@article {pmid41201943,
year = {2025},
author = {Yan, J and Ying, S and Du, S and Gao, Y},
title = {Graph Quality Matters on Revealing the Semantics behind the Data in Physical World.},
journal = {IEEE transactions on pattern analysis and machine intelligence},
volume = {PP},
number = {},
pages = {},
doi = {10.1109/TPAMI.2025.3630605},
pmid = {41201943},
issn = {1939-3539},
abstract = {The physical world is composed of graphs, such as the protein structures in life science, the patient relations in medical diagnosis, the user connections in social media, etc. Graphs help both build the world itself and understand the semantics behind the data for humans. However, how such graph structures work toward semantic representation is still unclear, where existing attempts focus on employing the graphs for special tasks. In this work, we first introduce two measures to evaluate graph quality, namely structural complexity and homophily. Structural complexity describes the quantity of graph structural information representing the graph structure's symmetry, and homophily describes the percentage of intra-class edges to quantify edge consistency. Using these two measures, we then discover the relationship between the graph quality and the corresponding performance for general tasks, that is the performance positively correlates with the structural complexity, and "J"-shaped correlates with homophily, which are proved mathematically. Based on these, we design a graph augmentation tool Graph+. Graph+ can enhance the natural graph structure and accordingly improve the general tasks. Empirical validation on tasks including Alzheimer's diagnosis and breast cancer subtype identification shows Graph+'s ability to improve both graph structure and task performance, revealing the underlying data semantics.},
}

@article {pmid41201919,
year = {2025},
author = {Serna Orozco, MF and Reinosa Rivera, H and Jaramillo-Losada, J and Payan-Salcedo, HA and Escudero, MM},
title = {Association of the Timed Up and Go Test With Alzheimer's Disease: Systematic Review and Meta-Analysis.},
journal = {Journal of applied gerontology : the official journal of the Southern Gerontological Society},
volume = {},
number = {},
pages = {7334648251394486},
doi = {10.1177/07334648251394486},
pmid = {41201919},
issn = {1552-4523},
abstract = {PurposeTo evaluate and estimate the association between Time and Go (TUG) test performance and mild cognitive impairment (MCI) or Alzheimer's disease (AD) in older adults.MethodsA systematic review and meta-analysis were conducted to synthesize data from studies examining the relationship between TUG test score and AD or MCI in adult subjects. The search strategy was applied to MEDLINE (OVID), Web of Science, Scopus, LILACS, and the Cochrane Central Register of Controlled Trials (CENTRAL). Studies were selected based on predefined inclusion criteria. For meta-analysis, effect sizes were pooled using a random-effects model to account for heterogeneity across studies. Heterogeneity was assessed using the I[2] statistic, and publication bias was evaluated through funnel plot analysis. Sensitivity analyses were performed to test the robustness of the findings.ResultsA total of 25 studies were included in this review, of which 15 were incorporated into the meta-analysis. Participants with AD (4.22 [95% CI 2.76-5.69 s], p < 0.00001) and those with MCI (1.83 [95% CI 1.03-2.57 s], p < 0.00001) exhibited significantly longer times in the simple TUG test compared to healthy controls. The Dual-Task TUG test showed a stronger association with AD in the studies included in the analysis. AD participants demonstrated significantly longer test times (12.28 [95% CI 6.56-18.0 s], p < 0.0001) compared to cognitively normal controls.ConclusionsThis review highlights a potential association between TUG completion time and cognitive impairment in individuals with AD and MCI. The TUG test shows promise as a tool for the early identification and screening of cognitive decline and AD.},
}

