@article {pmid41197929,
year = {2025},
author = {Pattanaik, SK and Sahoo, S and Acharya, SK and Barad, PK and Pattanaik, S and Rath, D},
title = {Crateva magna (Lour.) DC ameliorates rheumatoid arthritis via TNF-signalling pathways: An integration of in-silico, in-vitro and in-vivo approach.},
journal = {Journal of ethnopharmacology},
volume = {},
number = {},
pages = {120854},
doi = {10.1016/j.jep.2025.120854},
pmid = {41197929},
issn = {1872-7573},
abstract = {Crateva magna (Lour.) DC., used in traditional Indian medicine systems such as Ayurveda and Unani, is known for its anti-diabetic, anti-cancer, anti-Alzheimer's, and anti-inflammatory properties. Despite extensive ethnomedicinal applications, its therapeutic role in rheumatoid arthritis (RA) has not yet been scientifically executed.

AIM OF THE STUDY: This study utilized a systematic approach to examine the effects of C. magna on RA.

MATERIALS AND METHODS: Phytoconstituents investigation of C. magna using HR-LCMS-QTOF-MS/MS. Followed by a series of in-silico (network pharmacology, molecular docking), in-vitro (on TNF-α-induced inflammation on SW982), and lastly in-vivo (CFA-induced arthritis model in rats), was adopted to investigate the effects of C. magna.

RESULTS: From C. magna, fifteen compounds were tentatively identified. A network was constructed in which six active phytocompounds and the top ten potential targets were scrutinised. Further, GO and KEGG enrichment analysis were performed. The KEGG mapper was used to execute the pathway where C. magna exhibits anti-arthritis effects by modulating the TNF signalling pathway. Further Molecular docking revealed that all the compounds exhibit good binding affinity towards the target proteins involved in TNF signalling pathways. Lastly, the in-vitro and in-vivo findings suggest that C. magna effectively alleviates the arthritis symptoms and effectively attributes the downstream target genes involved in the TNF signalling pathway.

CONCLUSION: Overall, this study concludes that C. magna potentially alleviates RA via downregulating the TNF signalling pathway. This study supports the traditional use of C. magna against RA and suggests it is a good therapeutic candidate.},
}

@article {pmid41197914,
year = {2025},
author = {Yang, J and Xue, W and Zheng, W and Zhang, H and Tang, C},
title = {Psychiatric symptoms and alzheimer's disease: Depression-anxiety comorbidity effects and their neurobiological mediating mechanisms.},
journal = {Journal of affective disorders},
volume = {},
number = {},
pages = {120594},
doi = {10.1016/j.jad.2025.120594},
pmid = {41197914},
issn = {1573-2517},
abstract = {BACKGROUND: Depression and anxiety are common in Alzheimer's disease (AD), but their mechanisms of impact on disease progression remain unclear. This study investigates the relationships between psychiatric symptoms and AD, exploring potential neurobiological mediating mechanisms.

METHODS: The study analyzed 6209 participants divided into four groups: AD control, AD with depression, AD with anxiety, and AD with comorbid depression and anxiety. Multivariate regression and structural equation modeling assessed the impact of psychiatric symptoms on AD onset, examining 8 potential mediating variables: tau pathology, amyloid pathology (CRREAD score, Thal score), brain weight, cortical atrophy, hippocampal atrophy, Lobar score and APOE genotype, while controlling for age, gender, and education.

RESULTS: Both depressive (β = -1.8 years) and anxiety symptoms (β = -1.5 years) were associated with earlier AD onset, with a more significant effect when coexisting (β = -2.3 years). Depressive symptoms primarily affected executive function through cortical atrophy (32 %) and tau pathology (24 %), while anxiety symptoms mainly influenced memory function through hippocampal atrophy (61 %). The APOE ε4 allele significantly moderated these relationships, with more pronounced effects in ε4 carriers. Subgroup analyses showed more evident impacts in females and late-onset AD.

CONCLUSION: The study provides evidence that depressive and anxiety symptoms are associated with earlier AD onset and affect cognitive function through specific neuropathological pathways. These findings highlight the importance of screening and treating psychiatric symptoms in AD patients and suggest potential intervention strategies.},
}

@article {pmid41197782,
year = {2025},
author = {Ella, FA and Tchamgoue, J and Ambamba, BDA and Mountessou, BYG and Essouman, FM and Essola, NN and Wilhelm, A and Ngondi, JL and Njayou, FN and Kouam, SF},
title = {Anti-Alzheimer potential of Biflavonoids from Allanblackia floribunda: Multi-target inhibition of monoamine oxidase, β-secretase, and glycogen synthase kinase-3β.},
journal = {Fitoterapia},
volume = {},
number = {},
pages = {106967},
doi = {10.1016/j.fitote.2025.106967},
pmid = {41197782},
issn = {1873-6971},
abstract = {The pathogenesis of Alzheimer's disease (AD) is complex, involving multiple interrelated pathways. Consequently, developing multi-target-directed ligands may represent an effective therapeutic strategy. This study investigates the anti-Alzheimer potential of two biflavonoids isolated from Allanblackia floribunda against monoamine oxidase A (MAO-A), β-secretase (BACE-1), and glycogen synthase kinase-3β (GSK-3β), three key enzymes implicated in AD progression. The biflavonoids, (2S,3S)-volkensiflavone-7-O-β-glucopyranoside (1) and (2R,3S)-volkensiflavone-7-O-β-D-acetylglucopyranoside (2), were purified and structurally identified using spectroscopic methods. Enzymatic fluorimetric assays were conducted to assess their inhibition of MAO-A, BACE-1, and GSK-3β. The mode and reversibility of inhibition were characterized for both compounds, confirming them as potent MAO-A inhibitors. In silico simulations were performed on the three enzymes to gain insights into their interactions and modes of action. Compounds 1 and 2 were found to be reversible and moderately selective MAO-A inhibitors with IC50 of 35.85 ± 0.03 μM and 25.54 ± 0.05 μM, respectively. These compounds strongly inhibited BACE1 (IC50 = 2.48 ± 0.11 μM and 2.50 ± 0.17 μM, respectively) and GSK-3β (IC50 = 9.39 ± 0.06 μM and 7.17 ± 0.09 μM, respectively). In conclusion, this study is the first to report these compounds as triple inhibitors of MAO-A, BACE-1, and GSK-3β, offering a promising new therapeutic strategy for AD. Molecular docking simulations supported the observed interactions, reinforcing the selective potential of these inhibitors towards target enzymes. The lack of ethnobotanical precedent regarding the use of A. floribunda for managing neurological conditions highlights the novelty of the current study, which reveals, for the first time, the anti-Alzheimer activity of biflavonoids derived from this plant. This underscores the value of scientific investigation in uncovering previously unknown pharmacological properties of traditionally used plants.},
}

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

@article {pmid41197759,
year = {2025},
author = {Zheng, Z and Chen, C and Zhu, S and Zhu, X and Tu, H and Ding, X and Xia, T and Gu, X},
title = {TERT activator compound alleviates cigarette smoke-induced cognitive deficits by modulating hippocampal inflammation and neurogenesis: A comprehensive study integrating Mendelian randomization.},
journal = {Experimental neurology},
volume = {},
number = {},
pages = {115543},
doi = {10.1016/j.expneurol.2025.115543},
pmid = {41197759},
issn = {1090-2430},
abstract = {Cigarette smoking represents a major public health concern, yet its relationship with cognitive function remains controversial. Here, we integrated two-sample Mendelian randomization (MR) with an in vivo model to interrogate this relationship and evaluate a telomerase-based intervention. Two-sample MR provided genetic evidence for a causal effect of smoking behaviors on increased Alzheimer's disease (AD) risk in East Asian and European populations. Guided by these findings, we established a mouse model of cigarette smoke exposure using cigarette smoke extract (CSE) and confirmed significant neurocognitive impairment by fear conditioning and Y-maze behavioral tests. We also found that CSE elicited robust hippocampal inflammation, evidenced by increased IBA1 and elevated pro-inflammatory cytokines (IL-6, IL-1β, TNF-α). This inflammatory milieu was accompanied by reduced hippocampal brain-derived neurotrophic factor (BDNF) and compromised adult hippocampal neurogenesis (AHN), reflected by decreased doublecortin (DCX) expression. Bulk RNA sequencing with gene set enrichment analysis indicated downregulation of telomere maintenance gene set after CSE exposure, and RT-qPCR and Western blotting verified the suppression of telomerase reverse transcriptase (TERT) in the hippocampus. Notably, intraperitoneal administration of a TERT activator compound (TAC) to CSE-treated mice restored hippocampal TERT expression, attenuated neuroinflammation, enhanced BDNF levels and AHN, and ameliorated cognitive deficits. To sum up, our findings integrate population-based genetic evidence with experimental validation to show that cigarette smoke exposure impairs cognition and that pharmacologic activation of TERT confers neuroprotection, highlighting TERT as a promising therapeutic target for smoking-related cognitive disorders.},
}

@article {pmid41197747,
year = {2025},
author = {Ozturk, B and Demir, H and Silindir-Gunay, M and Akdag, Y and Sahin, S and Gulsun, T},
title = {Application of Artificial Neural Network to Determine Optimum Formulation Development and In Vitro Characterization of Methylene Blue and Galantamine Loaded Polymeric Nanoparticles for the Treatment of Alzheimer's Disease.},
journal = {European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences},
volume = {},
number = {},
pages = {107364},
doi = {10.1016/j.ejps.2025.107364},
pmid = {41197747},
issn = {1879-0720},
abstract = {Alzheimer's disease is a major neurodegenerative disorder characterized by complex pathophysiology and currently lacks a curative treatment. This study aims to develop and characterize methylene blue and galantamine co-loaded PLGA nanoparticles, surface-modified with poloxamer 188 and GSH, to increase blood residence time and improve brain-targeted delivery. The nanoparticles were prepared using the double emulsion solvent evaporation method, and their physicochemical properties were characterized by TEM, FT-IR, DSC, XRD, and [13]C NMR. Artificial neural network modeling was used to optimize the formulation parameters, including PLGA %, PVA %, and sonication time, for predicting particle size and encapsulation efficiencies of methylene blue and galantamine. Results showed that the optimized nanoparticles had particle sizes less than 200 nm, appropriate zeta potential, and high encapsulation efficiencies. DSC, FT-IR, XRD, and NMR analyses confirmed the absence of crystalline peaks for methylene blue and galantamine, indicating successful encapsulation. Artificial neural network models demonstrated high predictive accuracy, serving as a valuable tool for formulation optimization. This dual-drug, surface-modified nanoparticle approach offers promising potential for multi-target therapy in Alzheimer's disease.},
}

@article {pmid41197707,
year = {2025},
author = {Malarvannan, M and Naik, SBT and Soni, N and Mandar, CM and Paul, D},
title = {Exploring lipidomics in biomarker discovery.},
journal = {Clinica chimica acta; international journal of clinical chemistry},
volume = {},
number = {},
pages = {120698},
doi = {10.1016/j.cca.2025.120698},
pmid = {41197707},
issn = {1873-3492},
abstract = {Lipidomics, a fast-growing area of systems biology, provides an in-depth look at lipid species and how they dynamically change in healthy and diseased conditions. Lipids are increasingly understood to be bioactive molecules regulating inflammation, metabolic homeostasis, and cellular signaling, lipidomics has become a potent tool for finding new biomarkers for a wide range of clinical diseases and disorders. To identify disease-specific lipid signatures and biomarkers across various conditions, such as metabolic disorders (e.g., diabetes, obesity), cardiovascular diseases, neurodegenerative diseases (e.g., Alzheimer's, Parkinson's), cancer, and inflammatory disorders. Despite significant advancements, routine integration of lipidomics into clinical practice is hindered by problems such as inter-laboratory variability, data standardization, lack of defined procedures, and insufficient clinical validation. In this study, we examined the significance of lipidomics in various clinical applications, providing a thorough summary of lipidomic markers that have already been investigated and demonstrated their potential. We also discuss the importance of lipidomics methodologies and their comparisons, as well as lipidomics in biomarker discovery. Challenges in the lipidomic biomarker validation process and the translational potential of lipidomics in clinical settings are addressed, along with prospects for lipidomics research, which helps readers understand the future of lipidomic biomarkers. Ultimately, lipidomics-driven biomarker discovery is a revolutionary method that connects fundamental lipid research with clinical application. It has encouraging significance for risk assessment, early diagnosis, and targeted therapy plans for various human diseases and disorders.},
}

@article {pmid41197657,
year = {2025},
author = {Hansen, N and Wiltfang, J},
title = {[News on blood biomarker-based early diagnosis of the preliminary stages of Alzheimer's dementia].},
journal = {Fortschritte der Neurologie-Psychiatrie},
volume = {93},
number = {11},
pages = {446-452},
doi = {10.1055/a-2698-5992},
pmid = {41197657},
issn = {1439-3522},
mesh = {Humans ; *Alzheimer Disease/diagnosis/blood ; *Biomarkers/blood ; Early Diagnosis ; tau Proteins/blood ; Amyloid beta-Peptides/blood ; Cognitive Dysfunction/diagnosis/blood ; },
abstract = {The early diagnosis of Alzheimer's disease (ADD) has gained new significance through the further discovery of blood biomarkers. Blood biomarkers are less expensive, can be measured fully automatically with high throughput, are less invasive and provide faster information on specific dementia biomarkers than current methods used in routine clinical practice such as amyloid positron emission tomography (PET) or CSF examination of underlying pathological changes in Alzheimer's disease (AD) in patients with cognitive impairment. The aim of this review is to provide a presentation of the added value of blood-based biomarkers for the early diagnosis of ADD. Individual blood biomarkers are presented regarding their diagnostic reliability and predictive value for the diagnosis of AD in precursors of ADD ranging from subjective cognitive impairment (SCD) to mild cognitive impairment (MCI). In addition, the revised criteria for the diagnosis and staging of AD are discussed. Markers of tau pathology such as a phosphorylated tau protein 217 (p-tau217), a phosphorylated tau protein 181 (p-tau181), a phosphorylated tau protein 231 (p-tau231), but also amyloid-β (Aβ) markers such as the ratio of Aβ1-42/ 1-40 are described as specific biomarkers for the early diagnosis of AD. In addition, new amyloid peptide ratios such as Aβ-3-42/-3-40 are discussed, which may provide more insights into the pathogenesis of AD, as this N-terminal elongated Aβ peptides are cleaved from the amyloid precursor protein via a biochemical oligodendroglia-dependent pathway (ADAMTS4=disintegrin and metalloproteinase with thrombospondin motifs 4), which is important in AD pathophysiology due to oligodendroglia involvement. In addition, new promising composite hybrid ratios are explained, which could provide advantages in the early diagnosis of AD, such as the AT217-term or the AT181-term, which relates Aβ1-40 to Aβ1-42 and multiplies it by p-tau217 and p-tau181, respectively. Overall, the review provides an overview of the potential of blood biomarkers in the early diagnosis of ADD. However, these biomarkers should not be used alone for early diagnosis, but should always be evaluated in conjunction with other tests such as cerebrospinal fluid analysis.},
}

Humans
*Alzheimer Disease/diagnosis/blood
*Biomarkers/blood
Early Diagnosis
tau Proteins/blood
Amyloid beta-Peptides/blood
Cognitive Dysfunction/diagnosis/blood

@article {pmid41197609,
year = {2025},
author = {Margolis, MP and Tang, M and Gagliardi, M and Wen, C and Wu, Y and Wray, NR and Ziller, MJ and Gandal, MJ},
title = {From variants to mechanisms: Neurogenomics in the post-GWAS era.},
journal = {Neuron},
volume = {113},
number = {21},
pages = {3509-3529},
doi = {10.1016/j.neuron.2025.10.014},
pmid = {41197609},
issn = {1097-4199},
mesh = {Humans ; *Genome-Wide Association Study ; *Genomics/methods ; Autism Spectrum Disorder/genetics ; Genetic Predisposition to Disease/genetics ; Schizophrenia/genetics ; *Mental Disorders/genetics ; Alzheimer Disease/genetics ; Machine Learning ; *Genetic Variation/genetics ; Multifactorial Inheritance ; },
abstract = {Genome-wide association studies (GWASs) have identified thousands of variants associated with neuropsychiatric disorders (NPDs), including autism spectrum disorder (ASD), schizophrenia (SCZ), and Alzheimer's disease (AD). However, deciphering the "causal" biological mechanisms and pathways through which these variants act remains a major obstacle that hinders translational understanding of NPD pathogenesis. NPDs are highly polygenic with contributions from pleiotropic variants across the allelic spectrum, most of which reside within large haplotype blocks in non-coding regions of the genome. Successful mechanistic insight requires identifying disease-relevant cell types and states, mapping variant-to-gene effects, and integrating findings across loci, at scale, to pinpoint pathways of polygenic convergence. Here, we discuss functional genomic, machine learning, and experimental approaches to address each step of this daunting challenge. Ultimately, the convergence of results-across methodologies and within key underlying disease pathways-will be essential to realizing the promise of clinical translation for common, complex brain disorders.},
}

Humans
*Genome-Wide Association Study
*Genomics/methods
Autism Spectrum Disorder/genetics
Genetic Predisposition to Disease/genetics
Schizophrenia/genetics
*Mental Disorders/genetics
Alzheimer Disease/genetics
Machine Learning
*Genetic Variation/genetics
Multifactorial Inheritance

@article {pmid41197554,
year = {2025},
author = {Zhong, Z and Zhao, S and He, W and Li, R and Xia, S},
title = {SGLT2 inhibitors versus DPP-4 inhibitors and dementia risk in type 2 diabetes: A meta-analysis of cohort studies.},
journal = {Archives of gerontology and geriatrics},
volume = {141},
number = {},
pages = {106065},
doi = {10.1016/j.archger.2025.106065},
pmid = {41197554},
issn = {1872-6976},
abstract = {BACKGROUND: Sodium-glucose cotransporter 2 (SGLT2) inhibitors have shown neuroprotective potential. This meta-analysis aimed to compare the effects of SGLT2 inhibitors and dipeptidyl peptidase-4 (DPP-4) inhibitors on dementia risk in patients with type 2 diabetes mellitus (T2DM).

METHODS: A systematic search of PubMed, EMBASE, Cochrane Library, and Web of Science was conducted from inception through May 2025. Cohort studies comparing dementia incidence in T2DM patients treated with SGLT2 inhibitors versus DPP-4 inhibitors were included. Study quality was assessed using the Newcastle-Ottawa Scale (NOS). Data were pooled using a random-effects model in STATA 12.0, with incidence rate ratios (IRRs) and 95 % confidence intervals (CIs) calculated for dementia outcomes.

RESULTS: Eight cohort studies (1275,257 participants) were analyzed. SGLT2 inhibitor use was associated with a 33 % lower risk of all-cause dementia compared to DPP-4 inhibitors (I² = 0.0 %, P = 0.816; IRR = 0.666; 95 % CI: 0.484-0.918; P < 0.05). Subgroup analyses indicated non-significant risk reductions for Alzheimer's disease (I² = 0.0 %, P = 0.994; IRR = 0.654; 95 % CI: 0.352-1.212; P = 0.177) and vascular dementia (I² = 0.0 %, P = 0.971; IRR = 0.573; 95 % CI: 0.204-1.605; P = 0.289).

CONCLUSIONS: SGLT2 inhibitors are associated with a significantly reduced risk of all-cause dementia in T2DM patients compared to DPP-4 inhibitors. While trends favoring SGLT2 inhibitors were observed for dementia subtypes, further long-term studies are needed to confirm these associations.},
}

@article {pmid41197471,
year = {2025},
author = {Zhang, H and Dang, Y and Guo, Y and Chen, J and Zhang, J and Xu, Z and Hien, NTT and Musabaev, E and Pronyuk, K and Fisher, D and Ge, C and Zhao, L},
title = {Lunasin: Exploring the pharmacological potential of a soy-derived peptide.},
journal = {European journal of medicinal chemistry},
volume = {302},
number = {Pt 2},
pages = {118317},
doi = {10.1016/j.ejmech.2025.118317},
pmid = {41197471},
issn = {1768-3254},
abstract = {Lunasin is a multifunctional natural peptide that stands out among peptidic drugs for its broad therapeutic potential. This peptide can effectively intervene in the progression of various diseases, including but not limited to cancer, cardiovascular diseases, gastrointestinal disorders, and CNS conditions. Lunasin demonstrates potent anticancer effects, inhibiting proliferation and inducing apoptosis in breast cancer, melanoma, and colorectal cancer. Its mechanism involves the suppression of histone acetylation, disruption of integrin signaling, and regulation of cell cycle progression, making it a promising candidate for cancer therapy. Additionally, it aids in cardiovascular health by preventing the development of atherosclerosis through lowering cholesterol levels. Moreover, Lunasin shows potential in alleviating early-stage liver injury associated with non-alcoholic fatty liver disease and may help treat neurodegenerative diseases such as Alzheimer's disease by regulating monoamine levels in the brain. This article delves into the unique structure of Lunasin and its extensive pharmacological actions, highlighting its significance as a potential therapeutic agent for treating a variety of diseases in the future. From cancer to cardiovascular diseases, and from gastrointestinal issues to CNS disorders, Lunasin offers a multifaceted therapeutic platform, indicating significant potential in medical research and clinical applications moving forward.},
}

@article {pmid41197370,
year = {2025},
author = {Łosińska, K and Maszczyk, A},
title = {Can table tennis protect the aging brain? A systematic review and meta-analysis in neurodegenerative diseases.},
journal = {Acta psychologica},
volume = {261},
number = {},
pages = {105884},
doi = {10.1016/j.actpsy.2025.105884},
pmid = {41197370},
issn = {1873-6297},
abstract = {BACKGROUND: Table tennis (TT) is an increasingly investigated intervention for supporting cognitive, motor, and psychosocial functions in older adults with neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and dementia. However, evidence remains fragmented, and the effect sizes and reliability of TT-based programs remain unclear.

MATERIALS AND METHODS: Following PRISMA 2020 guidelines, a systematic search of four databases (PubMed, Scopus, Web of Science, SPORTDiscus) was conducted through June 30, 2025. Ten studies met inclusion criteria, with five eligible for quantitative synthesis. Random-effects meta-analyses (DerSimonian-Laird) were performed on cognitive and motor outcomes. Risk of bias was assessed using the JBI checklist, and certainty of evidence was graded using the GRADE framework. Out of 499 screened records, ten studies met the predefined eligibility criteria and were included in the systematic review. Of these, five studies provided sufficient statistical data for inclusion in the meta-analysis.

RESULTS: Meta-analysis revealed large effects for cognitive outcomes (MMSE: d = 1.44; MoCA: d = 1.31), motor function (UPDRS-III: d = 1.27), and dual-task gait (TUG: d = 0.93), with low-to-moderate heterogeneity estimated (I[2] = 18-42 %), though given the small number of studies, these estimates warrant cautious interpretation. Sensitivity analyses confirmed the robustness of pooled effects. GRADE evaluations indicated moderate certainty. No serious adverse events were reported.

