantially underrecognized clinically. The effects of APOE variants vary by dementia subtype, emphasizing the need for refined diagnostic tools and personalized dementia treatment and care approaches.

HIGHLIGHTS: Autopsy data revealed that pure Alzheimer's disease (AD) neuropathology is rare, whereas mixed pathologies are highly prevalent and frequently misdiagnosed as AD alone in clinical settings, underscoring the limitations of current diagnostic practices. Comprehensive neuropathological characterization of multiple-etiology dementia (MED) subtypes is crucial for uncovering the true complexity of dementia, which is often masked in clinical assessments. This approach enables a more accurate understanding of disease mechanisms and progression. We found that apolipoprotein E (APOE) ε4 was associated with increased mortality risk in AD with co-pathologies, but not in pure AD without other neuropathologies. Conversely, APOE ε4 was associated with decreased mortality risk in decedents who did not have AD neuropathology. APOE ε2 was protective in some AD-related subtypes but was associated with higher mortality risk in cerebral amyloid angiopathy with other vascular neuropathologies, highlighting the heterogeneous impact of genetic risk factors across subtypes. The differential effects of APOE variants across MED subtypes emphasize the need to evaluate biomarkers and risk factors within the context of underlying neuropathological profiles rather than broad clinical categories. These findings reinforce the need to develop and implement more refined, subtype-specific biomarkers and diagnostic protocols to enable precision prevention and personalized treatment strategies for the diverse forms of MED.},
}

Humans
Male
Female
*Dementia/genetics/mortality/pathology/classification
*Apolipoproteins E/genetics
*Alzheimer Disease/pathology/genetics/mortality
Aged
Aged, 80 and over
Autopsy
*Apolipoprotein E4/genetics
Brain/pathology
Mixed Dementias

@article {pmid41198603,
year = {2025},
author = {Crowley, P and Henry, AL and Flanagan, E and Antonsdottir, I and Bentley, A and Blackman, J and Bliwise, DL and Bubu, OM and Buysse, DJ and Camargos, EF and Cassidy-Eagle, E and Cote, K and Coulthard, E and D'Rozario, AL and Espie, CA and Falck, RS and Gabb, VG and Harvey, AG and Hmwe, NTT and Hoyos, CM and Jobbins, L and Kennelly, S and Kent, BA and Köpke, S and Krystal, A and Leroi, I and Liguori, C and Lim, YY and Lorenz, R and Lucey, BP and Mander, B and Moline, M and Naismith, SL and Ogunniyi, A and Rapaport, P and Reynolds, CF and Richards, K and Siengsukon, CF and Sindi, S and Singer, CM and Wirz-Justice, A and Yaffe, K and O'Caoimh, R},
title = {Development of a core outcome set for clinical trials of interventions to improve sleep in people with cognitive impairment-the Sleep in Cognitive Impairment Core Outcome Set (SCICOS).},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {11},
pages = {e70890},
doi = {10.1002/alz.70890},
pmid = {41198603},
issn = {1552-5279},
support = {HRB DTICTN-2021-003//Dementia Trials Ireland, Health Research Board Clinical Trial Network/ ; HRB DTICTN-2021-003/HRBI_/Health Research Board/Ireland ; },
mesh = {Humans ; *Cognitive Dysfunction/complications/therapy ; *Sleep Wake Disorders/therapy/etiology/complications ; *Clinical Trials as Topic ; *Outcome Assessment, Health Care ; Delphi Technique ; *Sleep ; },
abstract = {INTRODUCTION: Sleep disturbances are common in older people with cognitive impairment, potentially contributing to negative outcomes. A core outcome set (COS) is required to reduce heterogeneity in clinical trials and promote the development of high-quality evidence to support clinical management.

METHODS: A multi-stage mixed methods study was conducted in accordance with The Core Outcome Set Standards for Development.

RESULTS: A systematic review identified 287 sleep outcomes from previous clinical trials. Qualitative interviews ensured the COS was informed by what matters most to people with cognitive impairment and their caregivers. A modified Delphi process identified nine outcomes for the COS: total sleep time, sleep onset latency, wakefulness after sleep onset, number of night-time awakenings, sleep efficiency, and measures of sleep quality, daytime sleepiness, cognition, and mood.

