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

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

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

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

@article {pmid41110363,
year = {2025},
author = {Kuyrukcu Ozturk, O and Oyardi, O and Ilikci Sagkan, R and Dundar, Y},
title = {Synthesis and biological evaluation of some pyrimidine derivatives as multifunctional ligands for the treatment of Alzheimer's disease.},
journal = {Bioorganic & medicinal chemistry},
volume = {132},
number = {},
pages = {118445},
doi = {10.1016/j.bmc.2025.118445},
pmid = {41110363},
issn = {1464-3391},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder and acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), and sphingomyelinase (SMase) enzymes are among its therapeutic targets. In this study, a series of tetrahydropyrimidine and hexahydropyrimidine derivatives were synthesized and evaluated for their inhibition of Bacillus cereus SMase, electric eel AChE (EeAChE), and equine BuChE (eqBuChE) as potential agents against AD. Among the synthesized compounds, 4-oxo-6-(pyridin-2-yl)-2-thioxohexahydropyrimidine-5‑carbonitrile (compound 24) was found to be the most active compound against B. cereus SMase, with an IC50 value of 1.61 μM. In addition, 2-(benzylthio)-4-octyl-6-oxo-1,6-dihydropyrimidine-5‑carbonitrile (compound 14) and 4-octyl-6-oxo-2-(phenethylthio)-1,6-dihydropyrimidine-5‑carbonitrile (compound 16) exhibited selective eqBuChE inhibition with IC50 values of 3.68 and 1.65 μM, respectively. The mode of inhibition of the selected compounds was determined by enzyme kinetic study. These compounds were also examined for their metal-chelating properties with various biometals and effect of B. cereus-induced hemolysis on sheep erythrocytes. Additionally, compound 24 showed no cytotoxic effect on the HUVEC cell line at its IC50 concentration. The biological data were supported by the results of molecular docking studies, and in-silico physicochemical properties/ADME predictions of the selected compounds were determined.},
}

@article {pmid41109840,
year = {2025},
author = {Davidson, MH and Szarek, M and Scheltens, P and Vijverberg, E and Hsieh, A and Ditmarsch, M and Kling, D and Curcio, D and Nicholls, SJ and Ray, KK and Cummings, JL and Kastelein, JJ},
title = {Effect of obicetrapib, a potent cholesteryl ester transfer protein inhibitor, on p-tau217 levels in patients with cardiovascular disease.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {},
number = {},
pages = {100394},
doi = {10.1016/j.tjpad.2025.100394},
pmid = {41109840},
issn = {2426-0266},
abstract = {BACKGROUND: Cholesteryl ester transfer protein (CETP) inhibition reduces low density lipoprotein-cholesterol (LDL-C) while simultaneously increasing high density lipoprotein-cholesterol (HDL-C) levels and improving HDL-particle functionality. These lipoprotein modifications may provide a novel pathway for Alzheimer disease (AD) prevention through effects on lipid modulation, antioxidant activity, and neuro-inflammation. This approach could prove particularly beneficial for APOE4 carriers, who face elevated risks for both AD and atherosclerotic cardiovascular disease (ASCVD).

OBJECTIVES: To examine the effects of obicetrapib, an oral CETP inhibitor, on biomarker changes indicative of AD pathology among patients with ASCVD DESIGN: This was a pre-specified substudy of the BROADWAY trial, a phase 3, double-blind, placebo-controlled pivotal registration trial to evaluate the LDL-C lowering efficacy of obicetrapib in adult patients with established ASCVD and/or heterozygous familial hypercholesterolemia (HeFH), whose LDL-C was not adequately controlled, despite being on maximally tolerated lipid-lowering therapy.

SETTING: The trial was conducted across 188 sites in China, Europe, Japan, and the United States. Participants were recruited from cardiology clinics and lipid specialty centers from 2021 to 2024.

PARTICIPANTS: Participants with ASCVD in BROADWAY who had known ApoE status and phosphorylated tau-217 (p-tau217) measured at baseline and 12 months.

INTERVENTION: Participants in BROADWAY were randomized 2:1 to receive oral obicetrapib 10 mg daily or placebo for 12 months.

MEASUREMENTS: AD plasma biomarkers were measured at baseline and 12 months using standardized SIMOA assays. The key outcome measure of interest was change in plasma p-tau217 from baseline to 12 months. Other outcome measures included changes in p-tau217/(Aβ42:40), p-tau181, glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL).

RESULTS: The analysis population consisted of 1535 (61 %) of the 2530 BROADWAY participants. Median age was 67 years and 67.0 % were male. Baseline p-tau217 levels varied significantly by ApoE subgroups, with ApoE4 carriers generally having higher concentrations and ApoE4/E4 participants exhibiting the highest median concentration (0.56 pg/mL). Obicetrapib significantly attenuated p-tau217 increases compared to placebo (adjusted mean 2.09 % vs 4.94 %; P = 0.025). Treatment differences were most pronounced in ApoE4 carriers, where adjusted mean increases were 1.92 % and 6.91 %, for obicetrapib and placebo, respectively (P = 0.041). Furthermore, among ApoE4/E4 participants, there was a 7.81 % adjusted mean decrease in p-tau217 with obicetrapib compared to a 12.67 % increase with placebo, representing a 20.48 % treatment difference (P = 0.010). Positive trends were observed across secondary biomarkers, with obicetrapib also significantly limiting increases in the p-tau217/Aβ42:40 ratio compared to placebo (2.51 % vs 6.55 %; P = 0.004). In addition, among ApoE4/E4 participants, obicetrapib demonstrated significant effects on GFAP (-6.39 % vs +8.85 %; P = 0.006) and NfL (-10.49 % vs +6.82 %; P = 0.020). Strong correlations were observed between end-of-study obicetrapib plasma concentrations and biomarker improvements (r=-0.64), suggesting CETP inhibition as a potential mechanism, although other drug effects may also contribute to these changes.

CONCLUSIONS: Obicetrapib significantly slowed AD biomarker progression over 12 months in participants with ASCVD, with the greatest effects in ApoE4 carriers. Among ApoE4/E4 participants, obicetrapib reduced p-tau217 levels by a placebo-adjusted 20.48 % and demonstrated consistent effects across multiple AD biomarkers. These findings represent the first demonstration of an oral intervention capable of reducing both beta-amyloid and tau pathology biomarkers in ApoE4 carriers, offering a potential preventive strategy for this high-risk population who currently have no effective prevention options. Future research will need to establish whether these biomarker changes translate to clinical benefits in dedicated AD prevention trials.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05142722.},
}

@article {pmid41109234,
year = {2025},
author = {Boon, BDC and Piura, YD and Moloney, CM and Chalk, JL and Lincoln, SJ and Rutledge, MH and Rothberg, DM and Kouri, N and Hinkle, KM and Roemer, SF and Johnson, DR and Burkett, BJ and Lowe, VJ and Petersen, RC and Dickson, DW and Reichard, RR and Nguyen, AT and Graff-Radford, J and Knopman, DS and Graff-Radford, NR and Murray, ME},
title = {Neuropathological changes and amyloid-related imaging abnormalities in Alzheimer's disease treated with aducanumab versus untreated: a retrospective case-control study.},
journal = {The Lancet. Neurology},
volume = {24},
number = {11},
pages = {931-944},
doi = {10.1016/S1474-4422(25)00313-8},
pmid = {41109234},
issn = {1474-4465},
mesh = {Humans ; *Alzheimer Disease/drug therapy/diagnostic imaging/pathology/metabolism/genetics ; Male ; Female ; *Antibodies, Monoclonal, Humanized/therapeutic use/pharmacology ; Aged ; Retrospective Studies ; Case-Control Studies ; Positron-Emission Tomography ; *Amyloid beta-Peptides/metabolism ; *Brain/pathology/diagnostic imaging/drug effects ; Middle Aged ; Aged, 80 and over ; },
abstract = {BACKGROUND: Understanding the neuropathological effects of amyloid β (Aβ)-targeting therapies and amyloid-related imaging abnormalities (ARIA) in Alzheimer's disease is critical for optimising treatment efficacy and patient outcomes. Comparing Aβ PET imaging with neuropathological assessments provides context for evaluating the extent of Aβ clearance and interpreting in-vivo biomarkers. We aimed to assess clinicopathological changes and ARIA-related effects in aducanumab-treated versus untreated Alzheimer's disease.

METHODS: This retrospective case-control study included five aducanumab-treated participants from clinical trials conducted at the Mayo Clinic (2016-21) who underwent autopsy (2020-23). Treated participants were matched by autosomal dominant Alzheimer's disease mutation or APOE genotype, age at cognitive symptom onset, and sex to 12 untreated participants from the Mayo Clinic Alzheimer's Disease Research Center and Mayo Clinic Study of Aging cohorts in the Mayo Clinic brain bank (Jacksonville, FL, USA). Cognitive, imaging, and neuropathological outcomes were compared using descriptive analyses and Mann-Whitney U tests.

FINDINGS: Aducanumab-treated participants comprised four males and one female, all carrying at least one APOE ∊4 allele, with two harbouring a PSEN1 mutation. Cumulative dosages of aducanumab ranged from 5 mg/kg to 241 mg/kg; all participants cognitively declined during treatment, and two exhibited ARIA. Reductions in [[18]F]florbetapir PET Centiloid values ranged from -6% to -81% compared with baseline. Treatment-to-death intervals ranged from 5 months to 41 months. Neuropathological analyses revealed clearance of Aβaa1-8 and Aβ42 localised to cortical layer I in treated participants, with no significant clearance in deeper cortical layers. Regions corresponding to ARIA on MRI showed microinfarcts with haemosiderin, complement activation, and CD68-positive vessel walls originating from Aβ-laden leptomeningeal and penetrating vessels.

INTERPRETATION: Disproportionate Aβ clearance and ARIA-associated neuropathology localised to superficial cortical layers suggest a distinctive pattern of target engagement by aducanumab. These findings inform understanding and monitoring of similar Aβ-targeting therapies.

FUNDING: Alzheimer Nederland, National Institute on Aging, and Alzheimer's Association.},
}

Humans
*Alzheimer Disease/drug therapy/diagnostic imaging/pathology/metabolism/genetics
Male
Female
*Antibodies, Monoclonal, Humanized/therapeutic use/pharmacology
Aged
Retrospective Studies
Case-Control Studies
Positron-Emission Tomography
*Amyloid beta-Peptides/metabolism
*Brain/pathology/diagnostic imaging/drug effects
Middle Aged
Aged, 80 and over

@article {pmid41109226,
year = {2025},
author = {Iwatsubo, T},
title = {Neuropathology of Alzheimer's disease after anti-amyloid β antibody treatment.},
journal = {The Lancet. Neurology},
volume = {24},
number = {11},
pages = {897-899},
doi = {10.1016/S1474-4422(25)00348-5},
pmid = {41109226},
issn = {1474-4465},
}

@article {pmid41107348,
year = {2025},
author = {Zeng, Z and Zhou, F and Zheng, Y and Shi, W and Hu, W and Wang, X and Ye, M and Zhou, J and Ye, P and Yuan, F and Zou, Y and Yan, Q and Dai, Y and Tang, D},
title = {Comprehensive analysis of LncRNA-miRNA-mRNA CeRNA network associated with umbilical cord blood PBMC in down syndrome.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {36352},
pmid = {41107348},
issn = {2045-2322},
support = {No. 2017B020209001//Science and Technology Planning Project of Guangdong Province/ ; },
mesh = {Humans ; *RNA, Messenger/genetics/metabolism ; *Down Syndrome/genetics/blood ; *MicroRNAs/genetics ; *RNA, Long Noncoding/genetics ; *Fetal Blood/metabolism/cytology ; *Gene Regulatory Networks ; *Leukocytes, Mononuclear/metabolism ; Female ; Computational Biology/methods ; Gene Expression Profiling ; Gene Expression Regulation ; RNA, Competitive Endogenous ; },
abstract = {Down syndrome (DS), a typical chromosomal disease caused by all or part of an extra genomic copy of chromosome 21. Few reports have investigated roles of competing endogenous RNA (ceRNA)-mediated regulatory mechanisms in DS pathogenesis. RNA from PBMCs of cord blood from DS and non-DS fetuses was used for RNA-Seq to profile lncRNAs, miRNAs, and mRNAs. Bioinformatics revealed DS-associated differential gene expression. Predicted miRNA-mRNA/lncRNA interactions were used to build and visualize ceRNA networks in Cytoscape. A total of 216 DEmiRNAs, 651 DElncRNA and 15,789 DEmRNA transcripts were identified in umbilical cord blood PBMC RNA preparations from DS and non-DS control subjects. KEGG pathway enrichment analysis showed that DEmRNAs were involved in pathways such as Huntington's disease, Alzheimer's disease, Parkinson's disease, etc., which are closely related to DS. The 11 mRNAs corresponding to the highest degree PPI network nodes (RPS27A, UBA52, UBC, RPL11, RPS27, MRPS7, RPL23, RPL9, NFKB1, RBX1, and RELA) may play important roles in expression of DS-associated phenotypic characteristics. Finally, we constructed upregulated and downregulated lncRNA-miRNA-mRNA ceRNA sub-networks and found several pairs of ceRNAs that might be involved in DS. MIAT might serve as a ceRNA to sponge hsa-miR-378c and ultimately regulate the expression of RBX1 to affect the cell cycle and lead to DS occurrence. In this study, we comprehensively analysed gene regulatory mechanisms associated with DS progression. The lncRNA-associated ceRNAs identified here may contribute to DS diagnosis and treatment.},
}

Humans
*RNA, Messenger/genetics/metabolism
*Down Syndrome/genetics/blood
*MicroRNAs/genetics
*RNA, Long Noncoding/genetics
*Fetal Blood/metabolism/cytology
*Gene Regulatory Networks
*Leukocytes, Mononuclear/metabolism
Female
Computational Biology/methods
Gene Expression Profiling
Gene Expression Regulation
RNA, Competitive Endogenous

@article {pmid41107250,
year = {2025},
author = {Chang, JS and Huang, HZ and Yuan, M and Zhou, Y and Liu, D and Zhan, KB and Zhu, LQ},
title = {Alcohol addiction and Alzheimer's disease: a molecular collision course.},
journal = {Translational psychiatry},
volume = {15},
number = {1},
pages = {410},
pmid = {41107250},
issn = {2158-3188},
mesh = {Humans ; *Alzheimer Disease/metabolism/etiology ; *Alcoholism/complications/metabolism/therapy ; Oxidative Stress ; *Brain/metabolism ; Cognitive Dysfunction ; Neuroprotective Agents/therapeutic use ; },
abstract = {Chronic alcohol consumption is increasingly recognized as a risk factor for Alzheimer's disease (AD), contributing to cognitive decline through multiple biological pathways. Excessive alcohol intake accelerates neurodegeneration by impairing the brain's ability to clear toxic proteins, disrupting neurotransmitter balance, and exacerbating inflammation and oxidative stress. These effects collectively weaken neuronal resilience, making the brain more vulnerable to AD-related damage. Emerging therapeutic strategies focus on mitigating alcohol-induced harm through neuroprotective drugs, inflammation-targeting treatments, and neurotransmitter modulators. Lifestyle-based interventions, including early abstinence, cognitive training, and precision nutrition, also show promise in reducing risk and slowing disease progression. Future research should prioritize personalized treatment approaches and novel drug delivery methods to improve outcomes for individuals affected by both conditions.},
}

Humans
*Alzheimer Disease/metabolism/etiology
*Alcoholism/complications/metabolism/therapy
Oxidative Stress
*Brain/metabolism
Cognitive Dysfunction
Neuroprotective Agents/therapeutic use

@article {pmid41106565,
year = {2025},
author = {Sun, T and Li, Z and Xiao, B and Yang, J and Han, M and Zhang, J and Liu, S and Ma, H and Song, J and Su, Y and Cao, B and Zhang, X and Xie, Z and Zhu, H and Chen, Y and Ma, J and Wang, P and Zhang, Z},
title = {Multi-target neuroprotection of Atractylodes macrocephala ethyl acetate extract against Alzheimer's disease: from bioactivity-guided screening to mechanistic validation.},
journal = {Journal of ethnopharmacology},
volume = {},
number = {},
pages = {120735},
doi = {10.1016/j.jep.2025.120735},
pmid = {41106565},
issn = {1872-7573},
abstract = {Atractylodes macrocephala (AM) has traditionally been used for treating inflammatory conditions, edema, and digestive issues. It is now being explored for its potential in treating Alzheimer's disease (AD), which is characterized by cognitive decline and impairments in learning and memory. While AM shows promise as a potential treatment for AD, further research is needed to identify its specific bioactive components and understand its mechanisms of action.

AIM OF THE STUDY: This study aim to identify and evaluate bioactive fractions from AM for their potential to treat AD. The research focused on assessing the antioxidant, anti-inflammatory, and neuroprotective properties of these fractions to determine the most effective one. The ultimate goal was to find a basis for isolating active neuroprotective components from AM that could be used to develop new AD therapies.

MATERIALS AND METHODS: To identify AM fractions with potential against AD, the study began with in vitro assessments of their ability to inhibit amyloid-β (Aβ) aggregation and their antioxidant capacity. The neuroprotective effects of these fractions were then evaluated against Aβ1-42 and D-galactose-induced toxicity in neuronal and microglial cell lines. A C. elegans AD model (CL4176 strain) was employed to assess the impact on Aβ-induced neurodegeneration (paralysis). Based on this comprehensive screening, the ethyl acetate extract (AMEA) emerged as the most promising fraction. Its mechanism of action was investigated using network pharmacology and validated in vivo using APP/PS1 transgenic mice. Finally, key compounds within AMEA were isolated and characterized.

RESULTS: Compared to other extracts, AMEA showed stronger antioxidant, anti-inflammatory, and neuroprotective effects. In AD model mice, AMEA treatment protected the hippocampal neuronal structure, reduced damage to the pyramidal cell layer, and prevented dendritic spine loss. AMEA also significantly lowered the levels of key pro-inflammatory cytokines (IL-6, TNF-α, IL-1β) and reduced markers of microglial (IBA-1) and astrocyte (GFAP) activation, indicating reduced neuroinflammation. AMEA inhibited Aβ aggregation and improved cognitive function by reducing Aβ deposition in APP/PS1 transgenic mice. Network pharmacology analysis showed that AMEA is associated with neurodegenerative disease pathways and can regulate inflammatory mediators. UPLC-OE/MS analysis tentatively identified thirty-three phytochemicals in AMEA, including sesquiterpenoids, phenylpropanoids, coumarins, and flavonoids. Molecular docking revealed high binding affinity of compounds 3, 9, and 11 towards TNF-α, IL-6, and IL-1β, and ELISA results confirmed that compounds 3 and 11 markedly downregulated the expression of key neuroinflammatory factors. Structural isolation and bioactivity analysis of AMEA revealed that it contains bioactive components capable of protecting nerve cells from Aβ toxicity.

CONCLUSIONS: This research concludes that the AMEA fraction of AM demonstrates significantly superior neuroprotective effects against the primary pathological features of AD compared to other solvent fractions. AMEA exhibited greater efficacy in inhibiting Aβ aggregation, neutralizing free radicals, protecting nerve cells, and reducing brain inflammation across various models, including C. elegans and AD mice. Furthermore, chemical component isolation and structural identification of the AMEA fraction yielded compounds such as atractylenolide and atractylenolactam, along with their dimers, many of which possess neuroprotective properties. In conclusion, this study establishes a basis for the future identification and development of neuroprotective compounds from AM.},
}

@article {pmid41106076,
year = {2025},
author = {Yang, G and Li, J and Guo, J and Liu, Y and Yan, J and Huang, H and Liu, J and Peng, C and Gan, M and Shu, J},
title = {Monoterpenoids from Verbena officinalis exert anti-neuroinflammatory effect through suppression of the NF-κB/MAPK signaling cascades.},
journal = {Bioorganic chemistry},
volume = {166},
number = {},
pages = {109098},
doi = {10.1016/j.bioorg.2025.109098},
pmid = {41106076},
issn = {1090-2120},
abstract = {Using bioactivity-guided isolation, we identified 11 monoterpenoids from V. officinalis, including 7 previously undescribed compounds (1-3, 5, and 8-10), two of which feature a rare C4-4'/C5-2' skeleton. At 12.5 μM, all isolated compounds significantly suppressed NO and pro-inflammatory cytokine production in LPS-stimulated BV2 microglial cells. Notably, compound 5 demonstrated the most potent anti-neuroinflammatory effects by modulating the NF-κB/MAPK signaling pathway, positioning it as a potential lead compound for AD treatment. These findings not only underscore the therapeutic value of V. officinalis but also broaden the pharmacological understanding of its monoterpenoid constituents.},
}

@article {pmid41105718,
year = {2025},
author = {Lara-Simon, E and Gispert, JD and Garcia-Ojalvo, J and Villoslada, P and , },
title = {Multiscale networks in Alzheimer's disease identify brain hypometabolism as central across biological scales.},
journal = {PLoS computational biology},
volume = {21},
number = {10},
pages = {e1013583},
doi = {10.1371/journal.pcbi.1013583},
pmid = {41105718},
issn = {1553-7358},
abstract = {Alzheimer's disease encompasses multiple biological scales, spanning molecular factors, cells, tissues, and behavioral manifestations. The interplay among these scales in shaping the clinical phenotype is not yet fully comprehended. In particular, there is great interest in understanding the heterogeneity of the clinical aspects of AD in order to improve treatment and prevention, by targeting those aspects most susceptible to the disease. Here we employed a systems biology approach to address this issue, utilizing multilayer network analysis and deep phenotyping. This integrative analysis incorporated genomics, cerebrospinal fluid biomarkers, tau and amyloid beta (Aβ) PET imaging, brain MRI data, risk factors, and clinical information (cognitive tests scores, Clinical Dementia Rating and clinical diagnosis) obtained through the ADNI collaboration. Multilayer networks were built based on mutual information between the elements of each layer and between layers. Boolean simulations allowed us to identify paths that transmit dynamic information across layers. The most prominent path for predicting variables in the cognitive phenotype layer included the PET radiotracer fluorodeoxyglucose (FDG) in the posterior cingulate. Combinations of different symptomatic variables, mainly related to mental health (depression, mood swings, drowsiness) and vascular features (hypertension, cardiovascular history), were also part of the paths explaining the average phenotype. Our results show that integrating the flow of information across biological scales reveals relevant paths for AD, which can be subsequently explored as potential biomarkers or therapeutic targets. In particular, our results point for paths related with brain hypometabolism as a key feature in AD.},
}

@article {pmid41105605,
year = {2025},
author = {Bi, X and Xiao, X and Zhou, L and Liu, Q and Liu, Y and Tu, Q and Zhou, Y},
title = {Exploring multitarget molecular mechanisms of cannabidiol in Alzheimer's disease treatment using molecular simulations and modeling.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251386440},
doi = {10.1177/13872877251386440},
pmid = {41105605},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease is a progressive neurodegenerative disorder marked by amyloid-β (Aβ) plaque deposition and neurofibrillary tangles composed of hyperphosphorylated tau. Dysregulation of glycogen synthase kinase-3β (GSK3β) promotes tau hyperphosphorylation and amplifies Aβ-induced neurotoxicity, driving pathogenesis. Despite extensive research, current therapies targeting these core mechanisms remain largely ineffective at halting disease progression.ObjectiveBased on prior clinical and preclinical evidence, we hypothesize that cannabidiol (CBD), a non-psychoactive phytocannabinoid, may exert multitarget therapeutic effects in AD by modulating Aβ aggregation, tau hyperphosphorylation, and GSK3β activity.MethodsWe investigated CBD's interactions with Aβ-42/40, tau, and GSK3β using molecular docking, molecular dynamics simulations and ADMET predictions.ResultsOur results show that CBD binds to Aβ with binding free energies of -7.81 kcal/mol, -7.46 kcal/mol, and -7.25 kcal/mol, disrupting aggregation by interacting with key residues (HIS6, HIS13, HIS14, GLU14, GLU22, ASP15, and ASP23). MD simulations confirm that CBD destabilizes Aβ's β-sheet structure, preventing fibril formation. CBD binds tau with binding free energies of -9.91 kcal/mol, -9.70 kcal/mol, and -9.66 kcal/mol, disrupting tau aggregation and preventing neurofibrillary tangle formation. MD simulations show that CBD induces structural changes in tau, reducing β-sheet packing and inhibiting tau-tau interactions. CBD also binds to GSK3β with binding energies of -8.94 kcal/mol, -8.51 kcal/mol, and -8.41 kcal/mol, competing with ATP to inhibit its kinase activity and reduce tau phosphorylation. ADMET analysis indicates CBD's favorable oral bioavailability and low toxicity.ConclusionsThese findings support CBD as a promising multitarget therapeutic for AD, warranting further preclinical and clinical investigations.},
}

@article {pmid41105579,
year = {2025},
author = {Zhu, X and Liu, S and Wang, L and Liu, J and Gu, D and Huang, C},
title = {Predicting the conversion time from normal cognition to mild cognitive impairment based on dual attention convolutional networks.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251386078},
doi = {10.1177/13872877251386078},
pmid = {41105579},
issn = {1875-8908},
abstract = {BackgroundDementia, a progressive neurological disorder, is a leading cause of disability and death globally, often underdiagnosed in its early stages. Early diagnosis, prevention, and treatment are crucial for mitigating its impact on individuals and society.ObjectiveThis study aimed to predict the exact conversion time from normal cognition (NC) to mild cognitive impairment (MCI), and to provide insights for early diagnosis and treatment of dementia.MethodsA novel dual attention convolutional network model was proposed to handle high-dimensional features and limited patients' records in short-sequence time series data. It integrated feature and temporal attention modules to capture dependencies and used a custom loss function to enhance clinical interpretability.ResultsThe model significantly reduced mean squared error (MSE) by 9.67% and mean absolute error (MAE) by 26.24%, while increasing the r-square (R2) by 16.71% compared to a basic convolutional model. It effectively predicted NC to MCI conversion, offering valuable guidance for early intervention.ConclusionsThe dual attention convolutional network model effectively predicted NC to MCI conversion, providing a valuable tool for early dementia diagnosis and treatment.},
}

@article {pmid41104322,
year = {2025},
author = {Hyung, H and Jang, S and Kim, SY and Bae, JE and Park, JY and Lim, SG and Ko, J and Jang, S and Kim, JB and Chae, HY and Park, S and Yi, J and Choi, DK and Kim, MO and Lee, HS and Cho, DH and Young Ryoo, Z},
title = {Down-regulation of HSPA9 reduces tyrosine hydroxylase-positive neurons in mouse substantia nigra and induces Parkinson's disease-like motor impairments.},
journal = {Animal cells and systems},
volume = {29},
number = {1},
pages = {615-627},
pmid = {41104322},
issn = {1976-8354},
abstract = {Parkinson's disease (PD) is a progressive neurological disorder characterized by the degeneration of midbrain dopaminergic neurons and disabling motor impairments. Heat shock protein family A member 9 (HSPA9) play a crucial role in neuronal homeostasis by regulating the import of various mitochondrial proteins. HSPA9 is down-regulated in neurodegenerative diseases such as Alzheimer's disease and PD, and its loss leads to excessive mitochondrial fragmentation with oxidative stress, which subsequently causes damage to dopaminergic neurons. Moreover, HSPA9 interacts with multiple PD-associated proteins, including Pink1, DJ-1, and α-synuclein, however precise roles of HSPA9 in PD pathophysiology remain unclear. To further explore the contributions of HSPA9 in PD pathogenesis, we developed an HSPA9 knockout mouse. Haploinsufficiency of Hspa9 (Hspa9 [+/-]) was associated with the loss of tyrosine hydroxylase-positive neurons in the striatum and substantia nigra. Furthermore, Hspa9 haploinsufficiency induced excessive mitochondrial fission, enhanced apoptotic signaling, and resulted in diminished motor performance during the rotarod test. Administration of the mitochondrial neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in Hspa9 [+/-] mice further exacerbated the loss of dopaminergic neurons, aggravated motor impairments, and enhanced activation of apoptosis effector caspase-3. These results suggest that down-regulation of HSPA9 may contribute to the development and progression of PD, potentially offering a new therapeutic strategy for PD treatment.},
}

@article {pmid41104248,
year = {2025},
author = {Kasaei, A and Forouzanfar, M and Jafarinia, M},
title = {Neuroprotection by Resveratrol in Chronic Cerebral Hypoperfusion: A Study on Synaptogenesis Enhancement and Apoptosis Inhibition.},
journal = {Iranian journal of pharmaceutical research : IJPR},
volume = {24},
number = {1},
pages = {e162425},
pmid = {41104248},
issn = {1726-6890},
abstract = {BACKGROUND: Chronic cerebral hypoperfusion (CCH) is a key contributor to vascular dementia (VaD) and Alzheimer's disease. Resveratrol (RSV), a polyphenol with potential neuroprotective properties, may mitigate CCH-induced neuronal damage, but its mechanisms remain unclear.

OBJECTIVES: This study investigated RSV's effects on memory enhancement through synaptogenesis and apoptosis inhibition in the hippocampus in a rat CCH model.