CONCLUSIONS: Table tennis appears to be a safe, feasible, and effective non-pharmacological intervention for enhancing cognitive and motor outcomes in individuals with AD, PD, and dementia. Further high-quality trials with standardized protocols and mechanistic endpoints are needed to confirm these findings and expand clinical applicability. While preliminary findings suggest beneficial effects, the limited number of small trials, geographic concentration, and methodological limitations temper definitive conclusions.},
}

@article {pmid41197184,
year = {2025},
author = {Ryan, KC and Laboy, JT and Ashraf, R and Ashkavand, Z and Jayasinghe, I and Norman, KR},
title = {Presenilin mutations disrupt iron homeostasis to promote ferroptosis mediated neurodegeneration in Caenorhabditis elegans.},
journal = {Redox biology},
volume = {88},
number = {},
pages = {103910},
doi = {10.1016/j.redox.2025.103910},
pmid = {41197184},
issn = {2213-2317},
abstract = {Iron is a vital trace element involved in numerous physiological processes, but it becomes toxic when present in excess. Disruption of iron balance in the brain has been linked to the development of neurodegenerative diseases such as Alzheimer's disease (AD), though the underlying mechanisms remain poorly understood. Familial forms of AD are primarily caused by mutations in presenilin, which are known to disturb cellular calcium homeostasis. However, the role of iron in presenilin-related neurodegeneration has not been fully explored. Using C. elegans as a model organism, we investigated the function of SEL-12, the worm ortholog of presenilin, and found that loss of SEL-12 leads to elevated iron levels and increased expression of FTN-2/ferritin, an iron-sequestering protein. Notably, reducing mitochondrial calcium in sel-12 mutants prevented this iron accumulation, indicating that elevated mitochondrial calcium drives increased cellular iron levels. This iron overload depends on mitochondrial superoxide production, which occurs alongside heightened mitochondrial calcium, suggesting that oxidative stress contributes to iron dysregulation. The resulting iron imbalance causes mitochondrial and lysosomal dysfunction, ultimately impairing neuronal and behavioral function. Supporting the involvement of iron, sel-12 mutants exhibit elevated lipid peroxidation, and inhibition of ferroptosis restores neuronal function. Together, these findings reveal a novel role for presenilin in regulating iron homeostasis and identify a mechanism linking calcium signaling disruption to iron dyshomeostasis and neurodegeneration.},
}

@article {pmid41197136,
year = {2025},
author = {García-Chialva, DE and Itzcovich, T and Cifarelli, D and Apecetche, M and Chrem-Méndez, P and Magrath-Guimet, N and Vazquez, S and Bérgamo, Y and Allegri, R and Marazita, M and Sevlever, GE and Isaja, L and Surace, EI and Romorini, L},
title = {Clinical and functional evidence supporting the pathogenicity of the novel PSEN1 p.R358P variant in early-onset Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251392236},
doi = {10.1177/13872877251392236},
pmid = {41197136},
issn = {1875-8908},
abstract = {BackgroundPathogenic variants in PSEN1, PSEN2, or AβPP cause early-onset Alzheimer's disease (EOAD). Several novel variants remain of uncertain significance (VUS) due to limited evidence. The PSEN1 p.R358P variant has not been previously characterized or reported in EOAD cases.ObjectiveTo determine the pathogenicity of the PSEN1 p.R358P variant in a patient with EOAD and assess its effect on amyloid-β (Aβ) processing using a human cellular model.MethodsWe present the case of a 62-year-old female of Western European descent with memory impairment starting at 59 and a positive family history of Alzheimer's disease (AD). To evaluate the variant, a PSEN1 knockout HEK293T line was generated using CRISPR/Cas9. Cells were co-transfected with AβPP and either wild-type or mutant PSEN1, and Aβ42/Aβ40 levels were measured by ELISA in culture supernatants.ResultsThe proband exhibited multidomain cognitive impairment and imaging biomarkers (PiB-PET and FDG-PET) consistent with AD. Whole-exome sequencing revealed a PSEN1 (NM_000021.4:c.1073G > C:p.Arg358Pro) variant, classified as VUS by ACMG guidelines, together with a SORL1 p.G1536D variant and APOE ε4/ε4 genotype. Cells expressing PSEN1 p.R358P showed an increased Aβ42/Aβ40 ratio compared to wild-type, mainly due to reduced Aβ40 levels. This profile partially mimicked the pathogenic PSEN1 p.A246E variant. In silico analyses predicted deleterious effects for PSEN1 p.R358P.ConclusionsOur results support a likely pathogenic role for the PSEN1 p.R358P variant in EOAD. Nonetheless, in the absence of segregation data, the variant should be considered a hot VUS.},
}

@article {pmid41197132,
year = {2025},
author = {Wang, X and Yang, X and Duan, M and Duan, H and Sun, W},
title = {Mitochondrial energy metabolism and Alzheimer's disease: Identifying key differentially expressed genes in blood.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251387584},
doi = {10.1177/13872877251387584},
pmid = {41197132},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease (AD) is a neurodegenerative disorder linked to mitochondrial energy metabolism dysfunction. This study investigated differentially expressed genes (DEGs) related to this process.ObjectiveWe aimed to identify key mitochondrial energy metabolism-related DEGs in the blood of patients with AD, construct their regulatory networks, evaluate their diagnostic potential, and explore their link with the immune microenvironment.MethodsWe analyzed AD datasets from gene expression datasets (GEO) and mitochondrial genes from GeneCards using R to identify DEGs. Hub genes were screened via protein-protein interaction (PPI) network analysis. Functional enrichment analysis, gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), gene set enrichment analysis (GSEA), and regulatory network construction (mRNA-miRNA, mRNA-TF) were performed. Immune infiltration and receiver operating characteristic (ROC) analyses assessed immunological associations and diagnostic value.ResultsFifteen mitochondrial energy metabolism-related DEGs were identified. PPI analysis revealed nine hub genes. Regulatory networks were successfully constructed. ROC analysis confirmed the strong diagnostic potential of these hubs, which also showed significant correlations with eleven immune cell typesConclusionsWe developed an AD diagnostic framework based on mitochondrial metabolism DEGs. These findings reveal mitochondrial-immune interactions in AD and provide novel candidate biomarkers for early diagnosis.},
}

@article {pmid41197131,
year = {2025},
author = {Acampora, A and Angelici, L and Cacciani, L and Cascini, S and Canevelli, M and Bellomo, G and Contoli, B and Cova, I and Pomati, S and Bacigalupo, I and Vanacore, N and Agabiti, N and Bargagli, AM and , },
title = {Mortality in migrants with dementia living in Lazio, Italy: A 5-year cohort study.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251387134},
doi = {10.1177/13872877251387134},
pmid = {41197131},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease and other dementias are major causes of disability and death among older adults. With an increasing number of older migrants in Italy, dementia prevalence in this group is expected to rise. However, little is known about their health outcomes.ObjectiveThis study aimed to analyze mortality in migrants with dementia in Lazio, Italy, as part of the ImmiDem project (GR-2021-12372081).MethodsA cohort study was conducted on individuals aged ≥50 with dementia living in Lazio as of December 31, 2018, who were followed for 5 years. Migratory status was defined by country of birth: native Italians, migrants from High Migratory Pressure Countries (HMPCs), or Highly Developed Countries (HDCs). Age-standardized mortality proportion was calculated by migratory status, and time-to-event analysis was performed using Cox regression models.ResultsAs of December 31, 2018, 38,380 individuals with dementia lived in Lazio, with 2.1% born in HMPCs and 0.9% in HDCs. The age-standardized mortality proportion was lower in migrants born in HPMCs (30.7%; 95% CI: 26.4-35.8) than among natives (36.8%; 95% CI: 35.4-38.4). The age- and sex-adjusted hazard ratio (HR) confirmed lower mortality in migrants (HMPCs HR = 0.91, 95% CI:0.82-1; HDCs HR = 0.79, 95% CI:0.68-0.91) than natives.ConclusionsMigrants with dementia showed lower mortality than Italians, possibly due to health advantages, salmon bias, or migration dynamics. However, these findings may not accurately reflect better health status. Potential underdiagnosis of dementia and the use of country of birth as a proxy for migratory status may have influenced results and should be considered in future research.},
}

@article {pmid41196698,
year = {2025},
author = {Saari, TT and Aaltonen, A and Lohi, K and Palviainen, T and Schwarz, C and Urjansson, M and Palotie, A and Runz, H and Julkunen, V and Kaprio, J and Vuoksimaa, E and , },
title = {Validity of telephone-administered word list learning measures for assessment of episodic memory in aging and Alzheimer's disease.},
journal = {Neuropsychology},
volume = {},
number = {},
pages = {},
doi = {10.1037/neu0001019},
pmid = {41196698},
issn = {1931-1559},
support = {//Sigrid Jusélius Foundation/ ; //Business Finland/ ; //Finnish Cultural Foundation/ ; //Academy of Finland/ ; },
abstract = {OBJECTIVE: Remote assessment of episodic memory would be a cost-effective alternative to in-person visits for early detection of memory impairment related to Alzheimer's disease (AD), but there is a need for test development and studies in population-based samples. The aim of this study was to investigate the validity and correlates of a novel three-trial administration of 10-word list learning included in the modified Telephone Interview for Cognitive Status in a population-based study of 65- to 96-year-old individuals.

METHOD: A total of 800 participants completed telephone-administered word list learning task that yielded immediate and delayed recall measures. We compared these to corresponding measures from in-person neuropsychological assessment and tested differences between cognitively normal individuals and those with cognitive impairment or neurodegenerative disease. Furthermore, we studied the associations of age, sex, education, and genetic risk of AD with telephone-administered memory measures.

RESULTS: Telephone-administered three-trial word list learning task yielded normally distributed immediate and delayed recall measures that performed like corresponding measures from in-person assessment. Having cognitive impairment or AD-but not genetic risk of AD-were related to poorer memory performance. Younger age, being female, and having secondary education were related to better memory performance.

CONCLUSION: Our study supports the validity of telephone-administered word list task with multiple learning trials. Remote assessment of memory can be used as an alternative to inviting people to in-person assessment and is also easily accessible for people living in remote areas and for those with physical disabilities or during restrictions related to in-person contact. (PsycInfo Database Record (c) 2025 APA, all rights reserved).},
}

@article {pmid41196549,
year = {2025},
author = {Olvera-Rojas, M and Solis-Urra, P and Fernandez-Gamez, B and Coca-Pulido, A and Triviño-Ibáñez, EM and Zeng, X and Oberlin, LE and Gispert, JD and Erickson, KI and Gómez-Río, M and Karikari, TK and Ortega, FB and Esteban-Cornejo, I},
title = {Classification accuracies of plasma ptau217 vs. ptau217/Aβ1-42 for brain Aβ pathology in cognitively normal older adults.},
journal = {GeroScience},
volume = {},
number = {},
pages = {},
pmid = {41196549},
issn = {2509-2723},
support = {FPU 22/02476//Ministerio de Ciencia e Innovación/ ; MCIN/AEI/10.13039/501100011033//Ministerio de Ciencia e Innovación/ ; PID2022-137399OB-I00//Ministerio de Ciencia e Innovación/ ; FPU 21/02594//Ministerio de Ciencia e Innovación/ ; K23MH129882//National Institutes of Mental Health/ ; R01 AG083874/NH/NIH HHS/United States ; U24AG082930/NH/NIH HHS/United States ; P30 AG066468/NH/NIH HHS/United States ; RF1 AG077474/NH/NIH HHS/United States ; R01 AG083156/NH/NIH HHS/United States ; R37 AG023651/NH/NIH HHS/United States ; R01 AG025516/NH/NIH HHS/United States ; R01 AG073267/NH/NIH HHS/United States ; R01 AG075336/NH/NIH HHS/United States ; R01 AG072641/NH/NIH HHS/United States ; P01 AG025204/NH/NIH HHS/United States ; U01 NS131740/NH/NIH HHS/United States ; U01 NS141777/NH/NIH HHS/United States ; R01 MH108509/NH/NIH HHS/United States ; DAF2255207//Aging Mind Foundation/ ; },
abstract = {Alzheimer´s Disease (AD) and neurodegenerative blood-based biomarkers (BBMs) are transitioning from research settings to clinical practice, where accurate interpretation is critical for their appropriate use. Particularly, the limited alignment between AD pathology and metrics of cognitive performance suggest unappreciated factors of resilience or inter-individual variability that could be influencing clinical utility and interpretation of these measures. Ninety-one cognitively normal older adults from the AGUEDA trial (NCT05186090) (71.8 ± 3.9 years; 58% females) were cross-sectionally examined for plasma Aβ42/40 SIMOA, BD-tau, GFAP, NfL, ptau217, ptau181, ptau217/Aβ1-42 IPMS and ptau217/Aβ42 SIMOA. We evaluated BBMs classification accuracies for brain amyloid-beta and examined their associations with cognitive outcomes. We then examined whether selected individual characteristics impact BBMs. Ptau217 and ptau217/Aβ42 measured by both IPMS and SIMOA exhibited strong predictive accuracy for PET Aβ positivity (AUC > 0.8) with the inclusion of some individual characteristics lowering their accuracy. Episodic memory showed a positive association with BD-tau (r = 0.29; p = 0.018), attentional/inhibitory control correlated positively with ptau217/Aβ42 SIMOA (r = 0.26; p = 0.041) and processing speed was negatively linked to GFAP (r = -0.21; p = 0.047). Age, creatinine, depressive symptoms, comorbidities and sex were associated with BD-tau, GFAP, NfL, and ptau217/Aβ42 (both IPMS and SIMOA), with standardized β values ranging from -0.27 to 0.62 (all p < 0.05). These results highlight the utility of ptau217 and ptau217/Aβ42 ratios in identifying brain amyloid pathology in cognitively normal older adults. BBMs could be used complementarily to support differential diagnosis and better understand the origins of cognitive deficits.},
}

@article {pmid41196512,
year = {2025},
author = {Li, Y and Fan, H and Han, X and Ni, M and Hou, X and Xia, H and Shi, Y and Zhang, L and Sun, J},
title = {RRBP1 Inhibition Reduces Microglial M1 Polarization and Inflammation-Mediated Neuronal Loss and Oxidative Stress by Regulating ERK Pathway in Alzheimer's Disease.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {5},
pmid = {41196512},
issn = {1559-1182},
support = {No. ZC23456043 and No. ZC2020259//The 23456 Talent Project of Henan Provincial People's Hospital/ ; },
mesh = {*Oxidative Stress/drug effects/physiology ; *Microglia/metabolism/pathology/drug effects ; *Alzheimer Disease/pathology/metabolism ; Animals ; Humans ; *Neurons/metabolism/pathology/drug effects ; *Inflammation/pathology/metabolism ; *MAP Kinase Signaling System/drug effects/physiology ; Mice ; *Cell Polarity/drug effects ; Cell Line ; Reactive Oxygen Species/metabolism ; Amyloid beta-Peptides ; Cell Line, Tumor ; Apoptosis/drug effects ; },
abstract = {Ribosome-binding protein 1 (RRBP1) regulates ribosome assembly and stability to modify several important biological processes such as mitochondrial function, stress, cell differentiation, immunity, and axonal structure. This study aimed to investigate RRBP1 inhibition on microglial polarization and inflammation, and its mediated neuronal loss and oxidative stress in Alzheimer's disease (AD). Mouse microglia (BV-2), mouse hippocampal neuron (HT-22), human microglia (HMC3), and human neuroblastoma (SH-SY5Y) cell lines were cultured. A classical culture system containing BV-2 and HT-22, as well as HMC3 and SH-SY5Y, under β-amyloid treatment was applied to mimic AD cellular models. RRBP1 siRNA and control siRNA were transfected into BV-2 and HMC3 cells with no transfection as normal control; moreover, the ERK pathway was inactivated by PD98059 reagent. Microglial M1 phonotype marker (iNOS) and inflammatory cytokines (TNF-α and IL-1β levels) were decreased, while microglial M2 phonotype marker (ARG1) and pERK/ERK were increased by RRBP1 inhibition in BV-2 and HMC3 cells. Then microglial RRBP1 inhibition further elevated cell viability and superoxide dismutase (SOD), while reducing the cell apoptosis rate and reactive oxygen species (ROS) in HT-22 and SH-SY5Y cells. pERK/ERK was lowered after PD98059 treatment, which attenuated the effect of RRBP1 inhibition on microglial M1/M2 phenotypes and inflammatory cytokines in BV-2 and HMC3 cells, and further weakened the effect of microglial RRBP1 inhibition on cell viability, apoptosis rate, ROS, and SOD in HT-22 and SH-SY5Y cells. RRBP1 inhibition represses microglial M1 polarization and inflammation-mediated neuronal loss and oxidative stress by modifying the ERK pathway in AD.},
}

*Oxidative Stress/drug effects/physiology
*Microglia/metabolism/pathology/drug effects
*Alzheimer Disease/pathology/metabolism
Animals
Humans
*Neurons/metabolism/pathology/drug effects
*Inflammation/pathology/metabolism
*MAP Kinase Signaling System/drug effects/physiology
Mice
*Cell Polarity/drug effects
Cell Line
Reactive Oxygen Species/metabolism
Amyloid beta-Peptides
Cell Line, Tumor
Apoptosis/drug effects

@article {pmid41196470,
year = {2025},
author = {Vaja, R and Vohra, M and Ramachandran, AV and Baxi, D},
title = {Development of a Novel Aluminium Chloride-Induced Zebrafish Model of Alzheimer's Disease: Involvement of Oxidative Stress, Cholinergic Dysfunction, and Gut Pathophysiology.},
journal = {Neurotoxicity research},
volume = {43},
number = {6},
pages = {46},
pmid = {41196470},
issn = {1476-3524},
mesh = {Animals ; Zebrafish ; *Oxidative Stress/drug effects/physiology ; *Alzheimer Disease/chemically induced/physiopathology/pathology/metabolism ; *Disease Models, Animal ; Female ; Male ; *Aluminum Chloride/toxicity ; Brain/pathology/drug effects/metabolism ; },
abstract = {Alzheimer's Disease (AD) is a progressive and fatal neurodegenerative disorder (NDD), and the leading cause of dementia globally, with females being more susceptible than males. Existing animal models for AD are primarily pharmacologically induced or transgenic, yet many fail to recapitulate the full spectrum of human AD pathology and thereby elucidating its sex-based differences. This underscores the need for a cost-effective and robust experimental model that reliably mimics the multifactorial nature of AD taking into account the differences that arise due to sex. In recent years, the zebrafish (Danio rerio) has emerged as a promising model organism for studying central nervous system (CNS) disorders, including AD, owing to its high genetic and physiological homology to humans, transparent embryonic development, and amenability to high-throughput screening. This study aims to establish a novel chronic neurotoxicity induced ZF model, using AlCl3 as an inducing neurotoxic agent. The hypothesis centers on AlCl3-induced oxidative stress, cholinergic pathway dysfunction, and gut pathophysiological changes as drivers of AD-like pathology. Adult zebrafish, of both sexes were exposed to chronic AlCl3 treatment over a 28-day period. Post-treatment assessments included histopathological, biochemical, and behavioural analyses to evaluate changes in brain and gut tissues, oxidative stress biomarkers, and cognitive performance. Zebrafish exposed to AlCl3 exhibited distinct pathological changes in both brain and gut tissues compared to controls. In the brain, hallmarks such as pyknotic neurons, neuronal vacuolisation, and neural tissue necrosis was observed. Gut tissue displayed significant abnormalities, including reduced villi number, epithelial cell loss, and fused or shortened villi. Biochemical analyses revealed elevated oxidative stress, evidenced by altered levels of catalase (CAT), glutathione (GSH), and lipid peroxidation (LPO). Additionally, disruption of the cholinergic system was evident. Behavioural analyses using locomotor tracking revealed marked cognitive deficits, including reduced average speed, decreased distance travelled, and increased immobility. Lastly, our sex specific differences revealed that females were more affected by the biochemical, histological and neurobehavioural parameters as compared to males, thereby indicating that females pose a greater susceptibility towards developing AD. The AlCl3 -induced zebrafish model successfully replicates key features of human neurotoxicity, which may lead to AD like features including oxidative stress, cholinergic dysfunction, neurodegeneration, and gut-brain axis alterations. This novel and cost-effective model provides a comprehensive platform for exploring sex-mediated neurotoxicity experimental animal model and offers potential utility for screening therapeutic interventions and understanding disease-modifying mechanisms. Keywords: Alzheimer's Disease, Chronic Neurotoxicity, Gut-brain axis, Zebrafish, Sex differences, Alumnium chloride.},
}

Animals
Zebrafish
*Oxidative Stress/drug effects/physiology
*Alzheimer Disease/chemically induced/physiopathology/pathology/metabolism
*Disease Models, Animal
Female
Male
*Aluminum Chloride/toxicity
Brain/pathology/drug effects/metabolism

@article {pmid41196440,
year = {2025},
author = {Li, S and Gao, Y and Zhang, X and Lang, J and Liu, X and Zhang, Y and Zhang, J and Zhao, Y and Chang, C and Gao, X and Zhou, J and Yu, D and Yang, G},
title = {Bicyclol improves cognition deficits and inhibits oxidative stress-induced neuronal cell apoptosis in alzheimer's disease via Nrf2/HO-1 pathway.},
journal = {Metabolic brain disease},
volume = {40},
number = {8},
pages = {310},
pmid = {41196440},
issn = {1573-7365},
support = {Grant No. 20220997//the Medical Science Research Project of Hebei Provincial Health Commission/ ; Grant No. 82471453//the National Natural Science Foundation of China/ ; Grant No. H2022206231//the Hebei Natural Science Foundation/ ; },
mesh = {Animals ; *Apoptosis/drug effects ; *NF-E2-Related Factor 2/metabolism ; *Oxidative Stress/drug effects ; *Alzheimer Disease/drug therapy/metabolism ; *Biphenyl Compounds/pharmacology/therapeutic use ; Mice ; *Neurons/drug effects/metabolism ; *Heme Oxygenase-1/metabolism ; *Cognitive Dysfunction/drug therapy/metabolism ; Neuroprotective Agents/pharmacology/therapeutic use ; Signal Transduction/drug effects ; Male ; Mice, Transgenic ; Disease Models, Animal ; Antioxidants/pharmacology ; Amyloid beta-Peptides ; Membrane Proteins ; },
abstract = {Alzheimer's disease (AD) is identified as the prevalent neurodegenerative condition globally, ultimately resulting in dementia. Currently, the mechanisms that contribute to AD are not well comprehended, and there are few therapeutic alternatives available. Bicyclol, a substance extracted from the Chinese herb Schisandra Chinensis, has shown remarkable antioxidant, anti-inflammatory, anti-apoptotic, and neuroprotective characteristics. However, there is a shortage of research focusing on the therapeutic effects of bicyclol on AD as well as the molecular pathways that may be involved. This study sought to evaluate the effects of bicyclol on cognitive impairments in a mouse model of AD, explore its neuroprotective benefits associated with antioxidant functions and apoptosis suppression, and reveal the mechanisms involved. In this study, APP/PS1 mice underwent a 2-month treatment with bicyclol administered via gavage, after which their cognitive abilities were evaluated through behavioral assessments. The apoptosis of cortical neurons was evaluated using TUNEL staining and immunofluorescence techniques. N2A cells, which were exposed to Aβ1-42 oligomers, received a pretreatment with bicyclol, and their viability was subsequently measured. The expression levels of proteins such as nuclear factor E2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), NAD(P) H-quinine oxidoreductase-1 (NQO1), BCL2 associated X Protein (Bax), B-cell lymphoma-2 (Bcl-2), and Cleaved caspase-3 were quantified in vitro and in vivo using western blotting and qPCR methods. Moreover, N2A cells lacking Nrf2 were utilized to investigate the underlying mechanisms through which bicyclol exerts its effects in Alzheimer's disease. Bicyclol has been shown to enhance cognitive function while simultaneously reducing the levels of cortical Aβ1-40 and Aβ1-42, and it also protects against neuronal degeneration in the APP/PS1 mouse model. Moreover, it increases the activity of cortical SOD and GSH-Px, concurrently decreasing levels of ROS and MDA in vivo. Additionally, bicyclol significantly lessened oxidative stress and apoptosis induced by Aβ1-42 in N2A cells. It further elevated the expression of proteins such as Nrf2, HO-1, and NQO1, along with mRNA levels in both in vitro and in vivo experiments. Furthermore, the silencing of Nrf2 via siRNA transfection counteracted the regulatory effects of bicyclol on apoptotic markers including Bax, Bcl-2, and Cleaved caspase-3 in vitro. Our study provides compelling evidence that bicyclol effectively alleviates cognitive impairments observed in APP/PS1 mice. Furthermore, our findings indicate that bicyclol plays a significant role in reducing oxidative stress-induced injury and neuronal apoptosis. This protective effect is associated with the activation of the Nrf2/HO-1 signaling pathway. These results suggest that bicyclol has the potential to be developed as a therapeutic agent for the treatment of Alzheimer's disease, highlighting its promise in addressing the cognitive decline associated with this debilitating condition.},
}

Animals
*Apoptosis/drug effects
*NF-E2-Related Factor 2/metabolism
*Oxidative Stress/drug effects
*Alzheimer Disease/drug therapy/metabolism
*Biphenyl Compounds/pharmacology/therapeutic use
Mice
*Neurons/drug effects/metabolism
*Heme Oxygenase-1/metabolism
*Cognitive Dysfunction/drug therapy/metabolism
Neuroprotective Agents/pharmacology/therapeutic use
Signal Transduction/drug effects
Male
Mice, Transgenic
Disease Models, Animal
Antioxidants/pharmacology
Amyloid beta-Peptides
Membrane Proteins

@article {pmid41196439,
year = {2025},
author = {Yadav, P and Dabas, A and Singh, R},
title = {Six-membered N-heterocyclic alkaloids as ChE inhibitors in alzheimer's disease treatment.},
journal = {Metabolic brain disease},
volume = {40},
number = {8},
pages = {309},
pmid = {41196439},
issn = {1573-7365},
mesh = {*Alzheimer Disease/drug therapy/enzymology ; *Cholinesterase Inhibitors/therapeutic use/pharmacology ; Humans ; *Alkaloids/therapeutic use/pharmacology/chemistry ; Animals ; Butyrylcholinesterase/metabolism ; Acetylcholinesterase/metabolism ; *Heterocyclic Compounds/therapeutic use/pharmacology ; },
abstract = {Cholinesterase (ChE) refers to a group of enzymes that play a critical role in the hydrolysis of choline-based esters, particularly acetylcholine, a key neurotransmitter presents in the nervous system. The two types of cholinesterase are acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), each with distinct functions and locations found within the body. Cholinesterase inhibitors (ChEIs) have been utilized to treat Alzheimer's disease (AD). AD is a progressive neurodegenerative disorder characterized by memory loss, impacting on the quality of life. Many studies have highlighted the potential of alkaloids as inhibitors of cholinesterase enzymes. There are various alkaloids which have potential to treat AD with their different modes of actions. This review summarizes more than 14 well-known alkaloids possessing six-membered N-heterocycles as AChE and BuChE inhibitors, such as berberine, boldine, crytolepine, harmine, huperzine A, 6-hydroxycrinamine, nicotine, piperine, salsoline, skimmianine, trigonelline, valerianofal A, 7'-multijuguinone, and 12'-hydroxy-7'-multijuguinone, hamayne, and lycorine.},
}

*Alzheimer Disease/drug therapy/enzymology
*Cholinesterase Inhibitors/therapeutic use/pharmacology
Humans
*Alkaloids/therapeutic use/pharmacology/chemistry
Animals
Butyrylcholinesterase/metabolism
Acetylcholinesterase/metabolism
*Heterocyclic Compounds/therapeutic use/pharmacology

@article {pmid41196066,
year = {2025},
author = {Zhang, P and Ke, Z and Mao, X and Zhang, X and Xiao, W},
title = {Dual-Channel Multiscale Graph Transformer with Adversarial Contrastive Learning and Low-Rank Disentangled Stratified Negative Sampling for Drug Repositioning.},
journal = {Journal of chemical information and modeling},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.jcim.5c02298},
pmid = {41196066},
issn = {1549-960X},
abstract = {Drug repositioning accelerates therapeutic discovery, but existing computational methods are hampered by representation collapse, noisy supervision, and suboptimal negative sampling. To address these limitations, we introduce MGTAL-DR, a novel graph learning framework that integrates a dual-channel transformer architecture with adversarial contrastive learning and a purely negative sampling strategy. Its parallel graph encoders capture both multiscale similarity patterns and heterogeneous biological semantics. In one channel, structural neighborhoods are expanded via diffusion-based propagation to encode varying granularities of similarity. In the other, cross-entity relationships are contextualized through meta-path-guided attention over a unified drug-disease-protein graph. Adversarial perturbations enhance latent space robustness to prevent noise-induced collapse, while a low-rank decomposition strategy isolates informative hard negatives by disentangling global association trends from local residual signals. Together, these components sharpen the decision boundary under sparse and noisy conditions. Extensive experiments demonstrate that MGTAL-DR achieves state-of-the-art performance across three benchmark data sets. Furthermore, a case study on Alzheimer's disease highlights its practical utility by successfully identifying promising therapeutic candidates, thereby validating its real-world potential.},
}

@article {pmid41195757,
year = {2025},
author = {Namdul, T and MacLehose, R and Pasang, T and Madesclaire, O and Gyatso, G and Henderson, A and Buchwald, D},
title = {Community-based participatory research on Alzheimer's disease and related dementias among Tibetan Buddhist monks in South India: The Lifestyle Assessment and Monastic Aging Study (LAMAS).},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {11},
pages = {e70834},
doi = {10.1002/alz.70834},
pmid = {41195757},
issn = {1552-5279},
support = {TL1R002493/TR/NCATS NIH HHS/United States ; UL1TR002494/TR/NCATS NIH HHS/United States ; },
mesh = {Humans ; *Community-Based Participatory Research ; *Buddhism ; India/epidemiology ; *Alzheimer Disease/epidemiology/ethnology ; Male ; Female ; *Life Style ; Tibet/ethnology ; *Dementia/epidemiology ; Aged ; Prevalence ; Middle Aged ; *Aging ; },
abstract = {INTRODUCTION: This protocol paper describes the methodology used in designing and conducting community-based participatory research (CBPR) to estimate the prevalence of Alzheimer's disease and related dementias (ADRD) among Tibetan Buddhist monks. The CBPR approach laid the groundwork to examine monastic lifestyles, including meditative and cognitive practices.