DISCUSSION: This COS will support researchers to produce more reliable and coherent trial data to guide the management of sleep disturbances in people with neurodegenerative cognitive impairment.

HIGHLIGHTS: Evidence is lacking regarding the treatment of sleep disturbances in people with cognitive impairment. Heterogeneity of reported outcomes in clinical trials limits data synthesis. A qualitative analysis established what matters most to people with cognitive impairment and their caregivers when determining treatment effectiveness. A Delphi panel of experts agreed upon a core outcome set. This core outcome set will improve the reliability and comparability of data from future trials.},
}

Humans
*Cognitive Dysfunction/complications/therapy
*Sleep Wake Disorders/therapy/etiology/complications
*Clinical Trials as Topic
*Outcome Assessment, Health Care
Delphi Technique
*Sleep

@article {pmid41198506,
year = {2025},
author = {Lafon, PA and Prézeau, L and Pin, JP and Rondard, P},
title = {Nanobodies: a new paradigm for brain disorder therapies.},
journal = {Trends in pharmacological sciences},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.tips.2025.10.004},
pmid = {41198506},
issn = {1873-3735},
abstract = {Camelid-derived nanobodies offer a promising alternative to conventional antibodies for the treatment of brain disorders. Their current development in models of schizophrenia or Alzheimer's disease highlights their strong therapeutic potential. Optimizing their delivery and ensuring their safety are major challenges, but their modularity and low immunogenicity make them promising candidates for neurotherapy.},
}

@article {pmid41198224,
year = {2025},
author = {Yadav, D and Knight-Greenfield, A and Moirano, J and Nordvig, A and Salgado, MW and Hamed, M and Lin, M and RoyChoudhury, A and Blum, S and Keil, SA and Intorcia, B and Ebani, EJ and Osborne, J and Chiang, G and Ivanidze, J},
title = {Amyloid PET Z-score Quantification and correlation with visual semiquantitative grading.},
journal = {AJNR. American journal of neuroradiology},
volume = {},
number = {},
pages = {},
doi = {10.3174/ajnr.A9079},
pmid = {41198224},
issn = {1936-959X},
abstract = {BACKGROUND AND PURPOSE: Amyloid PET imaging plays a crucial role in the diagnosis of Alzheimer's disease (AD) and determines eligibility for anti-amyloid therapies. While visual interpretation using Regional Cortical Tracer Uptake (RCTU) and Brain Amyloid Plaque Load (BAPL) scores remains standard in clinical practice, it is subject to inter-reader variability and may not fully depict the amyloid distribution pattern. RCTU scoring evaluates cortical tracer uptake quantified as 1: no uptake, 2: focal and 3: diffuse uptake, while BAPL provides an overall summary score of amyloid plaque load depending on highest RCTU score. Quantitative techniques such as Centiloid scale or Z-scores may assist in diagnosis, grading and treatment monitoring. This study evaluates the feasibility of a Z-score quantification generated from normative database comparison and its correlation with visual RCTU grading.

MATERIALS AND METHODS: We retrospectively analyzed 100 patients who underwent [F18]-Florbetaben PET imaging between August and October 2024 for cognitive impairment. Visual interpretation was performed using RCTU scoring and overall BAPL score. Quantitative Z-scores were calculated for four cortical regions (frontal, parietal, posterior cingulate/precuneus, and lateral temporal) using a normative database. Correlation between visual and quantitative scores was assessed using Spearman's correlation. Z-score differences among RCTU categories were evaluated with Kruskal Wallis and Mann Whitney tests.

RESULTS: Among 100 patients (median age 78), 31 were amyloid negative (BAPL1), and 69 were amyloid positive (11 BAPL2, and 58 BAPL3). A total of 400 cortical regions were evaluated (143 RCTU1, 46 RCTU2, 211 RCTU3). Strong positive correlations were observed between RCTU and Z-scores in all regions (ρ = 0.78-0.88, p < 0.0001). The regional Z-scores showed significant differences between RCTU1 and RCTU2, RCTU1 and RCTU3, as well as between RCTU2 and RCTU3 across all four regions (p<0.05 for all comparisons. Pooled regional analysis also showed statistically significant differences in Z-scores between all RCTU groups (p < 0.0001).