METHODS: Forty male rats were randomly divided into four groups: Sham, 2-VO (bilateral carotid artery occlusion), 2-VO+RSV (2.5 mg/kg), and 2-VO+RSV (5 mg/kg). Initial group sizes (n = 10 each) were maintained by replacing deceased animals (2-VO: 7, 2-VO+RSV2.5: 4, 2-VO+RSV5: 6 deaths). The RSV was administered via intraperitoneal injection (ip) for 35 days post-surgery. Cognitive function was assessed using Morris water maze (MWM) and shuttle box tests. Hippocampal mRNA/protein levels of B-cell lymphoma 2-associated X (Bax), B-cell lymphoma 2 (Bcl-2), Caspase-3, Ras homolog family member A (RhoA), Rho-associated coiled-coil containing protein kinase 2 (ROCK2), calcium/calmodulin-dependent protein kinase II alpha (CaMKII-α), and N-methyl-D-aspartate receptor subunit 2B (NMDAR2B) were measured.

RESULTS: The RSV (5 mg/kg) significantly improved spatial memory in the MWM. Also, RSV at doses of 2.5 and 5 mg/kg significantly increased the entrance latency to the dark compartment (P < 0.05 and P < 0.01 vs 2-VO, respectively). There was a downregulation of pro-apoptotic markers (Bax, Caspase-3) and Rho/ROCK gene expressions, and an upregulation of anti-apoptotic Bcl-2 gene expression and synaptic proteins (CaMKII-α, NMDAR2B) after RSV treatment. The RSV at 5 mg/kg significantly reduced the Bax/Bcl-2 ratio compared to the 2-VO group.

CONCLUSIONS: The RSV protects against CCH-induced neuronal damage by inhibiting apoptosis and enhancing synaptic plasticity. These findings highlight RSV's therapeutic potential for vascular cognitive impairment.},
}

@article {pmid41103911,
year = {2025},
author = {Bhansali, PR and Sonkusare, SM and Savale, SS and Wijayasinghe, YS and Liao, Y and Sloan, DC and Chaturbhuj, GU and Muntean, BS},
title = {Comprehensive medicinal chemistry survey highlights a portfolio of lead molecules for Alzheimer's disease therapy.},
journal = {Frontiers in chemistry},
volume = {13},
number = {},
pages = {1642190},
pmid = {41103911},
issn = {2296-2646},
abstract = {The World Health Organization reports 10 million new patients with dementia each year. The most common form of dementia is Alzheimer's disease (AD), which constitutes up to 70% of cases. AD is mainly characterized by loss of memory, which, in addition to its debilitating individual effect, represents a burden of 1.3 trillion US dollars globally. The staggering scale of hardship has spurred intense investigations from the scientific community in search of therapeutic solutions. Recent advances to combat AD involve the identification of numerous neural targets and concomitant chemical interventions as nodes of therapy. Due to disparate biological and chemical facets of AD therapy, a comprehensive perspective covering both arenas is currently missing from the literature. This perspective aims to provide an extensive understanding of anti-AD mechanics alongside small-molecule drug design efforts from a medicinal chemist viewpoint. We are confident that this survey of the literature will provide a resourceful motivation to propel future research efforts towards successful Alzheimer's disease therapy.},
}

@article {pmid41103096,
year = {2025},
author = {Bulut, Z and Karaküçük-Iyidoğan, A and Bilge, M and Sicak, Y and Turgut-Solak, ZD and Oruç-Emre, EE},
title = {Structure-Based Design of Chiral Thioureas as Anticholinesterase Inhibitors Using Enantiopure α-Methylbenzylamines: Synthesis, Enzyme Inhibition, and In Silico Studies.},
journal = {Archiv der Pharmazie},
volume = {358},
number = {10},
pages = {e70124},
doi = {10.1002/ardp.70124},
pmid = {41103096},
issn = {1521-4184},
support = {//This study was funded by the Scientific and Technological Research Council of Türkiye (TUBITAK) with project number 222Z293./ ; },
mesh = {*Cholinesterase Inhibitors/chemical synthesis/pharmacology/chemistry ; *Thiourea/pharmacology/chemistry/chemical synthesis/analogs & derivatives ; Structure-Activity Relationship ; Butyrylcholinesterase/metabolism ; *Drug Design ; Acetylcholinesterase/metabolism ; Stereoisomerism ; Molecular Docking Simulation ; Molecular Structure ; Humans ; Dose-Response Relationship, Drug ; *Benzylamines/chemistry/pharmacology/chemical synthesis ; Animals ; Computer Simulation ; },
abstract = {A detailed analysis of the research on the treatment of Alzheimer's disease indicates that selective inhibition of butyrylcholinesterase (BChE) is the most promising strategy for identifying a drug target. According to this perspective, in this study, a new series of potential BChE inhibitors (1a-8a and 1b-8b) were designed using a structure-based design approach and synthesized as enantiomer pairs based on the benzyl thiourea attached to a chiral moiety. The in vitro anticholinesterase activity studies against acetylcholinesterase (AChE) and BChE consistently demonstrated that the majority of the designed compounds exhibited selective and potent BChE inhibition. Also, the present results of the study reveal that compound 6b, which has a methyl group at the para position of the phenyl ring and has an S configuration, was the most potent compound against BChE with an IC50 value of 1.46 ± 1.99 μM (SI = 8.47). In contrast, the chiral thioureas (8a and 8b) bearing a cyclohexyl group demonstrated higher selectivity toward AChE, with SI values of 2.10 and 2.32, respectively. Notably, compounds 2a and 2b showed dual inhibitory effects with similar potency for AChE and greater potency for BChE, compared to the standard drug galantamine. The molecular docking method, which showed a good correlation with our in vitro anticholinesterase activity results, was used to predict the interactions of all chiral thioureas within the binding pockets of AChE and BChE. Further structural improvement of these molecules in future studies may lead to the emergence of more potent AChE and BChE inhibitors.},
}

*Cholinesterase Inhibitors/chemical synthesis/pharmacology/chemistry
*Thiourea/pharmacology/chemistry/chemical synthesis/analogs & derivatives
Structure-Activity Relationship
Butyrylcholinesterase/metabolism
*Drug Design
Acetylcholinesterase/metabolism
Stereoisomerism
Molecular Docking Simulation
Molecular Structure
Humans
Dose-Response Relationship, Drug
*Benzylamines/chemistry/pharmacology/chemical synthesis
Animals
Computer Simulation

@article {pmid41102960,
year = {2025},
author = {Agarwal, U and Kapoor, G and Tonk, RK},
title = {A Review on the Pathophysiology of Alzheimer's Disease.},
journal = {Current protein & peptide science},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113892037416859250915091846},
pmid = {41102960},
issn = {1875-5550},
abstract = {INTRODUCTION: Alzheimer's disease is characterized by a complex and multifactorial pathogenesis, involving key features such as amyloid-beta plaques, tau tangles, and neuron loss. Understanding the disease requires investigating its underlying causes, as these hallmarks reflect the intricate physiological processes involved. Identifying the root factors driving AD is essential for developing effective treatments.

METHOD: This literature review was conducted using PubMed and Scopus databases, covering studies published from October 1999 to April 2025. The review included 190 references focused on the pathophysiology of Alzheimer's disease (AD). The selected studies analysed the primary pathophysiology leading to AD, particularly the accumulation of amyloid-beta plaques, tau tangles, and neuronal loss.

RESULT: The study highlights several key biological factors associated with Alzheimer's Disease (AD). These include genetic mutations, mitochondrial dysfunction, hormonal imbalances, inflammation, oxidative stress, cellular division abnormalities, and reduced levels of dopamine-related neurotransmitters. It also highlights issues with calcium regulation and the imbalance of metals, such as copper, iron, lead, and zinc, in the body. Lifestyle choices such as drinking alcohol and smoking, along with changes in blood vessels and problems with the blood-brain barrier, were also found to play a role in how the disease develops. Additionally, the presence of certain pathogens was suggested as a possible factor in the disease's underlying mechanisms.

DISCUSSION: The results indicate that a complex combination of genetic, biochemical, and environmental factors shapes the development and progression of Alzheimer's disease. Genetic mutations seem to play a significant role in affecting enzyme functions, which can disrupt vital biological processes. Problems with mitochondria and hormonal imbalances contribute to the deterioration of nerve cells, while oxidative stress and neuroinflammation are key mechanisms that worsen cellular damage. Disruptions in calcium signalling and imbalances in bio-metals further disturb neuronal stability. Lifestyle choices, blood vessel issues, and blood-brain barrier problems highlight the multifaceted nature of the disease. The study also highlights the close relationship between oxidative stress and neuroinflammation, suggesting that they may form a feedback loop that accelerates disease progression. Additionally, the possible involvement of infectious agents adds another layer of complexity, indicating that infections might trigger or worsen neurodegeneration in vulnerable individuals.

CONCLUSION: To better understand and address Alzheimer's disease, it is essential to examine the fundamental processes that trigger its development. The various and interconnected factors involved- such as genetic mutations, cellular problems, environmental factors, and exposure to pathogens- require a comprehensive and integrated approach to research and treatment. Recognizing that neuroinflammation and oxidative stress play key roles in the progression of the disease can help guide future efforts toward early detection and more precise interventions.},
}

@article {pmid41102777,
year = {2025},
author = {Lin, Y and Yoo, JM and Li, Y and Heo, Y and Okumura, M and Won, HS and Vendruscolo, M and Lim, MH and Lee, YH},
title = {Disease-disease interactions: molecular links of neurodegenerative diseases with cancer, viral infections, and type 2 diabetes.},
journal = {Translational neurodegeneration},
volume = {14},
number = {1},
pages = {52},
pmid = {41102777},
issn = {2047-9158},
support = {A439200//Korea Basic Science Institute/ ; C539200//Korea Basic Science Institute/ ; C512120//Korea Basic Science Institute/ ; C523200//Korea Basic Science Institute/ ; A412580//Korea Basic Science Institute/ ; A423310//Korea Basic Science Institute/ ; CCL22061-100//National Research Council of Science & Technology/ ; RS-2022-NR069719//National Research Foundation of Korea/ ; RS-2022-NR070709//National Research Foundation of Korea/ ; RS-2021-NR057690//National Research Foundation of Korea/ ; RS-2023-00221332//National Research Foundation of Korea/ ; RS-2024-00356469//National Research Foundation of Korea/ ; },
mesh = {Humans ; *Diabetes Mellitus, Type 2/metabolism ; *Neurodegenerative Diseases/metabolism ; Animals ; *Neoplasms/metabolism ; *Virus Diseases/metabolism ; },
abstract = {Neurodegenerative disorders, notably Alzheimer's and Parkinson's diseases, are unified by progressive neuronal loss and aberrant protein aggregation. Growing evidence indicates that these conditions are linked to cancer, infectious diseases, and type 2 diabetes through convergent molecular processes. In this review, we examine the mechanistic foundations of these links, focusing on shared features such as protein misfolding and aggregation, chronic inflammation, and dysregulated signalling pathways. We integrate cellular, animal, and human data to illustrate how pathogenic proteins may influence one another through cross-seeding and co-aggregation, and assess the implications of such interactions for disease susceptibility, progression, and treatment response. Understanding these underlying mechanisms may provide a conceptual framework for developing therapeutic approaches that target the molecular basis of multiple complex disorders.},
}

Humans
*Diabetes Mellitus, Type 2/metabolism
*Neurodegenerative Diseases/metabolism
Animals
*Neoplasms/metabolism
*Virus Diseases/metabolism

@article {pmid41102562,
year = {2025},
author = {, and Cao, H and Song, Z and Duggan, MR and Erus, G and Srinivasan, D and Tian, YE and Bai, W and Rafii, MS and Aisen, P and Belsky, DW and Walker, KA and Zalesky, A and Ferrucci, L and Davatzikos, C and Wen, J},
title = {MRI-based multi-organ clocks for healthy aging and disease assessment.},
journal = {Nature medicine},
volume = {},
number = {},
pages = {},
pmid = {41102562},
issn = {1546-170X},
support = {RF1AG092412//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; },
abstract = {Biological aging clocks across organ systems and tissues have advanced understanding of human aging and disease. In this study, we expand this framework to develop seven magnetic resonance imaging-based multi-organ biological age gaps (MRIBAGs), including the brain, heart, liver, adipose tissue, spleen, kidney and pancreas. Using data from 313,645 individuals curated by the MULTI Consortium, we link the seven MRIBAGs to 2,923 plasma proteins, 327 metabolites and 6,477,810 common genetic variants. Genome-wide associations identify 53 MRIBAG-locus pairs (P < 5 × 10[-8]). Genetic correlation and Mendelian randomization analyses support organ-specific and cross-organ interconnection, including 24 non-MRI biological aging clocks and 525 disease endpoints. Through functional gene mapping and Bayesian co-localization multi-omics evidence, we prioritize nine druggable genes as targets for future anti-aging treatments. Furthermore, the seven MRIBAGs are linked to future risk of systemic disease endpoints (for example, diabetes mellitus) and all-cause mortality. Finally, participants with more youthful versus more aged brain profiles exhibited distinct cognitive decline trajectories over 240 weeks of treatment with the Alzheimer's disease drug solanezumab, although this heterogeneity cannot be fully attributed to the drug. In summary, we developed seven MRIBAGs that enhance the existing multi-organ biological aging framework, and we demonstrate their clinical potential to advance aging research.},
}

@article {pmid41101301,
year = {2025},
author = {Sasidharan, A and Somayaji, Y and Fernandes, R},
title = {Shifting Microglial Phenotypes: Targeting Disease-Associated Microglia in Neurodegeneration.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.5c00159},
pmid = {41101301},
issn = {1948-7193},
abstract = {Neurodegenerative disorders are marked by the gradual degeneration of neurons and deterioration of cognitive function. One key underlying factor in these diseases is neuroinflammation. An essential component of this process is microglia, which are the innate immune cells that maintain homeostasis in the brain. A common outcome of microglial dysregulation in neurodegenerative diseases is chronic neuroinflammation, which exacerbates neuronal damage and impairs synaptic function. This review focuses on the dual roles that disease-associated microglia (DAMs) play in neural inflammation and neuroprotection as well as their distinct transcriptional profile in neurodegenerative diseases. DAMs engage in phagocytosis to remove debris, in addition to releasing cytokines that promote inflammation. To create an effective medicine, it is imperative to comprehend these dual functions. The roles of DAMs in Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS) are discussed, along with the mechanisms (such as the TREM2-APOE pathway) causing their activation. This review attempts to highlight the important aspects that could direct future investigations and treatment development by clarifying the interactions between DAMs and neurodegenerative diseases.},
}

@article {pmid41099783,
year = {2025},
author = {Alavian, F and Hajimohammadi, A},
title = {Interplay between gut Microbiome and glymphatic system in cognitive function and memory regulation.},
journal = {Molecular biology reports},
volume = {52},
number = {1},
pages = {1038},
pmid = {41099783},
issn = {1573-4978},
mesh = {*Gastrointestinal Microbiome/physiology ; Humans ; *Cognition/physiology ; *Glymphatic System/metabolism/physiology ; *Memory/physiology ; Animals ; Brain/metabolism ; Neurodegenerative Diseases/metabolism ; Dysbiosis ; Aquaporin 4/metabolism ; },
abstract = {The glymphatic system, a network of perivascular channels in the brain, clears toxins and metabolic products such as amyloid-β (Aβ), supporting cognitive function and preventing neurodegenerative diseases. The gut microbiome also affects brain health and cognitive functions by producing anti-inflammatory metabolites and neurotransmitters. In this narrative review study, recently published articles from reputable scientific databases were collected and analyzed. Characteristics related to the gut microbiome, its metabolites, and their impact on the glymphatic system and ultimately cognitive function were examined. These findings indicate that microbial metabolites such as short-chain fatty acids (SCFAs) and neurotransmitters such as serotonin and melatonin reduce brain inflammation and improve sleep quality and synaptic plasticity, which are essential for memory stabilization. Disruption of the gut microbiome (dysbiosis) leads to increased inflammation and dysfunction of the glymphatic system, resulting in the accumulation of toxic proteins and decreased cognitive function. Proper polarization of aquaporin-4 (AQP4), a water channel protein critical for fluid homeostasis in the brain, in astrocytes is essential for the effective functioning of this system, and its disruption is associated with diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD). Understanding the interaction between the gut microbiome and the glymphatic system presents a new pathway for regulating memory and cognitive health, which could be an important target for the prevention and treatment of neurodegenerative diseases. Enhancing the gut microbiome through probiotics and a healthy diet may improve glymphatic system function and brain health, thereby preventing cognitive disorders.},
}

*Gastrointestinal Microbiome/physiology
Humans
*Cognition/physiology
*Glymphatic System/metabolism/physiology
*Memory/physiology
Animals
Brain/metabolism
Neurodegenerative Diseases/metabolism
Dysbiosis
Aquaporin 4/metabolism

@article {pmid41099201,
year = {2025},
author = {Bolzetta, F and Durante, G and Tessari, A and Lazzarin, M and Busonera, F and Pontarin, A and Villanova, M and Vernuccio, L and Saccaro, C and Custodero, C and Portincasa, P and Barbagallo, M and Veronese, N},
title = {A simple nomogram to predict the onset of dementia in mild cognitive impairment: A retrospective study.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251379898},
doi = {10.1177/13872877251379898},
pmid = {41099201},
issn = {1875-8908},
abstract = {BackgroundCurrently there is no effective treatment to reverse Alzheimer's disease, thus prevention is crucial. Patients with mild cognitive impairment (MCI) have higher rate of progression to dementia. Two commonly used cognitive tests, Mini-Mental State Examination (MMSE) and Clock Drawing Test (CDT), have only modest accuracy at predicting conversion from MCI to dementia, whereas other potentially predicting factors are difficult to implement in clinical practice.ObjectiveThe aim of this study was to assess the performance of a combination of simple cognitive tests and routine clinical data to predict onset clinical dementia over 3-year follow-up in a cohort of outpatients with MCI.MethodsMedical history was collected, and an advanced neuropsychological assessment was performed at baseline and at follow-up.Results98 participants were included (mean age 76.6 ± 4.5 years), and 49 developed dementia. Participants who developed dementia had significantly lower MMSE and CDT scores, as well as higher presence of hypercholesterolemia at the baseline evaluation. In the multivariate binary logistic regression analysis, the OR were 0.71 (CI95% 0.58-0.87) for MMSE, 0.77 (CI95% 0.65-0.93) for CDT, and 3.9 (CI95% 1.4-10.9) for hypercholesterolemia. The ROC curve combining these three factors obtained a value of AUC of 0.825 (CI95% 0.74-0.91). A nomogram was then developed for the risk of evolution from MCI to dementia at 3 years.ConclusionsCombining history of hypercholesterolemia with CDT and MMSE tests, may result in a simple prediction model to predict the onset of dementia over 3 years.},
}

@article {pmid41099145,
year = {2025},
author = {García Ribas, G and Ferrer-Picón, E},
title = {Tolerability of rivastigmine transdermal patch in patients with Alzheimer's disease: a narrative review.},
journal = {Expert opinion on drug safety},
volume = {},
number = {},
pages = {},
doi = {10.1080/14740338.2025.2576520},
pmid = {41099145},
issn = {1744-764X},
abstract = {INTRODUCTION: The rivastigmine transdermal patch was developed to provide similar efficacy to oral rivastigmine in the treatment of Alzheimer's disease (AD), but with improved tolerability.

AREAS COVERED: Randomized clinical trials and observational studies reporting on the tolerability of the rivastigmine transdermal patch in patients with AD, identified through a systematic literature search.

EXPERT OPINION: Rivastigmine was the first cholinesterase inhibitor for which a transdermal formulation was developed; consequently, there is a substantial body of evidence on its efficacy and tolerability. The incidence of gastrointestinal AEs is markedly reduced with the transdermal patch compared with oral rivastigmine, while the efficacy of the patch remains similar to that of the oral formulation. Application site reactions are generally mild and do not cause much discomfort for the patient, and the risk of can be reduced by simple measures such as site rotation and good skin care. Tolerability of the patch improves over time, including at the highest dose level. Overall, the available evidence supports transdermal rivastigmine being generally well tolerated at doses up to 13.3 mg/24 h in patients with AD.},
}

@article {pmid41098825,
year = {2025},
author = {Zhang, X and Huang, S and Xu, H and Hu, Y and Gao, L},
title = {Research progress on plant-derived natural compounds regulating the MAPK signaling pathway for the prevention and therapy of Alzheimer's disease.},
journal = {Frontiers in pharmacology},
volume = {16},
number = {},
pages = {1666082},
pmid = {41098825},
issn = {1663-9812},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder. It is characterised by the following: amyloid-β (Aβ) deposition, tau hyperphosphorylation, neuroinflammation and oxidative stress. Unfortunately, there is no curative treatment available. Recently, natural products have attracted growing interest as potential therapeutic agents for AD, thanks to their multi-target actions and favourable safety profiles. This review highlights recent advances in the use of various natural compounds, including flavonoids, phenolic compounds, saponins, terpenoids, alkaloids and coumarins, with a particular focus on how they modulate the mitogen-activated protein kinase (MAPK) signaling pathway. Representative agents such as myricetin, nobiletin, resveratrol, gallic acid, paeoniflorin, ganoderic acid A, huperzine A, triptolide, berberine, crocin, and ginsenosides have been shown to regulate MAPK subpathways (ERK, JNK, p38), thereby attenuating oxidative stress, neuroinflammation, synaptic dysfunction, and neuronal apoptosis. Preclinical studies suggest that these compounds improve cognitive function and ameliorate AD-related pathology, thereby supporting the idea that MAPK signaling is a critical therapeutic target. Nevertheless, current evidence is limited by short-term animal experiments, insufficient toxicological evaluations, and challenges related to bioavailability and blood-brain barrier penetration. Future studies should emphasize long-term efficacy, safety assessments, optimized drug delivery systems, and high-quality clinical trials. Overall, natural products represent a valuable source for AD drug discovery, and targeting MAPK signaling offers promising opportunities for novel therapeutic development.},
}

@article {pmid41097927,
year = {2025},
author = {Kowa, H and Sato, S and Kamiki, E and Nishimoto, T},
title = {[Significance of Amyloid Plaque Removal in Alzheimer's Disease Treatment: Development of Amyloid β-Targeting Antibody Drugs Based on the Amyloid Cascade Hypothesis].},
journal = {Brain and nerve = Shinkei kenkyu no shinpo},
volume = {77},
number = {10},
pages = {1129-1136},
doi = {10.11477/mf.188160960770101129},
pmid = {41097927},
issn = {1881-6096},
mesh = {*Alzheimer Disease/drug therapy/metabolism ; Humans ; *Plaque, Amyloid/drug therapy/metabolism ; *Amyloid beta-Peptides/immunology/metabolism ; *Antibodies/therapeutic use ; },
abstract = {In a hyper-aging society, taking measures against dementia, especially against dementia due to Alzheimer's disease, which accounts for about two thirds of dementia cases, is an important task socially and economically. Forty years have passed since amyloid β was isolated from a patient, 30 years have passed since the amyloid cascade hypothesis was proposed and antibody drugs based on this hypothesis have emerged, which has led to the new era of Alzheimer's disease treatment. This article reviews the significance of amyloid plaque removal with amyloid β-targeting antibody treatment for Alzheimer's disease. (Recieved October 17, 2024; Accepted June 6, 2025; Published October 1, 2025).},
}

*Alzheimer Disease/drug therapy/metabolism
Humans
*Plaque, Amyloid/drug therapy/metabolism
*Amyloid beta-Peptides/immunology/metabolism
*Antibodies/therapeutic use

@article {pmid41097350,
year = {2025},
author = {Chakhari, S and Marco-Contelles, J and Iriepa, I and Carreiras, MDC and Chabchoub, F and Ismaili, L and Refouvelet, B},
title = {Multicomponent Synthesis of Multi-Target Quinazolines Modulating Cholinesterase, Oxidative Stress, and Amyloid Aggregation Activities for the Therapy of Alzheimer's Disease.},
journal = {Molecules (Basel, Switzerland)},
volume = {30},
number = {19},
pages = {},
doi = {10.3390/molecules30193930},
pmid = {41097350},
issn = {1420-3049},
mesh = {*Alzheimer Disease/drug therapy/metabolism ; *Oxidative Stress/drug effects ; *Quinazolines/chemical synthesis/pharmacology/chemistry ; *Amyloid beta-Peptides/metabolism/chemistry ; *Cholinesterase Inhibitors/pharmacology/chemical synthesis/chemistry ; Humans ; Antioxidants/pharmacology/chemical synthesis/chemistry ; Protein Aggregates/drug effects ; Acetylcholinesterase/metabolism ; *Cholinesterases/metabolism ; Peptide Fragments/metabolism/chemistry ; },
abstract = {Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder characterized by extracellular accumulation of amyloid-beta (Aβ) peptide, intracellular neurofibrillary tangles (NFTs), severe neuronal loss, and a marked decline in cholinergic function. Due to the limited efficacy of currently available therapies, the search for new chemical scaffolds able to target multiple pathological mechanisms remains an urgent priority. Among the most promising strategies are heterocyclic frameworks that can simultaneously interact with cholinesterase (ChE) enzymes and inhibit amyloid-β (Aβ) aggregation while also exhibiting antioxidant activity. In this context, we report a series of quinazoline derivatives synthesized via a sequential, one-pot multicomponent reaction, in good yields. Several of these compounds demonstrated notable antioxidant properties, as well as inhibitory effects on ChE activity and Aβ1-42 self-aggregation, highlighting their potential as multifunctional agents for the treatment of neurodegenerative disorders. Notably, 2-ethyl-4-(3,4-Dimethoxyphenyl)aminoquinazoline (3h) demonstrated the most balanced biological profile among the tested compounds, exhibiting an ORAC value of 5.73 TE, an acetylcholinesterase (AChE) inhibition IC50 = 6.67 μM, and 36.68% inhibition of Aβ1-42 aggregation, closely approaching the activity of curcumin. These findings highlight compound 3h as a promising quinazoline-based hit for the development of multifunctional agents targeting AD.},
}

*Alzheimer Disease/drug therapy/metabolism
*Oxidative Stress/drug effects
*Quinazolines/chemical synthesis/pharmacology/chemistry
*Amyloid beta-Peptides/metabolism/chemistry
*Cholinesterase Inhibitors/pharmacology/chemical synthesis/chemistry
Humans
Antioxidants/pharmacology/chemical synthesis/chemistry
Protein Aggregates/drug effects
Acetylcholinesterase/metabolism
*Cholinesterases/metabolism
Peptide Fragments/metabolism/chemistry

@article {pmid41097203,
year = {2025},
author = {Mohib, O and Bomans, S and Jimenez Garcia, B and Leemans, L and Ligneel, C and De Waele, E and Beckwée, D and Janssens, P},
title = {Clinical Benefits of Exogenous Ketosis in Adults with Disease: A Systematic Review.},
journal = {Nutrients},
volume = {17},
number = {19},
pages = {},
doi = {10.3390/nu17193125},
pmid = {41097203},
issn = {2072-6643},
support = {G075423N//Research Foundation - Flanders/ ; },
mesh = {Humans ; *Ketosis ; *Ketone Bodies/therapeutic use/administration & dosage ; Adult ; Cardiovascular Diseases ; *Metabolic Diseases ; COVID-19 ; Mental Disorders/drug therapy ; Nervous System Diseases ; },
abstract = {BACKGROUND/OBJECTIVES: Ketone bodies are increasingly studied for their potential therapeutic effects, particularly through exogenous ketosis, in a variety of diseases. This systematic review aimed to rigorously assess the clinical efficacy of exogenous ketosis in adults with medical conditions.

METHODS: Following PRISMA guidelines, we systematically searched MEDLINE and Scopus databases. Our inclusion criteria were defined according to the PICOS framework, focusing on studies involving exogenous ketosis in adult patients with specific diseases. The study is registered in the International Prospective Register of Systematic Reviews (PROSPERO; CRD42023492846).

RESULTS: After a stringent selection process, fifty-one studies were analyzed. Twenty-two studies focused on neurological disorders, one on psychiatric disorders, twenty-two on metabolic disorders, five on cardiovascular disorders, and one on an inflammatory disorder. Exogenous ketosis demonstrated potential benefits across multiple conditions, including Alzheimer's disease, mild cognitive impairment, McArdle's disease, various forms of heart failure, cardiogenic shock, pulmonary hypertension, and COVID-19-related acute respiratory distress syndrome, although evidence is mostly limited to surrogate endpoints with insufficient hard outcome data. Subtherapeutic ketone concentrations induced by medium-chain triglycerides and limited follow-up periods often precluded firm conclusions regarding clinically meaningful outcomes.