METHODS: The study used a CBPR approach to examine the prevalence of ADRD and assess lifestyle and meditative and cognitive practices among Tibetan Buddhist monks.

RESULTS: The study recruited 205 monks and collected a wide range of data, including monastic lifestyle, meditative and cognitive practices, mental health, sleep quality, physical measures, biospecimens, and other information.

DISCUSSION: The study was a first of its kind to use CBPR in estimating the prevalence of ADRD among Tibetan monks. The CBPR approach enabled us to engage with the monastic community at every phase of the study and provided a framework to design culturally sensitive surveys and cognitive measures.

HIGHLIGHTS: The study was the first of its kind to use a community-based participatory research (CBPR) approach to estimate the prevalence of Alzheimer's disease and related dementias (ADRD) among Tibetan Buddhist monks in South India. The CBPR approach allowed us to work closely with monastic partners and engage with them at every phase of the study. Such intimate collaboration facilitated the incorporation of relevant and appropriate Tibetan Buddhist ideas and concepts in designing study survey and specific questions related to their lifestyle, including cognitive practices. The successful implementation and conclusion of the study demonstrates the feasibility of conducting a larger epidemiological study-first cross-sectional and then longitudinal-in this population.},
}

Humans
*Community-Based Participatory Research
*Buddhism
India/epidemiology
*Alzheimer Disease/epidemiology/ethnology
Male
Female
*Life Style
Tibet/ethnology
*Dementia/epidemiology
Aged
Prevalence
Middle Aged
*Aging

@article {pmid41195659,
year = {2025},
author = {Sorby-Adams, A and Keo, M and Guo, J and Daly, D and Ahern, R and Zachary, K and Robbins, G and Gandhi, RT and Sveinsson, B and de Havenon, A and Sheth, KN and Rapalino, O and Iglesias Gonzales, JE and Kimberly, WT and Mukerji, SS},
title = {Portable Low-Field Magnetic Resonance Imaging in People With Human Immunodeficiency Virus.},
journal = {Annals of clinical and translational neurology},
volume = {},
number = {},
pages = {},
doi = {10.1002/acn3.70237},
pmid = {41195659},
issn = {2328-9503},
support = {//Massachusetts General Hospital/ ; //American Heart Association/ ; //AIDS Clinical Trials Group/ ; },
abstract = {OBJECTIVE: The aging population of people with HIV (PWH) raises heightened concerns regarding accelerated aging and dementia. Portable, low-field MRI (LF-MRI) is an innovative technology that could enhance access and facilitate routine monitoring of PWH. We sought to evaluate the feasibility of LF-MRI and apply a machine learning (ML) segmentation algorithm to examine atrophy and white matter hyperintensities (WMH) in PWH compared to people without HIV (PWoH) of similar age.

METHODS: Individuals with a confirmed diagnosis of HIV on antiretroviral therapy underwent LF-MRI (64 mT) acquisition in the outpatient neurology clinic. PWoH with > 1 vascular comorbidity (VC cohort, n = 25) or with mild cognitive impairment (MCI cohort, n = 24) due to Alzheimer's disease served as comparators. LF-MRI brain region segmentations were derived using the ML algorithm WMH-SynthSeg in FreeSurfer. Brain regions corrected for intracranial volume were compared between cohorts after adjusting for age and sex.

RESULTS: Thirty virally suppressed PWH were included. LF-MRI derived brain volumes from PWH demonstrated a reduction in volume of the caudate relative to PWoH with VC (p < 0.05). Volume of the putamen and white matter was reduced in PWH compared to VC (p < 0.05). Hippocampal volume was comparable between PWH and PWoH (p ≥ 0.05), while volume of the amygdala was reduced in those with MCI alone (p < 0.05). No differences in WMH were seen between these cohorts (p > 0.05).

INTERPRETATION: LF-MRI is feasible in an outpatient setting, and ML algorithms enable detection of regional atrophy and WMH in PWH. LF-MRI may enable more frequent monitoring and earlier detection of atrophy in at-risk populations.},
}

@article {pmid41195593,
year = {2025},
author = {Lehrer, S and Rheinstein, PH},
title = {rs140926439 Variant in the Fibronectin FN1 Gene Lowers Risk of Alzheimer Disease in APOEε4 Carriers in the UK Biobank Cohort.},
journal = {Alzheimer disease and associated disorders},
volume = {},
number = {},
pages = {},
doi = {10.1097/WAD.0000000000000692},
pmid = {41195593},
issn = {1546-4156},
abstract = {BACKGROUND: A genetic variant in the fibronectin FN1 gene reduces the odds of developing AD by up to 70%. This variant, rs140926439, appears to prevent the buildup of excess fibronectin at the blood brain barrier. Increased fibronectin levels are typically observed in people with Alzheimer disease (AD), but the variant appears to counteract its effects. Our study aims to replicate findings from previous research that identified a relationship between the fibronectin FN1 gene variant rs140926439 and a lower risk of Alzheimer disease (AD) in APOEε4 carriers.

METHODS: We analyzed the relationship of FN1 SNP rs140926439, APOEε4, and AD in the UK Biobank cohort.

RESULTS: When rs140926439 was absent, 0.10% of APOEε2/3 carriers had AD, while 0.43% of APOEε4 carriers or homozygotes had AD. This difference was significant (P<0.001, 2-tail the Fisher exact test). When rs140926439 was present, 0.10% of APOEε2/3 carriers had AD, while 0.10% of APOEε4 carriers or homozygotes had AD. This difference was insignificant (P=1). To examine the overall relationship of rs140926439 and APOE isoform to AD, we used the univariate general linear model, AD (present or absent) dependent variable, rs140926439 (present or absent) and APOE isoform (APOEε2/3 or APOEε4 carrier or homozygote) as fixed factors. The effect of rs140926439 was significant (P=0.025). The effect of the APOE isoform was significant (P=0.030). There was also a significant interaction between rs140926439 and APOE isoform (P=0.031).

CONCLUSION: Fibronectin is an adhesive molecule that is essential to wound healing, especially to the production of the extracellular matrix and reepithelialization. Some cases of AD may be due to the initiation of the brain wound healing process, often in the absence of any actual wound. NSAIDS may reduce the risk of AD because they potently inhibit wound healing. FN1 appears to be a key player in AD, and its risk-lowering variant could offer insights into potential therapeutic targets. However, further research is needed to fully understand the intricate mechanisms underlying AD and to develop effective treatments.},
}

@article {pmid41195529,
year = {2025},
author = {Lee, N and Youn, K and Kwon, H and Lee, J and Lee, E and Jung, JW and Moon, M and Lee, DS and Kim, DH and Ho, CT and Jun, M},
title = {Fucoxanthin suppresses amyloid-β and pyroglutamate-3-Aβ accumulation by modulating the PI3K/Akt/GSK-3β signaling pathway.},
journal = {Food & function},
volume = {},
number = {},
pages = {},
doi = {10.1039/d5fo04217h},
pmid = {41195529},
issn = {2042-650X},
abstract = {Aberrant aggregation of amyloid-β (Aβ) peptides is a hallmark of Alzheimer's disease (AD), contributing to synaptic dysfunction and cognitive decline. Recently, pyroglutamate-modified Aβ (pE3-Aβ) has emerged as a key contributor to Aβ pathology, as it is a highly aggregation-prone variant that enhances amyloid seeding and accelerates plaque propagation. β-Secretase (BACE1) and glutaminyl cyclase (QC) are essential enzymes for generating Aβ and pE3-Aβ, respectively, and represent key therapeutic targets. This study evaluated fucoxanthin, a marine carotenoid found in brown algae for its potential to modulate Aβ pathology and cognitive function. In SweAPP N2a cells, fucoxanthin (0.1-5 μM) significantly decreased BACE1 and QC expression, accompanied by reduced levels of Aβ1-42 and pE3-Aβ. Consistent with these changes, enhanced expression of ADAM10 and increased sAPPα secretion further supported a shift toward non-amyloidogenic APP processing by fucoxanthin. Fucoxanthin reduced both spontaneous and pE3-Aβ-seeded aggregation, reflecting its capacity to limit pathogenic amyloid assembly. Mechanistically, it activated Akt and inactivated GSK-3β, effects reversed by PI3K inhibition. In an Aβ1-42-injected mouse model, used for rapid induction of early amyloid pathology, oral administration of fucoxanthin (100 or 200 mg kg[-1]) improved memory performance, producing effects comparable to donepezil. Analysis of hippocampal tissue showed that inhibition of BACE1 and QC by fucoxanthin was associated with reduced Aβ and pE3-Aβ levels, consistent with cellular findings. These findings suggest that fucoxanthin exerts multi-targeted effects on Aβ-related pathology and supports its potential as a functional food component for the dietary prevention of early-stage AD.},
}

@article {pmid41195494,
year = {2025},
author = {Tang, BL},
title = {Applying the non-maleficence principle to basic research in Alzheimer's disease.},
journal = {Indian journal of medical ethics},
volume = {X},
number = {3},
pages = {233-239},
doi = {10.20529/IJME.2025.024},
pmid = {41195494},
issn = {0975-5691},
mesh = {*Alzheimer Disease/therapy ; Humans ; *Biomedical Research/ethics ; *Beneficence ; *Ethics, Research ; Reproducibility of Results ; },
abstract = {Despite the urgency for new leads towards Alzheimer's disease (AD) interventions, the impact of such basic research on patient welfare and potential socioeconomic repercussions are considered remote. Nonetheless, basic science research in AD must adhere to the highest level of ethical stringency. Even preliminary advances in AD basic research offer hope that percolates along the line from researchers to patients. A promising basic research result that is subsequently proven unreliable due to irreproducibility or research misconduct would not only dash hopes but might also misdirect downstream efforts. Furthermore, such misadventures could quash promising research directions that, if otherwise carefully and meticulously interrogated, could yield useful leads. Stringency and reproducibility in biomedical research should thus be framed in accordance with the principle of non-maleficence, which I posit should take priority over loose attempts at beneficence that offer more hype than hope.},
}

*Alzheimer Disease/therapy
Humans
*Biomedical Research/ethics
*Beneficence
*Ethics, Research
Reproducibility of Results

@article {pmid41195357,
year = {2025},
author = {Lee, S and Kaddouh, F},
title = {Hyperkinesia and early-onset dementia in a female with co-occurring PSEN1 and HTT mutations: A case report.},
journal = {Journal of Alzheimer's disease reports},
volume = {9},
number = {},
pages = {25424823251385559},
pmid = {41195357},
issn = {2542-4823},
abstract = {A middle-aged female with family history of early-onset dementia presented with progressive amnesia, behavioral dysregulation, and myoclonus. Workup revealed pathogenic PSEN1 variant and intermediate HTT allele (30 CAG repeats). This case illustrates that motor symptoms should not be neglected in early-onset familial Alzheimer's disease (EOFAD). Moreover, hyperkinetic phenomenology does not reliably differentiate EOFAD and Huntington's disease (HD) due to the possibility of co-occurring mutations. Patients undergoing EOFAD evaluation should be screened for HD as well. Finally, this first case of presenilin mutation and abnormal huntingtin in the same patient suggests that EOFAD and HD can genetically co-occur.},
}

@article {pmid41195356,
year = {2025},
author = {Zeng, J and Bao, Z and Huang, W and Fu, A and Liang, Z and Zhu, H},
title = {Social interaction mitigates cognitive impairments and tau pathology in socially isolated aged mice.},
journal = {Journal of Alzheimer's disease reports},
volume = {9},
number = {},
pages = {25424823251394408},
pmid = {41195356},
issn = {2542-4823},
abstract = {BACKGROUND: Social isolation significantly heightens the risk of dementia among the elderly. Maintaining social engagement has been proposed as a potential strategy to attenuate age-related cognitive decline.

OBJECTIVE: This study investigates whether social interaction with young conspecifics could improve cognitive function in aged mice with chronic social isolation.

METHODS: Twenty-month-old male C57BL/6 mice with long-term social isolation were randomly assigned to either cohousing with 3-month-old young mice or continued isolation for two months. Cognitive function was assessed using Y-maze spontaneous alternation and fear conditioning tests. Synaptic integrity and pathological markers were evaluated through western blotting and immunofluorescence.

RESULTS: Cohoused mice exhibited significantly enhanced novel arm exploration in the Y-maze and improved contextual fear memory compared to isolated controls. Molecular analyses revealed increased synapsin-1 expression and decreased tau phosphorylation at Ser214 in the cohousing group. Immunofluorescence demonstrated greater astrocyte density in the dentate gyrus of cohoused mice.

CONCLUSIONS: Our findings demonstrate that social interaction with young counterparts can rescue isolation-induced cognitive deficits in aged mice, potentially through mechanisms involving tau phosphorylation regulation and synaptic protein restoration. These results provide preclinical evidence supporting social intervention strategies for preventing cognitive decline in socially isolated elderly individuals.},
}

@article {pmid41195302,
year = {2025},
author = {Rezaii, N and Wong, B and Aisen, P and Beckett, L and Dage, JL and Eloyan, A and Foroud, T and Womack, K and Carrillo, MC and Kramer, JH and Jack, CR and Koeppe, R and Kukull, WA and Nudelman, K and Polsinelli, AJ and Raman, R and Rumbaugh, M and Taurone, A and Thangarajah, M and Toga, A and Vemuri, P and Atri, A and Clark, D and Day, GS and Duara, R and Graff-Radford, NR and Grant, I and Honig, LS and Johnson, ECB and Jones, DT and Masdeu, JC and Mendez, MF and Musiek, E and Onyike, CU and Riddle, M and Rogalski, E and Salloway, S and Sha, S and Scott Turner, R and Wingo, TS and Wolk, DA and Hammers, D and Kirby, K and Rabinovici, GD and Apostolova, LG and Dickerson, BC and , },
title = {Voiceprints of cognitive impairment: analyzing digital voice for early detection of Alzheimer's and related dementias.},
journal = {NPJ dementia},
volume = {1},
number = {1},
pages = {35},
pmid = {41195302},
issn = {3005-1940},
abstract = {Early detection of Alzheimer's disease (AD) is critical yet challenging, particularly in younger individuals. This study leverages artificial intelligence to analyze digital voice recordings from the Craft Story Recall task within the Longitudinal Early-onset AD Study (LEADS) to (1) detect cognitive impairment and (2) differentiate early-onset AD (EOAD) from early onset non-AD cognitive impairment (EOnonAD). Using speech samples from 120 patients and 68 cognitively unimpaired controls, we employed two classification approaches: feature-engineered machine learning and end-to-end deep learning incorporating a Large Language Model. To detect mild cognitive impairment, the feature-engineered model, using acoustic and linguistic features, achieved an AUC of 0.945 on the holdout test set, while the end-to-end model yielded an AUC of 0.988. For differentiating EOAD from EOnonAD, the feature-engineered model achieved an AUC of 0.804, and the end-to-end model yielded an AUC of 0.904 on the holdout set. Explainability analyses revealed reduced linguistic informativeness as a key AD indicator.},
}

@article {pmid41195301,
year = {2025},
author = {Dijkstra, JIR and Hulsman, M and Waterink, L and Holstege, H and Teunissen, CE and Christiaansen, WFL and de Jong, BA and Kochunov, P and Donohue, B and Zwan, MD and den Braber, A and Vermunt, L and van der Lee, SJ},
title = {Heritability and shared environmental effects of brain diseases in 12,040 extended families.},
journal = {NPJ dementia},
volume = {1},
number = {1},
pages = {34},
pmid = {41195301},
issn = {3005-1940},
abstract = {Brain diseases have complex patterns of genetic and environmental risk factors, and better understanding of these risks is required for more effective prevention strategies. Participants of the Dutch Brain Research Registry provided detailed information on family structure and occurrence of brain diseases. A total of 12,040 participants (73% female, aged 64.9 ± 11 years) provided information on 101,379 family members (53% female, aged 62 ± 25 years). We estimated heritability (h [2]) of the nine most common brain diseases using polygenic modeling in SOLAR and assessed variations in h [2] through bootstrapping; Alzheimer's disease (AD) (h [2] = 73, range 53-86, P fdr < 0.001), ALS (h [2] = 72, range 10-98, P fdr = 0.030), frontotemporal dementia (FTD) (h [2] = 48, range 0-97, P fdr = 0.132), vascular dementia (VaD) (h [2] = 41, range 7-64, P = 0.003), Lewy Body dementia (h [2] = 34, range 0-58, P = 0.132), iCVA (h [2] = 27, 6-59, P fdr = 0.013), hCVA (h [2] = 29, 8-57, P fdr = 0.007), Parkinson's disease (PD) (h [2] = 38, 6-66, P fdr = 0.013), and multiple sclerosis (h [2] = 10, 10-97, P fdr < 0.001). Shared environmental effects could be estimated for AD (c [2] = 5.8%, P fdr = 0.011), VaD (c [2] = 9.0%, P fdr = 0.021), FTD (c [2] = 9.7%, P fdr = 0.33), iCVA (c [2] = 15.9%, P fdr < 0.001), hCVA (c [2] = 14.9%, P fdr = 0.005), and PD (c [2] = 7.5%, P fdr = 0.25). These findings underscore the significance of genetic contribution to most brain diseases and the important role of shared environments in AD and vascular-related conditions, highlighting initiatives to mitigate modifiable risk factors.},
}

@article {pmid41195193,
year = {2025},
author = {van der Veere, PJ and Broulikova, HM and Hoogland, J and van Maurik, IS and van de Giessen, E and van Harten, AC and Bosmans, JE and Berkhof, J and van der Flier, WM},
title = {Long-term cost-effectiveness of a more accurate diagnostic work-up for dementia.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {17},
number = {4},
pages = {e70210},
pmid = {41195193},
issn = {2352-8729},
abstract = {INTRODUCTION: To address uncertainty about long-term clinical and economic impacts of an accurate dementia diagnosis, we evaluated the cost-effectiveness of adding amyloid positron emission tomography (PET) to memory clinic workup over 5 years.

METHODS: Inverse probability weighting was used to balance covariates between PET (n = 440) and no-PET (n = 460) participants from the Amsterdam Dementia Cohort. Time in community following diagnosis, time alive, and costs were combined in cost-effectiveness analyses.

RESULTS: PET participants lived longer in community (0.26 years, 95% confidence interval [CI]: 0.05 to 0.45) and overall (0.15, CI: 0.02 to 0.27), but did not have statistically different health insurance (€703, CI: -3974 to 5045) or total costs including institutionalization (-€8258, CI: -20,622 to 3377). The probability that PET was cost-effective for extending time in community was 76% at a €2530 willingness-to-pay threshold. The probability that PET yielded cost savings and was more effective for extending time alive was 90%.

DISCUSSION: Findings in this observational cohort suggest that using amyloid PET in memory clinics may be cost-effective.

HIGHLIGHTS: Participants with an amyloid PET in a memory clinic work-up were compared to those without.The amyloid PET group spent more time in community and alive over 5 years of follow-up.Amyloid PET had a 76% chance to cost-effectively extend time in community in uncertainty analysis.},
}

@article {pmid41195092,
year = {2025},
author = {Novoseltseva, A and Chandra, A and Gray, AJ and Li, S and Bradsby, M and Bigio, IJ},
title = {Accelerating myelin defect detection in neurodegenerative disorders: a human-in-the-loop deep learning approach with birefringence microscopy.},
journal = {Neurophotonics},
volume = {12},
number = {4},
pages = {045007},
pmid = {41195092},
issn = {2329-423X},
abstract = {SIGNIFICANCE: Myelin degradation is a critical yet understudied pathological feature in neurodegenerative disorders. Manual detection of myelin defects in volumetric microscopy images is prohibitively time-consuming, limiting large-scale studies. There is a need for rapid, accurate, and scalable defect-detection methods to accelerate advances in the field.

AIM: We aim to develop and evaluate a human-in-the-loop deep learning approach to accelerate myelin defect detection.

APPROACH: We imaged brain tissue samples from the dorsolateral prefrontal cortex from 15 subjects (i.e., five controls, five Alzheimer's disease, and five chronic traumatic encephalopathy) using RGB circular crossed-polarized birefringence microscopy. We created a dataset of 5600 manually annotated myelin defects and trained a YOLOv8-based defect detection model with iterative expert verification.

RESULTS: Our approach achieved 0.85 mAP@50 and reduced analysis time from 8 h to 33 min per 1    mm 2 of tissue while maintaining high accuracy for disease comparison studies. The method can process complete 3D volumetric images up to 300 GB, enabling comprehensive assessment across large tissue volumes.

CONCLUSIONS: This approach effectively streamlines myelin defect detection and can enable the scale up of myelin degradation studies in neurodegenerative disorders.},
}

@article {pmid41195067,
year = {2025},
author = {Ye, K and Li, L and Guan, L and Qin, MM and Xu, XY and Wu, J and Huang, LZ and Gao, JJ},
title = {Exploring the molecular mechanisms of Pueraria in Alzheimer's disease treatment using machine learning and network pharmacology.},
journal = {Frontiers in nutrition},
volume = {12},
number = {},
pages = {1683852},
pmid = {41195067},
issn = {2296-861X},
abstract = {BACKGROUND: Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder, characterized by amyloid-β deposition, tau pathology, neuroinflammation, and metabolic dysfunction. While conventional treatments have been widely studied, food-based interventions are emerging as potential neuroprotective strategies. Pueraria, a nutrient-rich food, has shown promise in promoting brain health, but its mechanisms in AD prevention and management remain insufficiently understood.

METHODS: In this study, we utilized network pharmacology, transcriptomics, and machine learning to investigate the neuroprotective effects of Pueraria. Through analysis of five transcriptomic datasets (GSE5281, GSE29378, GSE36980, GSE37263, and GSE138260), we identified genes associated with AD and screened 15 active compounds from Pueraria lobata using HERB and TCMSP databases. Machine learning models prioritized key targets, and molecular docking simulations assessed the binding affinities of Pueraria compounds to these targets. In vivo validation was performed in AD model mice to evaluate the cognitive-enhancing effects of Pueraria.

RESULTS: We identified 45 overlapping targets between Pueraria and AD, primarily related to synaptic plasticity and neurotransmission. Among these, PFKFB3 emerged as a key mediator of Pueraria's neuroprotective effects. Molecular docking confirmed strong binding affinities between Pueraria compounds and PFKFB3, supporting their functional role. Experimental data showed that Pueraria improved cognitive function in AD mice, underscoring its potential as a neuroprotective agent.