CONCLUSIONS: Quantitative regional Z-scores derived from amyloid PET imaging demonstrate a strong correlation with visual assessment (RCTU score), validating their feasibility in clinical interpretation. These findings support the integration of quantitative tools into routine practice to enhance diagnostic confidence, reduce reader variability, and monitoring for amyloid-targeted therapies.

ABBREVIATIONS: AD = Alzheimer's Disease; RCTU = Regional Cortical Tracer Uptake; BAPL = Brain Amyloid Plaque Load; PiB = Pittsburgh Compound B; SUVR = Standardized Uptake Value Ratio; SPM = Statistical Parametric Mapping; SSP = Stereotactic Surface Projections.},
}

@article {pmid41197936,
year = {2025},
author = {Choi, H and Hwang, SB and Cho, HY and Ahn, S and Yun, HY and Song, JS},
title = {Memantine modulates neuroinflammation and motor coordination in a Parkinson's disease model.},
journal = {Brain research},
volume = {},
number = {},
pages = {150034},
doi = {10.1016/j.brainres.2025.150034},
pmid = {41197936},
issn = {1872-6240},
abstract = {Memantine, an NMDA receptor antagonist clinically approved for Alzheimer's disease, has been implicated in modulating neuroinflammatory responses beyond its anti-excitotoxic actions. To explore its potential relevance in Parkinson's disease, this study evaluated memantine's effects in both LPS-activated microglial cells and a synucleinopathy mouse model. In BV-2 cells, memantine elicited a modest but measurable attenuation of TNF-α and IL-6 secretion, which was accompanied by downregulation of TLR4 and IκB signaling. In vivo, 5-month oral administration of memantine to mThy1-αSyn transgenic mice led to moderate improvements in motor function as assessed by beam-walk performance. Immunohistochemical analyses revealed decreased microglial activation in the cerebral cortex; however, phosphorylated α-synuclein accumulation and tyrosine hydroxylase expression remained unaffected. Furthermore, spatial working memory was not improved by treatment. Taken together, these findings suggest that memantine may exert beneficial effects on neuroinflammatory processes and behavioral deficits in PD-relevant models. However, its impact on the hallmark neuropathology of PD appears limited.},
}

@article {pmid41197760,
year = {2025},
author = {Yao, M and Li, Z and Lin, Y and Cai, H and Sun, C and Liu, L and Long, Y and Ge, Z},
title = {Hyperbaric oxygen therapy ameliorates Alzheimer's disease pathology by restoration of mitophagy and suppressing neuroinflammation in 5xFAD mice.},
journal = {Experimental neurology},
volume = {},
number = {},
pages = {115534},
doi = {10.1016/j.expneurol.2025.115534},
pmid = {41197760},
issn = {1090-2430},
abstract = {Alzheimer's disease (AD) is characterized by amyloid-β (Aβ) accumulation, synaptic dysfunction, and chronic neuroinflammation. Here, we demonstrate that hyperbaric oxygen therapy (HBOT) has multiple therapeutic effects in 5xFAD transgenic mice. HBOT significantly improved cognitive function. Treated mice increasingly moved to the center of the open field in Y-maze tests and preferred a new arm. Longitudinal [18]F-AV-45 PET-MR scans showed progressive reduction in amyloid tracer uptake, which was corroborated by histologically verified reduced plaque burden and upregulation of LRP1, a key Aβ clearance transporter. HBOT preserved neuronal density and enhanced synaptic proteins. Mechanistically, HBOT promoted mitochondrial quality control by upregulating PINK1 and parkin expression, enhancing autophagosome formation, and modulating mitophagy-associated pathways. The transition of microglia to a surveillance phenotype was reflected in decreased soma area and increased branching. The coordinated improvement in amyloid clearance, mitochondrial quality control and synaptic maintenance, and modulation of neuroinflammation suggest that the ability of HBOT to simultaneously act on multiple pathological cascades-in combination with its noninvasive nature and favorable safety profile-makes it a uniquely promising therapeutic strategy. Furthermore, these results suggest that HBOT may be particularly effective at an early stage of the disease. These studies will be critical in establishing the clinical applicability of HBOT in the treatment of Alzheimer's disease.},
}