CONCLUSIONS: Exogenous ketosis shows potential in neurological, metabolic, and cardiovascular disorders, while evidence in psychiatric and inflammatory conditions remains scarce and preliminary. Ketone esters appear preferable for effective and tolerable ketosis. Future research should focus on identifying responsive patient populations, optimizing treatment regimens, and conducting long-term clinical trials with hard endpoints to validate these findings.},
}

Humans
*Ketosis
*Ketone Bodies/therapeutic use/administration & dosage
Adult
Cardiovascular Diseases
*Metabolic Diseases
COVID-19
Mental Disorders/drug therapy
Nervous System Diseases

@article {pmid41097011,
year = {2025},
author = {Campagnoli, LIM and Varesi, A and Fahmideh, F and Hakimizad, R and Petkovic, P and Barbieri, A and Marchesi, N and Pascale, A},
title = {From Diabetes to Degenerative Diseases: The Multifaceted Action of Metformin.},
journal = {International journal of molecular sciences},
volume = {26},
number = {19},
pages = {},
doi = {10.3390/ijms26199748},
pmid = {41097011},
issn = {1422-0067},
mesh = {Humans ; *Metformin/therapeutic use/pharmacology ; *Hypoglycemic Agents/therapeutic use/pharmacology ; *Diabetes Mellitus, Type 2/drug therapy/metabolism ; Animals ; *Neurodegenerative Diseases/drug therapy/metabolism ; AMP-Activated Protein Kinases/metabolism ; Oxidative Stress/drug effects ; Signal Transduction/drug effects ; },
abstract = {Metformin, an oral antihyperglycemic drug, represents the cornerstone of pharmacological treatment for type 2 diabetes mellitus (T2DM). Its primary glucose-lowering effects are well established, predominantly mediated through the activation of AMP-activated protein kinase (AMPK). This activation leads to a reduction in hepatic glucose production (primarily by inhibiting gluconeogenesis and glycogenolysis) and an increase in peripheral glucose uptake and utilization. Beyond its direct impact on glucose metabolism, metformin also improves insulin sensitivity and has beneficial effects on lipid profiles. Increasingly, research shows that metformin has pleiotropic effects. In addition to its recognized antihyperglycemic action, metformin is emerging as a regulator of cellular processes implicated in aging. Indeed, emerging evidence suggests a potential role of metformin in modulating pathways associated with longevity and ameliorating the symptoms of age-related diseases, including neurodegenerative disorders (such as Alzheimer's and Parkinson's diseases), cardiovascular diseases, age-related macular degeneration, and osteoporosis. The proposed mechanisms for these broader effects involve AMPK activation, modulation of the mTOR pathway, reduction of oxidative stress, and promotion of autophagy. After exploring the established role of metformin in T2D, this review provides a comprehensive investigation of its promising applications in the context of age-related diseases, offering valuable insights into its multifaceted therapeutic potential beyond glycemic control.},
}

Humans
*Metformin/therapeutic use/pharmacology
*Hypoglycemic Agents/therapeutic use/pharmacology
*Diabetes Mellitus, Type 2/drug therapy/metabolism
Animals
*Neurodegenerative Diseases/drug therapy/metabolism
AMP-Activated Protein Kinases/metabolism
Oxidative Stress/drug effects
Signal Transduction/drug effects

@article {pmid41097004,
year = {2025},
author = {Daponte, A and Koros, C and Skarlis, C and Siozios, D and Rentzos, M and Papageorgiou, SG and Anagnostouli, M},
title = {Neurofilament Biomarkers in Neurology: From Neuroinflammation to Neurodegeneration, Bridging Established and Novel Analytical Advances with Clinical Practice.},
journal = {International journal of molecular sciences},
volume = {26},
number = {19},
pages = {},
doi = {10.3390/ijms26199739},
pmid = {41097004},
issn = {1422-0067},
mesh = {Humans ; *Biomarkers/metabolism/blood ; *Neurofilament Proteins/metabolism/blood ; *Neurodegenerative Diseases/metabolism/diagnosis ; *Neuroinflammatory Diseases/metabolism/diagnosis ; Animals ; },
abstract = {Neuroaxonal damage underlies permanent disability in various neurological conditions, both neuroautoimmune and neurodegenerative. It is crucial to accurately quantify and monitor axonal injury using biomarkers to evaluate disease progression and treatment effectiveness and offer prognostic insights. Neurofilaments (NFs), and especially neurofilament light chain (NfL), show promise for this purpose, as their levels increase with neuroaxonal damage in both cerebrospinal fluid and blood, independent of specific causal pathways. Recent advances in ultrasensitive immunoassays enable the reliable detection of NFs in blood, transforming them from research tools into clinically applicable measures. In multiple sclerosis (MS), serum NfL correlates with disease activity, treatment response, and long-term disability, and may complement MRI in monitoring subclinical progression. In MS, NfL is primarily emerging as a marker of disease activity and treatment response; in amyotrophic lateral sclerosis (ALS), it has progressed further, being integrated into clinical trials as a pharmacodynamic endpoint and considered by regulatory agencies as a drug development tool. Additionally, NFs are increasingly being investigated in Alzheimer's disease, frontotemporal dementia, and other neurodegenerative disorders, though their disease specificity is limited. Ongoing challenges include older and novel assay harmonization, normative range interpretation, biological and analytical variability, and integration with other molecular and imaging biomarkers. This critical narrative review synthesizes the existing literature on NFs as diagnostic, prognostic, predictive, and pharmacodynamic biomarkers and discusses their role in therapeutic development and precision medicine in neuroautoimmune and neurodegenerative diseases.},
}

Humans
*Biomarkers/metabolism/blood
*Neurofilament Proteins/metabolism/blood
*Neurodegenerative Diseases/metabolism/diagnosis
*Neuroinflammatory Diseases/metabolism/diagnosis
Animals

@article {pmid41096835,
year = {2025},
author = {Nairuz, T and Heo, JC and Park, HJ and Lee, JH},
title = {Photobiomodulation at 660 nm Alleviates Alzheimer's Disease Pathology Through Amyloid-β Reduction and SIRT1 Upregulation in the Hippocampus of 5xFAD Mice.},
journal = {International journal of molecular sciences},
volume = {26},
number = {19},
pages = {},
doi = {10.3390/ijms26199569},
pmid = {41096835},
issn = {1422-0067},
support = {DBSD1-06,NRF-2022R1I1A307278, RS-2023-00237791,HI21C0977, RS-2021-KH118978, RS-2024-00433896,RS-2022-00166898,2020R1A6C101B189//Korea government (MSIT and Daegu Metropolitan City), the Basic Research Program through the National Research Foundation of Korea,Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), the Korea government (th/ ; },
mesh = {Animals ; *Alzheimer Disease/metabolism/pathology/radiotherapy/genetics/therapy ; *Sirtuin 1/metabolism/genetics ; *Hippocampus/metabolism/radiation effects/pathology ; *Low-Level Light Therapy/methods ; Mice, Transgenic ; *Amyloid beta-Peptides/metabolism ; Mice ; Disease Models, Animal ; Up-Regulation/radiation effects ; Male ; Humans ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-β (Aβ) accumulation, synaptic dysfunction, and cognitive decline. Current pharmacological treatments provide only symptomatic relief without altering disease progression. Photobiomodulation therapy (PBMT), a light-based intervention, has shown neuroprotective potential, although its exact neurobiological mechanisms in AD pathogenesis remain obscure. In this study, we investigated the effects of PBMT using a 660 nm wavelength light-emitting diode (LED) in 5xFAD transgenic mouse, a well-established model of early-onset AD. Mice were subjected to once daily PBMT sessions over a defined treatment period and outcomes were assessed through immunohistochemical analysis of hippocampal regions (CA1, CA2, CA3, and dentate gyrus) alongside behavioral testing using the Y-maze spontaneous alternation task. PBMT significantly reduced Aβ plaque load across hippocampal regions, accompanied by improved preservation of neuronal morphology. Furthermore, PBMT significantly upregulated SIRT1 expression, a critical regulator of synaptic plasticity and memory processes. Behaviorally, PBMT-treated mice displayed enhanced spatial working memory compared with controls, indicating a functional benefit linked to the observed molecular and structural changes. These findings suggest that 660 nm PBMT attenuates hallmark AD pathology, promotes neuroprotective pathways, and improves cognition, highlighting its potential as a disease-modifying therapy that warrants further preclinical and clinical investigation.},
}

Animals
*Alzheimer Disease/metabolism/pathology/radiotherapy/genetics/therapy
*Sirtuin 1/metabolism/genetics
*Hippocampus/metabolism/radiation effects/pathology
*Low-Level Light Therapy/methods
Mice, Transgenic
*Amyloid beta-Peptides/metabolism
Mice
Disease Models, Animal
Up-Regulation/radiation effects
Male
Humans

@article {pmid41096792,
year = {2025},
author = {Athanasaki, A and Tsantzali, I and Theodorou, A and Michalopoulou, A and Constantinides, VC and Boufidou, F and Tzartos, JS and Tsalouchidou, PE and Zompola, C and Paraskevas, SG and Bonakis, A and Giannopoulos, S and Tsivgoulis, G and Kapaki, E and Paraskevas, GP},
title = {The Biomarker Profile of Alzheimer's Disease for Disease-Modifying Treatment Eligibility: Questions and Debates.},
journal = {International journal of molecular sciences},
volume = {26},
number = {19},
pages = {},
doi = {10.3390/ijms26199531},
pmid = {41096792},
issn = {1422-0067},
mesh = {*Alzheimer Disease/metabolism/diagnosis/drug therapy/therapy/blood ; Humans ; *Biomarkers/blood/metabolism ; tau Proteins/metabolism/blood ; Amyloid beta-Peptides/metabolism ; },
abstract = {Alzheimer's disease (AD) is the most common cause of cognitive decline; currently, anti-amyloid monoclonal antibodies are available for clinical use as disease-modifying treatments, while many other substances are being tested in clinical trials. Molecular biomarkers for AD have been studied for more than two decades, and various guidelines and diagnostic recommendations have been published. However, there are still questions and controversies about the biomarker profile needed to confirm AD and the eligibility for such established treatments and clinical trials. Is amyloid positivity sufficient for eligibility, or is a biomarker for tau biochemistry/pathology also needed? What is the role of hybrid ratios combining amyloid and tau? Should we rely on plasma biomarkers alone? This review aimed to describe and discuss such questions and controversies.},
}

*Alzheimer Disease/metabolism/diagnosis/drug therapy/therapy/blood
Humans
*Biomarkers/blood/metabolism
tau Proteins/metabolism/blood
Amyloid beta-Peptides/metabolism

@article {pmid41096715,
year = {2025},
author = {Mima, Y and Yamamoto, M and Iozumi, K},
title = {Review of Promising Off-Label Use of Deucravacitinib.},
journal = {International journal of molecular sciences},
volume = {26},
number = {19},
pages = {},
doi = {10.3390/ijms26199447},
pmid = {41096715},
issn = {1422-0067},
mesh = {Humans ; *Off-Label Use ; *Protein Kinase Inhibitors/therapeutic use/pharmacology ; Animals ; *TYK2 Kinase/antagonists & inhibitors/metabolism ; Signal Transduction/drug effects ; Clinical Trials as Topic ; Psoriasis/drug therapy ; Bridged-Ring Compounds ; Pyrimidines ; },
abstract = {Tyrosine kinase 2 (TYK2) mediates the signaling pathways of proinflammatory cytokines such as interleukin (IL)-12, IL-23, and type I interferons (IFNs) and plays a pivotal role in the pathogenesis of psoriasis and various other immune-mediated diseases. Deucravacitinib, a selective oral TYK2 inhibitor, has been approved for the treatment of psoriasis and demonstrated high efficacy and a favorable safety profile. This review summarizes the potential for expanding deucravacitinib indications based on case reports, clinical trials, and preclinical studies. Diseases in which TYK2 pathway has been demonstrated to be involved and for which clinical benefit of deucravacitinib has been reported include discoid lupus erythematosus, systemic lupus erythematosus, alopecia areata, lichen planus, palmoplantar pustulosis, psoriatic arthritis, systemic sclerosis, interstitial pneumonia, inflammatory bowel disease, and chronic recurrent multifocal osteomyelitis. Furthermore, emerging research suggests potential therapeutic applications in neurodegenerative diseases such as Alzheimer's disease, and malignancies such as type 1 diabetes, vascular calcification in chronic kidney disease, T-cell acute lymphoblastic leukemia, and multiple sclerosis. Deucravacitinib may exert therapeutic effects by broadly suppressing cytokine signaling in a diverse range of inflammatory disorders. Ongoing clinical trials and mechanistic studies are required to clarify the efficacy and support its future indications.},
}

Humans
*Off-Label Use
*Protein Kinase Inhibitors/therapeutic use/pharmacology
Animals
*TYK2 Kinase/antagonists & inhibitors/metabolism
Signal Transduction/drug effects
Clinical Trials as Topic
Psoriasis/drug therapy
Bridged-Ring Compounds
Pyrimidines

@article {pmid41096667,
year = {2025},
author = {Skarlis, C and Angelopoulou, E and Rentzos, M and Papageorgiou, SG and Anagnostouli, M},
title = {Monoclonal Antibodies as Therapeutic Agents in Autoimmune and Neurodegenerative Diseases of the Central Nervous System: Current Evidence on Molecular Mechanisms and Future Directions.},
journal = {International journal of molecular sciences},
volume = {26},
number = {19},
pages = {},
doi = {10.3390/ijms26199398},
pmid = {41096667},
issn = {1422-0067},
mesh = {Humans ; *Antibodies, Monoclonal/therapeutic use/pharmacology ; *Neurodegenerative Diseases/drug therapy/immunology ; Animals ; *Central Nervous System Diseases/drug therapy/immunology ; Neuromyelitis Optica/drug therapy ; Central Nervous System/drug effects/immunology ; Multiple Sclerosis/drug therapy ; },
abstract = {Monoclonal antibodies (mAbs) have revolutionized the treatment landscape for neurological diseases, providing targeted, mechanism-based therapies for conditions ranging from autoimmune demyelinating disorders to neurodegenerative diseases. In multiple sclerosis (MS), mAbs against CD20, CD52, and α4-integrins offer disease-modifying efficacy by altering immune responses, depleting B cells, or blocking leukocyte migration into the central nervous system (CNS). Similarly, novel agents under investigation, such as frexalimab and foralumab, modulate T and B cell interactions and regulatory immunity. In neuromyelitis optica spectrum disorder (NMOSD), mAbs targeting IL-6, the complement cascade, and B cell lineage have demonstrated significant clinical benefit in preventing relapses and disability. In Alzheimer's disease (AD), several anti-amyloid mAbs have gained regulatory approval. Anti-tau and anti-α-synuclein antibodies, though promising, have shown limited efficacy to date in AD and parkinson's disease (PD), respectively. The evolving armamentarium of mAbs reflects a paradigm shift toward personalized neuroimmunology and neurodegeneration-targeted treatments, based on ongoing clarification of molecular and neuroinflammatory mechanisms. In this context, the present review summarizes current evidence on mAbs used in CNS disorders, with an emphasis on their pathophysiological targets, molecular mechanisms, clinical efficacy, and safety.},
}

Humans
*Antibodies, Monoclonal/therapeutic use/pharmacology
*Neurodegenerative Diseases/drug therapy/immunology
Animals
*Central Nervous System Diseases/drug therapy/immunology
Neuromyelitis Optica/drug therapy
Central Nervous System/drug effects/immunology
Multiple Sclerosis/drug therapy

@article {pmid41096666,
year = {2025},
author = {Świątek, G and Nowakowska-Gołacka, J and Słomińska-Wojewódzka, M and Glac, W and Harackiewicz, O and Kurowska-Rucińska, E and Wrona, D},
title = {Minocycline Treatment Improves Memory and Reduces Anxiety by Lowering Levels of Brain Amyloid Precursor Protein and Indoleamine 2,3-Dioxygenase in a Rat Model of Streptozotocin-Induced Alzheimer's Disease.},
journal = {International journal of molecular sciences},
volume = {26},
number = {19},
pages = {},
doi = {10.3390/ijms26199397},
pmid = {41096666},
issn = {1422-0067},
mesh = {Animals ; *Indoleamine-Pyrrole 2,3,-Dioxygenase/metabolism ; *Alzheimer Disease/drug therapy/metabolism/chemically induced ; Male ; *Minocycline/pharmacology/therapeutic use ; Rats ; *Anxiety/drug therapy/metabolism ; Streptozocin ; Rats, Wistar ; Disease Models, Animal ; *Memory/drug effects ; *Amyloid beta-Protein Precursor/metabolism ; Brain/metabolism/drug effects ; Hippocampus/metabolism/drug effects ; Maze Learning/drug effects ; },
abstract = {Minocycline (MINO), a classic antibiotic, may have psychotropic activity related to the modulation of the tryptophan-kynurenine pathway. In this study, we investigated the effects of MINO on (1) memory and anxiety behaviors, (2) the modulation of brain levels of amyloid precursor protein (APP) and 2,3-indoleamine dioxygenase (IDO1) levels, and (3) peripheral inflammatory markers in a streptozotocin (STZ)-induced rat model of sporadic Alzheimer's disease (sAD). After repeated treatment with a dose of 35 mg/kg MINO for seven consecutive days, male Wistar rats with sAD showed (1) improvements in early (29 days after injection, probe test) reference memory (decreased latency to reach the platform, increased time in the critical quadrant of the Morris water maze) and anxiety disorders (increased time in the open arms of the elevated plus maze; increased exploration and entrances in the center of the white-light illuminated open field) 45-46 and 90-91 days after STZ injection; (2) reduced APP and IDO1 levels in the hippocampus and prefrontal cortex; and (3) induction of anti-inflammatory response in blood (increased TCD4[+] lymphocyte number and interleukin-10 production). This suggests that MINO, due to its anti-inflammatory action, improves memory and anxiety behavior related to sAD, indicating its neuroprotective and psychotropic properties.},
}

Animals
*Indoleamine-Pyrrole 2,3,-Dioxygenase/metabolism
*Alzheimer Disease/drug therapy/metabolism/chemically induced
Male
*Minocycline/pharmacology/therapeutic use
Rats
*Anxiety/drug therapy/metabolism
Streptozocin
Rats, Wistar
Disease Models, Animal
*Memory/drug effects
*Amyloid beta-Protein Precursor/metabolism
Brain/metabolism/drug effects
Hippocampus/metabolism/drug effects
Maze Learning/drug effects

@article {pmid41096642,
year = {2025},
author = {Mochol, M and Jablonowski, L and Pawlik, A and Rasławska-Socha, J and Chamarczuk, A and Lipski, M and Mazurek-Mochol, M},
title = {The Role of Vitamin C in Selected Autoimmune and Immune-Mediated Diseases: Exploring Potential Therapeutic Benefits.},
journal = {International journal of molecular sciences},
volume = {26},
number = {19},
pages = {},
doi = {10.3390/ijms26199375},
pmid = {41096642},
issn = {1422-0067},
mesh = {Humans ; *Autoimmune Diseases/drug therapy/metabolism/immunology ; *Ascorbic Acid/therapeutic use/pharmacology ; Antioxidants/therapeutic use ; Animals ; Dietary Supplements ; *Immune System Diseases/drug therapy ; Oxidative Stress/drug effects ; },
abstract = {Autoimmune diseases are characterized by immune response dysregulation against self-components, leading to chronic inflammation and tissue damage. Vitamin C (VitC), a water-soluble vitamin with established functions in antioxidant defence and collagen synthesis, has also been of interest based on its potential immunomodulatory effects. This review discusses the role of VitC in the course and progression of (A) autoimmune diseases (multiple sclerosis, rheumatoid arthritis, Sjögren's disease, type 1 diabetes, Hashimoto's thyroiditis, pernicious anaemia, antiphospholipid syndrome), (B) other immune-mediated diseases (Crohn's disease, periodontitis), and (C) Alzheimer's disease, a neurodegenerative disorder with autoimmune features. Results from clinical, observational, and experimental trials show that VitC deficiency is common in many of these diseases and may contribute to increased oxidative stress and immune disequilibrium. Supplementation has been associated with improved antioxidant levels, control of inflammatory mediators, and, in some cases, clinical outcomes like disease activity decrease or symptom load. Although findings vary across conditions and few large, randomized trials are available, the overall evidence indicates that maintaining good VitC status can be useful in maintaining immune homeostasis and reducing inflammation. VitC should be viewed as an adjunct to be employed safely, perhaps and ideally within larger treatment regimens, but not in place of effective therapies. Further research, including large-scale clinical trials, will be required to determine more clearly optimal dosing, timing of treatment, and patient population most likely to benefit. By integration of current knowledge, this review recognizes both promise in VitC for treatment of autoimmune/immune-mediated disease and promise in its potential use within future treatment regimens.},
}

Humans
*Autoimmune Diseases/drug therapy/metabolism/immunology
*Ascorbic Acid/therapeutic use/pharmacology
Antioxidants/therapeutic use
Animals
Dietary Supplements
*Immune System Diseases/drug therapy
Oxidative Stress/drug effects

@article {pmid41096572,
year = {2025},
author = {Zhang, X and Fu, Y and Li, X and Zhang, Y and Li, L and Yi, T and Jiang, H and Lu, Y},
title = {Phlorizin Ameliorates Amyloid-β Toxicity and Enhances Fatty Acid β-Oxidation in Caenorhabditis elegans via NHR-49-Dependent Pathway.},
journal = {International journal of molecular sciences},
volume = {26},
number = {19},
pages = {},
doi = {10.3390/ijms26199303},
pmid = {41096572},
issn = {1422-0067},
support = {7252230//Beijing Municipal Science & Technology Commission/ ; },
mesh = {Animals ; *Caenorhabditis elegans/metabolism/drug effects/genetics ; *Amyloid beta-Peptides/toxicity/metabolism ; *Caenorhabditis elegans Proteins/metabolism/genetics ; *Fatty Acids/metabolism ; Oxidation-Reduction/drug effects ; Reactive Oxygen Species/metabolism ; Alzheimer Disease/metabolism/drug therapy ; Lipid Metabolism/drug effects ; Longevity/drug effects ; Signal Transduction/drug effects ; Disease Models, Animal ; Receptors, Cytoplasmic and Nuclear ; },
abstract = {Phlorizin (PHZ) is a glucoside of phloretin, belonging to the dihydrochalcone class within flavonoids; It is one of the active ingredients of the plant Cynomorium, and it has been shown that PHZ can regulate lipid metabolism disorders as well as having anti-aging properties. However, no studies have investigated whether PHZ ameliorates Aβ-induced toxicity in Alzheimer's disease (AD) by regulating fatty acid β-oxidation. This study aims to investigate the effects of PHZ on the regulation of fatty acid β-oxidation and resistance to Aβ-associated toxicity on the AD Caenorhabditis elegans and the mechanisms of action. Wild-type N2 and AD model CL4176 C. elegans were used; lifespan, heat stress resistance, chronic paraquat stress, reactive oxygen species (ROS), behavioral performance, and lipofuscin accumulation assays were examined to evaluate the anti-aging effects; and non-esterified fatty acid (NEFA), triglyceride (TG) and lipidomic contents were quantified after PHZ treatment. The detection of genes related to fatty acid β-oxidation pathways was performed using qRT-PCR. nhr-49 knockout mutant RB1716; and GFP-binding mutants PMD150 WBM170 were used to observe the effect of PHZ on NHR-49 pathways, and molecular docking studies were performed by combining PHZ with NHR-49 proteins. Results showed that PHZ improved worms' survival and delayed senescence, as demonstrated by enhanced performance in lifespan, heat stress, ROS, and paraquat assays and chronic paraquat assays; PHZ also reduced lipid accumulation in worms, affected the unsaturated fatty acid pathway, and significantly increased the expression of fatty acid metabolism-related genes nhr-49, acs-2, and cpt-5, and can be tightly coupled to NHR-49 targets. PHZ may play an anti-Aβ toxicity role by regulating lipid metabolism disorders through the NHR-49-related pathway and anti-aging in AD worms.},
}

Animals
*Caenorhabditis elegans/metabolism/drug effects/genetics
*Amyloid beta-Peptides/toxicity/metabolism
*Caenorhabditis elegans Proteins/metabolism/genetics
*Fatty Acids/metabolism
Oxidation-Reduction/drug effects
Reactive Oxygen Species/metabolism
Alzheimer Disease/metabolism/drug therapy
Lipid Metabolism/drug effects
Longevity/drug effects
Signal Transduction/drug effects
Disease Models, Animal
Receptors, Cytoplasmic and Nuclear

@article {pmid41096196,
year = {2025},
author = {Siwecka, N and Golberg, M and Świerczewska, D and Filipek, B and Pendrasik, K and Bączek-Grzegorzewska, A and Stasiołek, M and Świderek-Matysiak, M},
title = {Sleep Disorders in Neurodegenerative Diseases with Dementia: A Comprehensive Review.},
journal = {Journal of clinical medicine},
volume = {14},
number = {19},
pages = {},
doi = {10.3390/jcm14197119},
pmid = {41096196},
issn = {2077-0383},
abstract = {Dementia is a growing problem of global relevance, currently affecting over 55 million people worldwide. The number of new dementia cases is still increasing, primarily due to the aging of society. Dementia is defined as a substantial decline in cognitive function, and it is inherently associated with neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, dementia with Lewy bodies, frontotemporal dementia, and vascular dementia. Of note, most patients suffering from neurodegenerative conditions, in addition to cognitive impairment, often experience various types of sleep disorders, including insomnia, rapid eye movement sleep behavior disorder, sleep-disordered breathing, and circadian rhythm disturbances. There is increasing evidence of a bidirectional interaction between sleep disturbances and mental health. Disrupted sleep may directly aggravate neuropsychiatric symptoms, like depression, anxiety, agitation, and hallucinations, and conversely, such symptoms can make sleeping more difficult. This creates a feedback loop that inevitably leads to disease progression and deterioration in quality of life. In this review, we provide an up-to-date overview of the nature and mechanisms behind sleep disorders in major neurodegenerative diseases, summarize treatment strategies for handling sleep disturbances, and discuss the clinical relevance of sleep-mental health interactions in the context of neurodegeneration-associated dementia. Neurodegeneration is a complex problem on the border between neurology and psychiatry, and it poses a challenge to the healthcare system, as it requires multidisciplinary approaches for optimal management. Understanding the connection between sleep and neuropsychiatric symptoms offers further opportunities for better symptom control, improved quality of life, and slower cognitive decline.},
}

@article {pmid41094207,
year = {2025},
author = {Chen, Z and Ma, S and Wang, C and Liu, J and Yang, X},
title = {A ratio electrochemiluminescence sensor for monitoring amyloid-beta based on g-C3N4-heme with luminol as the internal standard.},
journal = {Mikrochimica acta},
volume = {192},
number = {11},
pages = {737},
pmid = {41094207},
issn = {1436-5073},
support = {ZR2023MB083//Natural Science Foundation of Shandong Province/ ; },
mesh = {*Luminol/chemistry ; *Amyloid beta-Peptides/analysis/blood ; *Electrochemical Techniques/methods ; *Biosensing Techniques/methods ; Aptamers, Nucleotide/chemistry ; *Luminescent Measurements/methods ; Humans ; Graphite/chemistry ; Limit of Detection ; *Nitriles/chemistry ; Metal Nanoparticles/chemistry ; Electrodes ; Gold/chemistry ; Aniline Compounds/chemistry ; Tin Compounds/chemistry ; },
abstract = {Monitoring of the amyloid-beta (Aβ) peptide is crucial for the diagnosis and treatment of Alzheimer's disease. Here, a label-free, signal-on ratiometric electrochemiluminescence (ECL) aptasensor was fabricated for the detection of Aβ peptide. Specifically, graphite-like carbon nitride (g-C3N4) nanosheets and luminol served as the cathodic and anodic ECL emitters, respectively. K2S2O8 and H2O2 were used as the coreactants for the two emitters. Luminol was first coated on the indium tin oxide (ITO) electrode and used as the internal standard in the ratiometric biosensor. Polyaniline was then electrodeposited on the surface of the luminol-modified electrode to improve the biocompatibility and conductivity of the sensing interfaces. Gold nanoparticles were subsequently modified on the surface of polyaniline to immobilize a DNA aptamer. g-C3N4-heme incubated with different concentrations of Aβ solution to form g-C3N4-heme-Aβ complex, in which Aβ could specifically bind to the DNA aptamer and thus introduce g-C3N4 into the system. As a result, it was observed that the ratio value of ECL intensity (I1/I2) significantly increased with the increase of Aβ concentration. Under the optimized conditions, the biosensor has a good linear response in the range 10 fM to 10 nM with a detection limit of 4.2 fM. Consequently, the ratiometric ECL sensor, characterized by high sensitivity and favorable stability, offers a reliable method for the determination of Aβ.},
}

*Luminol/chemistry
*Amyloid beta-Peptides/analysis/blood
*Electrochemical Techniques/methods
*Biosensing Techniques/methods
Aptamers, Nucleotide/chemistry
*Luminescent Measurements/methods
Humans
Graphite/chemistry
Limit of Detection
*Nitriles/chemistry
Metal Nanoparticles/chemistry
Electrodes
Gold/chemistry
Aniline Compounds/chemistry
Tin Compounds/chemistry

@article {pmid41094020,
year = {2025},
author = {Makinde, IA and Hammed, SO and Kumar, N and Kuthi, NA and Umar, HI and Hassan, TA and Kehinde, IO and Bello, RO and Aborode, AT and Jimoh, TO and Mahamat, AO and Khalid, M and Almohammed, OA},
title = {Identification of novel DYRK1A inhibitors as treatment options for alzheimer's disease through comprehensive in silico approaches.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {36114},
pmid = {41094020},
issn = {2045-2322},
support = {ORF-2025-77//King Saud University/ ; },
mesh = {Dyrk Kinases ; *Protein-Tyrosine Kinases/antagonists & inhibitors/chemistry/metabolism ; *Protein Serine-Threonine Kinases/antagonists & inhibitors/chemistry/metabolism ; *Alzheimer Disease/drug therapy ; Quantitative Structure-Activity Relationship ; *Protein Kinase Inhibitors/chemistry/pharmacology/therapeutic use ; Humans ; Molecular Dynamics Simulation ; Molecular Docking Simulation ; Benzimidazoles/pharmacology/chemistry ; Computer Simulation ; Aminopyridines/pharmacology/chemistry ; },
abstract = {This study aims to identify potential DYRK1A inhibitors from a curated database and utilize a QSAR model to predict the bioactivity of drug compounds in inhibiting the enzyme involved in tau protein oligomerization, a key process in AD pathology. 192 compounds were sourced from the SuperNatural 3.0 database and docked against DYRK1A using Maestro 12.5. The top five lead compounds and the reference drug Abemaciclib underwent ADMET profiling via the AI Drug Lab Server and a 200 nanosecond molecular dynamics simulation using Desmond. A machine learning-based Quantitative Structure-Activity Relationship (QSAR) analysis was then performed to predict their biological activity based on pIC50 values. The top five compounds, identified as 45,934,388, CNP0344929, CNP0360040, CNP0309850, and CNP0426983, demonstrated binding affinities of -13.337, -12.746, -11.712, -11.656, and - 11.416 kcal/mol, respectively, outperforming Abemaciclib (-6.528 kcal/mol). None of the compounds violated Lipinski's Rule of Five, and all exhibited favorable ADMET profiles, including optimal blood-brain barrier penetration and structural stability. The QSAR model successfully predicted the pIC50 values of the hit compounds (6.16, 5.758, 5.752, 6.003, 5.982), comparable to Abemaciclib (6.32). These findings highlight five promising DYRK1A inhibitors with potential therapeutic applications for AD.},
}

Dyrk Kinases
*Protein-Tyrosine Kinases/antagonists & inhibitors/chemistry/metabolism
*Protein Serine-Threonine Kinases/antagonists & inhibitors/chemistry/metabolism
*Alzheimer Disease/drug therapy
Quantitative Structure-Activity Relationship
*Protein Kinase Inhibitors/chemistry/pharmacology/therapeutic use
Humans
Molecular Dynamics Simulation
Molecular Docking Simulation
Benzimidazoles/pharmacology/chemistry
Computer Simulation
Aminopyridines/pharmacology/chemistry

@article {pmid41093210,
year = {2025},
author = {Manzoor, SI and Ahanger, IA and Kamli, MR and Malik, MA and Dar, TA},
title = {Nano-conjugation of small molecule modulators of protein aggregation: Enhancing the therapeutic precision.},
journal = {International journal of biological macromolecules},
volume = {},
number = {},
pages = {148293},
doi = {10.1016/j.ijbiomac.2025.148293},
pmid = {41093210},
issn = {1879-0003},
abstract = {Protein aggregation is a central hallmark of several neurodegenerative and systemic diseases, including Alzheimer's, Parkinson's, cataract and type 2 diabetes. Consequently, targeting protein aggregation is emerging as a promising therapeutic strategy for these diseases. Small molecule modulators have exhibited considerable potential in stabilizing native protein conformations and promoting the dissolution of toxic aggregates, leading to delayed disease progression. Some also target proteostatic pathways, promoting clearance of misfolded proteins to prevent further aggregation. Despite being promising, their clinical efficacy often faces challenges due to poor bioavailability, limited stability, and lack of specificity. Recent advances in nanotechnology have introduced nano-conjugation as a potential strategy for maximizing the therapeutic efficacy of these small molecule modulators. By ensuring targeted delivery, increased availability, improved stability and controlled tissue release, nano-conjugation has not only overcome the limitations but also acts as a future pathway to precision medicine in protein aggregation diseases. The present review article provides a comprehensive overview of small molecule modulators of protein aggregation and explores how nano-conjugation enhances their therapeutic efficacy. Moreover, it highlights emerging clinical trials and explores future directions in the application of nano-conjugated small molecule modulators as a potential treatment strategy for protein aggregation diseases.},
}

@article {pmid41093142,
year = {2025},
author = {Marizzoni, M and Mombelli, E and Alboni, S and Rosa, M and Moretti, DV and Mirabelli, P and Coppola, L and Luongo, D and Salamone, D and Saleri, S and Piazza, F and Begni, V and Salvatore, M and Frisoni, GB and Cattaneo, A},
title = {Microbiota-gut-brain axis dysregulation in Alzheimer's disease and its modulation through probiotic supplementation.},
journal = {Brain, behavior, and immunity},
volume = {},
number = {},
pages = {106138},
doi = {10.1016/j.bbi.2025.106138},
pmid = {41093142},
issn = {1090-2139},
abstract = {BACKGROUND: The microbiota-gut-brain axis (MGBA) has been implicated in the pathophysiology of Alzheimer's Disease (AD).Probiotics reduced the progression of ADin different mouse models, possibly through MGBA modulation, but human data are still limited.