CONCLUSION: This study highlights Pueraria as a promising functional food for AD prevention and management, emphasizing the potential of plant-based dietary interventions for brain health. Our findings provide a basis for further exploration of food-derived neuroprotective strategies.},
}

@article {pmid41194888,
year = {2025},
author = {Tan, JXM and Kang, MS and Yeh, YH and Bezgin, G and Lussier, FZ and Hong, SJ and Isen, J and Rahmouni, N and Vitali, P and Montembeault, M and Klostranec, JM and Macedo, AC and Chan, T and McLaurin, J and Swardfager, W and Bernhardt, BC and Stefanovic, B and Soucy, JP and Gauthier, S and Black, SE and Rosa-Neto, P and Ottoy, J and Goubran, M},
title = {Stepwise connectivity of the entorhinal cortex along connectomic gradients in Alzheimer's disease.},
journal = {Brain communications},
volume = {7},
number = {6},
pages = {fcaf399},
pmid = {41194888},
issn = {2632-1297},
abstract = {The entorhinal cortex is one of the earliest sites of tau tangle deposition in Alzheimer's disease. Existing connectome studies focus on tau propagation along direct, first-order connections between brain regions, overlooking multi-step, higher-order connections that contribute to the spread of pathology in the brain. We propose a novel quantitative integration of graph theory-based stepwise connectivity with low-dimensional connectome gradient space, which reflects the brain's hierarchical organization. This allows us to elucidate multi-step connectivity between the entorhinal cortex (seed region) and the rest of the brain along the major axes of functional and structural brain organization. In this study, we included 213 participants from the Translational Biomarkers in Aging and Dementia (103 amyloid-negative cognitively normal, 35 amyloid-positive cognitively normal, and 75 cognitively impaired) with diffusion-weighted MRI, resting-state functional MRI, and 18F-MK6240 tau-PET. Through the novel integration between stepwise connectivity and connectome gradients, we observed hypoconnectivity from the entorhinal cortex to the transmodal end of the functional gradient and to the posterior end of the structural gradient. On the other hand, multi-step connections from the entorhinal cortex showed increased connectivity toward both unimodal (e.g. somatomotor) and transmodal (e.g. frontoparietal) networks of the functional gradient as well as anterior ends of the structural gradient, potentially initiating new paths for tau spread. Finally, tau-connectivity correlations shifted spatially within connectome gradient space, moving from the highest-order (default mode network/limbic) cognitive system of the functional gradient in the preclinical stage (amyloid-positive cognitively normal) to the second-highest order (frontoparietal) system in the clinical stage (cognitively impaired). In conclusion, we demonstrate widespread network reorganization of both direct and indirect, multi-step connections that are associated with patterns of tau spread in Alzheimer's disease.},
}

@article {pmid41194875,
year = {2025},
author = {Tseng, TS and Liaw, CC and Shiao, YJ and Huang, YI and Cheng, YH and Chen, WC and Tsai, KC},
title = {NeuproGemp, a polyphenol-rich botanical formula, ameliorates Alzheimer's-like pathology in APP/PS1 mice via inhibition of human glutaminyl cyclase.},
journal = {Frontiers in pharmacology},
volume = {16},
number = {},
pages = {1673532},
pmid = {41194875},
issn = {1663-9812},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and amyloid-β (Aβ) accumulation. Increasing evidence suggests that dietary bioactive compounds may modulate neurodegenerative processes. Here, we evaluated the neuroprotective potential of NeuproGemp, a traditional Chinese functional food formula composed of Gastrodia elata, Paeoniae Radix Rubra, and the immunomodulatory protein GMI from Ganoderma microsporum, in APP/PS1 transgenic mice. Oral supplementation (300 mg/kg/day, 6-8 weeks) significantly improved ethological behaviors, including a ∼150% enhancement in burrowing performance (150 ± 25 g vs. 60 ± 40 g in controls), and reduced escape latency in the Morris water maze (Day 4: p < 0.05; Day 6: p < 0.01). Histological analyses demonstrated attenuated plaque-associated gliosis, with microglial/astroglial clusters reduced from 95 ± 22 to 55 ± 11 per section (p < 0.01), alongside increased hippocampal neurogenesis (DCX + cells: 49 vs. 18 cells/mm, p < 0.001). ELISA revealed reductions of ∼30% in soluble Aβ1-42 and ∼50% in pyroglutamate-modified Aβ3-42 (pE-Aβ3-42). High-performance liquid chromatography identified pentagalloylglucose (PGG) as the principal polyphenolic constituent of Paeoniae Radix Rubra, which exhibited potent human glutaminyl cyclase (hQC) inhibition (IC50 = 0.09 μM; KD = 63.7 nM). Molecular modeling and dynamics simulations further supported stable binding interactions of PGG and tannic acid with hQC. Collectively, these findings indicate that NeuproGemp, enriched in neuroactive polyphenols, exerts multi-targeted modulation of amyloidogenic pathways and represents a promising botanical intervention for mitigating AD-related neuropathology.},
}

@article {pmid41194836,
year = {2025},
author = {Pereira, P and Andrade, J and Costa, H and Neves, F and Lourenço, A},
title = {Rectal Sleeve for Fecal Diversion in the Management of a Sacrococcygeal Stage IV Pressure Ulcer in a Dementia Patient: A Non-surgical Alternative to Colostomy.},
journal = {Cureus},
volume = {17},
number = {10},
pages = {e93868},
pmid = {41194836},
issn = {2168-8184},
abstract = {Pressure ulcers are a serious and frequent complication in patients with moderate-to-severe limitations in their mobility. Advanced sacral ulcers are particularly susceptible to fecal contamination, which has a negative impact on wound healing. Surgical colostomy is often considered for fecal diversion but carries significant risks. This case presents an innovative, minimally invasive alternative using a rectal sleeve. We report the case of a 67-year-old Caucasian male with Alzheimer's dementia, who presented with a chronic, stage IV sacrococcygeal pressure ulcer measuring 20 × 15 cm. Surgical debridement was performed, followed by the application of a rectal sleeve for fecal diversion. Combined with nutritional optimization and daily wound care, the ulcer showed marked improvement without the need for any surgical intervention. This case highlights the successful use of a rectal sleeve as a non-surgical alternative to colostomy in managing advanced sacral pressure ulcers. The technique allowed effective wound healing and avoided the risks associated with surgical fecal diversion. Further research may validate its broader clinical use.},
}

@article {pmid41194471,
year = {2025},
author = {Nicol, NI and Ma, T},
title = {Activation of the AMPK Signaling and Brain Function: A Friend or Foe?.},
journal = {Journal of neurochemistry},
volume = {169},
number = {11},
pages = {e70283},
doi = {10.1111/jnc.70283},
pmid = {41194471},
issn = {1471-4159},
support = {R01 AG073823/AG/NIA NIH HHS/United States ; RF1 AG082388/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; Animals ; *Brain/physiology/enzymology/drug effects ; *AMP-Activated Protein Kinases/metabolism ; *Signal Transduction/physiology/drug effects ; Enzyme Activation/physiology/drug effects ; Neuronal Plasticity/physiology ; Cognition/physiology/drug effects ; },
abstract = {AMP-activated protein kinase (AMPK) is a central regulator of cellular energy balance, and its activation presents a therapeutic strategy for various metabolic diseases and neuronal disorders. Yet its effects on brain function remain unclear. This review evaluates evidence from animal and human studies examining AMPK activation through pharmacological agents (synthetic or natural compounds) and exercise. The effects of AMPK activation on synaptic and cognitive function seem highly context-dependent. Peripheral or acute AMPK activation often improves cognition, whereas chronic or central nervous system (CNS) activation can impair synaptic plasticity and memory. Collectively, current studies underscore the need for rigorous research distinguishing peripheral versus central AMPK activation, clarifying isoform-specific signaling, and examining effects in healthy human populations.},
}

Humans
Animals
*Brain/physiology/enzymology/drug effects
*AMP-Activated Protein Kinases/metabolism
*Signal Transduction/physiology/drug effects
Enzyme Activation/physiology/drug effects
Neuronal Plasticity/physiology
Cognition/physiology/drug effects

@article {pmid41194436,
year = {2025},
author = {Daly, T},
title = {Blood biomarkers of Alzheimer's disease: Balancing clinical relevance with improved accessibility and sustainability.},
journal = {Advances in clinical and experimental medicine : official organ Wroclaw Medical University},
volume = {},
number = {},
pages = {},
doi = {10.17219/acem/208917},
pmid = {41194436},
issn = {1899-5276},
abstract = {The U.S. Food and Drug Administration (FDA) recently approved a blood-based biomarker to confirm diagnosis of Alzheimer's disease (AD-BBMs). When used in conjunction with human expertise in the diagnosis of neurocognitive disorder due to Alzheimer's disease (AD), blood-based biomarkers could increase both the accessibility and sustainability of medical practice and research. Indeed, AD-BBMs are likely to be more cost-effective in the long term and conservative calculations performed here suggest that they would have an approx. 10-fold and 36-fold lower carbon footprint compared to cerebrospinal fluid (CSF) lumbar punctures and amyloid positron emission tomography (PET) scans, respectively. Their use will require a careful balance of trade-offs to maximize benefits and minimize harms for current patients, while ensuring the sustainable integration of these tools into healthcare systems so that diagnostic precision remains accessible to present and future generations in an aging global population amid anthropogenic climate change.},
}

@article {pmid41194292,
year = {2025},
author = {Wang, W and Lv, J and Xu, Z and Yang, S and Wang, J and Le, W},
title = {Harnessing cervical lymphatic mechanics to enhance amyloid clearance: a paradigm shift in Alzheimer's therapeutics?.},
journal = {Translational neurodegeneration},
volume = {14},
number = {1},
pages = {56},
pmid = {41194292},
issn = {2047-9158},
support = {2022ZD0211604//National Science & Technology Major Program on "Brain Science and Brain-Inspired Research"/ ; 2022ZD0211607//National Science & Technology Major Program on "Brain Science and Brain-Inspired Research"/ ; 2025B-07-10//National Key Science and Technology Project - Changping National Laboratory Research Project/ ; GZC20251483//Postdoctoral Fellowship Program of China Postdoctoral Science Foundation/ ; },
}

@article {pmid41194168,
year = {2025},
author = {Chen, H and Verkhratsky, A and Yi, C and Oliver, BG},
title = {Evolutionary sex bias in cognitive response to new environmental risk factor - PM2.5.},
journal = {Biology of sex differences},
volume = {16},
number = {1},
pages = {88},
pmid = {41194168},
issn = {2042-6410},
mesh = {Humans ; *Particulate Matter/adverse effects ; Risk Factors ; *Sex Characteristics ; *Cognition/drug effects ; Male ; Female ; *Environmental Exposure/adverse effects ; *Air Pollutants/adverse effects ; *Biological Evolution ; Animals ; },
abstract = {The association between exposure to particulates in polluted air and cognitive impairment is an emerging and significant health concern, particularly among younger populations. Although exposure to particulate matter ≤ 2.5 μm (PM2.5) is linked with a lower estimated risk for dementia compared to traditional risk factors such as APOEɛ4 gene variants, the widespread and long-term population exposure to PM2.5 pose substantial implications for public health. This review explores the sex differences in cognitive function induced by PM2.5, which are age-dependent and distinct from the sex bias observed in Alzheimer's disease. In addition to biological sex and sex hormones, we also discuss the role of epigenetic regulation as a mechanism underlying sex-specific cognitive vulnerabilities to environmental toxins, particularly PM2.5. Understanding these differences is important for developing targeted interventions and public health strategies to mitigate the cognitive impacts of PM2.5 exposure.},
}

Humans
*Particulate Matter/adverse effects
Risk Factors
*Sex Characteristics
*Cognition/drug effects
Male
Female
*Environmental Exposure/adverse effects
*Air Pollutants/adverse effects
*Biological Evolution
Animals

@article {pmid41193962,
year = {2025},
author = {Jahani, S and Roshanaei, G and Tapak, L and , },
title = {Assessing the accuracy of survival machine learning and traditional statistical models for Alzheimer's disease prediction over time: a study on the ADNI cohort.},
journal = {BMC medical research methodology},
volume = {25},
number = {1},
pages = {250},
pmid = {41193962},
issn = {1471-2288},
mesh = {Humans ; *Alzheimer Disease/diagnosis/diagnostic imaging ; *Machine Learning ; Male ; Female ; Aged ; *Cognitive Dysfunction/diagnosis/diagnostic imaging ; Disease Progression ; *Models, Statistical ; Aged, 80 and over ; Neuroimaging/methods ; Prognosis ; Cohort Studies ; Proportional Hazards Models ; Survival Analysis ; },
abstract = {BACKGROUND: Mild cognitive impairment (MCI) represents a transitional stage to Alzheimer's disease (AD), making progression prediction crucial for timely intervention. Predictive models integrating clinical, laboratory, and survival data can enhance early diagnosis and treatment decisions. While machine learning approaches effectively handle censored data, their application in MCI-to-AD progression prediction remains limited, with unclear superiority over classical survival models.

METHODS: We analyzed 902 MCI individuals from Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset with 61 baseline features. Traditional survival models (Cox proportional hazards, Weibull, elastic net Cox) were compared with machine learning techniques (gradient boosting survival, random survival forests [RSF]) for progression prediction. Models were evaluated using C-index and IBS.

RESULTS: Following feature selection, 14 key features were retained for model training. RSF achieved superior predictive performance with the highest C-index (0.878, 95% CI: 0.877-0.879) and lowest IBS (0.115, 95% CI: 0.114-0.116), demonstrating statistically significant superiority over all evaluated models (P-value < 0.001). RSF demonstrated effective risk stratification across individual biomarker categories (genetic, imaging, cognitive) and achieved optimal patient separation into three distinct prognostic groups when combining all features (p < 0.0001). SHAP-based feature importance analysis of RSF revealed cognitive assessments as the most influential predictors, with Functional Activities Questionnaire (FAQ) achieving the highest importance score (1.098), followed by Logical Memory Delayed Recall Total (LDELTOTAL) (0.906) and Alzheimer's Disease Assessment Scale (ADAS13) (0.770). Among neuroimaging biomarkers, Fluorodeoxyglucose (FDG) emerged as the leading predictor (0.634), ranking fifth overall. Feature importance ranking differed between classical and machine learning approaches, with FDG maintaining consistent importance across all models. RSF demonstrated excellent predictive calibration with positive net benefit across risk thresholds from 0.2 to 0.8.

CONCLUSIONS: The RSF model outperformed other methods, demonstrating superior potential for improving prognostic accuracy in medical diagnostics for MCI to AD progression.},
}

Humans
*Alzheimer Disease/diagnosis/diagnostic imaging
*Machine Learning
Male
Female
Aged
*Cognitive Dysfunction/diagnosis/diagnostic imaging
Disease Progression
*Models, Statistical
Aged, 80 and over
Neuroimaging/methods
Prognosis
Cohort Studies
Proportional Hazards Models
Survival Analysis

@article {pmid41193931,
year = {2025},
author = {Nagarajan, R and Zhang, H and Lyu, J and Kambali, M and Wang, M and Rudolph, U},
title = {Intranasal Insulin Mitigates Memory Impairment and Neuroinflammation in a Mouse Model of Hippocampal Aging.},
journal = {Pharmacology research & perspectives},
volume = {13},
number = {6},
pages = {e70186},
pmid = {41193931},
issn = {2052-1707},
support = {R01GM128183/GM/NIGMS NIH HHS/United States ; R35GM153232/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Administration, Intranasal ; *Insulin/administration & dosage/pharmacology ; Mice ; *Memory Disorders/drug therapy ; Disease Models, Animal ; *Hippocampus/drug effects/metabolism ; *Aging/drug effects ; *Neuroinflammatory Diseases/drug therapy ; Male ; Somatostatin/metabolism ; Mice, Inbred C57BL ; Mice, Transgenic ; },
abstract = {Aging is a complex process that frequently includes cognitive decline with memory loss. In the hippocampus, the number of somatostatin-positive (Sst[+]) GABAergic interneurons in the hilar region of the dentate gyrus decreases with age. We previously showed that selective ablation of Sst[+] dentate hilar interneurons is sufficient to induce cognitive dysfunction, resulting in a model of hippocampal aging (pseudo-aged mice). Brain insulin levels and insulin receptor expression also decline with age, and intranasal insulin (INS) has shown promise in improving learning and memory in Alzheimer's disease. Here, we investigated the effects of INS in pseudo-aged mice with genetically ablated dentate hilar Sst[+] interneurons, which were generated by bilateral injection of AAV5-EF1α-mCherry-flex-dtA into the dentate hilus of Sst-IRES-Cre mice (3-5 months old). Following a 3-week recovery period post-injection, INS was administered daily for 9 days. INS treatment in pseudo-aged mice improved working memory in the Y-maze, recognition memory in the novel object recognition test, and non-declarative associative memory in trace fear conditioning. At the molecular level, INS reversed the increase in Iba-1 and pTBK1 expression, indicating attenuation of microglial activation and cGAS-STING pathway signaling, and restored hippocampal BDNF levels. No significant effects of INS were observed in control mice. These findings indicate that INS alleviates memory impairment and reduces neuroinflammation in this hippocampal aging model. Together, the results suggest that intranasal insulin may provide a non-invasive therapeutic approach for mitigating age-related cognitive decline by modulating neuroinflammatory and neurotrophic mechanisms.},
}

Animals
Administration, Intranasal
*Insulin/administration & dosage/pharmacology
Mice
*Memory Disorders/drug therapy
Disease Models, Animal
*Hippocampus/drug effects/metabolism
*Aging/drug effects
*Neuroinflammatory Diseases/drug therapy
Male
Somatostatin/metabolism
Mice, Inbred C57BL
Mice, Transgenic

@article {pmid41193839,
year = {2025},
author = {Sönmez, HR and Karakaş, Ş and Civaş, A and Kararenk, AC and Özer, EB and Tekman, E and Yuca, H and Bona, M and Çoban, F and Şahin, AA and Pınar, NM and Nobarirezaeyeh, M and Bona, GE and Demirci, B and Göger, G and Karakaya, S},
title = {Chemical, biological, morphological, and anatomical exploration of Tripleurospermum monticolum Born. (Asteraceae): A promising medicinal plant.},
journal = {Protoplasma},
volume = {},
number = {},
pages = {},
pmid = {41193839},
issn = {1615-6102},
abstract = {Diabetes mellitus and Alzheimer's disease are interconnected, with type 2 diabetes raising dementia risk. Decoctions and infusions of Tripleurospermum monticolum (Asteraceae) are traditionally used to treat cough, stomachaches, and fever, while its flowers are commonly brewed into tea to alleviate stomach discomfort. The study examined the inhibitory effects of methanol and aqueous extracts from T. monticolum (capitulum, root, and aerial parts) on key enzymes (acetylcholinesterase, butyrylcholinesterase, α-amylase, and α-glucosidase) and assessed antioxidant activity, as well as the total phenolics, flavonoids, and tannins. Essential oils were analyzed via GC-MS/MS, and morphological, anatomical, and metabolite tests were also performed. In the essential oil of the capitulum, (2Z,8Z)-matricaria ester (64.1%) is the dominant compound, while the aerial part is rich in pentacosane (22.2%) and caryophyllene oxide (13.5%). The root, on the other hand, contains high levels of geranyl isovalerate (30.7%). The aerial part methanol extract showed the highest phenolic (74.686 µg GAE/mg), flavonoid (259.083 µg RE/mg), and tannin (83.000 µg TAE/mg) contents. Root methanol extract had the strongest 2,2-Diphenyl-1-picrylhydrazyl radical (DPPH[•]) activity (20.855%), while capitulum methanol extract was most effective in 2,2'-Azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) radical cation (ABTS[•[+]]) scavenging (9.362%). T. monticolum extracts exhibited antibacterial activity with MIC values ranging from 1250 to 2500 µg/mL, and notable anticandidal effects (MIC = 625-2500 µg/mL), particularly against Candida tropicalis. Additionally, the essential oils from the root and flower demonstrated antifungal efficacy, with MIC values of 625 µg/mL and 1250-2500 µg/mL, respectively. The qualitative analysis revealed alkaloids, flavonoids, and tannins in all samples, while lipids were selectively detected in CM, APM, and RM, showing metabolic variability. T. monticolum exhibited promising antioxidant, enzyme inhibitory, antimicrobial, and phytochemical properties, highlighting its potential as a multifunctional medicinal plant, particularly in the context of diabetes and neurodegenerative disease management.},
}

@article {pmid41193812,
year = {2025},
author = {Ayata, P and Crowley, JM and Challman, MF and Sahasrabuddhe, V and Gratuze, M and Werneburg, S and Ribeiro, D and Hays, EC and Durán-Laforet, V and Faust, TE and Hwang, P and Mendes Lopes, F and Nikopoulou, C and Buchholz, S and Murphy, RE and Mei, T and Pimenova, AA and Romero-Molina, C and Garretti, F and Patel, TA and De Sanctis, C and Ramirez Jimenez, AV and Crow, M and Weiss, FD and Ulrich, JD and Marcora, E and Murray, JW and Meissner, F and Beyer, A and Hasson, D and Crary, JF and Schafer, DP and Holtzman, DM and Goate, AM and Tarakhovsky, A and Schaefer, A},
title = {Lymphoid gene expression supports neuroprotective microglia function.},
journal = {Nature},
volume = {},
number = {},
pages = {},
pmid = {41193812},
issn = {1476-4687},
abstract = {Microglia, the innate immune cells of the brain, play a defining role in the progression of Alzheimer's disease (AD)[1]. The microglial response to amyloid plaques in AD can range from neuroprotective to neurotoxic[2]. Here we show that the protective function of microglia is governed by the transcription factor PU.1, which becomes downregulated following microglial contact with plaques. Lowering PU.1 expression in microglia reduces the severity of amyloid disease pathology in mice and is linked to the expression of immunoregulatory lymphoid receptor proteins, particularly CD28, a surface receptor that is critical for T cell activation[3,4]. Microglia-specific deficiency in CD28, which is expressed by a small subset of plaque-associated PU.1[low] microglia, promotes a broad inflammatory microglial state that is associated with increased amyloid plaque load. Our findings indicate that PU.1[low] CD28-expressing microglia may operate as suppressive microglia that mitigate the progression of AD by reducing the severity of neuroinflammation. This role of CD28 and potentially other lymphoid co-stimulatory and co-inhibitory receptor proteins in governing microglial responses in AD points to possible immunotherapy approaches for treating the disease by promoting protective microglial functions.},
}

@article {pmid41193801,
year = {2025},
author = {Casamitjana, A and Mancini, M and Robinson, E and Peter, L and Annunziata, R and Althonayan, J and Crampsie, S and Blackburn, E and Billot, B and Atzeni, A and Puonti, O and Balbastre, Y and Schmidt, P and Hughes, J and Augustinack, JC and Edlow, BL and Zöllei, L and Thomas, DL and Kliemann, D and Bocchetta, M and Strand, C and Holton, JL and Jaunmuktane, Z and Iglesias, JE},
title = {A probabilistic histological atlas of the human brain for MRI segmentation.},
journal = {Nature},
volume = {},
number = {},
pages = {},
pmid = {41193801},
issn = {1476-4687},
abstract = {In human neuroimaging, brain atlases are essential for segmenting regions of interest (ROIs) and comparing subjects in a common coordinate frame. State-of-the-art atlases derived from histology[1-3] provide exquisite three-dimensional cytoarchitectural maps but lack probabilistic labels throughout the whole brain: that is, the likelihood of each location belonging to a given ROI. Here we present NextBrain, a probabilistic histological atlas of the whole human brain. We developed artificial intelligence-enabled methods to align roughly 10,000 histological sections from five whole brain hemispheres into three-dimensional volumes and to produce delineations for 333 ROIs on these sections. We also created a companion Bayesian tool for automatic segmentation of these ROIs in magnetic resonance imaging (MRI) scans. We showcase two applications of the atlas: segmentation of ultra-high-resolution ex vivo MRI and volumetric analysis of Alzheimer's disease using in vivo MRI. We publicly release raw and aligned data, an online visualization tool, the atlas, the segmentation tool, and ground truth delineations for a high-resolution ex vivo hemisphere used in validation. By enabling researchers worldwide to automatically analyse brain MRIs at a higher level of granularity, NextBrain holds promise to increase the specificity of findings and accelerate our quest to understand the human brain in health and disease.},
}

@article {pmid41193694,
year = {2025},
author = {Brezinova, M and Brotzakis, ZF and Horne, RI and Roy Chowdhury, V and Gregory, RC and Bian, Y and González Díaz, A and Gentile, F and Vendruscolo, M},
title = {Identification of potent high-affinity secondary nucleation inhibitors of Aβ42 aggregation from an ultra-large chemical library using deep docking.},
journal = {Molecular systems biology},
volume = {},
number = {},
pages = {},
pmid = {41193694},
issn = {1744-4292},
support = {10059436//UK Research and Innovation (UKRI)/ ; 10061100//UK Research and Innovation (UKRI)/ ; },
abstract = {Alzheimer's disease is characterized by the aggregation of the Aβ peptide into amyloid fibrils. According to the amyloid hypothesis, pharmacologically targeting Aβ aggregation could result in disease-modifying treatments. The identification of inhibitors of Aβ aggregation, however, is complicated by complex technical challenges, which typically restrict to tens of thousands the number of compounds that can be screened in experimental aggregation assays. Here, we report a computational route to increase by 4 orders of magnitude the number of screenable compounds. We achieve this result by developing an open source pipeline version of the Deep Docking protocol, and illustrate its application to the discovery of secondary nucleation inhibitors of Aβ aggregation from an ultra-large chemical library of over 539 million compounds. The pipeline was used to prioritize 35 candidate compounds for in vitro testing in Aβ aggregation assays. We found that 19 of these compounds inhibit Aβ aggregation (54% hit rate). The two most potent compounds showed potency better than adapalene, a previously reported potent inhibitor of Aβ aggregation. Consistent with the intended mechanism of action, these two compounds also proved to be high-affinity binders of Aβ fibrils with an equilibrium dissociation constant in the low nanomolar range in surface plasmon resonance experiments. These results provide evidence that structure-based docking methods based on deep learning represent a cost-effective and rapid strategy to identify potent hits for drug development targeting protein misfolding diseases.},
}

@article {pmid41193576,
year = {2025},
author = {Aggarwal, B and Sinha, S},
title = {CellSP enables module discovery and visualization for subcellular spatial transcriptomics data.},
journal = {Communications biology},
volume = {8},
number = {1},
pages = {1528},
pmid = {41193576},
issn = {2399-3642},
support = {R35GM131819//U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS)/ ; },
mesh = {Animals ; Mice ; *Transcriptome ; *Gene Expression Profiling/methods ; Humans ; Brain/metabolism ; *Computational Biology/methods ; Alzheimer Disease/genetics ; RNA, Messenger/genetics/metabolism ; *Software ; },
abstract = {Spatial transcriptomics has enabled the study of mRNA distributions within cells, a key aspect of cellular function. However, there is a dearth of tools that can identify and interpret functionally relevant spatial patterns of subcellular transcript distribution. To address this, we present CellSP, a computational framework for identifying, visualizing, and characterizing consistent subcellular spatial patterns of mRNA. CellSP introduces the concept of "gene-cell modules", which are gene sets with coordinated subcellular transcript distributions in many cells. It provides intuitive visualizations of the captured patterns and offers functional insights into each discovered module. We demonstrate that CellSP reliably identifies functionally significant modules across diverse tissues and technologies. We use the tool to discover subcellular spatial phenomena related to myelination, axonogenesis, and synapse formation in the mouse brain. We find immune response-related modules that change between kidney cancer and healthy samples, and myelination-related modules specific to mouse models of Alzheimer's Disease.},
}

Animals
Mice
*Transcriptome
*Gene Expression Profiling/methods
Humans
Brain/metabolism
*Computational Biology/methods
Alzheimer Disease/genetics
RNA, Messenger/genetics/metabolism
*Software

@article {pmid41193403,
year = {2025},
author = {Pahlke, S and Kahale, LA and Mahinrad, S and Sousa-Pinto, B and Vieira, RJ and McAteer, MB and Claessen, T and Contador, J and Hofmann, A and Kuchenbecker, LA and Machado, LS and Warmenhoven, N and Yakoub, Y and Palmqvist, S and Schindler, SE and Teunissen, C and Whitson, HE and Zetterberg, H and Edelmayer, R and Tampi, MP},
title = {Blood-based biomarkers for detecting Alzheimer's disease pathology in cognitively impaired individuals within specialized care settings: A systematic review and meta-analysis.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {11},
pages = {e70828},
pmid = {41193403},
issn = {1552-5279},
mesh = {Humans ; *Alzheimer Disease/blood/diagnosis/pathology ; *Biomarkers/blood ; *Cognitive Dysfunction/blood/diagnosis ; Amyloid beta-Peptides/blood ; *tau Proteins/blood ; Sensitivity and Specificity ; },
abstract = {BACKGROUND: This systematic review and meta-analysis aimed to assess the diagnostic test accuracy of blood-based biomarkers (BBMs) for detecting Alzheimer's disease (AD) pathology in cognitively impaired individuals in specialized care settings. The overarching goal is to inform the development of a clinical practice guideline, led by the Alzheimer's Association, for use in clinical practice.

METHODS: A systematic search of MEDLINE, Embase, and Cochrane Library was conducted from January 2019 to November 2024. Studies evaluating the diagnostic test accuracy of plasma phosphorylated tau (p-tau) and amyloid beta (Aβ) tests (p-tau217, %p-tau217, p-tau181, p-tau231, and Aβ42/Aβ40) compared to reference standard tests (cerebrospinal fluid [CSF] AD biomarkers, amyloid positron emission tomography [PET], or neuropathology) in individuals with cognitive impairment (mild cognitive impairment or dementia) in specialized care settings were included. Pooled diagnostic test accuracy measures were calculated, including sensitivity, specificity, and likelihood ratios. Across a range of pre-test probabilities, we evaluated how much a positive or a negative test result would lead to a change in the probability of having amyloid positivity (post-test probability). All analyses were conducted for each test within each biomarker. The Quality Assessment of Diagnostic Accuracy Studies 2 tool was used to evaluate the risk of bias, and the certainty of the evidence was assessed using the Grading of Recommendations, Assessment, Development, and Evaluation approach.

RESULTS: Across 49 observational studies meeting eligibility criteria, 31 different BBM tests were examined. When evaluated using a single cut-point, the diagnostic test accuracy varied considerably across tests: the pooled sensitivity ranged from 49.3% (95% confidence interval [CI]: 41.2-57.4) to 91.4% (95% CI: 86.6-94.6), and the pooled specificity ranged from 61.5% (95% CI: 45.6-75.3) to 96.7% (95% CI: 87.8-99.2). Differences in post-test probability based on a range of pre-test probabilities varied greatly across tests. Furthermore, the certainty of evidence across tests ranged from moderate to very low. Most included studies were judged to be at high risk of bias, particularly in domains related to patient selection, index test conduct, and reference standard.

CONCLUSION: This systematic review provides a comprehensive synthesis of the current evidence on the diagnostic accuracy of BBMs for detecting AD pathology in cognitively impaired individuals in specialized care settings. The findings serve as a foundation for an accompanying clinical practice guideline that provides evidence-based recommendations for BBM use in the clinical diagnostic pathway. Given continuous developments in this rapidly evolving field, ongoing evaluation will be critical to ensure the synthesized evidence and clinical guidelines remain up to date and maintain clinical relevance.

HIGHLIGHTS: This is the first comprehensive systematic review and meta-analysis to evaluate the diagnostic accuracy of blood-based biomarker (BBM) tests specifically in individuals with objective cognitive impairment seen in specialized care settings. Across 49 studies, BBM test performance varied widely. Pooled sensitivity ranged from 49.3% to 91.4% and specificity from 61.5% to 96.7%, depending on the analyte and assay platform. This review followed the Cochrane Handbook for Systematic Reviews of Diagnostic Test Accuracy, the Grading of Recommendations, Assessment, Development, and Evaluation approach to assess the certainty of evidence. This review served as the evidence base for the Alzheimer's Association's new clinical practice guidelines on BBMs, providing structured, evidence-based guidance for implementing BBMs in the diagnostic workup of suspected Alzheimer's disease. The review underscores that BBM test performance is assay- and platform specific and advises clinicians and laboratory directors to interpret results in the context of the specific test used and integrate the results with a comprehensive clinical assessment.},
}

Humans
*Alzheimer Disease/blood/diagnosis/pathology
*Biomarkers/blood
*Cognitive Dysfunction/blood/diagnosis
Amyloid beta-Peptides/blood
*tau Proteins/blood
Sensitivity and Specificity

@article {pmid41193381,
year = {2025},
author = {Dong, Y and Wang, S and Liu, X and Wang, Y and Song, Y and Wang, Y},
title = {Transcranial near-infrared therapy restores synaptic resilience by reshaping signaling landscapes in sleep-deprived tauopathy.},
journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics},
volume = {},
number = {},
pages = {e00780},
doi = {10.1016/j.neurot.2025.e00780},
pmid = {41193381},
issn = {1878-7479},
abstract = {Chronic sleep deprivation (SD) is a prevalent and modifiable risk factor that accelerates neurodegeneration and exacerbates cognitive decline in Alzheimer's disease (AD). Here, we demonstrate that 808 nm transcranial near-infrared (tNIR) therapy reverses cognitive impairment in tauopathy mice subjected to chronic SD through multi-level molecular and circuit restoration. Behavioral and electrophysiological assessments revealed that tNIR reinstated hippocampal-dependent memory and long-term potentiation. Multi-omics profiling uncovered that tNIR orchestrates a coordinated remodeling of GPCR-cAMP-CREB signaling, synaptic vesicle cycling, and excitatory-inhibitory neruotransmission, encompassing glutamatergic, GABAergic, and retrograde endocannabinoid pathways. Lipidomic analyses identified selective remodeling of membrane microdomains, with phospholipids such as MGDG(16:0/20:2) and LPC(20:4) positively correlating with genes governing calcium signaling, vesicle dynamics, and synaptic plasticity. In parallel, tNIR suppressed stress-associated lipid-gene networks linked to oxidative damage and apoptosis. Proteomic data revealed upregulation of antioxidant enzymes (e.g., SOD2) and suppression of pro-apoptotic mediators, supporting mitochondrial resilience. Collectively, these multi-omics signatures converge on restored neurotransmitter turnover, stabilized excitatory-inhibitory balance, and reestablished a synaptically supportive microenvironment. This study provides the first evidence that tNIR therapy counteracts the compounded effects of chronic sleep deprivation and tau pathology on memory, thereby establishing a clinically relevant dual-burden framework for investigating sleep-neurodegeneration interactions. Our findings position tNIR as a non-invasive, systems-level neuromodulatory approach for mitigating sleep-related cognitive vulnerability in neurodegeneration.},
}

@article {pmid41192882,
year = {2025},
author = {Shiiki, T and Ohtsuki, S},
title = {Inhibitory Effect of Insulin-Degrading Enzyme-Selective Inhibitor, Ii1, on the Elimination of Amyloid-β(1-40) from Rat Brain.},
journal = {Biological & pharmaceutical bulletin},
volume = {48},
number = {11},
pages = {1700-1707},
doi = {10.1248/bpb.b25-00424},
pmid = {41192882},
issn = {1347-5215},
mesh = {Animals ; *Amyloid beta-Peptides/metabolism ; *Insulysin/antagonists & inhibitors/metabolism ; *Peptide Fragments/metabolism ; *Brain/metabolism/drug effects ; Male ; Insulin/pharmacology ; Rats, Sprague-Dawley ; Rats ; Blood-Brain Barrier/metabolism ; *Enzyme Inhibitors/pharmacology ; Neprilysin/antagonists & inhibitors ; Thiorphan/pharmacology ; },
abstract = {Amyloid-β peptide (Aβ) is eliminated from the brain across the blood-brain barrier (BBB) by an insulin-sensitive process. To investigate the involvement of insulin-degrading enzyme (IDE) in this process, the present study was implemented to clarify the effect of a novel IDE-specific inhibitor, Ii1, on the elimination of [[125]I]Aβ(1-40) from rat brain via the brain efflux index method. The results showed that such elimination was significantly inhibited by the co-administration of Ii1. The maximum inhibitory effect of Ii1 and IC50 were 69.4% and 9.96 µM, respectively. Insulin alone inhibited the elimination of [[125]I]Aβ(1-40), but the inhibitory effect of co-administering insulin and Ii1 was not significantly different from that of Ii1 alone. Meanwhile, thiorphan, an inhibitor of neprilysin, showed an additive inhibitory effect with Ii1. Aβ(1-13) and Aβ(1-14), which are major fragments produced by the degradation of Aβ(1-40) by IDE, and inhibitors of receptor for advanced glycation end products (RAGE) did not significantly inhibit the [[125]I]Aβ(1-40) elimination. These results suggest that IDE is involved in the insulin-sensitive process of [[125]I]Aβ(1-40) elimination across the BBB, to which neprilysin and RAGE make minor contributions. These findings suggest that impairment of IDE may be involved in the onset of sporadic Alzheimer's disease.},
}

Animals
*Amyloid beta-Peptides/metabolism
*Insulysin/antagonists & inhibitors/metabolism
*Peptide Fragments/metabolism
*Brain/metabolism/drug effects
Male
Insulin/pharmacology
Rats, Sprague-Dawley
Rats
Blood-Brain Barrier/metabolism
*Enzyme Inhibitors/pharmacology
Neprilysin/antagonists & inhibitors
Thiorphan/pharmacology

@article {pmid41192777,
year = {2025},
author = {Lu, D and Ji, X and An, Y and Liu, H and Zheng, G and Liu, Y and Yang, H and Zhao, Y and Zhao, L and Xia, Y},
title = {The Associations of General, Central, Visceral Obesity and Body Fat Percentage with Cognitive Impairment in the Elderly: Meta-analysis and Mendelian Randomization Study.},
journal = {Advances in nutrition (Bethesda, Md.)},
volume = {},
number = {},
pages = {100550},
doi = {10.1016/j.advnut.2025.100550},
pmid = {41192777},
issn = {2156-5376},
abstract = {BACKGROUND: It is unclear whether various obesity phenotypes are differently associated with cognitive disorders. The aim of this study was to examine the associations of general obesity (measured by body mass index [BMI]), central obesity (measured by waist circumferences [WC], waist-to-hip ratio [WHR]) or body fat percentage (BFP), and visceral obesity with cognitive disorders in older adults using meta-analysis and Mendelian randomization (MR) approaches.

METHODS: We identified observational studies published from the inception of four (PubMed, Embase, Medline, and Web of Science) databases until November 2024. A random effect model was employed to construct the pooled odds ratio (OR) and 95% confidence interval (CI) for exploring the associations of general, central, and visceral obesity with cognitive impairment. The average, median, or range age of participants is 60 years and above. Subsequently, a two-sample MR analysis was performed using genetic variation data to investigate the potential causal relationships of general, central, and visceral obesity with cognitive impairment.

RESULTS: A total of 70 studies comprising 2,810,410 participants were included. In meta-analysis, general obesity (measured by BMI) showed an inverse association with cognitive disorders. Compared with normal BMI, the pooled ORs (95% CIs) were 1.29 (1.21-1.38) for underweight, 0.87 (0.84-0.90) for overweight, and 0.88 (0.85-0.91) for obesity. In contrast, no significant association was observed for central obesity (WC or WHR) or visceral obesity. Subgroup analyses by sex, study design, region, and disease type produced results consistent with the overall findings. In MR analyses, higher BMI, BFP, WC, and WHR were associated with a reduced risk of cognitive impairment, with WHR also inversely related to mild cognitive impairment. No causal association was observed for dementia or Alzheimer's disease.

CONCLUSIONS: The research results indicate that there might be a negative correlation between obesity (especially generalized obesity) and cognitive impairment in the elderly.},
}

@article {pmid41192771,
year = {2025},
author = {Shima, S and Kondo, T and Inoue, H},
title = {iPSC-derived neural organoids in dementia research: recent advances and future directions.},
journal = {Neuroscience research},
volume = {},
number = {},
pages = {104980},
doi = {10.1016/j.neures.2025.104980},
pmid = {41192771},
issn = {1872-8111},
abstract = {Neural organoids are self-assembled three-dimensionally shaped aggregates generated from pluripotent stem cells for the purpose of generating brain-like structures. Organoids derived from patient induced pluripotent stem cells (iPSCs) can recapitulate the features of the disease from molecular to functional levels, which are not fully reproduced by other culture systems or in vivo models. Neural organoids have been applied to model dementia including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis/frontotemporal dementia, and they have recapitulated aspects of their complex pathophysiology, including neuronal network dysfunction and accumulation of pathogenic proteins. Although there are some challenges for the research using neural organoids, including their heterogeneity and the lack of cells of non-neural lineage, researchers have tried to overcome these limitations and have demonstrated their utility in conjugation with gene editing technologies and the assembly system of organoids and specific types of cells. This article reviews current research on iPSC-derived organoids for dementia, discussing both the technical hurdles and the potential for translational applications.},
}

@article {pmid41192715,
year = {2025},
author = {Wang, J and Du, Z and Wang, W and Liang, Z and Hou, Y and Liu, Q and Wang, J and Wang, S and He, M and Li, Z and Yang, R and Wang, K and Zhao, L and Wei, Y and Huang, D},
title = {Lactoferrin-driven delivery of Kaixinsan nanomedicine for Alzheimer's disease neuroprotection: Mechanistic insights from bioinformatics and multi-target validation.},
journal = {International journal of biological macromolecules},
volume = {},
number = {},
pages = {148746},
doi = {10.1016/j.ijbiomac.2025.148746},
pmid = {41192715},
issn = {1879-0003},
abstract = {Alzheimer's disease (AD) is a common neurodegenerative disorder characterised by neurapoptosis and neuroinflammation-induced neuronal damage. However, the exact pathogenic mechanism of AD is still controversial, and the existing treatment methods are only effective for the early stage of the disease. Kaixinsan (KXS), a classic anti-amnestic traditional Chinese medicine, can effectively reduce oxidative stress and provide neuroprotection to the brain, but the exact molecular mechanism remains unclear. Herein, we synthesised a biomimetic KXS-delivery system (LTF@GO-PEG/KXS, LGPK), which significantly enhanced the blood-brain barrier (BBB) penetration efficiency was significantly improved, attributed to lactoferrin (LTF)-mediated receptor binding. LGPK exhibits excellent neuroprotection and repolarizes BV2 microglia from pro-inflammatory to anti-inflammatory phenotypes. Further bioinformatics analysis and western blot results indicated that LGPK could inhibit the progression of AD by inhibiting the production of amyloid precursor protein (APP) and hyperphosphorylated Tau (p-Tau), and downregulating TNF/NF-κB signalling pathways. In vivo studies using a transgenic Caenorhabditis elegans strain confirmed that LGPK both suppresses Aβ fibrillogenesis and attenuates oxidative stress, thereby highlighting its potential as a combination therapy for AD. Mechanistic investigations indicated that these neuroprotective effects were mediated through the suppression of the TNF/NF-κB signalling pathway, along with profound alterations in alternative splicing (AS) events. Collectively, these findings highlight LGPK as a promising multi-target nanomedicine for AD treatment by enhancing brain-targeted delivery and exerting combined anti-neuroapoptosis and anti-inflammatory.},
}

@article {pmid41192695,
year = {2025},
author = {Kong, M and Xu, Z and Lu, H and Chen, Y and Zhang, Y and Jiang, X and Wang, P},
title = {ShengHui Decoction mitigates oxidative stress and neuroinflammation in AlCl3-induced AD zebrafish via activating Nrf2/HO-1 and inhibiting NF-κB signaling pathway.},
journal = {Journal of ethnopharmacology},
volume = {},
number = {},
pages = {120785},
doi = {10.1016/j.jep.2025.120785},
pmid = {41192695},
issn = {1872-7573},
abstract = {ShengHui decoction (SHD), a traditional Chinese herbal formula, has long been used clinically to mitigate Alzheimer's disease (AD), demonstrating significant efficacy in alleviating cognitive impairment. However, its molecular mechanisms remain insufficiently understood.

AIM OF THE STUDY: To clarify the effects of SHD on oxidative stress-related markers and inflammatory cytokines in an aluminum chloride (AlCl3)-induced zebrafish model of AD and as well as uncover its underlying mechanisms in alleviating oxidative stress and neuroinflammation..

MATERIALS AND METHODS: Ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was employed to identify the bioactive constituents of SHD. Behavioral tests and histopathological analyses were then conducted to evaluate the effects of SHD (0.74, 1.48, and 2.96 mg/mL) on apoptosis and amyloid-beta (Aβ) deposition in an AlCl3-induced AD zebrafish model. Biochemical assays and enzyme-linked immunosorbent assay were used to quantify superoxide dismutase (SOD), malondialdehyde (MDA), glutathione peroxidase (GSH-Px), tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), IL-1 beta (IL-1β), and IL-18.. Western blot analysis was performed to determine the protein expression of nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), NAD(P)H quinone dehydrogenase 1 (NQO1), nuclear factor-kappa B p65 (NF-κB p65), phosphorylated NF-κB p65 (p-NF-κB p65), and NOD-like receptor family pyrin domain containing 3 (NLRP3).

RESULTS: UPLC-MS/MS profiling identified phenolic acids, saponins, lignans/coumarins, flavonoids, and aliphatic alcohols as the main constituents of SHD. SHD significantly ameliorated cognitive deficits and histopathological abnormalities in AlCl3-induced zebrafish. Moreover, SHD attenuated oxidative stress by upregulating Nrf2, HO-1, and NQO1 expression, while downregulating AlCl3-induced levels of NF-κB p65, p-NF-κB p65, NLRP3 and pro-inflammatory factors.

CONCLUSIONS: SHD effectively improved cognitive performance and reduced AD-like pathological lesions in AlCl3-induced zebrafish. Importantly, SHD exhibits both antioxidant and anti-inflammatory activities by activating the Nrf2/HO-1 axis and inhibiting NF-κB signaling, thereby alleviating oxidative stress and neuroinflammatory responses in AD. These findings provide experimental evidence supporting SHD as a potential therapeutic agent for AD, and substantiate the traditional Chinese medicine principle of tonifying the kidney and replenishing essence in the treatment of AD.},
}

@article {pmid41192561,
year = {2025},
author = {Kore, P and Patil, U and Bodkhe, S and Bandawane, D and Pandit, A and More, A},
title = {Salicin ameliorates Alzheimer's-like pathology by modulation of NTSP/CSP/GLM pathways: An integrated in silico and in vivo approach.},
journal = {Behavioural brain research},
volume = {498},
number = {},
pages = {115907},
doi = {10.1016/j.bbr.2025.115907},
pmid = {41192561},
issn = {1872-7549},
abstract = {Alzheimer's disease (AD) is marked by modifiable and non-modifiable risk factors. Despite existing treatments, effective therapies to halt or reverse AD progression remain limited, highlighting the urgent need for new multitarget strategies. Phytotherapy as an anti-AD approach has emerged as an increasingly promising strategy in combating neurodegeneration, triggered by suppression of neuronal oxidation and inflammation. Salicin is a natural substance found in willow bark with anti-inflammatory and antioxidant effects. The present study investigates the protective effects of Salicin on neurodegeneration triggered by Scopolamine (Scop). Network pharmacology identified target pathways and genes involved in AD pathogenesis and suggested Salicin as a potential therapeutic agent. Molecular docking elucidated interactions within these target pathways. Scop (1 mg/kg, i.p.) induced memory dysfunction, and Salicin was administered at 12.5, 25, and 50 mg/kg (i.p.). Behavioral parameters were assessed for recognition and spatial memory using Novel Object Recognition (NOR) and Radial Arm Maze (RAM), respectively. AChE, BDNF, and PSEN-1 levels were studied as per in silico predictions, and microscopic changes in hippocampus and cortex were observed via histopathology. Top three pathways of Salicin were identified. The results of in silico and in vivo analyses demonstrate that the protective effects of Salicin are mediated through the Neurotrophin Signaling Pathway (NTSP), Cholinergic Synapse Pathway (CSP), and Glycerolipid Metabolism Pathway (GLM), which are critically implicated in AD progression. Relevant behavioral and histopathological improvements were observed. This study provides preliminary evidence supporting the potential of Salicin as a therapeutic candidate for AD, offering valuable direction for future research.},
}

@article {pmid41192537,
year = {2025},
author = {Lisgaras, CP and Scharfman, HE},
title = {Opposing interictal dynamics in Alzheimer's disease and epilepsy.},
journal = {Progress in neurobiology},
volume = {},
number = {},
pages = {102844},
doi = {10.1016/j.pneurobio.2025.102844},
pmid = {41192537},
issn = {1873-5118},
abstract = {Advanced EEG technology has revealed that epileptiform activity occurs more frequently in Alzheimer's disease (AD) than previously recognized, prompting debate over the utility of EEG in AD diagnostics. Yet, unlike epilepsy, epileptiform activity is not always observed in AD, leading to skepticism. Historically, this absence has been attributed to limited recording depth or insufficient recording duration. We tested an alternative hypothesis that certain types of epileptiform activity, specifically high-frequency oscillations (HFOs, defined as 250-500Hz fast ripples), inhibit interictal spikes (IIS), which are currently used to assess hyperexcitability clinically. We recorded wideband (0.1-500Hz) hippocampal local field potentials in three AD (Tg2576, Presenilin 2[-/-], Ts65Dn Down syndrome model) and two epilepsy (intrahippocampal kainic acid, pilocarpine) mouse models during wakefulness and sleep. In both AD and epilepsy, HFOs consistently outnumbered IIS across behavioral states, age and recording contact. However, IIS and HFOs showed divergent relationships: a negative correlation between their rates was observed only in AD, in contrast to a positive correlation in epilepsy. HFOs preceded IIS at much shorter intervals in epilepsy than in AD. Co-occurrence of IIS with ripples did not differ between AD and epilepsy. These findings reveal a novel dissociation between clinically-relevant EEG biomarkers in AD and epilepsy. In AD, HFOs may inhibit IIS, which could lead to underestimation of hyperexcitability and hinder patient stratification for anti-seizure therapies. While non-invasive HFO detection remains challenging, we stress the need for wideband EEG/MEG, particularly in AD, to assess the full extent of hyperexcitability and biomarker interactions that would otherwise remain undetected.},
}

@article {pmid41192434,
year = {2025},
author = {Wagemann, O and Tesky, VA and Schall, A and Nübling, G and Wlasich, E and Hüer, T and Walendzik, A and Weitzel, M and Giebel, GD and Raszke, P and Wasem, J and Pantel, J and Levin, J},
title = {[A review and guideline for the adequate and interdisciplinary (socio-)medical care of people with Down syndrome and dementia development].},
journal = {Fortschritte der Neurologie-Psychiatrie},
volume = {},
number = {},
pages = {},
doi = {10.1055/a-2708-3648},
pmid = {41192434},
issn = {1439-3522},
support = {Projekt-Nr. 01VSF21030//Innovationsfonds des Gemeinsamen Bundesausschusses/ ; 022_EKEA.133//Else-Kröner-Fresenius-Stiftung/ ; },
abstract = {Alzheimer's disease (AD) is one of the most common neurodegenerative disorders in older age. Individuals with Down syndrome (DS) are at significantly increased risk due to trisomy 21 and the resulting overexpression of the amyloid precursor protein. Prevalence rates of AD-related dementia in DS (DSAD) reach up to 88% beyond the age of 65. Despite this, structured diagnostic and therapeutic guidelines for DSAD are lacking.A narrative review of current literature on etiology, diagnosis, treatment, and care pathways for DSAD was conducted. Currently employed dementia diagnostic standards were evaluated in regard to the specific needs of individuals with DS.Established diagnostic methods are applicable to individuals with DS but require adaptations regarding symptom recognition, test administration, and interpretation. Early awareness among caregivers and healthcare providers, as well as timely referral to specialized centers, is essential for accurate diagnosis and treatment planning.Improving care for individuals with DSAD requires close coordination between general healthcare services and specialized centers. This review highlights the medical, diagnostic, and structural challenges in suspected DSAD and provides practical recommendations for patient care. The proposed guideline aims to reduce uncertainties in clinical practice and support sustainable, needs-based care.},
}

@article {pmid41192405,
year = {2025},
author = {Lingad, JN and Vanderlip, CR and Wright, S and Sordo, L and Head, E and Stark, CEL},
title = {Hippocampal 1H-MR spectroscopy metabolites are linked to CSF tau pathology in cognitively unimpaired older adults along the Alzheimer's continuum.},
journal = {Neurobiology of aging},
volume = {157},
number = {},
pages = {89-97},
doi = {10.1016/j.neurobiolaging.2025.10.005},
pmid = {41192405},
issn = {1558-1497},
abstract = {Relationships between Alzheimer's disease (AD) pathologies in cognitively unimpaired adults and in vivo neurometabolic properties measured directly from the hippocampus, a vulnerable region early along the AD continuum, are not well-understood in the earliest stages of AD. In a 3T [1]H-MRS study, we assessed age and AD-related changes in estimates of absolute concentrations of neurometabolites in the right hippocampus. Participants included older adults (age range: 60-85, n = 19) primarily cognitively unimpaired (CU, n = 16), as well as some with cognitive impairment (n = 3). All participants previously received a lumbar puncture for AD disease staging from cerebrospinal fluid (CSF) AD biomarkers (Aβ42, p-tau181 and t-tau), where all were amyloid positive (A+) and most had subthreshold tau pathology (T-). Hippocampal [1]H-MRS metabolites included total N-acetylaspartate (tNAA), myo-inositol (mIns), total creatine (tCr) and total choline (tCho). Regression analyses were performed for assessing relationships among CSF biomarkers, age, and [1]H-MRS metabolites measured as tissue-corrected estimates of absolute concentrations (millimoles/kilogram) and as ratios (/tCr and tNAA/mIns). We identified age-related decreases to mIns/tCr, where estimated absolute concentrations revealed that tCr increased while mIns remained stable. Concentrations for tNAA and mIns were positively associated with CSF p-tau181 and t-tau. Levels of tCr and tCho were not associated with any CSF biomarkers. Overall, our results demonstrate that sub-threshold tau pathologies in cognitively unimpaired A+ individuals are associated with hippocampal metabolite changes related to neural metabolism and glial reactivity early in disease progression.},
}

@article {pmid40490537,
year = {2025},
author = {Frontzkowski, L and Gnörich, J and Gross, M and Dehsarvi, A and Roemer-Cassiano, SN and Palleis, C and Katzdobler, S and Dewenter, A and Steward, A and Biel, D and Hirsch, F and Zhu, Z and Levin, J and Stephens, AW and Müller, A and Koglin, N and Bischof, GN and Kovacs, GG and Höglinger, GU and Brendel, M and Franzmeier, N},
title = {Developing a novel reference region for [[18]F]PI-2620-PET imaging to facilitate the assessment of 4-repeat tauopathies.},
journal = {European journal of nuclear medicine and molecular imaging},
volume = {52},
number = {13},
pages = {5098-5112},
pmid = {40490537},
issn = {1619-7089},
abstract = {PURPOSE: Progressive supranuclear palsy (PSP) is a fatal 4-repeat (4R) tauopathy with progressive movement phenotypes. In-vivo 4R tau biomarkers are therefore crucial for PSP diagnosis, monitoring, and treatment evaluation. The tau-PET tracer [[18]F]PI-2620 binds to 4R tau and shows increased uptake in PSP-associated regions (e.g., globus pallidus), and is therefore a candidate 4R tau biomarker. However, commonly used cerebellar tau-PET reference regions show regional proximity to cerebellar 4R tau deposits in PSP, confounding semiquantitative [[18]F]PI-2620 assessments. Therefore, we employed bias-free image-derived input function (IDIF) PET quantification to identify an optimized data-driven reference region for assessing 4R tau in PSP.