OBJECTIVE: Here, we evaluated whether differences in the gut microbiome (GM), pro-inflammatory markers and other MGBA mediators were associated with probable AD (pAD). We also assessed the impact of a 12-week probiotic treatment on MGBA.

METHODS: Forty-five pAD patients and 47 healthy subjects (HC) were recruited at IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli of Brescia (Italy). An uncontrolled clinical investigation was performed to test the effects of 12-week probiotic supplementation in the pAD group. Fecal microbiota composition, intestinal and blood inflammatory markers, and microbiota-related metabolites were assessed before supplementation in all participants and after only in pAD.

RESULTS: pAD patients showed intestinal inflammation, an altered GM profile, blood changes in the tryptophan metabolism, and reduced glutamate levels compared with HC (p-value < 0.049). Probiotic supplementation partially modulated these alterations, determining a reduction in several pro-inflammatory mediators, and an increase of GM-related protective factors, such as butyrate (p-value < 0.040) in pAD.

CONCLUSIONS: These findings confirmed the presence of MGBA alterations in AD and suggested a potential beneficial effect of probiotic supplementation through modulation of GM functionality rather than composition. Further research is required to confirm these results and their clinical relevance.},
}

@article {pmid41093115,
year = {2025},
author = {Shen, Z and Wu, M and Sun, S and Ling, Y and Chen, X and Zhang, J and Zhou, X and Zhou, C},
title = {Lingguizhugan decoction improves cognitive impairment in APP/PS1 mice by promoting meningeal lymphatic drainage based on fatty acid degradation pathway.},
journal = {Journal of ethnopharmacology},
volume = {},
number = {},
pages = {120748},
doi = {10.1016/j.jep.2025.120748},
pmid = {41093115},
issn = {1872-7573},
abstract = {Lingguizhugan Decoction (LGZG), a classic traditional Chinese medicine formula, has been demonstrated in numerous studies to possess therapeutic potential for Alzheimer's disease (AD). However, it remains unclear whether its mechanism of action involves the meningeal lymphatic system.

AIM OF THE STUDY: Investigate if LGZG improves cognition in APP/PS1 mice by restoring mLVs drainage.

MATERIALS AND METHODS: Assessed cognitive behavior and pathology in LGZG-treated APP/PS1 mice. Used tracers and immunofluorescence (LYVE-1/TR-d3) to evaluate mLVs drainage and markers. Conducted untargeted brain metabolomics and dura mater micro-proteomics. Performed molecular docking and functional analysis focusing on fatty acid pathways.

RESULTS: LGZG ameliorated cognitive impairment and Aβ deposition in mice. Improved Aβ clearance correlated with enhanced mLVs function (confirmed by tracing). Metabolomics and micro-proteomics identified impaired fatty acid degradation as a key pathological factor. LGZG, at clinically relevant doses, restored mLVs drainage and rescued cognition by activating the fatty acid degradation pathway.

CONCLUSION: Lingguizhugan Decoction ameliorates AD-like pathologies and cognitive deficits in APP/PS1 mice by enhancing Aβ clearance via regulating the "fatty acid degradation-meningeal lymphatic axis." This finding reveals a novel multi-target mechanism of LGZG and offers a fresh perspective on metabolic intervention for AD treatment.},
}

@article {pmid41093093,
year = {2025},
author = {Tuo, C and Sui, X and Cui, C and Han, F and Jiao, J and Cai, H and Wu, M},
title = {Pramipexole improves cognitive deficits and synaptic plasticity impairments in 3xTg-AD mice through enhancing autophagy.},
journal = {Experimental neurology},
volume = {},
number = {},
pages = {115503},
doi = {10.1016/j.expneurol.2025.115503},
pmid = {41093093},
issn = {1090-2430},
abstract = {Autophagy dysfunction plays important roles in the pathogenesis of Alzheimer's disease (AD), and activation of autophagy might be a potential strategy in AD treatment. Although some autophagy inducers play beneficial roles in AD, no autophagy inducer has been available in AD clinical treatment due to lack of efficacy or obvious side effects. A recent study demonstrated that pramipexole (PPX) can activate autophagy in the brain without interfering with protein synthesis, thereby avoiding the side effects associated with prolonged use of an autophagy inducer. However, whether PPX can exert neuroprotective effects on AD and whether its potential mechanism is related to autophagy remains unclear. In the present study, the effects of PPX on the cognitive function of 3xTg-AD mice were observed using multiple behavioral tests, then synaptic plasticity was evaluated through in vivo hippocampal electrophysiological recordings and by measuring synaptic proteins, while Aβ and tau pathologies were detected using immunofluorescence staining and western blot. Finally, autophagy was detected and the potential target was predicted using bioinformatics analysis, qRT-PCR and molecular docking. Results demonstrated that PPX significantly improved cognitive deficits and hippocampal long-term potentiation (LTP) depression, increased the expression of PSD95, reduced Aβ deposition and tau hyperphosphorylation, activated autophagy by increasing LC3-II/LC3-I ratios and decreasing p62 levels, and restored Beclin1 expression. Bioinformatics analysis identified MAPK1 as a key target in PPX-ameliorated AD by enhancing autophagy. These findings suggest that PPX alleviates AD-related cognitive deficits and neuropathologies through increased autophagy, emphasising its potential as a disease-modifying therapeutic strategy for AD.},
}

@article {pmid41091591,
year = {2025},
author = {Magham, SV and Shanavas, S and Pindiprolu, SSSKS and Nagappan, K and More, S and Chaudhury, D and Ramakkamma, AR and Singh, MT and Wadhwani, A and Bose, B and Thaggikuppe Krishnamurthy, P},
title = {Targeting GSK-3β to Modulate the Wnt Pathway: A Promising Neuroprotective Strategy for Alzheimer's Disease.},
journal = {Molecular pharmaceutics},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.molpharmaceut.5c00329},
pmid = {41091591},
issn = {1543-8392},
abstract = {Alzheimer's disease (AD) is marked by amyloid-β plaques and neurofibrillary tangles. Glycogen synthase kinase-3β (GSK-3β) is a promising therapeutic target for mitigating several AD-related pathologies via modulation of the Wnt pathway. However, nonspecific GSK-3β inhibition by indirubin-3'-oxime (IMX) may result in significant off-target effects, necessitating the development of brain-targeted delivery systems. Solid lipid nanoparticles (SLNs) are biocompatible nanocarriers for brain-targeted delivery of therapeutics. Polysorbate 80 (PS80) and stearic acid (SA)-modified SLNs encapsulating IMX (PS80-SA SLNs-IMX) were prepared using the solvent injection method. The formula was optimized using full factorial design (FFD). The optimized formulation was biophysically characterized. The neuroprotective efficacy of PS80-SA SLNs-IMX was then evaluated in vitro using cell lines (IMR-32 & N2a). Biodistribution study was carried out in Wistar rats to evaluate the site-specific distribution of IMX and SLNs. The optimized PS80-SA SLNs-IMX exhibited a particle size of 185.7 ± 2.7 nm, a polydispersity index of 0.22 ± 0.01, a ζ potential of -21.02 ± 1.53 mV, and an entrapment efficiency of 99.4 ± 0.12%. Surface morphology analysis revealed that they are spherical in shape, and in vitro release study revealed the sustained release of PS80-SA SLNs-IMX until 48 h. Accelerated stability study results revealed the formulation stability with negligible changes in the PS, PDI, and ZP up to 6 months. MTT assay results have shown that PS80-SA SLNs-IMX has a negligible cytotoxic effect. ROS and neuroprotective assays have demonstrated antioxidant and neuroprotective effects of PS80-SA SLNs-IMX against OKA-induced neurotoxicity. ELISA depicted a significant reduction in Aβ1-42 and p-tau upon treatment with PS80-SA SLNs-IMX. Western blot analysis confirmed the effect of PS80-SA SLNs-IMX on the inhibition of GSK-3β and the activation of the Wnt pathway. Biodistribution study results revealed that PS80-SA SLNs-IMX has a significant increase in brain concentration when compared to naïve IMX, indicating the brain-specific distribution of PS80-SA SLNs-IMX. In conclusion, PS80-SA SLNs-IMX demonstrated enhanced neuronal cell uptake and significant neuroprotective activity in vitro. To our knowledge, this is the first report of PS80-SA SLNs-IMX with high entrapment and robust neuroprotection in an okadaic acid (OKA)-induced tauopathy model, underscoring the translational potential for AD therapy.},
}

@article {pmid41090735,
year = {2025},
author = {Shen, X and Li, H and Zhang, B and Li, Y and Zhu, Z},
title = {Tau-Targeted Therapeutic Strategies: Mechanistic Targets, Clinical Pipelines, and Analysis of Failures.},
journal = {Cells},
volume = {14},
number = {19},
pages = {},
pmid = {41090735},
issn = {2073-4409},
support = {A126H5//University of Nottingham/ ; },
mesh = {Humans ; *tau Proteins/metabolism/antagonists & inhibitors ; *Molecular Targeted Therapy ; Animals ; *Alzheimer Disease/metabolism/drug therapy ; Protein Processing, Post-Translational ; *Tauopathies/drug therapy/metabolism ; Phosphorylation ; },
abstract = {Tau protein, a neuron-enriched microtubule-associated protein encoded by the MAPT gene, plays pivotal roles in microtubule stabilisation, axonal transport, and synaptic plasticity. Aberrant post-translational modifications (PTMs), hyperphosphorylation, acetylation, ubiquitination, oxidative stress and neuroinflammation disrupt tau's normal functions, drive its mislocalization, and promote aggregation into neurofibrillary tangles, a hallmark of Alzheimer's disease (AD) and related tauopathies. Over the past two decades, tau-targeted therapies have advanced into clinical development, yet most have failed to demonstrate efficacy in human trials. This review synthesises mechanistic insights into tau biology and pathology, highlighting phosphorylation and acetylation pathways, aggregation-prone motifs, and immune-mediated propagation. We analyse the current therapeutic landscape, including kinase and phosphatase modulators, O-GlcNAcase inhibitors, aggregation blockers, immunotherapies, and microtubule-stabilising agents, while examining representative clinical programs and the reasons underlying their limited success. By combining mechanistic understanding with clinical experience, this review outlines emerging opportunities for rational treatment development, aiming to inform future tau-targeted strategies for AD and other tauopathies.},
}

Humans
*tau Proteins/metabolism/antagonists & inhibitors
*Molecular Targeted Therapy
Animals
*Alzheimer Disease/metabolism/drug therapy
Protein Processing, Post-Translational
*Tauopathies/drug therapy/metabolism
Phosphorylation

@article {pmid41090155,
year = {2025},
author = {Li, JM and Huang, J and Liao, Y and Hu, T and Wang, CL and Zhang, WZ and Huang, CW},
title = {Gene and RNA Editing: Revolutionary Approaches to Treating Diseases.},
journal = {MedComm},
volume = {6},
number = {10},
pages = {e70389},
pmid = {41090155},
issn = {2688-2663},
abstract = {Gene editing and RNA editing technologies are advancing modern medicine by enabling precise manipulation of genetic information at the DNA and RNA levels, respectively. The third-generation gene editing tools, particularly Clustered regularly interspaced shortpalindromic repeats (CRISPR)/CRISPR-associated (Cas) system, have transformed genetic disease treatment with high efficiency, precision, and cost effectiveness, while RNA editing, via adenosine deaminase acting on RNA (ADAR) enzymes and CRISPR-Cas13, offers reversible regulation to avoid genomic integration risks. Despite advancements, challenges persist in delivery efficiency, tissue specificity, and long-term safety, limiting their clinical translation. This review systematically discusses the molecular mechanisms and technological evolution of these tools, focusing on their promising applications in treating nervous system disorders (e.g., Alzheimer's, Parkinson's), immune diseases (e.g., severe combined immunodeficiency, lupus), and cancers. It compares their technical attributes, analyzes ethical and regulatory issues, and highlights synergies between the two technologies. By bridging basic research and clinical translation, this review provides critical insights for advancing precision medicine, reshaping disease diagnosis, prevention, and treatment paradigms.},
}

@article {pmid41089659,
year = {2025},
author = {Xu, B and Ding, S and Xu, W and Fredericks, C and Zhao, Y},
title = {GenCPM: a toolbox for generalized connectome-based predictive modeling.},
journal = {Frontiers in neuroscience},
volume = {19},
number = {},
pages = {1627497},
pmid = {41089659},
issn = {1662-4548},
abstract = {Understanding brain-behavior relationships and predicting cognitive and clinical outcomes from neuromarkers are central tasks in neuroscience. Connectome-based Predictive Modeling (CPM) has been widely adopted to predict behavioral traits from brain connectivity data; however, existing implementations are largely restricted to continuous outcomes, often overlook essential non-imaging covariates, and are difficult to apply in clinical or disease cohort settings. To address these limitations, we present GenCPM, a generalized CPM framework implemented in open-source R software. GenCPM extends traditional CPM by supporting binary, categorical, and time-to-event outcomes and allows the integration of covariates such as demographic and genetic information, thereby improving predictive accuracy and interpretability. To handle high-dimensional data, GenCPM incorporates marginal screening and regularized regression techniques, including LASSO, ridge, and elastic net, for efficient selection of informative brain connections. We demonstrate the utility of GenCPM through analyses of the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) Study and the Alzheimer's Disease Neuroimaging Initiative (ADNI), showing enhanced predictive performance and improved signal attribution compared to standard methods. GenCPM offers a flexible, scalable, and interpretable solution for predictive modeling in brain connectivity research, supporting broader applications in cognitive and clinical neuroscience.},
}

@article {pmid41089460,
year = {2025},
author = {Gerasimov, E and Berg, M and Bolshakova, A and Bezprozvanny, I and Vlasova, O},
title = {Chemogenetic Modulation of Astrocytic Activity Rescues Hippocampus Associated Neurodegeneration in Alzheimer's Disease Mice Model 5xFAD.},
journal = {Neural plasticity},
volume = {2025},
number = {},
pages = {9880933},
pmid = {41089460},
issn = {1687-5443},
mesh = {Animals ; *Alzheimer Disease/metabolism/pathology/drug therapy/genetics/physiopathology ; *Astrocytes/drug effects/metabolism ; Mice ; *Hippocampus/drug effects/pathology/metabolism/physiopathology ; *Clozapine/analogs & derivatives/pharmacology ; Mice, Transgenic ; Disease Models, Animal ; Male ; Long-Term Potentiation/drug effects ; Chemogenetics ; },
abstract = {Alzheimer's disease (AD) is a prevalent neurodegenerative disorder characterized by Aβ-amyloid accumulation and cognitive decline. Despite extensive research, effective treatments remain elusive. Astrocytes, the most abundant glial cells, play a crucial role in synaptic transmission, neuronal excitability, and plasticity. In AD, astrocytes become reactive, exhibiting aberrant calcium signaling and altered neurotransmitter release, making them promising targets for disease-modifying therapies. To address this, we explored designer receptors exclusively activated by designer drugs (DREADDs), specifically the hM3D(Gq) receptor, which selectively modulates intracellular Ca[2+] levels in astrocytes upon activation by clozapine-N-oxide (CNO). Using daily CNO administration in 8-month-old 5xFAD mice, we observed a significant enhancement of impaired long-term potentiation formation, accompanied by cognitive improvements in the fear conditioning (FC) and Morris water maze (MWM) tests. Additionally, anxiety levels and social preference deficits in 5xFAD mice were fully restored following astrocytic activity modulation. Importantly, this approach reduced Aβ-amyloid plaque burden and demonstrated a trend toward mitigating astrocytic reactivity, further highlighting its therapeutic potential. Our findings suggest that targeting astrocytic activity via Gq-coupled receptors represents a novel and promising strategy for AD treatment, offering a noninvasive and effective approach to mitigating disease progression.},
}

Animals
*Alzheimer Disease/metabolism/pathology/drug therapy/genetics/physiopathology
*Astrocytes/drug effects/metabolism
Mice
*Hippocampus/drug effects/pathology/metabolism/physiopathology
*Clozapine/analogs & derivatives/pharmacology
Mice, Transgenic
Disease Models, Animal
Male
Long-Term Potentiation/drug effects
Chemogenetics

@article {pmid41088943,
year = {2025},
author = {Haseeb, M and Hatiboglu, MA},
title = {Carbon Dot Nanoparticle-based Therapeutic Approaches in Major Neurological Disorders.},
journal = {Mini reviews in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113895575398775250811070903},
pmid = {41088943},
issn = {1875-5607},
abstract = {Neurological disorders (NDs) are diseases that arise due to deformities mainly in the central nervous system (CNS) and also affect the nerves throughout the human body. NDs, including Alzheimer's disease (AD), Parkinson's disease (PD), Multiple Sclerosis (MS), and a variety of brain malignancies, pose a major healthcare challenge and are the main cause of mortality on the global scale. There are very limited treatment options for the majority of the NDs, and the currently available drugs commonly fail to penetrate the BBB and deliver the drug to the target effectively. These challenges have necessitated the advent of new drug delivery methods that can cross the BBB with ease and deliver the drug by accurately targeting the diseased area in a safe and biocompatible manner. Nanoparticle-based drug delivery strategies offer significant advantages in BBB penetration and drug delivery due to their unique properties. Carbon dots, among nanoparticles with a size below 10 nm, are highly biocompatible, fluorescent molecules that offer ease of functionalization, drug conjugation, and effective detection within biological systems. The literature is rich in reviews on the synthesis, characterization, and application of CDs. However, a review specifically focused on the therapeutic potential of CDs in major NDs is missing. This review aims to fill that gap by presenting a detailed account of the carbon dot-based therapeutic approaches in the treatment of major NDs. It briefly discusses the properties of CDs, the main routes of synthesis, major raw materials, and key synthesis parameters that affect their properties, while placing a greater emphasis on their therapeutic potential. The review provides a detailed assessment of literature from the past 15 years on the development and current challenges in the application of CDs as therapeutic and drug delivery agents. Our analysis reveals that limited research has been conducted on CD-based therapeutics in NDs, particularly in MS and brain tumors, where original research is scarce. This review article highlights the major developments in the therapeutic uses of carbon dots in NDs, addresses a critical research gap, and provides a comprehensive overview of various studies related to carbon-dot-based therapeutic approaches for major NDs.},
}

@article {pmid41088853,
year = {2025},
author = {Collij, LE and Mattsson-Carlgren, N and Janelidze, S and Ossenkoppele, R and Hansson, O},
title = {Complementary utility of plasma biomarkers and Aβ-PET for diagnosis, risk-stratification, and treatment monitoring in Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {10},
pages = {e70763},
doi = {10.1002/alz.70763},
pmid = {41088853},
issn = {1552-5279},
mesh = {Humans ; *Alzheimer Disease/diagnostic imaging/blood/therapy/diagnosis ; *Positron-Emission Tomography ; *Biomarkers/blood ; *Amyloid beta-Peptides/blood/metabolism ; Risk Assessment ; },
abstract = {With the rapid development of blood biomarkers (BBMs) related to amyloid-β (Aβ) pathology in Alzheimer's disease (AD), the question arises whether these can replace the accepted reference standard, positron emission tomography (PET), for assessing Aβ burden. BBMs can differentiate Aβ status reliably in cognitively impaired patients, but two-threshold strategies to further improve their performance demonstrate the need for pathological confirmation by Aβ-PET in a non-negligible portion of individuals (∼10%-40%), especially in early-stage disease where BBM performance declines due to lower AD prevalence, reducing the test's positive predictive value (PPV) and increasing the risk for false-positives. This may be increasingly relevant in the future, considering the development of (very) early interventions against AD. Further, BBMs do not accurately reflect the actual Aβ load or change after immunotherapy. Consequently, there are clear remaining needs for Aβ-PET in several clinically important settings as (i) a confirmatory test and (ii) to determine treatment response. HIGHLIGHTS: When used as stand-alone tests, blood biomarkers (BBMs) demonstrate good sensitivity and specificity (84%-90%) relative to amyloid-β positron emission tomography (Aβ-PET). Two-threshold strategies improve BBM performance but require confirmatory testing by, for example, Aβ-PET in a non-negligible portion of patients that fall in an intermediate range or "gray-zone" (∼10%-40%). In early/preclinical populations, BBM performance declines due to lower AD prevalence, reducing the test's positive predictive value (PPV) and increases the gray-zone population. Currently available BBMs cannot reliably estimate Aβ-PET burden or track Aβ-plaque removal post-immunotherapy.},
}

Humans
*Alzheimer Disease/diagnostic imaging/blood/therapy/diagnosis
*Positron-Emission Tomography
*Biomarkers/blood
*Amyloid beta-Peptides/blood/metabolism
Risk Assessment

@article {pmid41088262,
year = {2025},
author = {Ritchie, M and Hussen, K and Langford, O and Navarro, C and Kotadiya, Z and Donohue, MC and Aisen, P and Sperling, RA and Grill, JD and Raman, R},
title = {Recruitment and retention in a preclinical AD trial: comparisons between academic and non-academic sites.},
journal = {Alzheimer's research & therapy},
volume = {17},
number = {1},
pages = {222},
pmid = {41088262},
issn = {1758-9193},
mesh = {Humans ; *Alzheimer Disease/drug therapy ; Male ; *Patient Selection ; Female ; Aged ; Patient Dropouts/statistics & numerical data ; Academic Medical Centers ; Middle Aged ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) clinical trials enroll participants at various site types including research-focused academic institutions and independent non-academic sites. Limited research has examined the impact of site type on recruitment and retention outcomes.

METHODS: To evaluate potential differences between site types, we used data from the Anti-Amyloid Treatment for Asymptomatic AD (A4) trial, the largest completed preclinical AD trial to date. We first compared the frequency of varying recruitment sources between site types. We then examined potential differences in participant- and site-level characteristics. To assess potential site type differences in retention, we fit a multivariable logistic regression model adjusting for variables associated with site type. For participants who prematurely discontinued, we examined potential differences by site type in reasons for dropout.

RESULTS: One thousand and fifty-eight participants were randomized at 50 academic (N = 835) and 15 non-academic (N = 223) sites in North America. Academic sites had higher proportions of participants recruited through earned media and organizational referrals and lower proportions recruited through internal referrals and advertisements, compared to non-academic sites. Participant-level characteristics differed between site types. Compared to non-academic sites, academic sites had higher proportions of participants with a family history of dementia and a professional degree (highest education category), but lower proportions of individuals with a history of diabetes, a CDR-SB score above 0, and belonging to a racial and ethnic underrepresented group. Though the results were not statistically significant, non-academic sites had a higher screening rate (number of participants screened/site/month), but a lower randomization rate (randomized/screened) compared to academic sites. No site type differences in completion rates were observed. When examining reasons for discontinuation, we found that among the 72 participants who discontinued the trial at non-academic sites, 56 (77.8%) withdrew consent or were lost to follow up. In contrast, 140 out of 243 (57.6%) participants who discontinued the trial in academic sites withdrew consent or were lost to follow up.