METHODS: Dynamic [[18]F]PI-2620 PET (60 min) was acquired in 58 PSP-Richardson Syndrome (PSP-RS) and 18 healthy controls (HC). IDIF-modelling with carotid timeseries derived total distribution volume (VT). Iteratively normalizing VT images to atlas-based white matter (WM), we identified reference candidates maximizing PSP-RS vs. HC pallidum differences. The best-performing WM references were combined to a temporo-orbital WM reference, validated in PSP-nonRS (n = 54), HC (n = 18), and disease controls (α-synucleinopathies, n = 21; Alzheimer’s disease (AD, n = 22) using VT-ratios (VTr) and 20-40min static standardized uptake value ratios (SUVr).

RESULTS: Using the data-driven temporo-orbital WM reference, PSP patients showed significantly higher basal ganglia [[18]F]PI-2620 signal vs. HC compared to cerebellar normalization. Receiver operating curve (ROC) analysis confirmed higher diagnostic accuracy using the temporo-orbital WM reference. Pallidum [[18]F]PI-2620 showed significant associations with clinical disease severity exclusively when using the novel temporo-orbital WM reference.

CONCLUSIONS: A data-driven temporo-orbital WM reference optimizes [[18]F]PI-2620 PET assessment for PSP diagnosis, outperforming conventional cerebellar references used in tau-PET imaging.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00259-025-07396-8.},
}

@article {pmid41192247,
year = {2025},
author = {Arivazhagan, M and Shanmugam, P and Prabu, S and Pavadai, R and Honnu, G and Shanmugaraj, K and Murugan, N and Kim, YA and Jakmunee, J},
title = {Surface enhanced sharp-edged gold microneedles decorated on pencil graphitic microelectrode as efficient electrochemical sensing platform for sensitive detection of NADH in serum and urine samples.},
journal = {Talanta},
volume = {298},
number = {Pt B},
pages = {129043},
doi = {10.1016/j.talanta.2025.129043},
pmid = {41192247},
issn = {1873-3573},
abstract = {Accurate detection of NADH levels plays a critical role in the diagnosis and management of conditions ranging from metabolic disorders to neurodegenerative diseases such as Parkinson and Alzheimer. It also holds potential for therapeutic interventions targeting mitochondrial function and energy metabolism. Herein, we designed the miniaturized sharp-edged hyper-branched gold microneedles (Au MNDs) decorated with pencil graphitic microelectrodes (PGME) via single-step, green electrochemical deposition strategy in the absence of any redox mediators, organic solvents and enzymes, etc. The as-prepared Au microneedles demonstrate impressive direct electrocatalytic properties for NADH oxidation. Their sharp edges of the microneedles and the optimized transducers ionic mobility effectively enhance electrochemically active surface area and intrinsic charge transfer efficiency, making this electrode a powerful enzyme-mimic platform for detecting NADH. This morphology, combined with the unique surface features, fosters a highly ideal conditions for the rapid electron transfer from NADH to the Au MNDs @PGME. The nanostructures improve the mobility directly influences the speed and efficiency of electronic charge carriers, which accelerates the rate of electron transfer. This enhances the electrochemical kinetics of the system, contributing to rapid and sensitive detection of NADH. These attributes indicate that Au MNDs-modified microsensor holds great potential for high sensitivity (62.80 μA/μM cm[-2]), two distinct linear ranges: 0.1-4.5 μM and 4.5-54.5 μM, fast response (<2 s), and lower LOD for the reliable NADH detection. The miniaturized microsensors had a strong ability to prevent anti-interference from sensing of NADH. Notably, the current micro sensing platform, which is based on Au MNDs @PGME, has proven to be useful in clinical diagnostics by successfully testing for NADH sensing in human serum and urine samples in biomedical application.},
}

@article {pmid41192057,
year = {2025},
author = {Meineche, JT and Wierer, M and Jensen, MK},
title = {The current landscape of prospective proteomics research into dementia using blood-based samples.},
journal = {Current opinion in lipidology},
volume = {},
number = {},
pages = {},
doi = {10.1097/MOL.0000000000001019},
pmid = {41192057},
issn = {1473-6535},
abstract = {PURPOSE OF REVIEW: Well conducted, prospective, blood-based biomarker studies on dementia risk are growing, providing valuable insights into disease mechanisms that precede clinical symptoms. These investigations are crucial for advancing our understanding of dementia pathology and identifying early biological changes.

RECENT FINDINGS: Emerging evidence shows that proteins detected in peripheral tissues and the circulatory system can also play a role in neurological diseases. Both neuronal and nonbrain-specific proteins have been associated with dementia prior to symptom onset, highlighting the complex and multisystem nature of disease development. Of the 11 studies included in this review that focused on prospective studies of dementia that applied plasma proteomics, 36 proteins were identified in at least two independent cohorts, suggesting that blood-based proteomics detects consistent protein levels that may be altered years before dementia diagnosis.

SUMMARY: Blood-based biomarkers hold promise for early diagnosis, patient stratification, and mechanistic research in dementia. The observed overlap in protein profiles across studies suggests we are beginning to uncover systemic biological differences that contribute to disease progression.},
}

@article {pmid41192010,
year = {2025},
author = {Yang, M and Wang, Z and Zhou, Q and Zhang, Q and Li, Y and Wang, Z},
title = {The adjunctive efficacy of repetitive transcranial magnetic stimulation with non-pharmacological interventions in cognitive disorders: A meta-analysis of randomized sham-controlled trials.},
journal = {Asian journal of psychiatry},
volume = {114},
number = {},
pages = {104758},
doi = {10.1016/j.ajp.2025.104758},
pmid = {41192010},
issn = {1876-2026},
abstract = {OBJECTIVE: This meta-analysis aimed to systematically evaluate the specific, adjunctive efficacy of repetitive transcranial magnetic stimulation (rTMS) when combined with non-pharmacological interventions-namely, transcranial direct current stimulation (tDCS), Tai Chi, or cognitive training (CT)-in patients with Alzheimer's disease (AD) or mild cognitive impairment (MCI). The goal is to isolate the net therapeutic contribution of rTMS beyond the effects of the base interventions alone.

METHODS: A comprehensive search of Chinese and English databases was conducted from their inception until April 26, 2025. Randomized controlled trials (RCTs) that compared "a non-pharmacological intervention plus active rTMS" versus "the same non-pharmacological intervention plus sham rTMS".This "add-on" study design was selected to precisely isolate the effect of rTMS. The risk of bias was assessed using the PEDro scale and Cochrane tools. Statistical analyses were performed using Review Manager 5.4 software.

RESULTS: 9 studies involving 391 participants were included. The pooled analysis revealed that the adjunctive use of rTMS was significantly superior to the sham control in improving global cognitive function at the immediate post-treatment assessment (SMD=0.38, 95 %CI[0.20,0.56], P < .001, n = 9). This benefit was consistent across the MMSE (SMD=0.38, n = 6), MoCA (SMD=0.37, n = 2), and ADAS-cog (SMD=0.39, n = 3) scores. Subgroup analysis suggested that the rTMS-tDCS combination might offer a short-term advantage in improving MMSE scores (MD=4.67, P = .008). Furthermore, the adjunctive effect of rTMS was sustained, as particularly evidenced by the ADAS-cog at follow-up (SMD=0.74, P = .02). The pooled analysis indicated that rTMS combined with non-pharmacological therapy demonstrated a short-term, sustained (4-8weeks) improvement in global cognitive function (SMD=0.34, 95 % CI[0.07, 0.60], P = .01). Subgroup analysis revealed that this sustained benefit reached statistical significance on the ADAS-cog scale (SMD = 0.41, 95 %CI[0.01, 0.81], P = .04) but showed a non-significant positive trend on the MMSE (SMD=0.26, 95 %CI[-0.19, 0.72], P = .26). However, a key limitation was that most studies did not systematically report outcomes related to activities of daily living or behavioral function.

CONCLUSION: The evidence indicates that rTMS as an adjunct to non-pharmacological interventions provides a significant specific effect on global cognitive function in patients with AD and MCI shortly after treatment, which may be sustained in the short-term. However, long-term follow-up data are extremely limited, and the effect on activities of daily living remains to be validated. The combination of rTMS and tDCS shows promise,but conclusions are constrained by the small number of studies,limited sample sizes,and heterogeneity in intervention protocols. Future large-scale studies incorporating long-term, standardized follow-up and assessments of daily living abilities are warranted to confirm the specific clinical value of rTMS as an augmentative therapy.},
}

@article {pmid41191970,
year = {2025},
author = {Sigvard, CS and Franco-Valiente, JM and Mato, G},
title = {Universal Black-Box Attacks Against a Third-Party Alzheimer's Diagnostic System.},
journal = {Biomedical physics & engineering express},
volume = {},
number = {},
pages = {},
doi = {10.1088/2057-1976/ae1baf},
pmid = {41191970},
issn = {2057-1976},
abstract = {Artificial intelligence (AI) systems are increasingly used in medical imaging for disease diagnosis, yet their vulnerability to adversarial attacks poses significant risks for clinical deployment. In this work, we systematically evaluate the susceptibility of VolBrain, a widely used third-party neuroimaging diagnostic platform, to universal black-box adversarial attacks. We generate adversarial perturbations using a surrogate convolutional neural network trained on a different dataset and with a different architecture, representing a worst-case scenario for the attacker where they have no access to the internals of the system. For this, we employ both the Fast Gradient Sign Method (FGSM) and DeepFool attacks. Our results show that these perturbations can reliably degrade the diagnostic performance of VolBrain, with DeepFool-based attacks being particularly effective for comparable perturbation sizes. We further demonstrate that a simple Mean Attack approach is also effective in degrading VolBrain performance, showing that this system is vulnerable to universal attacks, that is, perturbations agnostic to the input. These findings highlight the substantial risk posed by universal blackbox adversarial attacks, even when attackers lack access to the target model or its training data. Our study underscores the urgent need for robust defense mechanisms and motivates further research into the adversarial robustness of medical AI systems.},
}

@article {pmid41191851,
year = {2025},
author = {Williams, C and Anik, FI and Hasan, MM and Rodriguez-Cardenas, J and Chowdhury, A and Tian, S and He, S and Sakib, N},
title = {Advancing Brain-Computer Interface Closed-Loop Systems for Neurorehabilitation: Systematic Review of AI and Machine Learning Innovations in Biomedical Engineering.},
journal = {JMIR biomedical engineering},
volume = {10},
number = {},
pages = {e72218},
doi = {10.2196/72218},
pmid = {41191851},
issn = {2561-3278},
abstract = {BACKGROUND: Brain-computer interface (BCI) closed-loop systems have emerged as a promising tool in health care and wellness monitoring, particularly in neurorehabilitation and cognitive assessment. With the increasing burden of neurological disorders, including Alzheimer disease and related dementias (AD/ADRD), there is a critical need for real-time, noninvasive monitoring technologies. BCIs enable direct communication between the brain and external devices, leveraging artificial intelligence (AI) and machine learning (ML) to interpret neural signals. However, challenges such as signal noise, data processing limitations, and privacy concerns hinder widespread implementation.

OBJECTIVE: The primary objective of this study is to investigate the role of ML and AI in enhancing BCI closed-loop systems for health care applications. Specifically, we aim to analyze the methods and parameters used in these systems, assess the effectiveness of different AI and ML techniques, identify key challenges in their development and implementation, and propose a framework for using BCIs in the longitudinal monitoring of AD/ADRD patients. By addressing these aspects, this study seeks to provide a comprehensive overview of the potential and limitations of AI-driven BCIs in neurological health care.

METHODS: A systematic literature review was conducted following PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines, focusing on studies published between 2019 and 2024. We sourced research articles from PubMed, IEEE, ACM, and Scopus using predefined keywords related to BCIs, AI, and AD/ADRD. A total of 220 papers were initially identified, with 18 meeting the final inclusion criteria. Data extraction followed a structured matrix approach, categorizing studies based on methods, ML algorithms, limitations, and proposed solutions. A comparative analysis was performed to synthesize key findings and trends in AI-enhanced BCI systems for neurorehabilitation and cognitive monitoring.

RESULTS: The review identified several ML techniques, including transfer learning (TL), support vector machines (SVMs), and convolutional neural networks (CNNs), that enhance BCI closed-loop performance. These methods improve signal classification, feature extraction, and real-time adaptability, enabling accurate monitoring of cognitive states. However, challenges such as long calibration sessions, computational costs, data security risks, and variability in neural signals were also highlighted. To address these issues, emerging solutions such as improved sensor technology, efficient calibration protocols, and advanced AI-driven decoding models are being explored. In addition, BCIs show potential for real-time alert systems that support caregivers in managing AD/ADRD patients.

CONCLUSIONS: BCI closed-loop systems, when integrated with AI and ML, offer significant advancements in neurological health care, particularly in AD/ADRD monitoring and neurorehabilitation. Despite their potential, challenges related to data accuracy, security, and scalability must be addressed for widespread clinical adoption. Future research should focus on refining AI models, improving real-time data processing, and enhancing user accessibility. With continued advancements, AI-powered BCIs can revolutionize personalized health care by providing continuous, adaptive monitoring and intervention for patients with neurological disorders.},
}

@article {pmid41191808,
year = {2025},
author = {Lamba, AS and Gupta, M and Lehl, SS and Malhotra, AS and Parmar, UPS},
title = {Prevalence of Sarcopenia and Frailty in Geriatric Patients with Type 2 Diabetes Mellitus.},
journal = {Rambam Maimonides medical journal},
volume = {16},
number = {4},
pages = {},
doi = {10.5041/RMMJ.10554},
pmid = {41191808},
issn = {2076-9172},
abstract = {BACKGROUND: Sarcopenia and frailty are multi-factorial conditions, but few studies have examined their prevalence among older adults with diabetes in the Indian subcontinent. This study aimed to estimate prevalence of sarcopenia and frailty in ambulatory patients ≥65 years with type 2 diabetes mellitus (T2DM).

METHODS: Sarcopenia was assessed utilizing the Asian Working Group for Sarcopenia (AWGS) 2019 criteria. Frailty was assessed using the Fried Frailty phenotype criteria. The study enrolled ambulatory participants aged 65 years and above with T2DM visiting the outpatient clinic. Patients with degenerative or inflammatory arthritis of the lower limbs, disabling cerebrovascular accidents, Alzheimer's disease or other cognitive impairment, as well as those with chronic obstructive pulmonary disease, chronic liver disease, or chronic kidney disease were excluded from the study.

RESULTS: Among the 100 outpatients meeting the inclusion criteria, sarcopenia was present in 30% (including 17% with severe sarcopenia). Frailty was present in 27%, pre-frailty in 59%, and 14% were classified as robust.

CONCLUSION: This study demonstrated a high prevalence of both sarcopenia and frailty among older adults with T2DM. Routine screening for these conditions may facilitate early identification and intervention in this high-risk population.},
}

@article {pmid41191776,
year = {2025},
author = {Brady, LS and Mahinrad, S and Edelmayer, RM and Potter, WZ and Hutten, SJ and Anticevic, A and Taylor-Burds, C and Winston, CN and Coetzee, T and Paulsen, JS and Mantua, V and Childers, EP and Kolb, HC and Jack, CR and Jagust, WJ and Wagner, JA and Sivakumaran, S and Shaw, L and Sharma, VM},
title = {Beyond Alzheimer's disease-translating biomarker insights across CNS diseases.},
journal = {Science translational medicine},
volume = {17},
number = {823},
pages = {eadr2511},
doi = {10.1126/scitranslmed.adr2511},
pmid = {41191776},
issn = {1946-6242},
mesh = {Humans ; *Biomarkers/metabolism ; *Alzheimer Disease/metabolism ; *Central Nervous System Diseases/metabolism/diagnosis ; *Translational Research, Biomedical ; Huntington Disease/metabolism ; },
abstract = {Decades of research on biomarker identification and integration in Alzheimer's disease (AD) have helped to advance biologically driven disease models, disease subtypes, and disease-modifying treatments. Key lessons learned from AD biomarker development include the need for integration of new biological insights, investment in large cross-sectional and longitudinal studies, a multicomponent biomarker approach, and recruitment of clinical trial cohorts and biosamples that are representative of the target population. We describe how these lessons are being applied in Parkinson's disease, Huntington's disease, multiple sclerosis, and psychotic disorders as use cases to inform biomarker-based approaches across central nervous system disorders.},
}

Humans
*Biomarkers/metabolism
*Alzheimer Disease/metabolism
*Central Nervous System Diseases/metabolism/diagnosis
*Translational Research, Biomedical
Huntington Disease/metabolism

@article {pmid41191704,
year = {2025},
author = {Zambrana-Bonaparte, H},
title = {Cognitive test performance via videoconference in Spanish-speaking Puerto Rican older adults: An exploratory study.},
journal = {Applied neuropsychology. Adult},
volume = {},
number = {},
pages = {1-10},
doi = {10.1080/23279095.2025.2578830},
pmid = {41191704},
issn = {2327-9109},
abstract = {OBJECTIVE: This study aimed to develop the first exploratory, descriptive data on teleneuropsychological test performance for Spanish-speaking Puerto Rican older adults, addressing a critical gap in culturally, linguistically, and technologically relevant research in this population.

METHOD: A total of 127 community-dwelling Puerto Rican adults aged 55 and older (M = 64.6, SD = 7.2) completed a videoconference-administered cognitive battery. Measures included the Mini-Mental State Examination, Modified Boston Naming Test, Logical Memory subtests, Consortium to Establish a Registry for Alzheimer's Disease (CERAD) Word List Learning, Digit Span, and verbal fluency tasks. A novel, culturally appropriate phonemic fluency set ("P," "A," "N") tailored to Puerto Rican Spanish was also introduced. Sociodemographic variables (age, education, sex, bilingualism, and income) were examined as predictors of performance.

RESULTS: Analyses indicated significant effects of age and education on test measures. Older age was associated with lower scores, and participants with higher education consistently outperformed peers with fewer years of schooling. No robust sex differences were found. Although bilingualism and income initially showed associations with performance, their effects were attenuated after adjusting for education. Performance on the novel letter fluency task followed predicted frequency patterns ("P" > "A" > "N") and was sensitive to both age and education.

CONCLUSIONS: The findings provide preliminary reference points that describe demographic influences on videoconference-based cognitive performance in a sample of Puerto Rican older adults. While not intended as clinical norms, these descriptive data contribute to the growing evidence base for teleneuropsychology in underrepresented populations and may inform future regression-based normative or comparison studies.},
}

@article {pmid41191612,
year = {2025},
author = {Bansal, A and Sharma, AR and Chakraborty, A and Sunkaria, A and Jain, A},
title = {Machine Learning-Based Bioactivity Prediction and Descriptor-Guided Rational Design of Amyloid-β Aggregation Inhibitors.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.5c00649},
pmid = {41191612},
issn = {1948-7193},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder in which amyloid-β (Aβ) aggregation plays a pivotal role in its onset and progression. Inhibiting Aβ aggregation is a promising therapeutic strategy; however, its intrinsically disordered and conformationally flexible nature hinders both conventional and computational inhibitor design. Moreover, experimental development of Aβ inhibitors, encompassing molecular design, synthesis, and biological evaluation through repeated assays, is a slow, labor-intensive, and resource-intensive process. Therefore, robust design guidelines and predictive tools are essential for accelerating the discovery of Aβ inhibitors. To overcome these limitations, we developed a machine-learning-based, user-friendly web platform, Amylo-IC50Pred (https://amyloic50pred.vercel.app/), for rapid virtual screening of small molecules targeting Aβ aggregation. The platform integrates two classification models and one regression model, trained on 584 biologically validated compounds. For inhibitor-decoy discrimination, the Random Forest algorithm achieved perfect accuracy (100%). Potency classification into potent, moderately potent, and poor inhibitors was best achieved using Histogram-based Gradient Boosting (81% accuracy). The IC50 regression model, also based on Random Forest, achieved a coefficient of determination (R[2]) of 0.93, demonstrating strong predictive performance. 2D and 3D key molecular properties such as hydrophobicity, shape and charge distribution, and molecular symmetry were identified as critical contributors to model performance. Importantly, these identified properties provide valuable insights into the molecular features that govern Aβ aggregation inhibition and can serve as a foundation for rational design of potent and selective Aβ aggregation inhibitors. Amylo-IC50Pred thus represents a valuable resource for accelerating AD drug discovery.},
}

@article {pmid41191342,
year = {2025},
author = {Imperiale, D and Marcinnò, A and Atzori, C and Angeloro, DP and Murgioni, A and Bagatin, A and Secci, V and Calcagno, A and Capobianco, MA and Coletti Moja, M and Rota, E and Rosso, M and Bongioanni, MR and Godi, L and Barra, M and De Mattei, M and Bonzanino, M and Ferrandi, D and Rainero, I and Lopiano, L and Bozzali, M},
title = {Plasma pTau217/Aβ42 and pTau217 outperform pTau181/Aβ42 and pTau181 in predicting cerebrospinal fluid amyloid positivity: A real-world retrospective study.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251390897},
doi = {10.1177/13872877251390897},
pmid = {41191342},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease (AD) diagnosis often relies on invasive cerebrospinal fluid (CSF) sampling or expensive cerebral positron emission tomography (PET) imaging. Noninvasive tests could facilitate early detection. Plasma phosphorylated-tau (pTau) isoforms are promising AD biomarkers that correlate with brain amyloid-β (Aβ) deposition.ObjectiveTo explore the diagnostic accuracy of pTau-based plasma biomarkers to forecast CSF amyloid-positive status in a real-world consecutive population of subjects with cognitive impairment and complete plasma and CSF biomarker profiles.MethodsWe retrospectively studied 138 consecutive patients with cognitive impairment. Plasma biomarkers (pTau217, pTau181, Aβ42, Aβ40) were measured by automated immunoassay. Diagnostic accuracy for CSF amyloid status was assessed using area-under-the curve (AUC) values from receiver-operating characteristic (ROC) curve analysis. A dual-threshold strategy was used to define low- and high-risk groups and estimate how many lumbar punctures could be avoided.ResultsAmong 138 patients (37% CSF amyloid-positive), pTau217/Aβ42 ratio had the highest AUC (0.920) for predicting amyloid positivity, followed by pTau217 (AUC 0.904). These values exceeded the accuracy of pTau181-based markers. Using dual cut-offs, a 90% sensitivity-90% specificity strategy could avoid about 93.5% of lumbar punctures using pTau217/Aβ42 (10.9% misclassified), and 84.1% when using pTau217 (11.2% misclassified). Stricter thresholds (95%-95% and 97.5%-97.5%) further reduced misclassification rates but at the expense of fewer avoidable invasive procedures.ConclusionsPlasma pTau217 (alone or combined with Aβ42) shows high accuracy for detecting AD pathology and could serve as a scalable, noninvasive diagnostic tool. This approach may triage patients for confirmatory testing and substantially reduce the need for invasive CSF examination.},
}

@article {pmid41191331,
year = {2025},
author = {Ma, X and Yan, N and Song, J},
title = {Association between metabolic score for insulin resistance and cognitive impairment in Chinese middle-aged and older adults: Findings from the CHARLS study.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251392618},
doi = {10.1177/13872877251392618},
pmid = {41191331},
issn = {1875-8908},
abstract = {BackgroundCognitive impairment (CI), an early sign of Alzheimer's disease, may be identified using the metabolic score for insulin resistance (METS-IR), a novel insulin resistance marker.ObjectiveThis nationwide cohort study in China examined the association between METS-IR and CI in middle-aged and older adults, providing preliminary evidence for early prevention.MethodsData were obtained from the China Health and Retirement Longitudinal Study (CHARLS) 2011-2015. METS-IR was calculated using fasting plasma glucose, triglycerides, body mass index, and high-density lipoprotein cholesterol. CI was evaluated through episodic memory and mental status. Descriptive statistics, multivariable logistic regression, restricted cubic spline (RCS), subgroup, and interaction analyses were used to assess the association of METS-IR with CI, with sensitivity analysis confirming robustness.ResultsThe study included 5842 middle-aged and older adults in China. The incidence of CI throughout the follow-up period was 14.36%. The multivariable logistic regression models indicated that participants in Q3 and Q4 of METS-IR had 1.375-fold and 1.564-fold higher risks of CI, respectively, compared with those in Q1 (Q3: OR = 1.375, 95% CI = 1.075-1.758; Q4: OR = 1.564, 95% CI = 1.220-2.005). The trend analysis of METS-IR was also statistically significant. A substantial linear relation between METS-IR and CI was confirmed by the RCS analysis (p for nonlinearity = 0.462). Moreover, consistent associations were observed across extensive subgroup analyses.ConclusionsElevated METS-IR levels were significantly associated with increased CI risk in middle-aged and older Chinese adults. These findings provide support for early identification and intervention of CI.},
}

@article {pmid41191330,
year = {2025},
author = {Zhang, A and Chen, H and Chen, W and Cai, X and Zhou, M and Li, S and Jing, J and Wei, T and Wang, Y and Wang, Y and Pan, Y},
title = {Association of sleep duration with cognitive impairment: A mediation by metabolic factors and intracranial atherosclerosis.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251393525},
doi = {10.1177/13872877251393525},
pmid = {41191330},
issn = {1875-8908},
abstract = {BackgroundDespite the association between sleep disorders and mental impairments, controversies persist over the connection between sleep duration and cognitive impairment and the underlying mechanisms remain unexplored.ObjectiveWe investigated this controversial association in a Chinese population and explored the potential mediators.MethodsParticipants (aged 50-75 years) were recruited from a Chinese population-based cohort study, the PRECISE (PolyvasculaR Evaluation for Cognitive Impairment and vaScular Events) study. Sleep duration and Montreal Cognitive Assessment (MoCA) scores were collected during the baseline survey. Participants were divided by sleep duration into short sleep (<7 h), normal sleep (7-9 h), and long sleep (>9 h) groups. The association between sleep duration and MoCA scores was assessed by mediation analysis.ResultsOf the 3028 participants (mean age: 61.1 ± 6.7 years; females: 53.4%), 362 (12.0%) participants were enrolled in the short-sleep group, 2163 (71.4%) in the normal-sleep group, and 503 (16.6%) in the long-sleep group. Long sleep duration was negatively associated with MoCA scores (long versus normal: β = -0.82, 95% CI: -1.21 to -0.43, p < 0.001), after the adjustment for age, sex, education, body mass index, current smoking, and current drinking. The observed association was mediated by cardiometabolic factors (systolic blood pressure and fasting plasma glucose) and intracranial atherosclerotic plaque, with a cumulative mediating proportion of 12.4%.ConclusionsA long sleep duration may be associated with cognitive impairment, which is partially mediated by blood pressure, fasting plasma glucose, and intracranial atherosclerosis. Therefore, individuals who sleep excessively should be monitored for abnormal cardiometabolic factors.},
}

@article {pmid41191242,
year = {2025},
author = {Rose, DK and Pfund, GN and Waters, DK and Jones, C and Sugita, M and Kandiah, N and Liu, MY and Ng, KP and Liu, AJ},
title = {Toward Inclusive Screening of Cognitive Impairment: Validating the Visual Cognitive Assessment Test Among U.S.-Based Racially Diverse Older Adults.},
journal = {Journal of cross-cultural gerontology},
volume = {},
number = {},
pages = {},
pmid = {41191242},
issn = {1573-0719},
support = {P30 AG072947/GF/NIH HHS/United States ; P30 AG028716/AG/NIA NIH HHS/United States ; },
abstract = {Black/African American and Latino populations are disproportionately affected by Alzheimer's disease (AD), yet underrepresented in research due to biases in cognitive assessments like the Montreal Cognitive Assessment (MoCA). The Visual-based Cognitive Assessment Test (VCAT) minimizes these biases through a culturally neutral, visual-based approach. This study evaluates VCAT's comparability to MoCA and its association with plasma p-tau217, a validated AD biomarker. Cross-sectional study assessing cognitive performance in two cohorts, with plasma p-tau217 levels available in Cohort 2 only. Memory disorders clinic. Fifty-six ethnoracially diverse individuals diagnosed with normal cognition (NC), mild cognitive impairment (MCI), or dementia. Cognitive performance was assessed using VCAT and MoCA. Linear regression models analyzed differences in cognitive scores across diagnostic groups and associations with p-tau217 levels. VCAT scores were comparable to MoCA across diagnostic groups. In Cohort 1, NC had higher VCAT (β = 23.22, p < 0.001) and MoCA scores (β = 25.56, p < 0.001), while dementia had lower VCAT (β = -10.86, p < 0.001) and MoCA scores (β = -10.37, p < 0.001). Similar patterns were observed in Cohort 2. Plasma p-tau217 inversely correlated with both VCAT (β = -13.63, p < 0.001) and MoCA (β = -16.26, p < 0.001) in dementia, with no significant differences in MCI. VCAT strongly aligns with MoCA, providing a culturally unbiased alternative for cognitive screening. Its association with plasma p-tau217 highlights its potential to reflect AD pathology, supporting its clinical and research applications.},
}

@article {pmid41191186,
year = {2025},
author = {Zhang, Y and Liu, S and Xu, K and Shen, Y and Liu, Z and Wang, Y and Bai, Y and Wang, S},
title = {Repetitive transcranial magnetic stimulation for cognitive and emotional symptoms in neurodegenerative diseases: a systematic review and dose-response meta-analysis.},
journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology},
volume = {},
number = {},
pages = {},
pmid = {41191186},
issn = {1590-3478},
support = {2023ZX06C16//Heilongjiang Province Key Research and Development Project: Evidence-based Evaluation Study on the Interventions of Traditional Chinese Medicine at Key Stages of the Whole Cycle of Parkinson's Disease/ ; },
abstract = {OBJECTIVE: We summarized the existing clinical evidence of repetitive transcranial magnetic stimulation (rTMS) for cognitive and emotional symptoms in Parkinson's disease (PD) and alzheimer's disease (AD), and conducted a series of dose-response meta-analyses to determine the magnitude and curve relationship between pulse quantity changes and treatment effect sizes.