CONCLUSION: Our findings shed light on important site type differences that investigators should consider when making choices around site, design, and conduct in multisite preclinical AD trials.},
}

Humans
*Alzheimer Disease/drug therapy
Male
*Patient Selection
Female
Aged
Patient Dropouts/statistics & numerical data
Academic Medical Centers
Middle Aged

@article {pmid41087559,
year = {2025},
author = {Alghamdi, AM and Ashraf, MU and Bahaddad, AA and Almarhabi, KA and Al Shehri, WA and Daraz, A},
title = {A novel approach hybrid of ensemble learning and 3-D CNN mechanism: early-stage diagnosis of Alzheimer's disease using EEG signals.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {35893},
pmid = {41087559},
issn = {2045-2322},
support = {UJ-24-SUCH-1247//University of Jeddah/ ; },
mesh = {*Alzheimer Disease/diagnosis/physiopathology ; Humans ; *Electroencephalography/methods ; *Neural Networks, Computer ; *Deep Learning ; Early Diagnosis ; Male ; Aged ; Female ; *Diagnosis, Computer-Assisted/methods ; Ensemble Learning ; },
abstract = {Alzheimer's disease (AD) is a progressive neurological disorder that causes brain cell degeneration and leads to dementia. Early and accurate detection of AD is crucial, as it allows timely treatment before the brain suffers permanent damage. In recent years, computer-aided methods using Artificial Intelligence (AI) have shown promise in improving the diagnosis of AD, healthy cognition (HC), and other types of dementia. However, distinguishing between AD and HC using Electroencephalography (EEG) signals remains challenging, mainly due to difficulties in identifying meaningful features from the signals. To address this issue, we propose a novel method called EDL3DCNN, which combines Ensemble Deep Learning (EDL) with a 3D Convolutional Neural Network (3D-CNN). This model is designed to diagnose and classify AD and HC subjects accurately. We trained and evaluated the model using two publicly available EEG datasets related to AD. The EDL3DCNN model, leveraging multiple 3D-CNN classifiers, achieved a high classification accuracy of 99.02%. Our results demonstrate that integrating EDL with 3D-CNN offers a robust and scalable solution for computer-aided AD diagnosis.},
}

*Alzheimer Disease/diagnosis/physiopathology
Humans
*Electroencephalography/methods
*Neural Networks, Computer
*Deep Learning
Early Diagnosis
Male
Aged
Female
*Diagnosis, Computer-Assisted/methods
Ensemble Learning

@article {pmid41087268,
year = {2025},
author = {Liang, T and Liu, S and Dang, B and Luan, X and Guo, Y and Steimbach, RR and Hu, J and Lu, L and Yue, P and Wang, R and Zheng, M and Gao, J and Yin, X and Chen, X},
title = {Corrigendum to 'Multimechanism biological profiling of tetrahydro-β-carboline analogues as selective HDAC6 inhibitors for the treatment of Alzheimer's disease' [Eur. J. Med. Chem. 275 (2024) 116624].},
journal = {European journal of medicinal chemistry},
volume = {},
number = {},
pages = {118254},
doi = {10.1016/j.ejmech.2025.118254},
pmid = {41087268},
issn = {1768-3254},
}

@article {pmid41086934,
year = {2025},
author = {Piekarczyk, N and Berezka, P and Majkutewicz, I and Myślińska, D and Kaczor, JJ},
title = {Combined vitamin D3 and dimethyl fumarate treatment alleviates cognitive dysfunction, oxidative stress, and inflammation in a rat model of sporadic Alzheimer's disease.},
journal = {Free radical biology & medicine},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.freeradbiomed.2025.10.259},
pmid = {41086934},
issn = {1873-4596},
abstract = {Alzheimer's disease (AD) concerns early oxidative and inflammatory disturbances that accelerate tau pathology and cognitive decline. We investigated whether combined treatment with vitamin D3 (VitD3) and dimethyl fumarate (DMF), two agents with complementary antioxidant and immunomodulatory actions, provides additive neuroprotection in the intracerebroventricular streptozotocin (ICV-STZ) rat model of sporadic AD. Male Wistar rats (n=50) were divided into SHAM, STZ, VITD (STZ+VitD3 2000 IU/kg), DMF (STZ+DMF 50 mg/kg), or COMBO (STZ+VitD3+DMF) groups and treated orally for 90 days. Spatial learning and memory were assessed in the Morris Water Maze. Hippocampal oxidative stress indices (8-isoprostanes (8-Izo)), glutathione (GSH), glutathione disulfide (GSSG), and -SH groups and tau phosphorylation (pTau Ser396) were measured, and circulating vitamin D metabolites quantified by LC-MS/MS. STZ-induced cognitive impairment, elevated lipid peroxidation, increased the GSSG/GSH ratio, and raised pTau in CA1-CA3. VitD3 or DMF each improved acquisition and attenuated the 8-Izo increase; DMF normalized glutathione redox parameters, whereas VitD3 alone decreased GSH despite reducing lipid peroxidation. The COMBO provided the most consistent behavioral improvement and mitigated region-specific pTau elevations while maintaining redox balance. VitD3 treatment increased 25(OH)D3 and 3-epi-25(OH)D3 and reduced the 24,25(OH)2D3/25(OH)D3 ratio, indicating altered vitamin D metabolism. All treated groups showed a decrease in plasma TNF-α. These findings suggest that simultaneous modulation of vitamin D signaling and DMF may synergistically target oxidative, inflammatory, and tau-related mechanisms involved in sporadic AD. Future research should clarify brain-region vitamin D metabolite dynamics and the long-term impacts on protein thiol levels and cognitive function.},
}

@article {pmid41085546,
year = {2025},
author = {Chander, R and Sharma, R and Agnihotri, VK},
title = {Natural β-citronellol derivatives as potential dual enzyme inhibitors for the treatment of type 2 diabetes and Alzheimer's diseases.},
journal = {Natural product research},
volume = {},
number = {},
pages = {1-6},
doi = {10.1080/14786419.2025.2572038},
pmid = {41085546},
issn = {1478-6427},
abstract = {Effective strategies for treating type-2 diabetes mellitus (T2DM) and Alzheimer's disease (AD) involve inhibition of α-amylase, α-glucosidase for T2DM and block acetylcholinesterase (AChE) enzymes for treating AD. To explore this potential natural β-citronellol, isolated from Dracocephalum heterophyllum Benth essential oil, was derivatized to yield three derivatives (Compounds 2-4), analysed using NMR and GC-MS techniques. The results showed that compounds 2 and 4 had the most significant α-glucosidase and AChE inhibition. Parent compound 1, along with 3 and 4, displayed the highest α-amylase inhibition. Network pharmacology identified CXCR4 (score: 14) and PIK3CA (score: 12) as top-ranked targets. These findings suggest that PIK3CA, which regulates glucose metabolism, insulin signalling, and cell survival, while CXCR4 suggests potential for neuroprotective and anti-inflammatory roles. Structure-activity relationship indicated that alkoxy group functionalization at β-carbon of β-citronellol is essential for activity. It highlights, a single β-citronellol derivative can manage dual T2DM and AD diseases.},
}

@article {pmid41085520,
year = {2025},
author = {Mathai, A and Kannoth, S and Nambiar, V and Gopinath, S and Thevarkalam, M and Anandakuttan, A and Kalingavarman, S and Mony, U and Raj, M and Bhaskaran, R},
title = {Immune system modifications in atypical parkinsonism related to autoimmunity - a case control study.},
journal = {Neurodegenerative disease management},
volume = {},
number = {},
pages = {1-6},
doi = {10.1080/17582024.2025.2573597},
pmid = {41085520},
issn = {1758-2032},
abstract = {BACKGROUND: Inflammation is known in atypical parkinsonism (AP), but the role of autoimmunity is unclear. This study evaluates immune system modifications suggesting autoimmunity in AP.

METHODS: Included patients with AP diagnosed at Amrita Institute of Medical Sciences, Kochi (December 2018-May 2019), and age- and sex-matched controls. Fifteen immune parameters, including T regulatory cells, RORγt, and cytokines (IL-2, IL-4, IL-6, IL-10, IL-17A, IL-21, IL-22, IL-23, TNF, IFN-γ, GM-CSF, NF-κB, TGF-β), were assessed in peripheral blood (flow cytometry and ELISA).

RESULTS: Twenty-six cases (mean age 67.8 ± 7.5 years; 16 males) and 15 controls (mean age 68.1 ± 3.5 years; 10 males) studied. Diagnoses included progressive supranuclear palsy (n = 15), multiple system atrophy (n = 1), frontotemporal dementia with parkinsonism (n = 2), and unspecified AP (n = 8). AP cases had significantly higher RORγt (p = 0.041), IL-6 (p = 0.004), TNF (p = 0.020), IL-10 (p = 0.027), and IL-4 (p = 0.048).

CONCLUSIONS: Elevated RORγt and cytokines suggest immune dysregulation and possible autoimmune mechanisms in AP, warranting further investigation.},
}

@article {pmid41085169,
year = {2025},
author = {Ismail, Z and Sivananthan, S and Main, S and Ménard, A and McLaren-Beato, J and Chambers, LW and Welch, V and Vedel, I and Smith, EE and Ewa, V and Feldman, S},
title = {Culturally sensitive CLEAR guidelines on disclosing and communicating a diagnosis of dementia.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {10},
pages = {e70744},
doi = {10.1002/alz.70744},
pmid = {41085169},
issn = {1552-5279},
support = {P004637//Public Health Agency of Canada/ ; BMS-20-002//Academic Health Science Centre (AHSC)/ ; //University of Toronto Academic Health Science Centre (AHSC) Alternative Funding Plan (AFP) Innovation Fund./ ; },
mesh = {Humans ; *Dementia/diagnosis/psychology/ethnology ; Canada ; *Communication ; *Disclosure ; *Cultural Competency ; *Physician-Patient Relations ; *Truth Disclosure ; Primary Health Care ; *Practice Guidelines as Topic ; *Culturally Competent Care ; },
abstract = {Providing a dementia diagnosis is challenging, especially in primary care and considering diverse patient backgrounds. The Alzheimer Society of Canada (ASC), the College of Family Physicians of Canada, and the Canadian Consensus Conference on the Diagnosis and Treatment of Dementia (CCCDTD) guideline group partnered with patients, care partners, and clinicians to generate contemporaneous guidance for primary care practitioners. While relevant to all communities, Black and Chinese Canadians were formally represented in working groups. A literature review identified needs areas. Informed by Guidelines International Network (GIN) principles and through iterative group meetings with all partners, these needs were explored and incorporated into guidance. The Compassionate Language and Empathetic Approaches for Respectful Dementia Disclosure (CLEAR) offers recommendations on: holistic engagement, fostering hope, acknowledging care partners, identifying disclosing clinicians, appointment structure and environment, person-centered communication, specific discussion topics, and emotional supports, all through a cultural competence lens. These guidelines address communication challenges in disclosing a dementia diagnosis and enhancing care and support for persons living with dementia and their care partners. HIGHLIGHTS: Healthcare practitioners (HCPs) struggle with disclosing and communicating dementia diagnoses. Guidance is limited in primary care and different patient ethnocultural groups. We developed culturally sensitive guidelines with scripts and practical materials. Appropriate communication techniques and terminology are recommended in Compassionate Language and Empathetic Approaches for Respectful Dementia Disclosure (CLEAR). Patient-centered and holistic approaches for the patient and care partner are emphasized.},
}

Humans
*Dementia/diagnosis/psychology/ethnology
Canada
*Communication
*Disclosure
*Cultural Competency
*Physician-Patient Relations
*Truth Disclosure
Primary Health Care
*Practice Guidelines as Topic
*Culturally Competent Care

@article {pmid41085158,
year = {2025},
author = {Fischer, DL and Grinberg, LT and Ahrendsen, JT and Beach, TG and Bieniek, KF and Castellani, RJ and Chkheidze, R and Cobos, I and Cohen, M and Crary, JF and Dickson, DW and Dugger, BN and Dunlop, SR and Farrell, K and Ghetti, B and Haeri, M and Harrison, W and Head, E and Hiniker, A and Huang, EJ and Huttner, A and Jamshidi, P and Kapasi, A and Keene, CD and Kofler, J and Latimer, CS and McKee, AC and Mente, K and Miller, MB and Montine, TJ and Morris, M and Murray, ME and Nelson, PT and Newell, KL and Perrin, RJ and Ramani, B and Reichard, RR and Roy, S and Schlachetzki, JCM and Seeley, WW and Serrano, GE and Spina, S and Teich, AF and Wang, SJ and Wisniewski, T and Lee, EB},
title = {Celebrating neuropathology's contributions to Alzheimer's Disease Research Centers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {10},
pages = {e70734},
doi = {10.1002/alz.70734},
pmid = {41085158},
issn = {1552-5279},
support = {UE5NS070680/GF/NIH HHS/United States ; R01AG075802/GF/NIH HHS/United States ; P30AG072976/GF/NIH HHS/United States ; P30AG019610/GF/NIH HHS/United States ; P30AG072980/GF/NIH HHS/United States ; P30AG072977/GF/NIH HHS/United States ; P30AG066515/GF/NIH HHS/United States ; P30AG066514/GF/NIH HHS/United States ; R01AG054008/GF/NIH HHS/United States ; R01NS095252/GF/NIH HHS/United States ; R01AG062348/GF/NIH HHS/United States ; P30AG062677/GF/NIH HHS/United States ; R01AG062517/GF/NIH HHS/United States ; U24NS133949/GF/NIH HHS/United States ; P30AG072972/GF/NIH HHS/United States ; K01AG070326/GF/NIH HHS/United States ; RF1NS128908/GF/NIH HHS/United States ; P30AG066508/GF/NIH HHS/United States ; P30AG072947/GF/NIH HHS/United States ; R24AG073199/GF/NIH HHS/United States ; P30AG066509/GF/NIH HHS/United States ; P30AG062715/GF/NIH HHS/United States ; U19AG066567/GF/NIH HHS/United States ; U19AG060909/GF/NIH HHS/United States ; UM1MH130981/GF/NIH HHS/United States ; UM1MH134812/GF/NIH HHS/United States ; U24AG072458/GF/NIH HHS/United States ; U24NS133945/GF/NIH HHS/United States ; U24NS135651/GF/NIH HHS/United States ; R24AG073137/GF/NIH HHS/United States ; U01NS137500/GF/NIH HHS/United States ; U01NS137484/GF/NIH HHS/United States ; U01AG082350/GF/NIH HHS/United States ; R01AG082730/GF/NIH HHS/United States ; R01AG087226/GF/NIH HHS/United States ; R01AG088656/GF/NIH HHS/United States ; R01AG060942/GF/NIH HHS/United States ; R01AG080585/GF/NIH HHS/United States ; R01NS129609/GF/NIH HHS/United States ; R01AG069912/GF/NIH HHS/United States ; P30AG066468/GF/NIH HHS/United States ; U19AG068054/GF/NIH HHS/United States ; R01MH116046/GF/NIH HHS/United States ; R01AG090551/GF/NIH HHS/United States ; P30AG072959/GF/NIH HHS/United States ; DP2AG086138/GF/NIH HHS/United States ; R01AG082346/GF/NIH HHS/United States ; P30AG066507/GF/NIH HHS/United States ; P01AG003991/GF/NIH HHS/United States ; P30AG066444/GF/NIH HHS/United States ; U19AG024904/GF/NIH HHS/United States ; U19AG032438/GF/NIH HHS/United States ; R01AG068319/GF/NIH HHS/United States ; R01AG053267/GF/NIH HHS/United States ; R01NS111978/GF/NIH HHS/United States ; UF1NS120463/GF/NIH HHS/United States ; P50AG023501/GF/NIH HHS/United States ; P01AG019724/GF/NIH HHS/United States ; U01AG057195/GF/NIH HHS/United States ; U19AG063911/GF/NIH HHS/United States ; P30AG072958/GF/NIH HHS/United States ; P30AG066512/GF/NIH HHS/United States ; R01AG077422/GF/NIH HHS/United States ; U01OH012486/GF/NIH HHS/United States ; U24NS135568/GF/NIH HHS/United States ; R01AG087280/GF/NIH HHS/United States ; R13AG059336/GF/NIH HHS/United States ; P30AG072979/GF/NIH HHS/United States ; P01AG066597/GF/NIH HHS/United States ; P01AG084497/GF/NIH HHS/United States ; RF1AG065341/GF/NIH HHS/United States ; P30AG062429/GF/NIH HHS/United States ; P30AG062421/GF/NIH HHS/United States ; P30AG066530/GF/NIH HHS/United States ; P30AG066518/GF/NIH HHS/United States ; P30AG066462/GF/NIH HHS/United States ; P30AG072975/GF/NIH HHS/United States ; P30AG072978/GF/NIH HHS/United States ; P30AG066519/GF/NIH HHS/United States ; P30AG079280/GF/NIH HHS/United States ; P30AG062422/GF/NIH HHS/United States ; P30AG066511/GF/NIH HHS/United States ; P30AG072946/GF/NIH HHS/United States ; P30AG072973/GF/NIH HHS/United States ; P30AG066506/GF/NIH HHS/United States ; P30AG072931/GF/NIH HHS/United States ; P30AG066546/GF/NIH HHS/United States ; P30AG086401/GF/NIH HHS/United States ; P30AG086404/GF/NIH HHS/United States ; P20AG068082/GF/NIH HHS/United States ; /ALZ/Alzheimer's Association/United States ; //The Fred and Barbara Erb Family Foundation/ ; //Rainwater Charitable Trust/Tau Consortium/ ; //Karen Strauss Cook Research Scholar Award/ ; //Rainwater Charitable Trust/ ; SG-25-1416824//Alzheimer's Association Florida Gulf Coast/ ; 2024-351073//Chan Zuckerberg Initiative/ ; //Silicon Valley Community Foundation/ ; 685-2023-06//CurePSP/ ; //Allen Institute for Brain Science/ ; //Nancy and Buster Alvord Endowment/ ; //Shanahan Family Foundation/ ; //Barrist Family Foundation/ ; W81XWH-21-S-TBIPH2//U.S. Department of Defense/ ; //Stuart Katz and Dr. Jane Martin/ ; //10,000 Brains NeuroAI Inc/ ; //DeCrane Family Fund for PPA Research/ ; //Bluefield Project to Cure FTD/ ; },
mesh = {Humans ; *Alzheimer Disease/pathology ; *Neuropathology/history ; National Institute on Aging (U.S.) ; United States ; *Biomedical Research/history ; History, 20th Century ; History, 21st Century ; },
abstract = {Our understanding of Alzheimer's disease (AD) and related dementias (ADRD) has grown exponentially, thanks to significant investments by the National Institute on Aging (NIA). This article celebrates the 40th anniversary of the NIA's Alzheimer's Disease Research Centers, highlighting the pivotal role of neuropathology as the bedrock for neurodegeneration research. Neuropathology has championed the key principles of proteinopathy, selective vulnerability, and stereotypic spread. Furthermore, neuropathologic studies advanced our understanding of ADRD prevalence, heterogeneity, clinical-pathological correlations, and genetic underpinnings, spurring biomarker development for target engagement and disease monitoring. Disease-modifying therapies for AD were inspired and informed by neuropathology. The neuropathology community is poised to refine diagnostics, leveraging digital pathology and integrating genetics and pathomics to enhance subtyping for novel precision medicine approaches. Despite some common misconceptions and logistical challenges, neuropathology continues to be a critical component of the ADRD research infrastructure, serving as a key bridge between allied basic and clinical sciences. HIGHLIGHTS: We celebrate 40 years of NIA-funded ADRCs and their contributions through neuropathology studies that have significantly advanced our understanding and treatment of ADRD. Neuropathology uncovers principles of neurodegenerative disease: proteinopathy, selective vulnerability, and stereotypic spread, informing diagnostics and therapies. Development of AD biomarkers with reference to neuropathology enhances accuracy in diagnosis and monitoring, paving the way for targeted disease-modifying therapies. Integration of digital pathology, genetics, and novel tools in neurodegeneration research promises advanced precision medicine approaches and refined diagnostics. Misconceptions and logistical challenges to neuropathological research are addressed to improve understanding and collaboration.},
}

Humans
*Alzheimer Disease/pathology
*Neuropathology/history
National Institute on Aging (U.S.)
United States
*Biomedical Research/history
History, 20th Century
History, 21st Century

@article {pmid41085151,
year = {2025},
author = {Zhu, CW and Flournoy, C and Raman, R and Sano, M},
title = {Employment, volunteering, and health-related resource use in pre-symptomatic AD: Results from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) study.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {10},
pages = {e70641},
doi = {10.1002/alz.70641},
pmid = {41085151},
issn = {1552-5279},
support = {P30 AG066514/AG/NIA NIH HHS/United States ; U19AG010483/AG/NIA NIH HHS/United States ; R01AG063689/AG/NIA NIH HHS/United States ; U24AG057437/AG/NIA NIH HHS/United States ; //Eli Lilly/ ; NIRG-12-243012/ALZ/Alzheimer's Association/United States ; //GHR Foundation/ ; //C.W.Z. and M.S. are also supported by the Department of Veterans Affairs, Veterans Health Administration/ ; },
mesh = {Humans ; *Alzheimer Disease/drug therapy ; Male ; Female ; *Employment/statistics & numerical data ; Aged ; Longitudinal Studies ; *Volunteers/statistics & numerical data ; Prodromal Symptoms ; },
abstract = {INTRODUCTION: Little is known about productive time use and health-related resource use during "pre-symptomatic" AD, defined by the presence of brain amyloid in the absence of cognitive symptoms. We compared changes in resource use and participation in paid employment and/or volunteering in cognitively unimpaired older adults with amyloid accumulation (Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease [A4] study, N = 1165) to otherwise matched participants without amyloid accumulation (Longitudinal Evaluation of Amyloid Risk and Neurodegeneration [LEARN] study, N = 507).

METHODS: Health-related resource use was self-reported using the Resource Use Inventory (RUI). Longitudinal analyses examined effect on RUI from study (A4 vs LEARN), time, and their interaction, controlling for Alzheimer's Disease Cooperative Study-Preclinical Alzheimer's Cognitive Composite (ADCS-PACC) and the Clinical Dementia Rating (CDR) scale, and their change scores from baseline.

RESULTS: Over time, paid employment and volunteering decreased, and unpaid help and hospitalization increased. Results showed clear associations between ADCS-PACC and CDR with RUI.

DISCUSSION: Little detectable impact of amyloid levels on RUI was found in pre-symptomatic AD that has been identified as an ideal stage to target for dementia prevention.

HIGHLIGHTS: Using data from a cohort of cognitively unimpaired older adults with evidence of amyloid accumulation enrolled in the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) study and otherwise matched participants who did not meet subthreshold levels of amyloid accumulation enrolled in the Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) study, this study showed clear associations between clinical variables and resource use and participation in paid employment and volunteering but suggested little detectable impact of amyloid levels on rate of change during the preclinical stage. Our results suggest that economic benefits from currently available treatment that effectively removes amyloid may not be immediately or concurrently observed during the short timeline of clinical trials. It is critical that our examination of economic consequence of treatment include broad ranges of items on resource use and productivity loss, longer time horizon, and that we balance between cost of detection, treatment, and burden and benefit.},
}

Humans
*Alzheimer Disease/drug therapy
Male
Female
*Employment/statistics & numerical data
Aged
Longitudinal Studies
*Volunteers/statistics & numerical data
Prodromal Symptoms

@article {pmid41085131,
year = {2025},
author = {Bauer, A and Rabe, C and Schiffman, C and Rose, F and Respondek, G and Gullotta, F and Schlieker, L and Jethwa, A and Schrurs, I and Manuilova, E and Ostrowitzki, S and Bittner, T},
title = {Blood-based pre-screening in the SKYLINE secondary prevention Ph3 gantenerumab study.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {10},
pages = {e70676},
doi = {10.1002/alz.70676},
pmid = {41085131},
issn = {1552-5279},
support = {//F. Hoffmann-La Roche Ltd/ ; //Roche Diagnostics International Ltd (Rotkreuz, Switzerland)/ ; },
mesh = {Humans ; *Alzheimer Disease/blood/drug therapy/diagnosis/prevention & control ; *tau Proteins/blood ; Female ; Biomarkers/blood/cerebrospinal fluid ; Male ; Retrospective Studies ; Aged ; *Secondary Prevention/methods ; Amyloid beta-Peptides/blood ; Apolipoprotein E4/blood ; Positron-Emission Tomography ; *Antibodies, Monoclonal, Humanized/therapeutic use ; },
abstract = {INTRODUCTION: SKYLINE was a secondary prevention study that used blood-based biomarker (BBBM) pre-screening to screen out participants with a low likelihood of amyloid positivity by positron emission tomography (PET) or cerebrospinal fluid (CSF) testing.

METHODS: This retrospective analysis used data from SKYLINE (ClinicalTrials.gov: NCT05256134; terminated prematurely) and the Anti-Amyloid Treatment in Asymptomatic Alzheimer's (A4) study to compare predicted and actual clinical performance characteristics of various biomarker combinations using prototype Elecsys[®] plasma immunoassays (Roche Diagnostics International Ltd, Rotkreuz, Switzerland).

RESULTS: In >3500 participants screened in SKYLINE, tau phosphorylated at threonine 181 (pTau181) and apolipoprotein E4 protein (ApoE4p) was the highest-performing BBBM combination. Actual clinical performance of the BBBM pre-screening in SKYLINE was similar to predictions based on A4 in terms of screen-out rate, positive predictive value, and 1-negative predictive value.

DISCUSSION: BBBM pre-screening in SKYLINE using prototype plasma pTau181 and ApoE4p immunoassays effectively alleviated participant burden by avoiding unnecessary PET or CSF testing.

HIGHLIGHTS: We compared blood-based biomarker (BBBM) performance in SKYLINE and Anti-Amyloid Treatment in Asymptomatic Alzheimer's (A4). Pre-screening improved amyloid positivity (defined by positron emission tomography/cerebrospinal fluid) screen failure rate. Tau phosphorylated at threonine 181 (pTau181) and apolipoprotein E4 protein was the highest-performing combination among BBBMs tested. Pre-screening eased participant burden by reducing subsequent screening procedures.},
}

Humans
*Alzheimer Disease/blood/drug therapy/diagnosis/prevention & control
*tau Proteins/blood
Female
Biomarkers/blood/cerebrospinal fluid
Male
Retrospective Studies
Aged
*Secondary Prevention/methods
Amyloid beta-Peptides/blood
Apolipoprotein E4/blood
Positron-Emission Tomography
*Antibodies, Monoclonal, Humanized/therapeutic use

@article {pmid41084412,
year = {2025},
author = {Lee, A and Al-Dahwi, S and Angell, T and Arulalagan, A and Bloxsom, R and Clarkson, H and Faure, R and Goodarzi, S and Gupta, M and Kale, A and Lam, K and Mahon-Daly, F and Parry, C and Pradhan, V and Ryan-Phillips, F and Shah, S and Sidhu, S and Smiddy, J and Sridhar, A and Tahmid, SF and Wight, R and Roberts, N and Topiwala, A},
title = {A systematic review of brain health in adults with chronic pain.},
journal = {Anaesthesia},
volume = {},
number = {},
pages = {},
doi = {10.1111/anae.70021},
pmid = {41084412},
issn = {1365-2044},
abstract = {INTRODUCTION: Recent research has linked chronic pain with an increased risk of clinical dementia diagnosis. Yet structural and functional brain changes associated with chronic pain and their potential role in accelerating brain ageing have not been characterised comprehensively. Understanding these effects is crucial to developing targeted prevention and management strategies.

METHODS: We conducted a systematic review of all English language articles in MEDLINE and Embase. Studies were eligible if they compared neuroimaging, clinical, biological, cognitive or mental health outcomes in adults with chronic pain to healthy controls. Following screening, data were extracted and the risk of bias was assessed.

RESULTS: Of 5805 identified studies, 365 met the inclusion criteria. Most were cross-sectional studies with small sample sizes; conducted in middle-aged populations in China or the USA; had moderate to high risk of bias; and represented > 30 distinct pain phenotypes. Magnetic resonance imaging was the most common method for assessing brain health. Key findings in patients with chronic pain included: lower grey matter volumes and reduced fractional anisotropy; evidence of accelerated brain ageing including older brain age and higher white matter hyperintensities; mixed results in resting state functional connectivity; increased power densities and connectivity on electroencephalography; and higher levels of serum brain-derived neurotrophic factor. The most consistently affected brain regions across magnetic resonance imaging studies were the insula; anterior and posterior cingulate; thalamus; hippocampus; primary motor cortex; and cerebellum.

DISCUSSION: Adults with chronic pain exhibit widespread alterations in brain health compared with healthy controls. Several observed features overlap with biomarkers of Alzheimer's disease and other forms of neurodegeneration. These findings highlight the need for larger, well-designed studies incorporating clearly defined pain phenotypes, multimodal imaging and causal inference methods to clarify the role of chronic pain in brain ageing and dementia risk.},
}

@article {pmid41084258,
year = {2025},
author = {Raabe, AC and Correa, RAS and Rodrigues, CCPR and Vieira, RP},
title = {History, Challenges, and Perspectives of CNS-Targeted Transdermal Formulations.},
journal = {Current pharmaceutical design},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113816128409331250915220233},
pmid = {41084258},
issn = {1873-4286},
abstract = {Central nervous system (CNS) disorders, such as Alzheimer's disease (AD), Parkinson's disease (PD), and Schizophrenia (Sch) present significant challenges for healthcare systems, both in terms of prevalence and the complexity of pharmacological treatment. While current therapies offer symptomatic relief, there is a high rate of failure in addressing the full spectrum of clinical symptoms and patient adherence issues, especially in long-term care. Since ancient times, various civilizations, including the Chinese, Egyptians, and indigenous South African cultures, have investigated and utilized the transdermal route for therapeutic and medicinal applications. Recent advances in transdermal drug delivery systems (TDS) offer a promising alternative to traditional routes of administration, enhancing drug absorption and minimizing side effects, such as gastrointestinal distress. This review explores the potential of TDS for improving the pharmacotherapy of AD, PD, and Sch. We also highlight the ongoing challenges in optimizing TDS formulations, such as drug absorption through the skin, skin irritation, and maintaining therapeutic efficacy. Furthermore, the review discusses the progress in prodrug design strategies aimed at enhancing skin permeation and bioavailability, particularly in the context of CNS-targeted drugs. The need for continued research into TDS technology is emphasized, as it holds promise for improving treatment adherence, patient quality of life, and caregiver burden, thereby advancing therapeutic options for CNS disorders.},
}

@article {pmid41084249,
year = {2025},
author = {Tamaddon-Abibigloo, Y and Dastmalchi, S and Mahdipanah, F and Asadi, E and Khezrpour, S and Valizadeh, P and Shahbazi-Mojarrad, J},
title = {Isatin Derivatives as Emerging Promising Anti-Alzheimer Agents: Focusing on Their Chemical Structure and Biological Targets.},
journal = {Current topics in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115680266394265250828164308},
pmid = {41084249},
issn = {1873-4294},
abstract = {Alzheimer's disease (AD) is a progressive and irreversible neurodegenerative disorder with a complex pathology. Until now, there is no generally effective treatment for AD. Isatin is a natural alkaloid whose derivatives have shown a wide spectrum of biological activities. This molecule is also the basic scaffold for several compounds with useful biological properties against AD. In this review, for the first time, we focus on the anti-AD properties of isatin derivatives. We tried to present comprehensive data about their structure and mechanism of action. Results showed that indirubins, isatin Schiff Bases, and spiro derivatives of isatin were the most studied molecules. The most studied targets were the glycogen synthase kinase-3, cholinesterases, and amyloid beta aggregation. It was concluded that isatin could be considered an important scaffold for the development of new anti-AD compounds.},
}

@article {pmid41082949,
year = {2025},
author = {Ye, Q and Gast, G and Holmes, TC and Xu, X},
title = {Hippocampal neural circuit mechanisms in Alzheimer's disease revealed by viral-genetic circuits mapping.},
journal = {Neurobiology of disease},
volume = {},
number = {},
pages = {107139},
doi = {10.1016/j.nbd.2025.107139},
pmid = {41082949},
issn = {1095-953X},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder with growing major health impacts in countries with aging populations. Existing therapeutic approaches that have been based on neurochemical and neuropathological findings are largely ineffective. This lack of progress suggests we require a new framework for future AD therapies. The examination of neural circuit mechanisms in AD mouse models is an emerging focus for identifying new AD treatment strategies. We know now there are neural circuit-level maladaptive alterations in AD brains, some of which appear very early in the disease process before neuropathological features are detectable. Recent advancements in viral-genetic technologies allow us to quantitatively map the cell-type-specific neural circuit connections in AD mouse models. Monosynaptic rabies virus mapping reveals age-progressive changes in both long-range and local hippocampal neural circuit connectivity in AD mouse models - and provides explanations for human AD behavioral defects, such as sex differences and higher level visual deficits. These recent developments in neural circuits level concepts and technology present new opportunities for studying AD pathogenesis for early identification of the disease and for developing novel therapeutic interventions.},
}

@article {pmid41082483,
year = {2025},
author = {Hao, X and Ding, N and Zhang, Y and Wu, M and Ning, Y and Wang, Z and Li, Z},
title = {Acupuncture Strategies in a Mouse Model of Alzheimer's Disease.},
journal = {Journal of visualized experiments : JoVE},
volume = {},
number = {223},
pages = {},
doi = {10.3791/68809},
pmid = {41082483},
issn = {1940-087X},
mesh = {*Alzheimer Disease/therapy/microbiology ; Animals ; *Acupuncture Therapy/methods/instrumentation ; Mice ; Disease Models, Animal ; Brain ; Male ; Gastrointestinal Microbiome/physiology ; Mice, Inbred C57BL ; Intestines/microbiology ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disease. Numerous studies have demonstrated that alterations in intestinal flora can influence the central nervous system (CNS) through multiple pathways, ultimately contributing to the onset and progression of AD. Recent research suggests the limitations of pharmacological therapies, emphasizing the need for multi-targeted interventions in AD treatment. Traditional Chinese medicine (TCM) highlights the physiological and pathological relationship between the brain and the intestine. Therefore, therapeutic strategies targeting gastrointestinal regulation to enhance brain function are of great importance for delaying the pathological progression of AD. This protocol introduces a brain-intestine coordination acupuncture method. The experimental results showed that this acupuncture protocol could modulate intestinal flora, suppress intestinal inflammation and neuroinflammation in AD model mice, thereby achieving bidirectional therapeutic effects on brain-intestine regulation. Moreover, a mouse bag fixation device for acupuncture treatment was described in this study, which can reduce stress reaction and improve experimental efficiency.},
}

*Alzheimer Disease/therapy/microbiology
Animals
*Acupuncture Therapy/methods/instrumentation
Mice
Disease Models, Animal
Brain
Male
Gastrointestinal Microbiome/physiology
Mice, Inbred C57BL
Intestines/microbiology

@article {pmid41082320,
year = {2025},
author = {Verrienti, G and Lombardozzi, G and Albergo, G and De Filippis, S},
title = {Trazodone in neurology, a new life for an old molecule - an updated, comprehensive, systematic review of clinical trials.},
journal = {International journal of psychiatry in clinical practice},
volume = {},
number = {},
pages = {1-11},
doi = {10.1080/13651501.2025.2572291},
pmid = {41082320},
issn = {1471-1788},
abstract = {INTRODUCTION: The triazolopyridine derivative trazodone is approved for the treatment of major depressive disorder (MDD) in adults; according to the available literature, this molecule, through a specific dose-dependent profile of action, was found to be a potential therapeutic option in some neurological conditions. This systematic review aimed to synthesise the available evidence on the use of trazodone in neurological patients.

METHODS: PubMed was searched for articles published from inception until March 2025. Article reference lists were screened, and relevant articles were retrieved for consultation. Clinical trials specifically investigating trazodone in neurological populations were included, following PRISMA guidelines for systematic reviews.

RESULTS: Out of 69 records initially retrieved, 14 studies met the inclusion criteria, comprising 13 randomised controlled trials and 1 retrospective study, with a total of 608 patients. Most of the included studies focused on individuals with dementia, while others explored its use in different neurological disorders.

CONCLUSIONS: Despite being an older antidepressant, trazodone remains widely prescribed. Beyond treating depression in neurological patients, it may may be useful in the treatment of some neurological aspects. However, current evidence remains limited. Further high-quality research is necessary to better define the therapeutic potential of trazodone in the management of neurological conditions.},
}

@article {pmid41082199,
year = {2025},
author = {Lu, M and Kim, MJ and Collins, EC and Shcherbinin, S and Ellinwood, AK and Yokoi, Y and Brooks, DA and Hansson, O and Knopman, DS and Sims, JR and Mintun, MA},
title = {Posttreatment Amyloid Levels and Clinical Outcomes Following Donanemab for Early Symptomatic Alzheimer Disease: A Secondary Analysis of the TRAILBLAZER-ALZ 2 Randomized Clinical Trial.},
journal = {JAMA neurology},
volume = {},
number = {},
pages = {},
doi = {10.1001/jamaneurol.2025.3869},
pmid = {41082199},
issn = {2168-6157},
abstract = {IMPORTANCE: Accumulation of amyloid plaque drives pathogenesis of Alzheimer disease (AD). Reduction of amyloid via amyloid-targeting therapies may result in clinical benefit.

OBJECTIVE: To assess the correlation of posttreatment amyloid levels with clinical outcomes and biomarkers in AD.

This was a post hoc exploratory analysis from the randomized, placebo-controlled phase 3 trial, TRAILBLAZER-ALZ 2, conducted June 2020 through April 2023 at 277 medical research centers/hospitals in 8 countries. A total of 8240 participants aged 60 to 85 years with early symptomatic AD with amyloid and tau pathology based on positron emission tomography (PET) imaging were assessed for eligibility. Of these, 6504 participants were excluded predominantly due to inadequate amyloid or tau pathology. The current analysis included 1582 participants (766 in the donanemab group and 816 in the placebo group) with baseline and at least 1 posttreatment assessment. Data analysis took place from July 2024 to March 2025.

INTERVENTIONS: Participants were randomized 1:1 to receive donanemab (700 mg for the first 3 doses and 1400 mg thereafter) or placebo intravenously every 4 weeks for up to 72 weeks, with outcomes assessed through 76 weeks.

MAIN OUTCOMES AND MEASURES: Participants were categorized into 1 of 10 groups (deciles) based on their lowest amyloid value observed posttreatment. Clinical progression was assessed via changes in integrated Alzheimer's Disease Rating Scale (iADRS) and Clinical Dementia Rating-Sum of Boxes (CDR-SB) scores. Plasma biomarkers measured included phosphorylated tau 217 (p-tau217), p-tau181, glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL). Correlations between the median amyloid level in each decile were assessed with 76-week least-squares mean changes in each outcome and biomarker.

RESULTS: Analyses included 1582 participants, including 766 treated with donanemab and 816 with placebo. The mean (SD) age was 72.9 (6.2) years, and 900 participants (56.9%) were female. Participants who received donanemab had lower posttreatment amyloid values than those in the placebo group. Across the trial population, lower posttreatment amyloid levels were correlated with slower clinical progression as measured by iADRS score (R2, 0.73 [95% CI, 0.37-0.97]) and CDR-SB score (R2, 0.87 [95% CI, 0.70-0.97]) and with decreases in p-tau217 (R2, 0.86 [95% CI, 0.73-0.97]), p-tau181 (R2, 0.88 [95% CI, 0.77-0.97]), and GFAP (R2, 0.87 [95% CI, 0.76-0.97]). There was no correlation between posttreatment amyloid value and NfL (R2, 0.03 [95% CI, 0.00-0.54]).

CONCLUSIONS AND RELEVANCE: The findings in this secondary analysis of a randomized clinical trial demonstrating a correlation between posttreatment amyloid plaque level and clinical benefit support amyloid plaque removal as the mechanism of action for donanemab treatment and the level of amyloid plaque as a potential surrogate biomarker in amyloid-targeting therapies.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04437511.},
}

@article {pmid41082159,
year = {2025},
author = {Ntondini, TL and Naki, T and Alven, S},
title = {The therapeutic efficacy of nanoparticles in the treatment of alzheimer's disease.},
journal = {Acta neurologica Belgica},
volume = {},
number = {},
pages = {},
pmid = {41082159},
issn = {2240-2993},
abstract = {The build-up of beta-amyloid plaques in the brain leads to Alzheimer's disease (AD), a neurodegenerative condition. AD affects more than 30 million individuals globally every year. No cure for AD has been discovered yet. The available therapeutic options are administered to slow down the progress of the disease. The currently available treatment plans are used to relieve symptoms and improve cognitive abilities, thus slowing progression. Nanotechnology is highly effective and has demonstrated significant benefits across various medical applications. Nanoparticles have been explored as promising drug delivery systems for the targeted delivery of anti-AD therapeutics and for the precise diagnosis of the condition. Nanoparticles, such as dendrimers, lipid-based nanoparticles, polymer-based nanoparticles, and metal-based nanoparticles, have been designed and reported to inhibit Aβ aggregation, fibril formation, and disaggregating mature fibrils, prevent neuroinflammation and Aβ1-42-induced cell damage, treat oxidative stress and lower hallmark of Aβ, and display excellent capability to bypass blood-brain barrier (BBB). This review is focused on the preclinical therapeutic outcomes of nanoparticles and the challenges encountered in the treatment of AD. This review highlights the significant advancements of nanoparticles that are currently undergoing clinical trials for management of AD.},
}

@article {pmid41081549,
year = {2025},
author = {Bellio, TA and Krunic, A and Campion, MS and Dupaguntla, R and Labadorf, A and Stein, TD and Lin, H and Mellott, TJ and Blusztajn, JK},
title = {Perinatal Choline Supplementation Promotes Resilience Against Progression of Alzheimer's Disease-Like Brain Transcriptomic Signatures in App[NL-G-F] Mice.},
journal = {Aging cell},
volume = {},
number = {},
pages = {e70148},
doi = {10.1111/acel.70148},
pmid = {41081549},
issn = {1474-9726},
support = {P30 AG072978/NH/NIH HHS/United States ; R01 AG045031/NH/NIH HHS/United States ; R21 AG 059195/NH/NIH HHS/United States ; R21 AG056901/NH/NIH HHS/United States ; RF1 AG057768/NH/NIH HHS/United States ; RF1 AG078299/NH/NIH HHS/United States ; //NIH Office of Dietary Supplements/ ; },
abstract = {Alzheimer's disease (AD)-the leading cause of dementia-has no cure, inadequate treatment options, and a limited understanding of prevention measures. We have previously shown that perinatal dietary supplementation with the nutrient choline ameliorates cognitive deficits and reduces amyloidosis across the brain in App[NL-G-F] AD model mice. Here, we analyzed transcriptomic abnormalities in these mice and tested the hypothesis that they may be attenuated by perinatal choline supplementation (PCS). Wild-type (WT) and App[NL-G-F] dams consumed a diet containing 1.1 (control) or 5 g/kg (supplemented) of choline chloride from 2 weeks prior to mating until weaning. At 3, 6, 9, or 12 months of age, the offspring RNA was sequenced in the hippocampus and cerebral cortex. As compared to WT, the App[NL-G-F] mice reared on the control diet had age-dependent upregulation of expression of mRNAs and lncRNAs related to inflammation and reduced expression of mRNAs related to neuronal function. As compared to App[NL-G-F] mice on the control diet, PCS App[NL-G-F] mice increased expression of synaptic genes and downregulated inflammation-related genes starting at 6 months in the cortex; increased expression of GABAergic function and ATP metabolism genes, and decreased expression of inflammatory genes in the hippocampus at 12 months. These changes counteracted the effects of App[NL-G-F] genotype seen in mice on the control diet. The expression of many of these choline-protected genes correlated with clinical dementia rating, inflammation, and tauopathy in human postmortem dorsolateral prefrontal cortex AD samples, indicating their relevance to the disease process. The results suggest that adequate choline intake could be a preventive strategy for AD.},
}

@article {pmid41080679,
year = {2025},
author = {Mishra, K and Tripathi, S and Tiwari, AK and Rana, R and Yadav, P and Chourasia, MK},
title = {Cerium-based nanoparticles for neurodegeneration: emerging redox therapeutics beyond pharmaceuticals.},
journal = {RSC advances},
volume = {15},
number = {45},
pages = {37540-37569},
pmid = {41080679},
issn = {2046-2069},
abstract = {Delivering therapeutic agents across the blood-brain barrier (BBB) remains a formidable hurdle in the treatment of neurodegenerative diseases, which are primarily driven by mitochondrial dysfunction, oxidative stress, and neuroinflammation. Although our understanding of these disease mechanisms has advanced, effective treatments are still limited due to the restrictive nature of the BBB. In this context, nanotechnology has emerged as a promising approach, offering engineered nanocarriers capable of traversing the BBB and enabling targeted drug delivery to the brain. Amongst the various nanomaterials explored, cerium-based nanoparticles have gained particular attention as promising candidates for neurodegenerative disease therapy. Their multifunctionality stemming from reversible redox behaviour, enzyme-mimicking activity, sustained antioxidant effects, and anti-inflammatory properties, combined with their ability to penetrate the BBB and provide neuroprotection, positions them as a powerful platform for future therapeutic strategies. This review begins with a concise overview of the shared pathological mechanisms underlying neurodegenerative diseases, highlights BBB-related drug delivery challenges, and discusses nanocarrier strategies for brain targeting, focusing on cerium-based nanoparticles. We then delved into the structural features, synthesis techniques, and distinctive redox properties of cerium-based nanomaterials, with emphasis on cerium oxide and cerium vanadate. Their therapeutic potential is explored across Alzheimer's and Parkinson's diseases, as well as in stroke, multiple sclerosis, and glioblastoma. Key insights into their physicochemical properties, BBB permeability, and neuroprotective mechanisms are provided. We also address current limitations, including nanoparticle stability, toxicity, and translational barriers, and conclude with future directions for optimizing cerium-based nanozymes in neurotherapeutics.},
}

@article {pmid41079916,
year = {2025},
author = {Alba, LCO and Anlacan, VMM and Navarra, CJA and Jamora, RDG},
title = {YouTube as an educational resource: Evaluating the quality and reliability of videos for family caregivers of persons living with Alzheimer's disease dementia.},
journal = {Journal of Alzheimer's disease reports},
volume = {9},
number = {},
pages = {25424823251368887},
pmid = {41079916},
issn = {2542-4823},
abstract = {BACKGROUND: YouTube is increasingly used by patients and caregivers as a source of health information. However, the quality and reliability of content on Alzheimer's disease dementia (ADD) remain uncertain.

OBJECTIVE: This study aimed to determine whether YouTube videos on ADD provide reliable and high-quality information for caregivers and to assess whether the most popular videos are also the most trustworthy.

METHODS: In December 2024, YouTube was systematically searched for ADD-related videos. Two independent physicians reviewed each video, scoring it using modified DISCERN (mDISCERN) for reliability and the Global Quality Scale (GQS) for content quality. Videos were categorized by goal and assessed for quality, accuracy, comprehensiveness, and specific content.

RESULTS: There were 117 videos included in the study. Using the mDISCERN scale, 70 videos (59.8%) were deemed with good reliability, 33 videos (28.2%) have moderate reliability, and 14 videos (12%) have poor reliability. Using the GQS, 61 videos (51.1%) have high quality, 16 videos (28%) were assessed as excellent quality, 34 videos (29%) as moderate quality, and 7 videos (6%) as low quality. Videos from academic institutions, news agency and physicians exhibited higher mDISCERN and GQS scores compared to other groups and a significant correlation was seen between mDISCERN and GQS (p < 0.001).

CONCLUSIONS: The videos on ADD produced by healthcare professionals and academic institutions have high quality and good reliability, covering disease properties, treatment choices, and patient experiences. However, video popularity does not significantly correlate with content reliability and quality.},
}

@article {pmid41078387,
year = {2025},
author = {Zapata-Restrepo, LM and Miller, BL and Rivas, J and Possin, K and Valcour, V and Piña-Escudero, SD and Ibañez, A and Kosik, KS},
title = {Case of early onset Alzheimer's disease associated with a novel PSEN1 variant identified in Colombia.},
journal = {NPJ dementia},
volume = {1},
number = {1},
pages = {31},
pmid = {41078387},
issn = {3005-1940},
abstract = {Early-onset Alzheimer's disease (EOAD) is a rare form of dementia that often progresses more quickly than late-onset cases, and is more commonly associated with autosomal dominant mutations. A 47-year-old male presented with progressive cognitive and behavioral decline, a family history of EOAD, and was later found to have a novel pathogenic PSEN1 variant (c.519 G > T, p.Leu173Phe). Initial evaluations, including neuroimaging and laboratory tests, were unremarkable. Neuropsychological testing later revealed memory impairment, executive dysfunction, and neuropsychiatric symptoms. These features, alongside the identified mutation, are consistent with phenotypic presentations of EOAD involving the third transmembrane domain of PSEN1. Pharmacological treatment with cholinesterase inhibitors and antipsychotics yielded limited benefit. Notably, the extended follow-up time, of more than 10 years from the early symptomatic stage, is a unique and valuable feature of this case study, providing rare longitudinal insight into the natural course of genetically confirmed EOAD.},
}

@article {pmid41078145,
year = {2025},
author = {Wang, F and Liu, J and Bai, D and Li, L and Fedgchin, M and Henley, D and Li, H and Zhang, F},
title = {A Phase 1 Study of the Pharmacokinetics, Safety, and Tolerability of Posdinemab (JNJ-63733657) in Healthy Chinese Adults.},
journal = {Journal of clinical pharmacology},
volume = {},
number = {},
pages = {},
doi = {10.1002/jcph.70116},
pmid = {41078145},
issn = {1552-4604},
support = {//Johnson & Johnson/ ; },
abstract = {Posdinemab, a humanized immunoglobulin G1/κ monoclonal antibody, binds with high affinity to phosphorylated tau protein which is associated with Alzheimer's disease (AD) pathophysiology. Posdinemab reduced tau seeding in murine models and was well tolerated in Phase-1 clinical studies. This open-label, single-arm, Phase-1 study examined the effects of posdinemab with single intravenous dose (60 mg/kg) in healthy adults from China. The main objectives were to assess posdinemab serum pharmacokinetics (PK, primary), safety and tolerability (secondary), and presence of anti-drug antibodies (ADAs; secondary). Results were compared with Phase-1 European first-in-human (NCT03375697) and Japanese (NCT03689153) studies. Healthy Chinese participants (N = 10), mean age 60.0 (SD 3.80) years and 60% female, received posdinemab. Mean posdinemab serum Cmax was 1401 µg/mL, median tmax was 0.08 days, mean AUCinf was 18162 µg·day/mL, mean CL was 3.36 mL/day/kg, and mean elimination t1/2 was 17.5 days. Most participants (n = 8; 80%) experienced ≥1 treatment-emergent adverse event (TEAEs), most common (20%) of which were arthralgia and back pain. Four participants (40.0%) were positive for posdinemab ADAs post-dose with peak titers of 1:22.5 (n = 3) and 1:360 (n = 1). Serum posdinemab concentrations in ADA-positive and ADA-negative participants were generally comparable. In conclusion, PK profile of posdinemab in healthy participants from China was in the expected range and comparable to previous Phase-1 studies in Europe and Japan. There were no new safety concerns. These results support further global development of posdinemab in AD.},
}

@article {pmid41077117,
year = {2025},
author = {Elamin, SA and Al Shibli, AN and Shaito, A and Al-Maadhadi, MJMB and Zolezzi, M and Pedersen, S},
title = {Anti-amyloid monoclonal antibody therapies in Alzheimer's disease - a scoping review.},
journal = {Neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuroscience.2025.10.011},
pmid = {41077117},
issn = {1873-7544},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder affecting millions worldwide, and with advancements in the medical field, Anti-amyloid monoclonal antibodies (AA mAbs) targeting amyloid-β have emerged as potential disease-modifying agents altering AD pathology. This scoping review mapped the characteristics, patterns, and gaps in clinical trials investigating the efficacy and safety of AA mAbs in AD treatments, with focus on cognitive, functional, biochemical, imaging, and safety outcomes. It highlighted patterns, gaps, and limitations of the existing literature. A systematic search of PubMed/MEDLINE, Embase, Scopus, and Web of Science was conducted for studies published since inception to February 2022, and eligible studies that investigated efficacy and safety outcomes of AA mAbs in treatment of AD were included. A majority of the included trials reported a combination of cognitive, functional, biochemical, and imaging outcomes. Across the sample, reductions in amyloid burden were frequently reported (10 trials), with a smaller subset of studies reporting significant cognitive and functional improvements (4 trials), primarily lecanemab and aducanumab in addition to one pooled analysis of solanezumab. ARIA-E and ARIA-H were frequently reported among the safety concerns, particularly in high-dose and APOE ε4 carrier populations. Notable limitations were observed in the reviewed literature including a disconnect between biomarker changes and consistent clinical benefits and, importantly, limited population diversity and patient-reported outcomes. This review highlights the need for rigorous, diverse, and patient-centered research. Addressing these gaps is critical in ensuring safe, effective, and equitable treatment for all patients living with Alzheimer's disease.},
}

@article {pmid41076749,
year = {2025},
author = {Kunath, N and Ramfjord, HAB and Kvisvik, EV and Konyves-Kolonics, M and Rolfseng Grøntvedt, G and Serysheva, II and Komorowski, L and Wildemann, B and Jarius, S},
title = {ITPR1 autoantibody-associated autoimmunity as a cause of newly emerging cognitive decline mimicking Alzheimer's disease: Case report and brief review of the literature.},
journal = {Journal of neuroimmunology},
volume = {409},
number = {},
pages = {578774},
doi = {10.1016/j.jneuroim.2025.578774},
pmid = {41076749},
issn = {1872-8421},
abstract = {BACKGROUND: Since its first description in 2014, anti-inositol 1,4,5-trisphosphate receptor type 1 (ITPR1, also termed IP3R1) autoimmunity has been recognized as causing a clinically heterogeneous spectrum of symptoms. While first described in patients with autoimmune cerebellar ataxia, this facultative paraneoplastic disease has been associated also with peripheral neuropathy, dysautonomia, sleep disorders, neuropsychiatric/psychotic symptoms, and cognitive decline.

METHODS: Retrospective case study.

RESULTS: We report the case of a 58-year-old patient who was admitted with acute confusion, rapidly progressive cognitive decline, and hallucinations. A history of mild cognitive impairment over several years and low cerebrospinal fluid (CSF) amyloid beta-42 and elevated CSF tau protein were suggestive of Alzheimer's disease (AD). However, pleocytosis, intrathecal IgG synthesis and blood-CSF barrier dysfunction prompted screening for antineuronal antibodies, which revealed ITPR1-IgG1/anti-Sj antibodies in both serum and CSF. Brain MRI showed limbic hyperintensities and hippocampal atrophy. No neoplastic disease was found. Immunosuppressive treatment stabilized the disease course but did not lead to symptom improvement.

CONCLUSIONS: This case underscores the clinical importance of CSF analysis and testing for anti-neural autoantibodies, including less common reactivities, in case of rapid cognitive decline even in patients with known or suspected neurodegenerative disease, such as AD, with ITPR1 representing a novel autoimmune target antigen.},
}

@article {pmid41076604,
year = {2025},
author = {Ebadpour, N and Abavisani, M and Karav, S and Kesharwani, P and Sahebkar, A},
title = {Exosome/Extracellular Vesicles-Based Therapeutics in Alzheimer's Disease: Neuroprotective Roles and Future Perspectives.},
journal = {Journal of molecular neuroscience : MN},
volume = {75},
number = {4},
pages = {137},
pmid = {41076604},
issn = {1559-1166},
mesh = {*Alzheimer Disease/therapy/metabolism ; Humans ; *Exosomes/metabolism/transplantation ; *Extracellular Vesicles/metabolism/transplantation ; Animals ; },
abstract = {Alzheimer's disease (AD), a progressive neurodegenerative disorder, is marked by memory loss, cognitive decline, and characteristic pathological features including β-amyloid (Aβ) plaques, tau tangles, and neuroinflammation. Despite extensive research, effective therapies remain elusive. Exosome/EVs-based therapeutics have emerged as a promising avenue for AD treatment. Neuron-derived exosomes/extracellular vesicles (EVs) (NDEs) and stem cell-derived exosomes/EVs exhibit neuroprotective effects by promoting Aβ degradation, modulating tau pathology, and reducing inflammation. Notably, NDEs carry insulin-degrading enzyme (IDE) and cellular prion proteins (PrPC), aiding Aβ clearance. However, exosomes also present challenges, such as the potential propagation of pathogenic tau and complement-mediated neurotoxicity. Neural and mesenchymal stem cell-derived exosomes further demonstrate therapeutic efficacy by altering amyloid precursor protein processing and activating PI3K/Akt/mTOR signaling to reduce AD pathology. Despite these advancements, clinical translation requires a deeper understanding of exosome/EVs biology, improved isolation techniques, and personalized strategies. Continued research may establish exosomes as a transformative approach in AD therapy.},
}

*Alzheimer Disease/therapy/metabolism
Humans
*Exosomes/metabolism/transplantation
*Extracellular Vesicles/metabolism/transplantation
Animals

@article {pmid41076002,
year = {2025},
author = {Pantiya, P and Chattipakorn, N and Chattipakorn, SC},
title = {Exploring the role of CD147 in cerebrovascular and Alzheimer's pathologies: Insights into mechanisms and interventions.},
journal = {Experimental neurology},
volume = {},
number = {},
pages = {115498},
doi = {10.1016/j.expneurol.2025.115498},
pmid = {41076002},
issn = {1090-2430},
abstract = {Cluster of Differentiation 147 (CD147), a multifunctional transmembrane glycoprotein, has been identified as a key regulator in the pathophysiology of cerebrovascular diseases and Alzheimer's disease (AD). In cerebrovascular conditions, CD147 contributes to neurological dysfunction by modulating pathways related to extracellular matrix remodeling, angiogenesis, and neuroinflammation. In AD, CD147 exhibits a complex, context-dependent role. Upregulation of CD147 has been implicated in increased amyloid-beta (Aβ) production and impaired energy metabolism, both of which contribute to cognitive decline. Paradoxically, other studies suggest that CD147 may exert neuroprotective effects by promoting Aβ degradation and preserving blood-brain barrier (BBB) integrity. These contradictory findings highlight the dualistic nature of CD147's functions, suggesting it may act as both a pathogenic and protective factor in AD. As evidence regarding its roles continues to grow, a more integrated understanding is needed to determine whether CD147 should be pursued as a viable biomarker or therapeutic target in cerebrovascular and neurodegenerative diseases. Therefore, this review aims to comprehensively synthesize current findings from clinical data, animal models, and in vitro studies to elucidate CD147's functions in cerebrovascular disease and AD. Additionally, we explore emerging therapeutic strategies targeting CD147-related pathways, which may offer promising avenues for neuroprotection.},
}

@article {pmid41075815,
year = {2025},
author = {Wu, JY and Lin, YM and Hsu, WH and Liu, TH and Tsai, YW and Huang, PY and Chuang, MH and Yu, T and Lai, CC},
title = {Glucagon-Like Peptide-1 Receptor Agonists and Dementia Risk Reduction in Older Adults With Type 2 Diabetes: A Retrospective Cohort Study.},
journal = {Journal of the American Medical Directors Association},
volume = {},
number = {},
pages = {105901},
doi = {10.1016/j.jamda.2025.105901},
pmid = {41075815},
issn = {1538-9375},
abstract = {OBJECTIVE: To evaluate the effect of glucagon-like peptide-1 receptor agonists (GLP-1RAs) on dementia risk compared with dipeptidyl peptidase-4 inhibitors (DPP-4is) among older adults with type 2 diabetes (T2D).

DESIGN: Retrospective cohort study using an active-comparator, new-user design with propensity score matching.

SETTING AND PARTICIPANTS: Data were obtained from the TriNetX Global Collaborative Network, which includes electronic health records from 134 health care organizations worldwide. Participants were adults aged ≥65 years with T2D who initiated GLP-1RA or DPP-4i therapy between January 2017 and November 2024.

METHODS: Eligible participants were matched 1:1 on baseline characteristics using propensity score matching (PSM). The primary outcome was incident dementia. Secondary outcomes included prescriptions for dementia-related drugs, Alzheimer's disease, and vascular dementia. Hazard ratios (HRs) with 95% confidence intervals (CIs) were estimated using Cox proportional hazards models, and subgroup and sensitivity analyses were performed.

RESULTS: After PSM, 82,689 patients were included in each treatment group. GLP-1RA use was associated with a lower risk of dementia compared with DPP-4i (HR, 0.58; 95% CI, 0.55-0.61; P < .0001). Stratified analyses revealed consistent risk reductions across age, sex, and GLP-1RA type. In addition, GLP-1RA was also associated with lower risks of dementia-related drug prescriptions (HR, 0.76; 95% CI, 0.70-0.81), Alzheimer's disease (HR, 0.62; 95% CI, 0.56-0.70), and vascular dementia (HR, 0.62; 95% CI, 0.55-0.70). Sensitivity analyses supported the robustness of these findings.