METHODS: We retrieved existing evidence from 5 databases and collected relevant results data on rTMS treatment for cognitive and emotional symptoms in PD and AD. We analyzed the data using R software to evaluate the effect size using MD or SMD and 95% confidence intervals (CI), used heterogeneity tests to evaluate the differences in efficacy among the evidence, and used restricted cubic splines (RCS) to fit the dose-response curve.

RESULTS: A total of 17 studies were included in this study. We found that the total pulse quantity showed a significant bell-shaped curve in MoCA (χ[2] = 6.82, df = 2, p = 0.03), HAMA (χ[2] = 9.16, df = 2, p = 0.01), and ADL (χ[2] = 8.22, df = 2, p = 0.01), with optimal effects achieved at 16153, 12138, and 17,237 pulses respectively-indicating that clinical application should control pulses within these ranges to avoid insufficient or excessive doses weakening efficacy. A significant upward curve was observed in MMSE (χ[2] = 12.94, df = 2, p = 0.001), meaning higher pulse counts (up to the 80,000-pulse upper limit in this study) may further improve basic cognitive function, providing a reference for dose adjustment in patients with cognitive impairment.

CONCLUSION: Our meta-analysis results show that rTMS exhibits significant efficacy in cognitive and emotional symptoms of PD and AD. The dose-response results show that the total pulse quantity in MoCA, HAMA, and ADL of PD and AD patients presents a typical bell-shaped curve, and a typical upward curve in MMSE. This indicates that there is a curve relationship between pulse stimulation quantity and efficacy, and the pulse stimulation quantity should be emphasized in the clinical application of rTMS.},
}

@article {pmid41191158,
year = {2025},
author = {Pal, B and Panda, S and Bashir, B and Vishwas, S and Chaitanya, M and Hussain, MS and Gupta, G and Kumbhar, P and Gupta, S and Singh, SK},
title = {Nanomedicine-enabled neuroprotection: therapeutic role of berberine in neurodegenerative diseases.},
journal = {Molecular biology reports},
volume = {53},
number = {1},
pages = {49},
pmid = {41191158},
issn = {1573-4978},
mesh = {Humans ; *Berberine/therapeutic use/pharmacology ; *Neurodegenerative Diseases/drug therapy/metabolism ; *Neuroprotective Agents/therapeutic use/pharmacology ; *Nanomedicine/methods ; Animals ; *Neuroprotection/drug effects ; Nanoparticles/chemistry ; Oxidative Stress/drug effects ; Blood-Brain Barrier/metabolism/drug effects ; },
abstract = {Neurodegenerative diseases (NDs), including Alzheimer's, Amyotrophic lateral sclerosis, Huntington's, and Parkinson's, present an increasingly widespread health burden globally with limited curative or treatment modalities, mostly having symptomatic attenuation. Berberine (BBR) is an isoquinoline alkaloid that occurs naturally and has been proposed as a potential neuroprotectant, since it has been found to exert multiple effects to modulate most of the pathological hallmarks of NDs, including neuroinflammation, oxidative stress, mitochondrial dysfunction, and protein aggregation. Although it shows promise, the practical utilization of BBR is marred by low oral bioavailability, high rate of oxidation, and low blood-brain barrier permeability. To combat these issues, recent developments in nanotechnology, especially in the use and creation of lipidic, inorganic, and polymeric nano-particles, have dramatically altered the pharmacokinetics and pharmacodynamics of BBR. This article summarizes recent advances in BBR-based nanoformulations and emphasizes the translational potential of BBR-based nanopreparations to improve treatment response in NDs. It also describes the molecular foundation of the neuroprotective effects of BBR and its possible place in clinical practice. Future nanocarrier development and investigation of BBR mechanisms will be essential to the development of the next generations of therapeutics in NDs.},
}

Humans
*Berberine/therapeutic use/pharmacology
*Neurodegenerative Diseases/drug therapy/metabolism
*Neuroprotective Agents/therapeutic use/pharmacology
*Nanomedicine/methods
Animals
*Neuroprotection/drug effects
Nanoparticles/chemistry
Oxidative Stress/drug effects
Blood-Brain Barrier/metabolism/drug effects

@article {pmid41191142,
year = {2025},
author = {Kumar, H and Vashisht, K and Kushawaha, SK and Bhatia, V and Ashawat, MS and Arora, R and Baldi, A},
title = {Saroglitazar at the Crossroads of Metabolic and Neurodegenerative Disease: A Critical Review of the Hepato-Neuro Axis and Translational Horizons.},
journal = {Neurochemical research},
volume = {50},
number = {6},
pages = {348},
pmid = {41191142},
issn = {1573-6903},
mesh = {Humans ; Animals ; *Neurodegenerative Diseases/drug therapy/metabolism ; *Non-alcoholic Fatty Liver Disease/drug therapy/metabolism ; *Phenylpropionates/therapeutic use/pharmacology ; *Liver/drug effects/metabolism ; *Neuroprotective Agents/therapeutic use/pharmacology ; PPAR gamma/agonists/metabolism ; *Propionates/therapeutic use/pharmacology ; Oxidative Stress/drug effects ; Brain/drug effects/metabolism ; Translational Research, Biomedical ; PPAR alpha/agonists/metabolism ; Pyrroles ; },
abstract = {Non-Alcoholic Fatty Liver Disease (NAFLD) is increasingly recognized as a systemic disorder with implications far beyond the liver, notably in the progression of cognitive decline and neurodegenerative disorders such as Alzheimer's disease (AD) and traumatic brain injury (TBI). At the center of this liver-brain axis lies Saroglitazar (SGZ), a dual PPAR-α/γ agonist initially developed for diabetic dyslipidemia. Emerging evidence suggests that SGZ exerts neuroprotective effects via multiple molecular mechanisms, including modulation of oxidative stress, inflammation, and mitochondrial integrity. This review critically evaluates the mechanistic intersections of SGZ's hepatic and neural actions and proposes a unified framework for its therapeutic impact. We contextualize SGZ's role alongside alternative therapies, explore its translational readiness, and propose testable hypotheses to guide future research. While preclinical evidence is promising, robust human studies are essential to validate SGZ's potential in mitigating NAFLD-associated cognitive impairment. This article aims to advance a novel conceptual synthesis and call for integrative strategies targeting the hepato-neuro axis.},
}

Humans
Animals
*Neurodegenerative Diseases/drug therapy/metabolism
*Non-alcoholic Fatty Liver Disease/drug therapy/metabolism
*Phenylpropionates/therapeutic use/pharmacology
*Liver/drug effects/metabolism
*Neuroprotective Agents/therapeutic use/pharmacology
PPAR gamma/agonists/metabolism
*Propionates/therapeutic use/pharmacology
Oxidative Stress/drug effects
Brain/drug effects/metabolism
Translational Research, Biomedical
PPAR alpha/agonists/metabolism
Pyrroles

@article {pmid41191004,
year = {2025},
author = {Shaw, BC and Kaiser, KE and Smith, BC and Timken, JP and Louveau, A and Williams, JL},
title = {Astrocytes upregulate interleukin-15 in response to neuroinflammation during Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251393275},
doi = {10.1177/13872877251393275},
pmid = {41191004},
issn = {1875-8908},
abstract = {BackgroundInterleukin (IL)-15 is a pleiotropic cytokine linked to cognition that is increased in the cerebrospinal fluid of Alzheimer's disease (AD) patients; however, the cellular source of IL-15 and IL-15-sensing cells in AD has not been described.ObjectiveWe sought to determine the cell types responsible for IL-15 secretion in AD and their spatial relationship with amyloid-β (Aβ) pathology.MethodsWe performed immunofluorescent labeling of human postmortem frontal cortex tissue from cognitively intact and dementia patients and used RNA-sequencing and in vitro assays to confirm the stimulus and source of IL-15. We also assessed the hippocampus of 6-7-month-old 5xFAD mice for cytokine levels using multiplex ELISA.ResultsIn the prefrontal cortex of AD patients, we observed increased IL-15 colocalization with GFAP[+] astrocytes (p = 0.0181) near Aβ plaques and demonstrate that astrocytes, but not neurons, upregulate IL-15 in response to interferon-γ and tumor necrosis factor-α in vitro (p = 0.0003 and p < 0.0001, respectively). We also show that neurons express increased IL2Rγ and IL2Rβ colocalization as Braak score increases (p = 0.0002) and that IL-15 is increased in the 5xFAD hippocampus compared to control animals (p = 0.0021).ConclusionsAstrocytes are a source of IL-15 in AD, particularly near localized Aβ pathology, and neurons are poised to respond. The 5xFAD model recapitulates the hippocampal inflammatory milieu associated with AD and may be a useful tool to study the role of IL-15 in the context of Aβ pathology.},
}

@article {pmid41191003,
year = {2025},
author = {Inui, S and Kaneda, D and Sakurai, K and Uchida, Y and Morimoto, S and Abe, O and Hashizume, Y},
title = {Distinct brain atrophy patterns in Lewy body disease: The impact and interaction of comorbid neuropathologies revealed by voxel-based morphometry.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251392228},
doi = {10.1177/13872877251392228},
pmid = {41191003},
issn = {1875-8908},
abstract = {BackgroundIt has become evident that various different neuropathologies including Alzheimer's disease neuropathologic change, limbic-predominant age-related TDP-43 encephalopathy neuropathological change (LATE-NC), and argyrophilic grain disease (AGD) coexist in patients with Lewy body disease (LBD). However, the effect of these comorbidities on brain atrophy remains understudied.ObjectiveThis study aimed to explore the morphological impacts of comorbidities using voxel-based morphometry (VBM).MethodsThirty-four individuals with a neuropathological diagnosis of LBD were included. Antemortem whole-brain 3D-T1-weighted images were preprocessed using Computational Anatomy Toolbox 12. Associations between gray matter (GM) atrophy and specific comorbid neuropathology, as well as interactions among them, were analyzed using VBM.ResultsNeurofibrillary tangle (NFT) pathology exhibited inverse correlations with GM volumes of the right temporal, bilateral frontal lobes, and left posterior cingulate gyrus. Neuritic plaque (NP) pathology-related GM atrophy was localized to the left posterior cingulate gyrus and parts of the parietal lobes. LATE-NC exhibited inverse correlations mainly in the left temporal lobe and left-dominant limbic lobes including the hippocampi. AGD pathology-related GM atrophy was predominant in the left-dominant limbic lobes and left temporal pole. Small vessel disease (SVD) scores were inversely correlated with GM volumes in the left frontal lobe and bilateral cerebellar hemispheres. Interactions between NFT and LATE-NC were limited to limbic and temporal lobes, while interactions between NFT and NP, SVD and NFT or LATE-NC showed more posterior-dominant distributions.ConclusionsVBM analyses revealed distinct atrophy patterns reflective of isolated neuropathologies. Furthermore, the study suggests that interactions between neuropathologies may influence brain atrophy patterns.},
}

@article {pmid41191002,
year = {2025},
author = {Zeng, Z and Dai, M and Jing, Y and Zhao, K and Xu, X and Cheng, L and Huang, R and Song, C and He, J and You, Q and Jin, S},
title = {Exploring toxicity and mechanisms of DDTs in Alzheimer's disease through network toxicology and molecular docking insights.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251393503},
doi = {10.1177/13872877251393503},
pmid = {41191002},
issn = {1875-8908},
abstract = {BackgroundDichlorodiphenyltrichloroethane (DDT) and its metabolites (DDTs), such as dichlorodiphenyldichloroethylene (DDE) and dichlorodiphenyldichloroethane (DDD), are synthetic organochlorine pesticides with long environmental persistence. Although DDT has been phased out in many countries, DDE and DDD remain prevalent worldwide. Growing evidence links DDTs exposure to Alzheimer's disease (AD), though underlying molecular targets and mechanisms remain unclear.ObjectiveIn this study, we investigated molecular targets and pathways through which DDTs potentially induce AD using network toxicology combined with molecular docking techniques.MethodsAD-related targets associated with DDTs were identified through bioinformatics searches. Key targets were selected via STRING protein-protein interaction analysis and Cytoscape, followed by signaling pathway enrichment analysis. Diagnostic efficacy was evaluated using ROC curve analysis and nomogram modeling based on GEO datasets. Molecular docking validated binding affinity between DDTs and core target proteins predicted by AlphaFold 3.ResultsWe identified 1732 potential molecular targets linking DDTs exposure to AD. Pathway analysis revealed DDTs predominantly affect AD pathogenesis by modulating apoptosis, p53 signaling, TNF signaling, and IL-17 signaling pathways. STRING and Cytoscape analyses identified seven core targets. GEO dataset validation indicated RPL23, RPS6, and RPS8 as pivotal targets, with RPL23 having strongest predictive capacity. Molecular docking confirmed binding interactions between DDTs and RPL23, with binding energies of -7.2 kcal mol[-1] for DDT, -6.5 kcal mol[-1] for DDE, and -7.1 kcal mol[-1] for DDD.ConclusionsThis research provides novel insights into neurotoxic mechanisms of DDT and its persistent metabolites DDE and DDD, and supports enhanced public health strategies for AD prevention.},
}

@article {pmid41191001,
year = {2025},
author = {Cao, Y and Liu, S and He, Z and Pan, W and Wang, D},
title = {Unfriendly dialogue of gut microbiota and lipid metabolism in Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251391771},
doi = {10.1177/13872877251391771},
pmid = {41191001},
issn = {1875-8908},
abstract = {Alzheimer's disease (AD) is a major neurodegenerative disease in the aging global population. Exploring the underlying mechanism is helpful to develop the novel strategy. Lipid metabolism disorder is the core accelerator of the occurrence and development of AD. Lipid deposition exacerbates the aging of microglia and astrocytes, leading to neural dysfunction, and consequently, neurodegeneration. In recent years, the crosstalk of gut microbiota and lipid metabolism has gained increasing attention. The gut microbiota and its metabolic products interfere with brain lipid metabolism via the gut-brain axis. This review explores the detrimental interactions between the disorder of lipid metabolism and gut microbiota, discusses its implications in potential pathogenesis, and highlights how restoring the imbalance ameliorates AD progression.},
}

@article {pmid41190994,
year = {2025},
author = {Webster, H and Zelinsky, M and Rico, V and Martinez, K and Sankary, L},
title = {Reconciling recommendations for ethical sharing of biomarker results with Alzheimer's disease research participants: A systematic review and qualitative synthesis.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251392555},
doi = {10.1177/13872877251392555},
pmid = {41190994},
issn = {1875-8908},
abstract = {BackgroundThe shift toward a biological definition of Alzheimer's disease (AD) has led to increased use of biomarkers (e.g., amyloid, tau, APOE genotype) in research settings. As return of biomarker results becomes more common in AD research, understanding how participants perceive and make decisions about receiving individual research results is essential for ethical trial design and informed consent practices.Objective(1) To map and appraise the landscape of qualitative and mixed-methods research focused on perspectives of AD research community members related to biomarker result sharing in AD research settings; and (2) to synthesize findings on decisional needs of research participants considering whether to receive individual biomarker or genetic risk information.MethodsWe searched PubMed and EMBASE for qualitative and mixed-methods studies published between January 2012 and January 2025. Eligibility criteria included empirical studies reporting qualitative data on experiences, attitudes, or decision-making processes related to receiving AD biomarker or genetic results in research contexts.ResultsOf 3269 records screened, 42 records were assessed for eligibility and 8 met inclusion criteria and were included in our final analysis. Participants emphasized empowerment through research participation and desire for knowledge related to research results. Across studies, decisional needs, characterized as "aspects of decision-making" clustered around four domains: (1) clarity of biomarker meaning and limitations, (2) emotional readiness and support, (3) social consequences of disclosure, and (4) alignment with personal values and future planning.ConclusionsFindings can inform the development of ethically grounded protocols for returning individual research results in preclinical AD trials.},
}

@article {pmid41190993,
year = {2025},
author = {Yang, L and Zeng, J and Li, L and Zhang, Y},
title = {C-reactive protein-triglyceride glucose index and risk of cognitive decline in Chinese middle-aged and older adults: A 9-year national cohort study from CHARLS.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251393522},
doi = {10.1177/13872877251393522},
pmid = {41190993},
issn = {1875-8908},
abstract = {BackgroundCognitive decline is a pressing global health issue in aging populations. The novel composite biomarker, C-reactive protein-triglyceride glucose index (CTI), may provide a superior tool for early risk stratification.ObjectiveThis study examined CTI's capacity to independently predict cognitive decline.MethodsThis retrospective cohort analysis utilized data from 5464 middle-aged and older adults without baseline cognitive impairment from the China Health and Retirement Longitudinal Study (CHARLS). The incidence of cognitive decline served as the primary outcome. CTI was calculated as: CTI = 0.412× Ln (CRP [mg/L]) + Ln (TG [mg/dl] ×FPG [mg/dl])/2. Cognitive performance was assessed in 2020 using the Chinese Mini-Mental State Examination (MMSE). Logistic regression and complementary approaches were used to analyze associations.ResultsOver the 9-year follow-up, a significant positive association between CTI and cognitive decline risk was observed. After multifactorial adjustment, individuals in the highest CTI quartile (Q4) demonstrated a 34% elevated risk relative to the lowest quartile (Q1) (HR = 1.34, 95%CI: 1.10-1.63; p = 0.004). A monotonic dose-response gradient was evident (p = 0.005), with restricted cubic splines confirming linearity (p = 0.025). Sensitivity analyses substantiated robustness.ConclusionsElevated CTI is independently associated with increased risk of cognitive decline, suggesting its potential as a dual-pathway biomarker for early screening.},
}

@article {pmid41190991,
year = {2025},
author = {Jalapally, P and Emani, LS and Izudheen, S and K S, JR},
title = {Multifractal detrended fluctuation analysis and persistent homology of α-synuclein aggregates across Parkinson's disease stages.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251390838},
doi = {10.1177/13872877251390838},
pmid = {41190991},
issn = {1875-8908},
abstract = {Backgroundα-Synuclein (α-syn) is a prominent protein associated with neurodegenerative conditions such as Parkinson's disease (PD), dementia, and multiple system atrophy, and is a key player in synucleinopathies. Despite its significance, the specific changes in α-syn fibril conformations during the progression of PD remain a subject of uncertainty.ObjectiveThis study investigates the structural alterations in α-syn aggregation from cerebrospinal fluid samples at different PD stages (pre-PD, mid-PD, and late-PD).MethodsIn the present study, we used multifractal detrended fluctuation analysis (MFDFA) and persistent homology. The analysis involves constructing protein contact networks for major and minor α-syn polymorphs. The subsequent application of MFDFA to vertex degree, vertex clustering coefficients, and vertex closeness centrality on this time series data reveals multifractal properties and scaling behaviors. Simultaneously, topological analyses, including Rips complexes, Alpha complexes, and Betti numbers, uncover essential structural features and connectivity patterns in α-syn networks.ResultsThis study illuminates α-syn multifractal dynamics and topological characteristics, providing valuable insights into disease-related protein aggregation and network alterations in the progression of PD.ConclusionsThis study provides unique information on MFDFA and persistent homology of α-syn aggregates across disease stages.},
}

@article {pmid41190990,
year = {2025},
author = {Fernandez, FX and Grandner, MA},
title = {Amyloid-β as a cytokine-like somnogen: Rethinking its role in sleep homeostasis and Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251392186},
doi = {10.1177/13872877251392186},
pmid = {41190990},
issn = {1875-8908},
abstract = {Amyloid-β (Aβ) is recognized as a pathological hallmark of Alzheimer's disease, but accumulating evidence suggests that it also serves physiological roles in the healthy brain. Notably, Aβ secretion is tightly linked to neuronal activity and wakefulness, and its clearance is facilitated by sleep, raising the possibility that Aβ regulates sleep homeostasis. We propose that Aβ functions as a cytokine-like somnogen: a molecule whose accumulation during wakefulness promotes sleep onset and maintenance via synaptic and immune mechanisms. This framework reframes Aβ not as a toxic byproduct but as a key intermediary between neural activity and restorative sleep processes. We synthesize findings from molecular biology, electrophysiology, animal models, and human sleep studies, including research on AβPP processing, activity-dependent Aβ release, oligomeric signaling, and the effects of anti-amyloid therapies on sleep. Particular emphasis is placed on evidence that Aβ modulates synaptic excitability, engages glial immune pathways, and fulfills formal criteria for cytokine classification. Across multiple systems, Aβ exhibits properties consistent with homeostatic downscaling: it dampens neurotransmitter release, suppresses excitatory receptor trafficking, and activates sleep-promoting neuronal populations. Disruption of endogenous AβPP cleavage impairs sleep consolidation, while depletion of Aβ can lead to network hyperexcitability and disturbed sleep. Post-marketing reports of insomnia and abnormal dreams with plaque-clearing agents further support a physiological role. Recognizing Aβ as a somnogen offers a unifying model for sleep disruption in AD and raises caution about therapies that neutralize Aβ indiscriminately. Future interventions may benefit from preserving Aβ's homeostatic roles while mitigating its pathological aggregation.},
}

@article {pmid41190989,
year = {2025},
author = {Alshaheri Durazo, A and McDonough, IM},
title = {Midlife brain vulnerability: Sex differences in functional magnetic resonance imaging and Alzheimer's disease risk.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251392238},
doi = {10.1177/13872877251392238},
pmid = {41190989},
issn = {1875-8908},
abstract = {Midlife marks a critical period for detecting Alzheimer's disease (AD) risk because biological and lifestyle factors exceedingly influence brain aging. Konishi et al. used functional magnetic resonance imaging to examine sex differences and risk factors (apolipoprotein E (APOE) ε4, hypertension, type 2 diabetes, depression) on memory-related brain activity starting in midlife. High-risk women showed greater hippocampal hyperactivity, amyloid-β accumulation, and memory deficits than other groups. However, limited sample diversity, lack of tau imaging, unmeasured hormonal levels, and vascular influences constrain interpretations. These findings emphasize the need for sex-informed, mechanistically precise approaches in AD research targeting preclinical stages of disease progression.},
}

@article {pmid41190908,
year = {2025},
author = {},
title = {In brief: Updates for lecanemab (Leqembi) for Alzheimer's disease.},
journal = {The Medical letter on drugs and therapeutics},
volume = {67},
number = {1741},
pages = {182-183},
doi = {10.58347/tml.2025.1741d},
pmid = {41190908},
issn = {1523-2859},
}