CONCLUSIONS AND IMPLICATIONS: GLP-1RA use in older adults with T2D is associated with a significantly lower risk of dementia compared with DPP-4i. These findings suggest the potential neuroprotective benefits of GLP-1RAs and highlight their importance in managing T2D with a view toward reducing dementia risk. Further studies are warranted to explore the underlying mechanisms and validate these observations in randomized controlled trials.},
}

@article {pmid41075024,
year = {2025},
author = {Abedimanesh, N and Miri, SA and Mohammadi, A and Shahmohammadi, F and Danafar, H and Eskandari, MR and Hejazi, S and Andalib, S and Motlagh, B},
title = {Protective and therapeutic effects of betanin nanoparticles in an alzheimer's rat model: modulation of behavior and expression of AQP4, BDNF, SIRT6, and Seladin-1.},
journal = {Metabolic brain disease},
volume = {40},
number = {7},
pages = {286},
pmid = {41075024},
issn = {1573-7365},
support = {A-12-898-19//The Vice Chancellor for Research of Zanjan University of Medical Sciences, Zanjan, Iran/ ; },
mesh = {Animals ; *Brain-Derived Neurotrophic Factor/genetics/metabolism/biosynthesis ; *Alzheimer Disease/drug therapy/metabolism ; Rats ; *Nanoparticles/administration & dosage ; *Sirtuins/genetics/biosynthesis/metabolism ; *Neuroprotective Agents/administration & dosage/pharmacology/therapeutic use ; Male ; *Aquaporin 4/genetics/biosynthesis/metabolism ; *Betacyanins/administration & dosage/therapeutic use/pharmacology ; *Nerve Tissue Proteins/biosynthesis/genetics/metabolism ; Disease Models, Animal ; Hippocampus/metabolism/drug effects ; Microfilament Proteins/biosynthesis/genetics/metabolism ; Antioxidants ; Behavior, Animal/drug effects ; Maze Learning/drug effects ; },
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder characterized by cognitive decline, oxidative stress, and neuroinflammation. Betanin, a natural antioxidant, has shown neuroprotective potential, but its clinical use is limited by poor bioavailability. This study investigates the effects of betanin-loaded nanomicelles, designed to enhance brain delivery, in a scopolamine-induced rat model of AD. Nanomicelles were synthesized and characterized using TEM, DLS, and FT-IR. Rats received either pre- or post-treatment with betanin nanomicelles, free betanin, donepezil, or saline. Cognitive performance was assessed using the Morris Water Maze. Gene expression levels of AQP4, BDNF, SIRT6, and Seladin-1 were measured using real-time PCR, and antioxidant activity was evaluated by assessing glutathione (GSH) and glutathione reductase (GR) in hippocampal tissue. Betanin nanomicelles improved spatial memory, increased BDNF and SIRT6 expression, and reduced AQP4 levels, indicating potential neuroprotection. Seladin-1 expression was notably elevated in the pre-treatment group, suggesting support for neuronal survival. Antioxidant assays showed restoration of GSH and GR activity. These findings suggest that betanin nanomicelles may enhance cognitive function and modulate neuroprotective pathways more effectively than free betanin, supporting their potential as a novel therapeutic strategy for AD.},
}

Animals
*Brain-Derived Neurotrophic Factor/genetics/metabolism/biosynthesis
*Alzheimer Disease/drug therapy/metabolism
Rats
*Nanoparticles/administration & dosage
*Sirtuins/genetics/biosynthesis/metabolism
*Neuroprotective Agents/administration & dosage/pharmacology/therapeutic use
Male
*Aquaporin 4/genetics/biosynthesis/metabolism
*Betacyanins/administration & dosage/therapeutic use/pharmacology
*Nerve Tissue Proteins/biosynthesis/genetics/metabolism
Disease Models, Animal
Hippocampus/metabolism/drug effects
Microfilament Proteins/biosynthesis/genetics/metabolism
Antioxidants
Behavior, Animal/drug effects
Maze Learning/drug effects

@article {pmid41074172,
year = {2025},
author = {Chen, J and Zhang, X and Sun, J and Zhi, Y and Xie, Z and Guan, Y and Zhang, Z and Wu, C},
title = {Photothermal nano-agents: an innovative trident weapon for accurate and effective treatment of alzheimer's disease.},
journal = {Journal of nanobiotechnology},
volume = {23},
number = {1},
pages = {650},
pmid = {41074172},
issn = {1477-3155},
support = {82404876//National Natural Science Foundation of China/ ; 2024M760845//China Postdoctoral Science Foundation/ ; 2025T181064//China Postdoctoral Special Funding Project/ ; 232301420087//The Joint Fund of Science and Technology Development Program of Henan Province/ ; HN2025064//Postdoctoral funding in Henan Province/ ; },
mesh = {*Alzheimer Disease/therapy ; Humans ; *Photothermal Therapy/methods ; Animals ; Blood-Brain Barrier/metabolism/drug effects ; tau Proteins/metabolism ; Amyloid beta-Peptides/metabolism ; Infrared Rays ; *Nanoparticles/chemistry/therapeutic use ; Brain/metabolism ; Phototherapy/methods ; },
abstract = {Alzheimer's disease (AD) is a degenerative neurological illness for which effective therapy alternatives are currently lacking. Photothermal therapy (PTT) employs the localized thermal effects of nano-photothermal agents (NPTAs) under near-infrared (NIR) light for the treatment of diverse conditions. PTT presents numerous benefits for AD therapy, including operational flexibility, non-invasiveness, spatiotemporal modulation, and synergistic multimodal treatment approaches. The primary mechanisms of PTT for AD treatment encompass the following facets: Initially, localized heat impacts may transiently disrupt the blood-brain barrier (BBB), facilitating the trans-BBB transport of therapeutic medicines. Secondly, the photothermal action can efficiently dissociate Aβ aggregates and Tau protein while inhibiting Aβ aggregation, hence diminishing neurotoxicity and reinstating cognitive function. Third, during PTT, NPTAs can achieve imaging of biomarkers such as Aβ and Tau at the site of AD lesions and actively monitor the therapy process. Despite being in its nascent stages for AD treatment and encountering numerous challenges, such as poor biocompatibility, inadequate penetration of deep brain tissue by NIR light, and cumulative toxicity risks, PTT remains a promising therapeutic strategy to overcome the limitations of AD treatment. This study elucidates the pathophysiology of AD, the processes by which NPTAs enter the brain, and the mechanism of NPTAs in AD theranostics, with a particular focus on current developments in NIR-activated NPTAs for AD treatment. It further discusses the challenges in this emerging field and proposes future research directions, thereby facilitating the clinical translation of PTT-based strategies in AD treatment.},
}

*Alzheimer Disease/therapy
Humans
*Photothermal Therapy/methods
Animals
Blood-Brain Barrier/metabolism/drug effects
tau Proteins/metabolism
Amyloid beta-Peptides/metabolism
Infrared Rays
*Nanoparticles/chemistry/therapeutic use
Brain/metabolism
Phototherapy/methods

@article {pmid41073674,
year = {2025},
author = {Woo, MS and Therriault, J and Hosseini, SA and Wang, YT and Macedo, AC and Rahmouni, N and Aumont, É and Servaes, S and Tissot, C and Fernandez-Arias, J and Trudel, L and Hall, B and Bezgin, G and Quispialaya-Socualaya, K and Goncalves, M and Chan, T and Stevenson, J and Zheng, Y and Mitchell, S and Hopewell, R and Pola, I and Tan, K and Di Molfetta, G and Lussier, FZ and Massarweh, G and Vitali, P and Soucy, JP and Gauthier, S and Ashton, NJ and Blennow, K and Pascoal, TA and Zetterberg, H and Benedet, AL and Rosa-Neto, P},
title = {Glia inflammation and cell death pathways drive disease progression in preclinical and early AD.},
journal = {EMBO molecular medicine},
volume = {},
number = {},
pages = {},
pmid = {41073674},
issn = {1757-4684},
support = {MOP-11-51-31; RFN 152985, 159815, 162303//Canadian Government | Canadian Institutes of Health Research (CIHR)/ ; MOP-11-51-31 -team 1//Canadian Consortium of Neurodegeneration and Aging/ ; NIRG-12-92090, NIRP-12-259245//Alzheimer's Association (AA)/ ; #ADSF-21-831376-C, #ADSF-21-831381-C, #ADSF-21-831377-C, and #ADSF-24-1284328-C//Alzheimer's Association (AA)/ ; ZEN-21-848495, SG-23-1038904 QC//Alzheimer's Association (AA)/ ; CFI Project 34874; 33397//Brain Canada Foundation/ ; 2020-VICO-279314//FRQ | Fonds de Recherche du Québec - Santé (FRQS)/ ; IT27627//Mitacs Graduate Fellowship/ ; F225864C02//Max E Binz Fellowship-Medicine/ ; M159875C51//Grad Excellence Award in Neurology and Neurosurgery/ ; 2023_EKMS.03//Else Kröner Fresenius Foundation/ ; WO 2835/1-1//Deutsche Forschungsgemeinschaft (DFG)/ ; S0199/10110/2025//Corona-Stiftung (Corona Foundation)/ ; #2023-00356, #2022-01018 and #2019-02397//Swedish Research Council/ ; #2017-00915 and #2022-00732//Swedish Research Council/ ; 101053962//European Union Horizon Europe research and innovation programme/ ; #ALFGBG-71320//Swedish State Support for Clinical Research/ ; #201809-2016862//Alzheimer Drug Discovery Foundation, USA/ ; #22HLT07//European Partnership on Metrology (EPM)/ ; #FO2022-0270//Swedish State/ ; #ALZ2022-0006, #FO2024-0048-TK-130 and FO2024-0048-HK-24//Swedish State/ ; 860197//European Union's Horizon 2020 research and innovation programme Marie Sklodowska-Curie grant/ ; JPND2021-00694//European Union Joint Programme - Neurodegenerative Disease Research/ ; UKDRI-1003//UK Dementia Research Institute (UK DRI)/ ; #AF-930351, #AF-939721, #AF-968270, and #AF-994551//Swedish Alzheimer Foundation/ ; #ALZ2022-0006, #FO2024-0048-TK-130 and FO2024-0048-HK-24//Swedish State/ ; #ALFGBG-965240 and #ALFGBG-1006418//ALF agreement/ ; JPND2019-466-236//European Union Joint Programme for Neurodegenerative Disorders/ ; },
abstract = {Accumulation of amyloid-β (Aβ) and neurofibrillary tangles (NFTs) are followed by the activation of glia cells and infiltration of peripheral immune cells that collectively accelerate neurodegeneration in preclinical AD models. Yet, the role of neuroinflammation for neuronal injury and disease progression in preclinical and early symptomatic AD remains elusive. Here, we combined multiplexed immunoassays and SomaScan proteomics of the cerebrospinal fluid (CSF) with MRI and PET brain imaging of people across the AD continuum to identify pathways that are associated with AD progression. Unbiased clustering revealed that glia-mediated inflammation, activation of cell death pathways (CDPs) and synaptic pathologies were among the earliest Aβ-induced changes, and were associated with disease progression in preclinical AD. Mediation analysis revealed that activation of CDPs were decisive drivers of inflammation in early symptomatic AD. The cycle of glia-mediated neuroinflammation and neuronal injury characterizes preclinical AD and has implications for novel treatment approaches.},
}

@article {pmid41073581,
year = {2025},
author = {Lanskey, JH and Jafarian, A and Hughes, LE and Karadag, M and Kocagoncu, E and Rouse, MA and Adams, NE and Naessens, M and Raymont, V and Woolrich, M and Singh, KD and Henson, RN and Rowe, JB},
title = {Alzheimer's disease and memantine effects on NMDA-receptor blockade: non-invasive in vivo insights from magnetoencephalography.},
journal = {Molecular psychiatry},
volume = {},
number = {},
pages = {},
pmid = {41073581},
issn = {1476-5578},
support = {ARUK-PG2017B-19//Alzheimer's Research UK (ARUK)/ ; 220258/WT_/Wellcome Trust/United Kingdom ; SUAG/092 G116788; SUAG/096 G116788//RCUK | MRC | Medical Research Foundation/ ; },
abstract = {To accelerate new treatments for Alzheimer's disease, there is the need for human pathophysiological biomarkers that are sensitive to treatment and disease mechanisms. In this proof-of-concept study, we assess new biophysical models of non-invasive human MEG imaging to test the pharmacological and disease modulation of NMDA-receptor inhibition. Magnetoencephalography was recorded during an auditory mismatch negativity paradigm from (1) neurologically-healthy people on memantine or placebo (n = 19, placebo-controlled crossover design); (2) people with Alzheimer's disease at baseline and 16-months (n = 42, amyloid-biomarker positive, longitudinal observational design). Optimised dynamic causal models inferred voltage-dependent NMDA-receptor blockade using Parametric Empirical Bayes to test group effects. The mismatch negativity amplitude was attenuated when Alzheimer's disease was more severe (lower baseline mini-mental state examination) and after follow-up (versus baseline). Memantine increased NMDA-receptor inhibition, compared to placebo. Alzheimer's disease reduced NMDA-receptor inhibition in proportion to severity and over time. In line with preclinical studies, we confirm in humans that memantine and Alzheimer's disease have opposing effects on NMDA-receptor inhibition. The ability to infer such receptor dynamics and pharmacology from non-invasive physiological recordings has wide applications, including the assessment of other neurological disorders and novel drugs intended for symptomatic or disease-modifying treatments.},
}

@article {pmid41073019,
year = {2025},
author = {Li, A and Yu, Y and Zhang, Z and Wufuer, R and Wang, D and Zhang, L},
title = {Pd-modified MXene enabled electrochemical sensing platform for ratiometric detection of acetylcholinesterase inhibitors via modulation effect of Prussian blue.},
journal = {Analytica chimica acta},
volume = {1376},
number = {},
pages = {344625},
doi = {10.1016/j.aca.2025.344625},
pmid = {41073019},
issn = {1873-4324},
mesh = {*Ferrocyanides/chemistry ; *Electrochemical Techniques/methods ; *Cholinesterase Inhibitors/analysis ; *Palladium/chemistry ; Acetylcholinesterase/metabolism ; Humans ; Limit of Detection ; *Nanocomposites/chemistry ; *Metal Nanoparticles/chemistry ; Electrodes ; Nitrites ; Transition Elements ; },
abstract = {BACKGROUND: Sensitive detection of acetylcholinesterase (AChE) inhibitors is crucial for pharmaceutical screening, managing neurodegenerative diseases, and drug development. However, their therapeutic use is often limited by toxicity and side effects. Current detection methods for AChE inhibitors suffer from issues like low sensitivity, high cost, and interference from complex biological matrices. Therefore, there is a growing and urgent demand for sensitive, reliable, and cost-effective sensors that enable early diagnosis, accurate monitoring of drug efficacy, and personalized treatment plans in various clinical settings.

RESULTS: In this work, a novel ratiometric electrochemical sensor was developed using Pd-modified MXene integrated with Prussian blue (PB) nanocomposites for AChE inhibitor detection. The Pd-modified MXene provides high electrical conductivity and abundant surface sites for nanoparticle immobilization, enhancing electron transfer and signal strength. Pd nanoparticles improve the electrocatalytic activity of the electrode, boosting electron transfer. PB acted as a redox mediator that oxidized thiocholine (TCh), the enzymatic product of AChE-catalyzed hydrolysis of ATCh, and was reoxidized to generate a stable redox potential serving as an internal reference. This enabled dual-signal ratiometric detection, improving accuracy and resistance to background interference. Using berberine as a model inhibitor, the sensor exhibited a linear range of 0.13-41 μmol/L and a detection limit of 10.0 nmol/L. The sensor demonstrated excellent reproducibility, retaining 93.1 % of its initial response after 28 days, and detected berberine in tablet and serum samples with high recovery, showing broad applicability.

SIGNIFICANCE: This work highlights the synergistic effects of Pd-MXene and PB, offering a portable, cost-effective strategy for highly sensitive AChE inhibitor detection. The dual-signal ratiometric detection system enhances both sensitivity and accuracy, making it ideal for biomedical and pharmaceutical applications, with significant potential for early diagnosis and monitoring of neurodegenerative diseases.},
}

*Ferrocyanides/chemistry
*Electrochemical Techniques/methods
*Cholinesterase Inhibitors/analysis
*Palladium/chemistry
Acetylcholinesterase/metabolism
Humans
Limit of Detection
*Nanocomposites/chemistry
*Metal Nanoparticles/chemistry
Electrodes
Nitrites
Transition Elements

@article {pmid41068898,
year = {2025},
author = {Climacosa, FMM and Ornos, EDB and Gapaz, NCLL and Guantia, MGR and Cruz, JMC and Manalo, RVM and Yu, ML and Qureshi, AP and Carampel, AC and Asis, JLB and Reyes, JCB and Dacasin, AB and Anlacan, VMM},
title = {The role of genetic polymorphisms on drug response in Alzheimer's disease: a systematic review.},
journal = {BMC medical genomics},
volume = {18},
number = {1},
pages = {154},
pmid = {41068898},
issn = {1755-8794},
abstract = {UNLABELLED: Alzheimer’s disease (AD) is the most common neurodegenerative disorder, affecting over 32 million people globally. The variability in treatment response to AD medications is influenced by genetic factors, sex, comorbidities, and medication history. Pharmacogenomics, the study of how an individual’s genetic makeup influences drug response, offers a promising approach to understanding these differences. This systematic review investigated the role of genetic polymorphisms in affecting treatment outcomes in AD. Following PRISMA guidelines, we systematically searched PubMed, Scopus, Cochrane, and PharmGKB databases for studies on AD, pharmacogenomics, and treatment response. Ten researchers independently screened the articles, with two independent reviewers resolving conflicts. A total of 1126 records were identified, and after removing duplicates and screening, 58 studies met inclusion criteria. APOE emerged as the most consistently studied gene, with ε2 and ε3 alleles generally associated with better responses to acetylcholinesterase inhibitors (AChEIs) and NMDA receptor antagonists, while ε4 carriage predicted poorer outcomes. The CYP2D610 allele, common in East Asian populations, was linked to enhanced donepezil response due to slower drug metabolism. Other genes, including ABCA1, A2M, CHRNA7, CHRFAM7A, and CHAT, showed potential associations with treatment response, particularly with AChEIs, though results varied across populations and study designs. Polymorphisms in inflammatory, metabolic, and vascular genes such as IL6, IDE, and ACE were also associated with cognitive outcomes, but findings were largely exploratory. In conclusion, APOE and CYP2D6 remain the most promising pharmacogenetic markers in AD, particularly for guiding donepezil therapy. However, evidence remains inconsistent due to varying study designs, populations, and clinical metrics. Additional genes show potential but require further validation. Larger, multiethnic studies with standardized treatment protocols and outcomes are needed to establish the clinical utility of pharmacogenomics in AD therapy.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12920-025-02225-1.},
}

@article {pmid41037798,
year = {2025},
author = {Park, HJ and Kim, J and Choi, J and Ryou, C and Shin, E and Lee, JY},
title = {Targeted genome editing of ZKSCAN3 mitigates the neurotoxicity caused by mutant HTT (huntingtin) in a Huntington disease animal model and three-dimensional cell culture of Huntington disease.},
journal = {Autophagy},
volume = {},
number = {},
pages = {1-15},
doi = {10.1080/15548627.2025.2569965},
pmid = {41037798},
issn = {1554-8635},
abstract = {Huntington disease (HD) is a neurodegenerative disease caused by the expression of a mutant form of HTT (huntingtin; mHTT), caused by an abnormal expansion of polyglutamine in HTT. In HD, macroautophagy/autophagy dysfunction can cause mHTT accumulation. Moreover, the promotion of autophagy is considered a therapeutic strategy for the treatment of HD. ZKSCAN3 (zinc finger with KRAB And SCAN domains 3) has been identified as a transcriptional repressor of TFEB (transcription factor EB), a master regulator of autophagy and lysosomal functions. In this study, we conducted CRISPR-Cas9-based gene ablation to disrupt ZKSCAN3 in HD animal models and HD patient-induced pluripotent stem cell (iPSC) -derived three-dimensional (3D) spheroids. In animal models of HD, targeted in vivo zkscan3 ablation via a single adeno-associated virus (AAV) mediated CRISPR-Cas9 approach resulted in reduced mHTT levels, leading to improvements in both behavioral symptoms and the brain environment. Furthermore, CRISPR-Cas9 mediated ablation of ZKSCAN3 in 3D spheroids from HD patient-derived iPSC resulted in increased autophagy and lysosomal function, along with reduced mHTT accumulation. Specifically, in iPSC-derived neurons from HD patients, ZKSCAN3-depleted neurons demonstrated increased lysosomal function and reduced oxidative stress compared to controls. Additionally, transcriptional analysis of ZKSCAN3-edited neurons revealed an increased expression of genes involved in synaptic function and transporter activity. Taken together, these results suggest that in HD treatment strategies for improving neuronal function and the brain environment, ZKSCAN3 downregulation in neurons by autophagy activation may improve the brain environment through neuronal self-repair.Abbreviations: 2D: two-dimensional; 3D: three-dimensional; 4-HNE: 4-hydroxynonenal; AAV: adeno-associated virus; AD: Alzheimer disease; Aβ: beta-amyloid; DAPI: 4,6-diamidino-2-phenylindole; GFP: green fluorescent protein; HD: Huntington disease; HTT: huntingtin; IXMC: ImageXpress microconfocal high-content imaging system; Indel: insertion or deletion; iPSC: induced pluripotent stem cell; LAMP1: lysosomal-associated membrane protein 1; mHTT: mutant huntingtin; NPCs: neural precursor cells; RBFOX3/NeuN: RNA binding fox-1 homolog 3; PD: Parkinson disease; RNP: ribonucleoprotein; sgRNAs: single guide RNAs; ST: striatum; TFEB: transcription factor EB; TUBB3/Tuj-1: tubulin beta 3 class III; ZKSCAN3: zinc finger with KRAB and SCAN domains 3.},
}

@article {pmid41072129,
year = {2025},
author = {Guo, G and Wen, G and Liu, L and Song, R and Cao, P and Yang, J and Zaiane, OR},
title = {BrainOSM: Outlier screening for multi-view functional brain network analysis.},
journal = {Computer methods and programs in biomedicine},
volume = {273},
number = {},
pages = {109092},
doi = {10.1016/j.cmpb.2025.109092},
pmid = {41072129},
issn = {1872-7565},
abstract = {PURPOSE: Identifying biomarkers for mental diseases is vital for understanding their underlying mechanisms, facilitating early diagnosis, and enabling more personalized treatment strategies. In this study, we focus on diagnosing autism spectrum disorder (ASD) and alzheimer's disease (AD) by analyzing functional brain networks (FBNs), which are represented as graphs capturing the functional connectivity patterns of the brain. The primary challenges in modeling FBNs for this disorder stem from two key issues: (i) the heterogeneity among graphs, and (ii) the disease-unrelated information within graphs.

METHOD: We introduce a two-stage framework, BrainOSM, which combines outlier screening in datasets with a multi-view graph pooling module for enhanced graph classification. Specifically, the first stage employs progressive uncertainty-based outlier screening to reduce the interference of inter-graph heterogeneity. The second stage integrates multi-graph pooling, multi-view learning, and prior subnetwork regularization to refine graph structures, effectively tackling the challenge of disease-unrelated information within graphs.

RESULTS: To validate the effectiveness of our method, we assess its performance on two public datasets: the Autism Brain Imaging Data Exchange (ABIDE) dataset and the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset. On the ABIDE dataset, BrainOSM achieved an average accuracy of 70.23% and an AUC of 70.42%, corresponding to improvements of 8.55% and 7.74% over the traditional GCN method. On the ADNI dataset, it reached an average accuracy of 82.29% and an AUC of 83.23%, showing gains of 8.97% and 11.78%, respectively. Our code is publicly available at https://github.com/guoguiliang111/BrainOSM.

CONCLUSION: Our extensive experiments confirm the generalizability and the effectiveness of BrainOSM for mental disease classification. Visual analyses further demonstrate that the model effectively identifies subnetworks associated with mental diseases, highlighting its potential for clinical interpretation. Moreover, our findings indicate that outlier screening plays a crucial role in improving classification accuracy when dealing with heterogeneous datasets.},
}

@article {pmid41071446,
year = {2025},
author = {Li, S and Gao, Y and Zhang, Y and Zhang, J and Zhao, Y and Chang, C and Gao, X and Zhang, J and Yang, G},
title = {Picroside II Alleviates the Progression of Alzheimer's Disease via the NLRP3/Caspase-1/GSDMD Pathway.},
journal = {Neuromolecular medicine},
volume = {27},
number = {1},
pages = {68},
pmid = {41071446},
issn = {1559-1174},
support = {Grant No. 20220997//the Medical Science Research Project of Hebei Provincial Health Commission/ ; Grant No. 21377745D//the Key Research and Development Plan of Hebei Province/ ; },
mesh = {Animals ; *Alzheimer Disease/drug therapy/pathology ; *NLR Family, Pyrin Domain-Containing 3 Protein/physiology/genetics ; Mice ; *Cinnamates/therapeutic use/pharmacology ; *Caspase 1/physiology/genetics ; Signal Transduction/drug effects ; *Iridoid Glucosides/therapeutic use/pharmacology ; Male ; Disease Progression ; Mice, Transgenic ; *Neuroprotective Agents/therapeutic use/pharmacology ; Plaque, Amyloid ; Mice, Inbred C57BL ; Cytokines ; Disease Models, Animal ; Amyloid beta-Protein Precursor/genetics ; Inflammasomes ; },
abstract = {Alzheimer's disease (AD), an irreversible, degenerative disorder, affects the central nervous system. However, its accurate pathology remains unclear, and studies on treatment modalities are ongoing. Picroside II (PII) is an active compound in the medicinal herb Rhizoma coptis. It has strong effects, including antioxidation, anti-inflammatory, antiapoptotic, and neuroprotective effects. In this study, we analyzed how PII affects cognitive impairment in mice with AD and its underlying mechanism. PII at doses of 20 or 40 mg/kg was given to APP/PS1 mice through intraperitoneal injection for 2 months. Moreover, we carried out the Morris water maze test to evaluate cognitive function. Immunofluorescence analysis was performed to observe cortical Aβ plaque deposition, neuronal loss, and inflammatory cell expression. An enzyme-linked immunosorbent assay (ELISA) was performed to measure the levels of the cortical inflammatory factors tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-1β. Western blotting and quantitative polymerase chain reaction (qPCR) were performed to measure NLRP3, ASC, GSDMD, and caspase-1 expression. PII improved cognitive function, reduced Aβ plaque deposition and glial activation, and alleviated cortical neuronal loss in APP/PS1 mice. Furthermore, PII decreased the levels of cortical inflammatory factors (TNF-α, IL-6, and IL-1β). In addition, it suppressed NLRP3, ASC, GSDMD, and caspase-1 expression at the mRNA and protein levels. PII enhances the cognitive function of APP/PS1 mice by reducing inflammation and pyroptosis via the suppression of the NLRP3/caspase-1/GSDMD pathway. Therefore, PII is a candidate anti-AD therapeutic agent.},
}

Animals
*Alzheimer Disease/drug therapy/pathology
*NLR Family, Pyrin Domain-Containing 3 Protein/physiology/genetics
Mice
*Cinnamates/therapeutic use/pharmacology
*Caspase 1/physiology/genetics
Signal Transduction/drug effects
*Iridoid Glucosides/therapeutic use/pharmacology
Male
Disease Progression
Mice, Transgenic
*Neuroprotective Agents/therapeutic use/pharmacology
Plaque, Amyloid
Mice, Inbred C57BL
Cytokines
Disease Models, Animal
Amyloid beta-Protein Precursor/genetics
Inflammasomes

@article {pmid41070709,
year = {2025},
author = {Chen, S and Ou, R and Wei, Q and Li, C and Song, W and Zhao, B and Yang, J and Fu, J and Ma, Y and Liu, J and Wang, X and Fang, D and Hu, T and Xiao, L and Zhang, S and Huang, R and Guo, X and Feng, F and Chen, X and Shang, H},
title = {Lecanemab treatment for Alzheimer's Disease of varying severities and associated plasma biomarkers monitoring: A multi-center real-world study in China.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {10},
pages = {e70750},
doi = {10.1002/alz.70750},
pmid = {41070709},
issn = {1552-5279},
support = {82271272//National Natural Science Foundation of China/ ; 2023YFQ0098//Science and Technology Bureau Fund of Sichuan Province of China/ ; YCXJ-JZ-2022-007//Beijing E town Coorperation & Development Foundation/ ; 2025-108//the Sichuan Provincial Cadre Healthcare Research Project/ ; No.2022ZD0211605//the Sci-Tech Innovation 2023 "Brain Science and Brain-like Research/ ; },
mesh = {Humans ; *Alzheimer Disease/drug therapy/blood ; Male ; Female ; Biomarkers/blood ; China ; Aged ; Prospective Studies ; tau Proteins/blood ; Middle Aged ; Treatment Outcome ; Amyloid beta-Peptides ; Neuropsychological Tests ; Aged, 80 and over ; Severity of Illness Index ; },
abstract = {INTRODUCTION: We investigated real-world efficacy, safety, and plasma biomarker dynamics of Lecanemab in Chinese patients with Alzheimer's disease (AD).

METHODS: A multi-center prospective cohort study enrolled 68 AD patients. Cognitive scales and plasma biomarkers were assessed at baseline (V0), 2.5 months (V1), and 7 months (V2).

RESULTS: Alzheimer's Disease Assessment Scale-Cognitive Subscale 14-item version (ADAS-cog14) scores improved significantly at both follow-ups, and plasma p-tau181 consistently declined. Both p-tau181 and p-tau217 correlated with cognition and partially predicted treatment response (area under the curve [AUC] = 0.734 and 0.713). Mixed-effects modeling confirmed their dynamic association with ADAS-cog14 scores. Subgroup analyses indicated benefits across sex and apolipoprotein E4 status, while moderate-to-severe cases showed limited response. Lecanemab was well tolerated, with asymptomatic amyloid-related imaging abnormalities in 17.65% and mild infusion reactions in 5.88%.

DISCUSSION: These findings support the short-term efficacy and safety of Lecanemab in early AD and highlight plasma biomarkers as a treatment-responsive biomarker.

HIGHLIGHTS: Lecanemab improved cognitive function in Chinese patients with mild cognitive impairment due to Alzheimer's disease (AD-MCI) and mild AD over a short period. Plasma p-tau181 and p-tau217 showed significant correlation with cognitive scores, and their baseline level could partially predict the efficacy of lecanemab. Lecanemab showed a favorable safety profile with low, manageable rates of amyloid-related imaging abnormalities (ARIA) and infusion reactions.},
}

Humans
*Alzheimer Disease/drug therapy/blood
Male
Female
Biomarkers/blood
China
Aged
Prospective Studies
tau Proteins/blood
Middle Aged
Treatment Outcome
Amyloid beta-Peptides
Neuropsychological Tests
Aged, 80 and over
Severity of Illness Index

@article {pmid41070364,
year = {2025},
author = {Igarashi, A and Kimura, N and Ataka, T and Ito, T and Sasaki, K and Kobayashi, C and Tani, M and Sakata, Y and Azuma, M and Chida, A and Takeshima, T and Iwasaki, K and Matsubara, E},
title = {Simulation of Alzheimer's diagnostic flows with blood biomarker test options in Japan.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {11},
number = {4},
pages = {e70157},
pmid = {41070364},
issn = {2352-8737},
abstract = {INTRODUCTION: This study projected the diagnostic testing landscape for lecanemab treatment in Japan under different workflows.

METHODS: A dynamic simulation estimated wait times and treatment-eligible patient numbers under four scenarios: current diagnostic workflow, blood biomarker (BBM) tests as triage tools, BBM tests for confirmatory diagnostics, and both combined. Willingness-to-pay (WTP) and intangible costs were assessed via an online survey to estimate testing demand.

RESULTS: The maximum mean wait time under the current workflow was projected at 6.4 months, decreasing with BBM integration. The number of treatment-eligible patients increased considerably with BBM-based confirmatory diagnostics. BBM triage testing reduced wait times but temporarily increased treatment-eligible patients.

DISCUSSION: Replacing positron emission tomography (PET) or cerebrospinal fluid with BBM-based diagnostics may increase treatment eligibility because of lower costs, driving higher demand for testing.

HIGHLIGHTS: A dynamic simulation models Alzheimer's diagnostic workflows in Japan.Blood biomarker (BBM) tests reduce diagnostic wait times for Alzheimer's in Japan.Implementing BBM tests improves access to Alzheimer's diagnostics.Study quantifies demand for diagnostic testing based on costs and accessibility.Testing costs impact the number of treatment-eligible Alzheimer's patients.},
}

@article {pmid41070139,
year = {2025},
author = {Weber, DM and Stroh, MA and Taylor, SW and Lagier, RJ and Louie, JZ and Clarke, NJ and Vaillancourt, DE and Rayaprolu, S and Duara, R and Racke, MK},
title = {Development and Clinical Validation of Blood-Based Multibiomarker Models for the Evaluation of Brain Amyloid Pathology.},
journal = {Neurology. Clinical practice},
volume = {15},
number = {6},
pages = {e200546},
pmid = {41070139},
issn = {2163-0402},
abstract = {BACKGROUND AND OBJECTIVES: Plasma biomarkers provide new tools for evaluating patients with mild cognitive impairment (MCI) for Alzheimer disease (AD) pathology. Such tools are needed for anti-amyloid therapies that require efficient and accurate diagnostic evaluation to identify potential treatment candidates. This study sought to develop and evaluate the clinical performance of a multimarker combination of plasma beta-amyloid 42/40 (Aβ42/40), ptau-217, and APOE genotype to predict amyloid PET positivity in a diverse cohort of patients at a memory clinic and evaluate >4,000 results from "real-world" specimens submitted for high-throughput clinical testing.

METHODS: Study participants were from the 1Florida AD Research Center. Demographics, clinical evaluations, and amyloid PET scan data were provided along with plasma specimens for model development in the intended-use cohort (MCI/AD: n = 215). Aβ42/40 and ApoE4 proteotype (reflecting high-risk APOE ɛ4 alleles) were measured by mass spectrometry and ptau-217 by immunoassay. A likelihood score model was determined for each biomarker separately and in combination. Model performance was optimized using 2 cutpoints, 1 for high and 1 for low likelihood of PET positivity, to attain ≥90% specificity and sensitivity. These cutpoints were applied to categorize 4,326 real-world specimens and an expanded cohort stratified by cognitive status (normal cognition [NC], MCI, AD).

RESULTS: For the intended-use cohort (46.0% prevalence of PET positivity), a combination of Aβ42/40, ptau-217, and APOE4 allele count provided the best model with a receiver operating characteristic area under the curve of 0.942 and with 2 cutpoints fixed at 91% sensitivity and 91% specificity, yielding a high cutpoint with 88% positive predictive value and 87% accuracy and a low cutpoint with 91% negative predictive value and 85% accuracy. Incorporating the APOE4 allele count also reduced the percentage of patients with indeterminate risk from 15% to 10%. The cutpoints categorized the real-world clinical specimens as having 42% high, 51% low, and 7% indeterminate likelihood of PET positivity and differentiated between NC, MCI, and AD dementia cognitive status in the expanded cohort.

DISCUSSION: Combining plasma biomarkers Aβ42/40, ptau-217, and APOE4 allele count is a scalable approach for evaluating patients with MCI for suspected AD pathology.},
}

@article {pmid41069980,
year = {2025},
author = {Ghaleb, J and Khouzami, KK and Nassif, N and Attieh, P and Ajlani, MFA and Sleiman, JB and Khalouf, A and Harb, F and Azar, S and Kannan, A and Ghadieh, HE},
title = {Unveiling Tirzepatide's Therapeutic Spectrum: A Dual GIP/GLP-1 Agonist Targeting Metabolic, Neurological, and Cardiovascular Health.},
journal = {International journal of endocrinology},
volume = {2025},
number = {},
pages = {2876156},
pmid = {41069980},
issn = {1687-8337},
abstract = {Tirzepatide, a novel dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist, has emerged as a groundbreaking treatment for Type 2 diabetes mellitus (T2DM) and obesity. Initially developed for glycemic control, recent clinical and preclinical data reveal its broader therapeutic potential across a range of metabolic and systemic conditions. This review explores tirzepatide's mechanisms of action, clinical efficacy, and safety profile, with particular attention to its impact on T2DM, obesity, cardiovascular health, metabolic-associated fatty liver disease (MAFLD), chronic kidney disease (CKD), and neurological disorders such as Alzheimer's and Parkinson's diseases. By addressing multiple pathophysiological pathways, including insulin resistance, inflammation, and oxidative stress, Tirzepatide presents a unique opportunity to redefine treatment paradigms beyond glycemic management. Our review also synthesizes recent evidence on the efficacy and safety of tirzepatide for obesity management specifically in Asian populations; a group frequently underrepresented in global trials. This demographic focus introduces a valuable dimension to the existing body of knowledge. As ongoing trials continue to evaluate its long-term effects, tirzepatide stands at the forefront of a new era in integrated cardiometabolic and neuroprotective therapeutics.},
}

@article {pmid41069798,
year = {2025},
author = {Stites, SD and Lee, BN and Kuz, C and Adams, M and Harkins, K and Xie, SX and Walke, L and Sankar, P and Hamilton, R},
title = {An online vignette study of diagnostic testing: Racial and ethnic differences in Alzheimer's disease diagnosis confidence and stigma.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {17},
number = {4},
pages = {e70178},
pmid = {41069798},
issn = {2352-8729},
abstract = {INTRODUCTION: Understanding how biomarker testing affects Alzheimer's disease (AD) diagnosis confidence and AD stigma among race and ethnicity groups is essential for supporting early diagnosis and treatment.

METHODS: Adults (N = 3548) rated confidence in an AD diagnosis based on four diagnostic evaluations and answered questions about AD stigma based on a clinical vignette. The sample reflects response and completion rates of 53% and 91.3%, respectively. Bivariate and multivariable regression analyses were conducted.

RESULTS: Black participants showed the smallest increase (11.86 points) in diagnosis confidence of all race groups when a brain scan was included in the diagnostic evaluation. AD diagnosis confidence changed across diagnostic evaluation categories based on level and type of AD stigma domain and race group.

DISCUSSION: Use of brain scans in evaluations can heighten diagnosis confidence in all race groups. Yet, no group had 100% confidence in an AD diagnosis with any evaluation. Recommendations are discussed.

HIGHLIGHTS: Confidence in an Alzheimer's disease (AD) diagnosis varies across racial groups.Within racial groups, AD diagnosis confidence differs with diagnostics.Even with cutting-edge biomarker testing, no racial group had 100% confidence in an AD diagnosis.Patient-centered care and systemic changes are needed to widen distribution of diagnostic technologies and improve access to care.},
}

@article {pmid41069328,
year = {2025},
author = {Tettevi, EJ and Simpong, DL and Maina, M and Adjei, S and Asuming-Brempong, E and Osei-Atweneboana, MY and Ocloo, A},
title = {Antibiotic-Induced Gut Dysbiosis Modulates Alzheimer's Disease-Associated Gene Expression and Protein Aggregation in 3xTg-AD Mice via the Gut-Brain Axis.},
journal = {Brain and behavior},
volume = {15},
number = {10},
pages = {e70946},
doi = {10.1002/brb3.70946},
pmid = {41069328},
issn = {2162-3279},
support = {//Council for Scientific and Industrial Research - Water Research Institute/ ; },
mesh = {Animals ; *Dysbiosis/chemically induced/metabolism ; *Alzheimer Disease/metabolism/genetics/microbiology ; Mice ; *Gastrointestinal Microbiome/drug effects/physiology ; *Anti-Bacterial Agents/pharmacology/adverse effects ; Female ; *Brain/metabolism ; Mice, Transgenic ; Disease Models, Animal ; *Brain-Gut Axis/drug effects/physiology ; Amyloid beta-Peptides/metabolism ; Gene Expression/drug effects ; tau Proteins/metabolism ; Anxiety/metabolism ; },
abstract = {INTRODUCTION: Alzheimer's disease (AD) is a progressive neurodegenerative disorder that poses a major global health challenge due to its increasing prevalence and lack of effective treatments. Emerging evidence suggests the gut-brain axis may play a pivotal role in AD pathogenesis. However, causal links between dysbiosis and late-stage AD pathology remain unclear.

METHODS: This study evaluated the effects of antibiotic-induced gut dysbiosis in aged 3xTg-AD mice (46-48 weeks). Female mice were randomly assigned to control or treatment groups and administered a broad-spectrum antibiotic cocktail (ampicillin, vancomycin, and neomycin) for 14 days. Behavioral tests (Y-maze, elevated plus maze) were performed to assess cognitive and anxiety-like behaviors. Gut microbiota composition was assessed via 16S rRNA qPCR. Gene expression of Acetylcholinesterase (AChE), Butyrylcholinesterase (BChE), and Tumor Necrosis Factor-Alpha (TNF-α) was analyzed via qRT-PCR, and cerebral amyloid-β1-42 and tau protein levels were quantified by ELISA.

RESULTS: Antibiotic treatment induced significant dysbiosis, with > 90% reduction in Firmicutes and Bacteroidetes. Dysbiotic mice displayed impaired spatial working memory, heightened anxiety-like behavior, and reduced locomotor activity. Molecular analyses revealed region-specific dysregulation of cholinergic genes: AChE was upregulated in the hippocampus but downregulated in the cortex, while BChE showed the opposite trend. TNF-α was significantly elevated in both regions, indicating neuroinflammation. Dysbiosis also led to increased brain levels of amyloid-β1-42 and tau.

CONCLUSION: Gut microbiome disruption exacerbates late-stage AD pathology, driving cognitive deficits, neuroinflammation, and hallmark protein aggregation. These findings support the gut-brain axis as a critical modulator of AD and highlight the microbiome as a potential therapeutic target.},
}

Animals
*Dysbiosis/chemically induced/metabolism
*Alzheimer Disease/metabolism/genetics/microbiology
Mice
*Gastrointestinal Microbiome/drug effects/physiology
*Anti-Bacterial Agents/pharmacology/adverse effects
Female
*Brain/metabolism
Mice, Transgenic
Disease Models, Animal
*Brain-Gut Axis/drug effects/physiology
Amyloid beta-Peptides/metabolism
Gene Expression/drug effects
tau Proteins/metabolism
Anxiety/metabolism

@article {pmid41069042,
year = {2025},
author = {Kennemer, AA and Gao, Z and Davis, PB and Kaelber, DC and Xu, R},
title = {Timing of neurorehabilitation and subsequent Alzheimer's disease risk in patients with moderate to severe traumatic brain injury: A nationwide retrospective cohort study in the United States.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251385262},
doi = {10.1177/13872877251385262},
pmid = {41069042},
issn = {1875-8908},
abstract = {BackgroundTraumatic brain injury (TBI) is associated with an increased risk of Alzheimer's disease (AD). It is unknown if prompt neuro-rehabilitative treatment following moderate or severe TBI mitigates this risk compared with delayed treatment.ObjectiveTo determine whether immediate neuro-rehabilitative treatment following moderate or severe TBI reduces the risk of AD and related cognitive outcomes compared with delayed treatment.MethodsWe conducted a retrospective cohort using the TriNetX Analytics Platform, which includes health records from over 100 million US patients. Adults aged 50-90 years with moderate or severe TBI were included if they received immediate treatment (within 1 week) or delayed treatment (>1 week). Outcomes were AD risk at 3- and 5-year follow-up, with additional outcomes of mild cognitive impairment (MCI), dementia, and AD-related medication prescriptions. Cox proportional hazards models were applied to propensity score-matched cohorts, and hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated.ResultsOf 37,081 eligible patients, 17,636 remained after propensity score matching. Immediate treatment was associated with lower AD risk compared with delayed treatment (HR, 0.59; 95% CI, 0.41-0.86 at 3 years; HR, 0.70; 95% CI, 0.52-0.94 at 5 years). Similar risk reductions were observed for MCI, dementia, and AD-related medication use.ConclusionsImmediate treatment following moderate or severe TBI was associated with significantly reduced risk of AD and related cognitive decline. These findings suggest that prompt intervention may mitigate long-term neurodegenerative consequences of TBI.},
}

@article {pmid41069006,
year = {2025},
author = {Kang, W and Gao, C and Li, X and Wang, X and Zhong, H and Wei, Q and Tang, Y and Huang, P and Shen, R and Chen, L and Zhang, J and Fang, R and Wei, W and Zhang, F and Zhou, G and Yuan, W and Chen, X and Yang, Z and Wu, Y and Xu, W and Zhu, S and Zhang, L and He, N and Fang, W and Zhang, M and Zhang, Y and Ju, H and Bai, Y and Liu, J},
title = {Safety and effectiveness of lecanemab in Chinese patients with early Alzheimer's disease: Evidence from a multidimensional real-world study.},
journal = {Chinese medical journal},
volume = {},
number = {},
pages = {},
doi = {10.1097/CM9.0000000000003888},
pmid = {41069006},
issn = {2542-5641},
abstract = {INTRODUCTION: Lecanemab has shown promise in treating early Alzheimer's disease (AD), but its safety and efficacy in Chinese populations remain unexplored. This study aimed to evaluate the safety and 6-month clinical outcomes of lecanemab in Chinese patients with mild cognitive impairment (MCI) or mild AD.

METHODS: In this single-arm, real-world study, participants with MCI due to AD or mild AD received biweekly intravenous lecanemab (10 mg/kg). Safety assessments included monitoring for amyloid-related imaging abnormalities (ARIA) and other adverse events. Clinical and biomarker changes from baseline to 6 months were evaluated using cognitive scales (mini-mental state examination [MMSE], montreal cognitive assessment [MoCA], clinical dementia rating-sum of boxes [CDR-SB]), plasma biomarker analysis, and advanced neuroimaging.

RESULTS: A total of 64 patients were enrolled in this ongoing real-world study. Safety analysis revealed predominantly mild adverse events, with infusion-related reactions (20.3%, 13/64) being the most common. Of these, 69.2% (9/13) occurred during the initial infusion and 84.6% (11/13) did not recur. ARIA-H (microhemorrhages/superficial siderosis) and ARIA-E (edema/effusion) were observed in 9.4% (6/64) and 3.1% (2/64) of participants, respectively, with only two symptomatic cases (one ARIA-E presenting with headache and one ARIA-H with visual disturbances). After 6 months of treatment, cognitive scores remained stable compared to baseline (MMSE: 22.33 ± 5.58 vs. 21.27 ± 4.30, P = 0.733; MoCA: 16.38 ± 6.67 vs. 15.90 ± 4.78, P = 0.785; CDR-SB: 2.30 ± 1.65 vs. 3.16 ± 1.72, P = 0.357), while significantly increasing plasma amyloid-β 42 (Aβ42) (+21.42%) and Aβ40 (+23.53%) levels compared to baseline.

CONCLUSIONS: Lecanemab demonstrated a favorable safety profile in Chinese patients with early AD. Cognitive stability and biomarker changes over 6 months suggest potential efficacy, though high dropout rates and absence of a control group warrant cautious interpretation. These findings provide preliminary real-world evidence for lecanemab's use in China, supporting further investigation in larger controlled studies.

REGISTRATION: ClinicalTrials.gov, NCT07034222.},
}

@article {pmid41068796,
year = {2025},
author = {Mu, Z and Chen, Y and Hu, Y and Wang, H and Li, J},
title = {Tailored brain metastatic tumor cells-derived apoptotic bodies ameliorate Alzheimer's disease by promoting microglia efferocytosis and neuroinflammation mitigation.},
journal = {Journal of nanobiotechnology},
volume = {23},
number = {1},
pages = {633},
pmid = {41068796},
issn = {1477-3155},
support = {No. KYCX25_3261//Postgraduate Research & Practice Innovation Program of Jiangsu Province/ ; No. 81502997//National Natural Science Foundation of China/ ; },
mesh = {Animals ; *Alzheimer Disease/metabolism/drug therapy/pathology ; *Microglia/metabolism/drug effects ; Mice ; *Brain Neoplasms/secondary/pathology/metabolism ; Liposomes/chemistry ; Humans ; Cell Line, Tumor ; Manganese Compounds/chemistry/pharmacology ; Sirolimus/pharmacology/chemistry ; Apoptosis ; *Neuroinflammatory Diseases ; Disease Models, Animal ; Amyloid beta-Peptides/metabolism ; Nanocomposites/chemistry ; Brain/pathology ; Male ; Phagocytosis/drug effects ; Efferocytosis ; Oxides ; },
abstract = {Neuroinflammation, characterized by microglial overactivation and oxidative stress, plays a critical role in the initiation and progression of Alzheimer's disease (AD). In this study, we focus on simulating the natural efferocytosis process to reprogram microglial and mitigate chronic neuroinflammation for combinational AD therapy. To achieve this goal, engineered apoptotic bodies derived from brain metastatic tumor cells (LAbs) are successfully developed. Specifically, LAbs-based nanocomposites were fabricated by hybridizing LAbs with liposomes co-loaded with manganese dioxide nanoenzyme (BMn) and autophagy-activating rapamycin (Rapa), referred to as LAbs@Lip@BMn/Rapa. LAbs@Lip@BMn/Rapa exhibits efficient BBB penetration via LAbs-associated brain metastasis propensity of apoptotic bodies. Within the AD microenvironment, oxygen produced through BMn catalyzation in response to H2O2 triggers the structural disintegration of LAbs-camouflaged liposomes and their reassembly into ultra-small vesicles, thereby significantly enhancing intracranial delivery efficiency. In vitro and in vivo experiments confirm that this multi-target strategy effectively normalizes microglia toward anti-inflammatory M2 phenotype, scavenges reactive oxide species (ROS) accumulation, promotes β-amyloid and phosphorylated tau clearance through synergistic intervention, restores the pathological microenvironment in the brain, and enhances cognitive functions in AD model mice. This study demonstrates a novel LAbs-based biomimetic construction strategy that effectively penetrates the BBB and regulates microglia functions, offering a promising approach for AD treatment.},
}

Animals
*Alzheimer Disease/metabolism/drug therapy/pathology
*Microglia/metabolism/drug effects
Mice
*Brain Neoplasms/secondary/pathology/metabolism
Liposomes/chemistry
Humans
Cell Line, Tumor
Manganese Compounds/chemistry/pharmacology
Sirolimus/pharmacology/chemistry
Apoptosis
*Neuroinflammatory Diseases
Disease Models, Animal
Amyloid beta-Peptides/metabolism
Nanocomposites/chemistry
Brain/pathology
Male
Phagocytosis/drug effects
Efferocytosis
Oxides

@article {pmid41066687,
year = {2025},
author = {Reichau, K and Scheiner, M and Poeta, E and Bringmann, G and Monti, B and Decker, M},
title = {Total Syntheses of the Amaryllidaceae Alkaloids Carltonines A-C and the Neuroprotective and Immunomodulatory Evaluation of Carltonine B.},
journal = {Journal of natural products},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.jnatprod.5c00841},
pmid = {41066687},
issn = {1520-6025},
abstract = {The inhibition of butyrylcholinesterase (BChE) represents an emerging approach for the treatment of Alzheimer's disease (AD). In 2020, three previously undescribed Amaryllidaceae alkaloids, carltonines A-C (1-3), were isolated, and their inhibitory activity on BChE was reported. Herein, we describe the first, nonstereoselective total synthesis of carltonine A-C (1-3) and confirmed their inhibitory activity using Ellman's assay, with nanomolar BChE inhibition by carltonine B (2). Further kinetic studies revealed that carltonine B (2) acts as a reversible, competitive inhibitor of BChE. In addition, racemic carltonine B (2) was evaluated in a phenotypic screening using murine hippocampal nerve cells, where it demonstrated protective effects against glutamate-induced oxytosis and ferroptosis at concentrations ranging from 5 to 10 μM and against iodoacetic acid-induced ATP depletion. Finally, in studies using lipopolysaccharide-activated microglial N9 cells, carltonine B (2) exhibited immunomodulatory effects by downregulating pro-inflammatory markers such as NOS2 and IL-1β without affecting anti-inflammatory signaling pathways.},
}

@article {pmid41066449,
year = {2025},
author = {Hanson, M and Liu, Y and Ozawa, T and Yin, H and Mattke, S},
title = {Potential barriers to timely Alzheimer's disease diagnosis and treatment: Tracer delivery and patient travel to amyloid PET scanners in the United States.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251385118},
doi = {10.1177/13872877251385118},
pmid = {41066449},
issn = {1875-8908},
abstract = {Several disease-modifying Alzheimer's disease treatments are available or in clinical trials. Participation in these trials and access to approved treatments often require amyloid positron emission tomography (PET) scans. Amyloid PET requires a radioactive tracer with a short half-life so PET scanner must be near a cyclotron facility that produces and delivers viable tracers. We examined the size and composition of the US population that faces likely geographic obstacles due to travel time constraints. Our estimate that 1.5 million older Americans would drive more than one hour to a qualifying PET site raises concern for differences in access to memory care.},
}

@article {pmid41066226,
year = {2025},
author = {Weiss, S and Harris, K and Carney, OL and Maza, VI and Wickline, S and Henderson, A and Widjaja, T and Garrett, B and Hill, DL and Liskovec, L and Chen, P and LeRoy, AS},
title = {Initial development of the writing to heal app: A structured writing series for caregivers of spouses living with Alzheimer's disease and related dementias.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251378478},
doi = {10.1177/13872877251378478},
pmid = {41066226},
issn = {1875-8908},
abstract = {BackgroundCaregiving for a spouse living with Alzheimer's disease and related dementias (ADRD) is incredibly stressful, which puts caregivers at risk for developing health problems themselves.ObjectiveTo develop an intervention that supports caregivers and helps mitigate the stress associated with caregiving.MethodsIn Part I, we used qualitative methods (e.g., data collected via focus groups with people caring for a spouse living with ADRD) to identify opportunities for targeted treatment and potential barriers to a cognitive-based online expressive writing (EW) intervention tailored to spousal caregivers. In Part IIa, we conducted a second wave of focus groups, throughout which we iteratively adapted a mobile app-based writing intervention for stress and grief among spousal caregivers, while continuously monitoring caregivers' perceived acceptability and feasibility of each proposed feature. Finally, to prepare for app development, we conducted preliminary usability testing (Part IIb), during which caregivers interacted with a prototype of the future app to complete a number of proposed task flows.ResultsCaregivers reported having dynamic needs and requested an intervention that was efficient, mobile, and readily accessible. Further, people caregiving for a spouse living with ADRD have specific motivations for writing (e.g., needing an outlet to release their emotions) as well as unique barriers to the intervention (e.g., lack of time, security concerns).ConclusionsA mobile-based writing intervention catering to the specific needs of these individuals may be a helpful coping resource for caregivers.},
}

@article {pmid41066175,
year = {2025},
author = {Toyoda, H and Kim, D and Koh, BG and Sano, T and Kanematsu, T and Oh, SB and Kang, Y},
title = {Chronic stress impairs autoinhibition in neurons of the locus coeruleus to increase asparagine endopeptidase activity.},
journal = {eLife},
volume = {14},
number = {},
pages = {},
doi = {10.7554/eLife.106362},
pmid = {41066175},
issn = {2050-084X},
support = {20K06926//Japan Society for the Promotion of Science/ ; 23K06346//Japan Society for the Promotion of Science/ ; 26290006//Japan Society for the Promotion of Science/ ; 21K06441//Japan Society for the Promotion of Science/ ; Brain Pool Program//Ministry of Science and ICT/ ; Naito Grant//Naito Foundation/ ; RS-2023-00264409//Ministry of Science and ICT/ ; RS-2023-00302281//Ministry of Science and ICT/ ; },
mesh = {Animals ; *Locus Coeruleus ; *Neurons/physiology/enzymology/metabolism ; Mice ; *Cysteine Endopeptidases/metabolism ; Male ; Monoamine Oxidase/metabolism ; Norepinephrine/metabolism ; *Stress, Physiological ; Mice, Inbred C57BL ; G Protein-Coupled Inwardly-Rectifying Potassium Channels/metabolism ; },
abstract = {Impairments of locus coeruleus (LC) are implicated in anxiety/depression and Alzheimer's disease (AD). Increases in cytosolic noradrenaline (NA) concentration and monoamine oxidase A (MAO-A) activity initiate the LC impairment through production of NA metabolite, 3,4-dihydroxyphenyl-glycolaldehyde (DOPEGAL), by MAO-A. However, how NA accumulates in soma/dendritic cytosol of LC neurons has never been addressed despite the fact that NA is virtually absent in cytosol while NA is produced exclusively in cytoplasmic vesicles from dopamine by dopamine-β-hydroxylase. Since reuptake of autocrine-released NA following spike activity is the major source of NA accumulation, we investigated whether and how chronic stress can increase the spike activity accompanied by NA autocrine. Overexcitation of LC neurons is normally prevented by the autoinhibition mediated by activation of α2A-adrenergic receptor (AR)-coupled inwardly rectifying potassium-current (GIRK-I) with autocrine-released NA. Patch-clamp study revealed that NA-induced GIRK-I in LC neurons was decreased in chronic restraint stress (RS) mice, while a similar decrease was gradually caused by repeated excitation. Chronic RS caused internalization of α2A-ARs expressed in cell membrane in LC neurons and decreased protein/mRNA levels of α2A-ARs/GIRKs in membrane fraction. Subsequently, chronic RS increased the protein levels of MAO-A, DOPEGAL-induced asparagine endopeptidase (AEP), and tau N368. These results suggest that chronic RS-induced overexcitation due to the internalization of α2A-ARs/GIRK is accompanied by [Ca[2+]]i increases, subsequently increasing Ca[2+]-dependent MAO-A activity and NA autocrine. Thus, it is likely that internalization of α2A-AR increased cytosolic NA, as reflected in AEP increases, by facilitating reuptake of autocrine-released NA. The suppression of α2A-AR internalization may have a translational potential for anxiety/AD treatment.},
}

Animals
*Locus Coeruleus
*Neurons/physiology/enzymology/metabolism
Mice
*Cysteine Endopeptidases/metabolism
Male
Monoamine Oxidase/metabolism
Norepinephrine/metabolism
*Stress, Physiological
Mice, Inbred C57BL
G Protein-Coupled Inwardly-Rectifying Potassium Channels/metabolism