@article {pmid41190832,
year = {2025},
author = {Tomoe, R and Waki, S and Morimoto, K and Ogaki, T and Tanaka, T and Yoshino, T},
title = {Orthogonal in vivo and in vitro membrane engineering enables human-like lipid remodeling of bacterial magnetosomes for functional TrkA display.},
journal = {Applied and environmental microbiology},
volume = {},
number = {},
pages = {e0171025},
doi = {10.1128/aem.01710-25},
pmid = {41190832},
issn = {1098-5336},
abstract = {The magnetotactic bacterium Magnetospirillum magneticum produces biogenic magnetic nanoparticles called magnetosomes, each comprising a magnetite core surrounded by a lipid bilayer. By expressing the human neurotrophin receptor TrkA, which is implicated in Alzheimer's disease, cancer, and other pathologies, on magnetosomes, we created a functional human transmembrane receptor platform that enables magnetic recovery and ligand screening. However, TrkA has limited activity within the native bacterial membrane, likely due to the absence of key eukaryotic lipids such as phosphatidylcholine (PC) and cholesterol (Chol). To overcome this limitation, we combined in vivo and in vitro membrane engineering to remodel the magnetosome envelope and closely mimic the human cell membrane. Specifically, PC was biosynthesized in vivo by co-expressing phosphatidylcholine synthase, and purified magnetosomes were subsequently enriched in vitro with Chol using methyl-β-cyclodextrin. This dual-lipid strategy significantly enhanced TrkA-ligand-binding and autophosphorylation. These findings show that orthogonal membrane engineering can precisely tailor the lipid composition of bacterial magnetosomes to recreate mammalian-like bilayers, rescuing the function of complex human receptors in a microbial environment. This approach expands the metabolic and synthetic biology toolkit for producing functional membrane proteins on scalable magnetic supports and establishes a cost-effective platform for the discovery of TrkA and other membrane receptors.IMPORTANCEMembrane receptors drive essential signaling in health and disease; however, they are difficult to study and screen because most platforms fail to reproduce human-like membranes at scale. Magnetosomes from the bacterium Magnetospirillum magneticum AMB-1 offer a simple alternative: lipid-bounded, magnetic nanoparticles that can be purified in one step. This work establishes human-like remodeling of magnetosome membranes by combining in vivo phosphatidylcholine synthesis with the first in vitro cholesterol loading of these particles. Displaying human tropomyosin receptor kinase A on the remodeled membranes preserved and enhanced the receptor function without complex purification or reconstitution. Because magnetosomes can be produced inexpensively and recovered magnetically, this approach enables practical, high-throughput assays for ligand discovery and inhibitor testing. The strategy is broadly applicable to other human membrane proteins, linking microbial biotechnology with human membrane biology to accelerate translational research.},
}

@article {pmid41190345,
year = {2025},
author = {Wei, J and Cui, F and Huang, Z and Li, Z and Mao, Z and Zhang, P},
title = {Acid sensing to inflammaging: mechanisms and therapeutic promise of GPR68 (OGR1) in aging-related diseases.},
journal = {Frontiers in aging},
volume = {6},
number = {},
pages = {1684450},
pmid = {41190345},
issn = {2673-6217},
abstract = {GPR68 is a proton-sensing G protein-coupled receptor with an activation threshold at extracellular pH values between 6.5 and 7.0. It is widely expressed in diverse cell types, particularly in fibroblasts and cancer cells, within inflammatory and tumor microenvironments. In inflammatory bowel disease patients, GPR68 expression is also significantly increased in macrophages and monocytes. GPR68 primarily modulates inflammatory responses through the Gq/11-phospholipase C-inositol 1,4,5-trisphosphate/Ca[2+] signaling axis. Extracellular acidification first promotes GPR68 coupling with Gq/11, subsequently enhancing phospholipase Cβ activity and increasing IP3 production; IP3 then mediates Ca[2+] release from the endoplasmic reticulum, activating calmodulin-dependent kinase and calcineurin, ultimately inducing NF-κB and NFAT nuclear translocation to upregulate inflammatory mediators such as IL-6, TNF-α, and COX-2. This cascade activates inflammatory signaling pathways, thereby driving cellular and tissue senescence and creating favorable conditions for the progression of age-related diseases. However, its long-term causal relationship requires further validation through prospective studies. Abnormal GPR68 expression is closely associated with chronic inflammation, acidosis, and fibrosis in diseases including osteoarthritis, atherosclerosis, chronic kidney disease, Alzheimer's disease, Parkinson's disease, glioblastoma (GBM), and pancreatic cancer. In GBM, knocking down GPR68 or using the GPR68 inhibitor ogremorphin significantly reduces tumor cell survival. Despite its potential as a therapeutic target, challenges remain, such as the unresolved crystal structure, the lack of in vivo causality, cell-type specificity, and context-dependent signaling mechanisms. Targeting GPR68 may offer novel therapeutic strategies for these pathological processes.},
}

@article {pmid41190332,
year = {2025},
author = {Zhang, X and Liao, K and Seidlitz, J and McHugo, M and Avery, SN and Huang, A and Alexander-Bloch, A and Woodward, N and Heckers, S and Vandekar, S},
title = {Semiparametric confidence sets for cross-sectional and longitudinal neuroimaging.},
journal = {Imaging neuroscience (Cambridge, Mass.)},
volume = {3},
number = {},
pages = {},
pmid = {41190332},
issn = {2837-6056},
abstract = {The majority of neuroimaging inference focuses on hypothesis testing rather than effect estimation. With concerns about replicability, there is growing interest in reporting standardized effect sizes from neuroimaging group-level analyses. Confidence sets for effect sizes were recently developed for neuroimaging, but are restricted to simple univariate contrasts (e.g., one-sample or two-sample test Cohen's d) and cross-sectional data. Thus, existing methods exclude increasingly common longitudinal associations of biological brain measurements with, potentially nonlinear, inter- and intra-individual variations in diagnosis, development, or symptoms. We use modern methods for confidence sets combined with a recently proposed robust effect size index to provide a very general approach and software for effect size confidence set inference in neuroimaging. Our method involves robust estimation of the effect size image and spatial and temporal covariance function based on generalized estimating equations. We use a nonparametric bootstrap to estimate the joint distribution of the robust effect size image across voxels to construct confidence sets. These confidence sets identify regions of the image where the lower or upper simultaneous confidence interval is above or below a given threshold with high probability. We evaluate the coverage and simultaneous confidence interval width of the proposed procedures using realistic simulations and perform longitudinal analyses of aging and diagnostic differences of cortical thickness in Alzheimer's disease and diagnostic differences of resting-state hippocampal activity in psychosis. This comprehensive approach, along with the visualization functions integrated into the pbj R package, offers a robust tool for analyzing repeated neuroimaging measurements.},
}

@article {pmid41190161,
year = {2025},
author = {Espinoza-Vinces, C and Aviles-Olmos, I and Núñez-Córdoba, JM and Jiménez-Vázquez, M and Calvo-Imirizaldu, M and Montoya-Murillo, G and Martí-Andrés, G and Arbizu, J and Luquin, MR},
title = {Peripheral immunity patterns, imaging features, and clinical outcomes in patients with gait impairment and ventriculomegaly on brain MRI.},
journal = {Frontiers in aging neuroscience},
volume = {17},
number = {},
pages = {1685288},
pmid = {41190161},
issn = {1663-4365},
abstract = {INTRODUCTION: Ventricular enlargement is a common finding on brain MRI in patients with gait impairment, particularly in those with idiopathic normal pressure hydrocephalus (iNPH). However, iNPH shares several clinical and radiological features with neurodegenerative diseases, which complicates accurate diagnosis. This study aimed to explore the associations between peripheral immune markers, imaging biomarkers, and final diagnosis in patients with gait disturbance and ventriculomegaly.

METHODS: We retrospectively analyzed 55 patients with gait impairment and ventriculomegaly, and 40 age-comparable healthy controls. Clinical assessments included the iNPH Grading Scale (iNPHGS) and cognitive tests. The neutrophil-to-lymphocyte ratio (NLR) was calculated as a peripheral immune marker. Imaging biomarkers included Evans' index (EI), callosal angle (CA), and disproportionately enlarged subarachnoid space hydrocephalus (DESH) score. Additional cerebrospinal fluid biomarkers and [[18]F]-fluorodopa PET/CT were used when clinically indicated. Patients were classified into two groups at the 5-year follow-up based on current clinical diagnostic criteria, integrating longitudinal clinical evaluation and ancillary investigations. The first group consisted of 35 patients (64%) with a neurodegenerative disorder (ND group), of whom 24 (69%) met criteria for progressive supranuclear palsy, 8 (23%) for Alzheimer's disease, 2 (6%) for Lewy body dementia, and 1 (3%) for Parkinson's disease. The remaining 20 patients (36%) fulfilled criteria for probable iNPH and were classified into the iNPH group.

RESULTS: ND patients had significantly higher NLR (M = 2.4, SD = 0.5) than iNPH patients (M = 1.9, SD = 0.4) and controls (M = 1.6, SD = 0.2; p < 0.001). NLR distinguished ND from iNPH with an AUC of 0.79 (80% sensitivity, 70% specificity at a cutoff of 2.0). CA demonstrated strong discrimination (95% sensitivity, 86% specificity). Compared to iNPH, ND had higher iNPHGS scores, greater DESH, and lower CA. Baseline NLR correlated with iNPHGS in ND patients (rs = 0.48, p = 0.004) but not in iNPH. NLR predicted tap test response differently; higher NLR was linked to non-response in ND, and lower NLR associated with improvement in iNPH.

CONCLUSION: NLR may serve as a promising peripheral biomarker to differentiate ND from iNPH in patients with gait impairment and ventriculomegaly. Integrating immune, clinical, and imaging markers could improve diagnostic accuracy and guide appropriate therapeutic strategies.},
}

@article {pmid41190077,
year = {2025},
author = {Kays, M and Kelly, A and McGinnis, F and Woods, C and Herron, E and Brown, C and Coulibaly, AP},
title = {Neutrophils from Alzheimer's disease mice fail to phagocytose debris and show altered release of immune modulators with age.},
journal = {Frontiers in immunology},
volume = {16},
number = {},
pages = {1672768},
pmid = {41190077},
issn = {1664-3224},
mesh = {Animals ; *Alzheimer Disease/immunology/metabolism ; *Neutrophils/immunology/metabolism ; *Phagocytosis/immunology ; Mice ; Female ; Male ; Amyloid beta-Peptides/metabolism/immunology ; Mice, Transgenic ; Neurons/immunology/metabolism ; Disease Models, Animal ; *Aging/immunology ; Cells, Cultured ; Cytokines/metabolism ; },
abstract = {Recent reports show that neutrophil activity plays a role in the cognitive decline associated with Alzheimer's Disease (AD). There is evidence of altered functions in neutrophils isolated from AD patients. Whether these altered functions are inherent to the AD disease state is unknown. The goal of this study was to determine if neutrophil functions are altered in AD mice and if these changes occur only after symptoms appear. To address this hypothesis, we used a primary neuronal culture model, generated from 3xTg perinatal mice, since AD is considered a CNS disease. The 3xTg primary neuronal culture gradually increase the release of Aβ (40 and 42) as the culture ages. To assess neutrophil functions, neutrophils isolated from young male/female mice (3-6 months of age) or aged male/female mice (16-18 months of age) of WT or 3xTg mice were exposed to 3xTg primary neuronal cultures. To assess phagocytosis, we characterized the effect of neutrophils on pathogenic amyloid beta (Aβ) 42 levels. To assess the levels of immune modulators (cytokines, chemokines, growth factors, NETosis, and neutrophil granular content), culture media were assessed using Luminex multiplex assay. Our results show that neutrophils from young AD mice have impaired phagocytosis, as observed in a decreased ability to remove Aβ and cellular debris in vitro. Neutrophils from young AD mice also increased release of pro-inflammatory cytokines, granule content, and NETs in 3xTg primary neuronal cultures. Interestingly, neutrophils from aged 3xTg mice decreased Aβ levels in culture and expression of proinflammatory cytokines when compared to neutrophils from aged WT mice. These neutrophils increased their release of granule content and NETs in 3xTg primary neuronal cultures. These data show that in AD neutrophil function is altered in (young mice) and diseased (old mice) stage.},
}

Animals
*Alzheimer Disease/immunology/metabolism
*Neutrophils/immunology/metabolism
*Phagocytosis/immunology
Mice
Female
Male
Amyloid beta-Peptides/metabolism/immunology
Mice, Transgenic
Neurons/immunology/metabolism
Disease Models, Animal
*Aging/immunology
Cells, Cultured
Cytokines/metabolism

@article {pmid41190075,
year = {2025},
author = {Bao, X and Chen, L and Yu, H and Xie, Y and Luo, L and Luo, L and Wang, H and Chen, R and Cheng, Y and Sun, D and Zhang, C},
title = {Exosome-based modulation of ferroptosis in neurological disorders: mechanisms, therapeutic potential, and translational challenges.},
journal = {Frontiers in immunology},
volume = {16},
number = {},
pages = {1677808},
pmid = {41190075},
issn = {1664-3224},
mesh = {*Ferroptosis ; Humans ; *Exosomes/metabolism/transplantation ; Animals ; *Nervous System Diseases/metabolism/therapy/etiology ; Translational Research, Biomedical ; Iron/metabolism ; Oxidative Stress ; },
abstract = {Neurological disorders, including acute insults such as stroke and traumatic brain injury and chronic neurodegenerative diseases like Alzheimer's disease and Parkinson's disease, exert a profound global health burden. Ferroptosis, a distinct form of regulated cell death driven by iron accumulation, lipid peroxidation, and oxidative stress, has emerged as a central pathological mechanism across these conditions. Exosomes, nanoscale extracellular vesicles capable of crossing the blood-brain barrier and delivering functional cargos such as microRNAs, long non-coding RNAs, and proteins, have demonstrated remarkable potential in modulating ferroptotic signaling. Through regulation of the GPX4-GSH axis, ferritinophagy, iron homeostasis, and antioxidant pathways, exosome-based interventions offer neuroprotective benefits in diverse models of neurological injury. This review synthesizes current advances in the mechanistic understanding of ferroptosis and highlights emerging strategies leveraging exosomes as precision delivery platforms for ferroptosis-targeted therapy. We also discuss the translational challenges and future directions necessary to realize exosome-guided neuroprotection as a viable clinical paradigm.},
}

*Ferroptosis
Humans
*Exosomes/metabolism/transplantation
Animals
*Nervous System Diseases/metabolism/therapy/etiology
Translational Research, Biomedical
Iron/metabolism
Oxidative Stress

@article {pmid41190025,
year = {2025},
author = {Alhassan, HH and Janiyani, K and Surti, M and Adnan, M and Patel, M},
title = {The dual role of glycogen synthase kinase-3 beta (GSK3β) in neurodegenerative pathologies: interplay between autophagy and disease progression.},
journal = {Frontiers in pharmacology},
volume = {16},
number = {},
pages = {1693805},
pmid = {41190025},
issn = {1663-9812},
abstract = {Glycogen Synthase Kinase-3 Beta (GSK3β), a multifunctional serine/threonine kinase, plays a central role in cellular signaling pathways and autophagy regulation, processes critical to neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease and Amyotrophic Lateral Sclerosis (ALS). Dysregulation of autophagy leads to the toxic accumulation of misfolded proteins and damaged organelles, contributing to neuronal loss in these disorders. This review explores the mechanistic interplay between GSK3β and autophagy, highlighting its modulation through key pathways, including mTOR, AMPK and Bcl-2 and its direct impact on autophagy-related proteins such as Beclin-1 and LC3. This review systematically discusses the disease-specific roles of GSK3β in autophagy dysregulation and protein aggregation, providing evidence from recent studies on neurodegenerative models. Additionally, therapeutic approaches targeting GSK3β are evaluated, including preclinical and clinical trials of GSK3β inhibitors and combination therapies with autophagy modulators, emphasizing their potential for improving neuroprotection and cellular homeostasis. Despite its promise, challenges such as off-target effects and pathway complexity remain significant. This review highlights the importance of GSK3β as both a therapeutic target and a biomarker, offering avenues for future research into selective GSK3β modulators that enhance autophagy and mitigate ND progression.},
}

@article {pmid41189844,
year = {2025},
author = {Geng, J and Zhang, C and Zhi, N and Dai, X and Wang, G},
title = {Alzheimer's Disease Concurrent With Patent Foramen Ovale-Related Lacunar Infarcts and Extensive White Matter Hyperintensities: A Case Highlighting Biomarker-Clinical Staging Discordance.},
journal = {Cureus},
volume = {17},
number = {10},
pages = {e93738},
pmid = {41189844},
issn = {2168-8184},
abstract = {An elderly man with progressive memory decline met the 2024 National Institute on Aging and the Alzheimer's Association (NIA-AA) biological criteria for Alzheimer's disease (AD) - classified as stage C biologically but mild dementia clinically - revealing a clear staging mismatch. Recognizing this discordance led us to investigate additional comorbidities. He was found to have extensive white matter hyperintensities (WMHs) (Fazekas grade 3) and experienced multiple recurrent lacunar infarcts. Subsequent evaluation identified a patent foramen ovale (PFO) causing right-to-left shunting and paradoxical embolism. This case underscores the necessity of detecting biological-clinical discordance in AD, actively screening for cerebrovascular comorbidities such as WMHs and infarcts, and accurately identifying underlying causes to optimize patient management and enrich AD clinical research.},
}

@article {pmid41189842,
year = {2025},
author = {Disu, F and Iwudibia, BG and Olatunbosun, O},
title = {Ten-Year Death Trends Related to Dementia, Alzheimer's Disease, and Epilepsy in England and Wales (2014-2023): A Descriptive Analysis of National Death Registration Data.},
journal = {Cureus},
volume = {17},
number = {10},
pages = {e93837},
pmid = {41189842},
issn = {2168-8184},
abstract = {Dementia, including Alzheimer's disease, and epilepsy are major neurological conditions contributing to mortality in England and Wales. Recent data suggest increasing dementia‑related deaths, particularly in ageing populations, while epilepsy remains a less frequent but significant cause of premature mortality. Methods: This descriptive study analyzed national death registration data from the Office for National Statistics between 2014 and 2023. Deaths attributed to dementia (International Classification of Diseases, Tenth Revision (ICD-10) codes, F01, F03, G30) and epilepsy (ICD-10 codes, G40-G41) were included for individuals aged ≥20 years in England and Wales. Data were cleaned, filtered, and analyzed using Stata Statistical Software: Release 18 (StataCorp LLC., College Station, Texas, United States). Frequencies and percentages were calculated using frequency weights to reflect true death counts, and trends were visualized using line and bar graphs. Results: A total of 622,965 deaths were recorded over the 10‑year period. Dementia and Alzheimer's disease accounted for nearly all deaths (99.98%) as the recorded underlying (primary) cause of death on death certificates, predominantly among females (67.5%) and individuals aged ≥80 years (89.9%). Mortality increased from 2014 (7.7%) to 2018 (11.1%), declined in 2021 (9.2%) during the COVID‑19 pandemic, and rebounded in 2022 (10.5%) and 2023 (10.7%). Conclusion: Dementia‑related mortality in England and Wales remains high and predominantly affects older women. Targeted prevention, improved care pathways, and continued monitoring of post‑pandemic trends are recommended.},
}

@article {pmid41189817,
year = {2025},
author = {Aygun, N},
title = {Analytical Review on Normal Brain Aging, Alzheimer's Disease, and Stage 4S Neuroblastoma: Novel Insights Into Neuroprotection, Neurodegeneration, and Spontaneous Regression.},
journal = {Cureus},
volume = {17},
number = {10},
pages = {e93818},
pmid = {41189817},
issn = {2168-8184},
abstract = {The normal aging brain does not show massive neuron loss. However, neurodegenerative diseases are characterized by the progressive loss of neurons that differentiate from neuroblasts arising in the neural tube. Oxidative stress induces protein misfolding and aggregation that generates endoplasmic reticulum (ER) stress, leading to the activation of the unfolded protein response (UPR). Oxidative stress can also impair autophagy and mitophagy. Prolonged ER stress and impaired autophagy or mitophagy together can promote neuronal death. Neuroblastoma is an embryonal tumor developing from sympathetic neuroblasts. Stage 4S neuroblastoma is frequently associated with spontaneous regression. Autophagy decreases in stage 4S neuroblastoma, whereas apoptosis increases. The present review focuses on the molecular and cellular fundamentals of normal brain aging, neurodegenerative diseases, and neuroblastoma with spontaneous regression. Differential gene expressions and associated potential mechanisms of the normal aging brain, Alzheimer's disease (AD) brain, and stage 4S neuroblastoma are investigated by analyzing the Gene Expression Omnibus (GEO) datasets and publications. In conclusion, there are gender- and region-specific differential expressions and connected differential molecular mechanisms in the normal aging brain and AD brain. PRH1 and MIR181A1HG are likely to play neuroprotective roles in certain brain regions of elderly females. The loss of myelinating oligodendrocytes in the entorhinal cortex (EC) and repressed adult hippocampal neurogenesis can contribute to cognitive impairment in AD. Neurodegeneration of mature neurons and spontaneous regression of immature sympathetic neuroblast-derived neuroblastomas may occur via similar cellular behavior of mature and immature nerve cells. Impaired autophagy and apoptosis can play crucial roles in both synaptic dysfunction and neuron death in AD and the spontaneous regression of stage 4S neuroblastoma. Finally, the present analytical review provides novel insights into apoptosis, neuronal differentiation, immune response, impaired autophagy, and impaired double-strand break (DSB) repair, considered potential mechanisms underlying spontaneous regression in stage 4S neuroblastoma.},
}

@article {pmid41189812,
year = {2025},
author = {Oishi, Y and Kitatani, M and Nakajima, K and Ogi, H and Kusakabe, K},
title = {Computational study of conformational interconversion of an amyloid β double layer system.},
journal = {RSC advances},
volume = {15},
number = {50},
pages = {42395-42401},
pmid = {41189812},
issn = {2046-2069},
abstract = {The formation of amyloid fibrils comprising amyloid β (Aβ) peptides is associated with the pathology of Alzheimer's disease. In this study, we theoretically investigated conformational changes of a flat double-layer structure of two Aβ[20-34] peptides using the density functional theory calculation. Several twisted conformations were identified as local energy minima in which a part of the peptide chain bends upward while the rest remains bound to the lower Aβ[20-34] monomer. Flat-to-twisted conformational transition exhibited endothermic behavior, with endothermic energy increasing as more backbone hydrogen bonds were broken. In addition, the loss of van der Waals interaction from the hydrophobic sidechain contributed to endothermicity. The nudged elastic band method was applied to analyze the potential energy surface connecting the flat and twisted conformations. Comparison of the activation barriers between different twisted conformations revealed that certain twisted conformations returned relatively easily to the flat conformation, whereas others encountered a higher activation barrier and reverted less readily. Detailed structural analysis revealed that the twisted conformation's propensity to return originates from the local steric hindrance imposed by the sidechain near the torsional axis.},
}

@article {pmid41189798,
year = {2025},
author = {Sudevan, ST and Oh, JM and Prabhakaran, P and Abdelgawad, MA and Ghoneim, MM and Al-Serwi, RH and Kim, H and Mathew, B},
title = {Inhibition of monoamine oxidase by fluorobenzyloxy chalcone derivatives.},
journal = {RSC advances},
volume = {15},
number = {50},
pages = {42376-42394},
pmid = {41189798},
issn = {2046-2069},
abstract = {Inhibition of monoamine oxidase-B (MAO-B) decelerates the breakdown of dopamine in the brain, consequently augmenting dopaminergic neurotransmission, which is a critical pathway for ameliorating motor symptomatology of Parkinson's disease (PD). Chalcones are widely recognized as the lead inhibitors of MAO-B and hold significant therapeutic value for PD. Inspired by safinamide's pharmacophoric features, the study focuses on designing, synthesizing, and evaluating a novel series of fluorinated benzyloxy chalcone derivatives as selective MAO-B inhibitors. Thirteen fluorobenzyloxy chalcone derivatives were synthesized and evaluated for their inhibition of monoamine oxidase (MAO). All compounds showed better inhibition of MAO-B than of MAO-A. Compound (E)1-(4-bromophenyl)-3-(2-((3-fluorobenzyl)oxy)phenyl)prop-2-en-1-one (FBZ13) most potently inhibited MAO-B with an IC50 value of 0.0053 μM, followed by (E)3-(2-((3-fluorobenzyl)oxy)phenyl)-1-(thiophen-2-yl)prop-2-en-1-one (FBZ6) (IC50 = 0.023 μM). The IC50 value of FBZ13 was 4.0 times lower than that of reference drug safinamide. All compounds showed weak MAO-A inhibition, FBZ13 and FBZ6 displayed exceptionally high selectivity for MAO-B. Kinetic studies confirmed that these two compounds function as competitive and reversible MAO-B inhibitors. Additionally, PAMPA results indicated excellent membrane permeability and CNS bioavailability for FBZ13 and FBZ6, highlighting their promise as central nervous system-active agents. In vitro antioxidant assays evaluated the activities of enzymes (SOD, CAT, GSH, and GPx) in human neuroblastoma cells exposed to lipopolysaccharide (LPS). Treatment with compounds FBZ6 and FBZ13 (10 μM each) significantly enhanced enzyme activities, mitigating LPS-induced oxidative stress. Lead compounds were stabilized in protein-ligand complexes by the π-π stacking, which enabled them to bind to the active site of hMAO-B effectively. These results suggest that FBZ6 and FBZ13 are potent reversible selective MAO-B inhibitors, and they can be used as potential agents for the treatment of neurological disorders such as Alzheimer's diseases and PD.},
}

@article {pmid41189746,
year = {2025},
author = {Cisternas, P and Kim, J and Ashfeld, B and Zartman, J},
title = {DYRK1A in the physiology and pathology of the neuron-astrocyte axis.},
journal = {Frontiers in neuroscience},
volume = {19},
number = {},
pages = {1626062},
pmid = {41189746},
issn = {1662-4548},
abstract = {Dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) is a dosage-sensitive kinase with critical roles in the neuron-astrocyte axis. During brain development, DYRK1A ensures the proper number of differentiated neurons and astrocytes. In neurons, this DYRK1A regulates neuronal morphogenesis and synaptic transmission. However, its functions in astrocytes are not yet well defined, with limited evidence indicating roles in astrocyte reactivity and excitotoxicity. Due to trisomy 21, DYRK1A is overexpressed in individuals with Down syndrome (DS). This imbalance directly contributes to neuronal death and likely astrocyte pathology, accelerating the onset of Alzheimer's disease (AD) in this population. Notably, DYRK1A overexpression also correlates with neurodegeneration and AD progression in elderly euploid adults. This correlation positions DYRK1A as a potential bridge between DS and AD, mechanistically connecting gene overdosage and neuropathology in both conditions. However, research on DYRK1A pathophysiology has primarily centered on neurons, leaving astrocytes largely understudied. Considering the vital neuroprotective functions of astrocytes, broadening DYRK1A research to encompass these cells presents an opportunity to uncover novel mechanisms contributing to the neurodegenerative process in AD. In this review, we highlight the physiology and pathology of DYRK1A in the neuron-astrocyte axis, analyzing its roles in neurons and positing hypothetical functions in astrocytes, with particular emphasis on the contribution of DYRK1A's cell-specific overexpression to neurodegeneration and AD progression.},
}