@article {pmid41201693,
year = {2025},
author = {Parithathvi, A and Harshitha, P and Mumbrekar, KD and Dsouza, HS},
title = {Systematic Review on Neurotoxic Implications of Lead-Induced Gene Expression Alterations in the Etiology of Alzheimer's Disease.},
journal = {Cellular and molecular neurobiology},
volume = {45},
number = {1},
pages = {98},
pmid = {41201693},
issn = {1573-6830},
mesh = {*Alzheimer Disease/genetics/chemically induced/pathology/etiology ; Humans ; *Lead/toxicity ; Animals ; *Gene Expression Regulation/drug effects ; Amyloid beta-Peptides/metabolism ; },
abstract = {Lead (Pb) is a hazardous heavy metal frequently used because it is readily available and inexpensive. Due to contaminated soil, dust, and items like paints and batteries, lead exposure is still an issue of concern in many nations. There is no known safe threshold of exposure, and it can have serious adverse effects on human health. Exposure to lead has been linked to detrimental effects on the developing nervous system of both children and adults. Alzheimer's disease (AD) is the most prevalent type of dementia affecting adults over the age of 65, resulting in a decrease in memory and thinking skills. In this review, we describe the role of lead in exacerbating the build-up of hyperphosphorylated tau proteins and formation of amyloid-β (Aβ) plaques, major neurotoxicants which can impair neuronal function leading to AD. We highlight the effect of developmental and lifelong lead exposure on various gene expression changes resulting in the formation of the neurotoxicants responsible to AD. Understanding the mechanisms related to Aβ plaques and neurofibrillary tangles (NFTs) formation serves as a novel approach to identify biomarkers for lead-induced AD and developing therapeutic interventions. Lead exposure has been related to adverse effects on the developing neurological systems of both adults and children.},
}

*Alzheimer Disease/genetics/chemically induced/pathology/etiology
Humans
*Lead/toxicity
Animals
*Gene Expression Regulation/drug effects
Amyloid beta-Peptides/metabolism

@article {pmid41201687,
year = {2025},
author = {Hazra, A and Hoda, M and Jethwa, M and Saha, A and Das, S},
title = {Metabolomic Based Insight Reveals a few Metabolites at Various Germination Stages of Black Rice, Demonstrating Potential Efficacy Against Dementia and Other Neurodegenerative Conditions.},
journal = {Applied biochemistry and biotechnology},
volume = {},
number = {},
pages = {},
pmid = {41201687},
issn = {1559-0291},
support = {Jagadish Chandra Bose Research Fellowship Award under Research Fellowship Award (RFA) (Sanction No. & Date: 230/STBT-12014/22/2021WBSCST SEC Dept. of STBT; 26.04.2022)//Department of Science and Technology, Government of West Bengal/ ; },
abstract = {Dementia is a brain disorder that impairs the cognitive abilities like memory, thinking, reasoning, and judgement, thereby restricts an individual's capacity to carry out daily activities. Alzheimer's disease (AD) is a prominent example of one such condition, representing approximately 60-70% of dementia cases and is characterized as an irreversible multifaceted neurodegenerative disorder. The enzyme Acetylcholinesterase (AChE) is a significant contributor to dementia and other neurodegenerative disorder, where this enzyme hydrolyses acetylcholine, a crucial neurotransmitter, thereby disrupting neurotransmission. AChE inhibitors (AChEi) can help delay or mitigate this degradation process. Black rice (purple rice, forbidden rice), a glutinous pigmented rice variety rich in bioavailable phytonutrients like phenols, has shown the potential in alleviating several biological disorders. It has also been reported to possess anti-Alzheimer's properties. This study aims to investigate the metabolomic changes in an indigenous variety of black rice throughout its different germination stages, as well as the impact of metabolite dynamics on the inhibition of acetylcholinesterase. The germination stages exhibited significant variation in terms of their metabolomic constituents. The G2 stage showed the highest AChE inhibition potential among the germination stages, with an IC50 value of 0.217 ± 0.009 mg mL[- 1]. Among the compounds identified in the black rice extract, benzene-1,2,4-triol, pyrogallol, hydroquinone, and phloroglucinol* (reported for the first time) exhibited superior activity than the standard drug galantamine. Furthermore, the combination of these authentic compounds with the standard drug (galantamine) showed promising results in reducing the complications associated with the synthetic drug in both in vitro and in silico studies.},
}

@article {pmid41201670,
year = {2025},
author = {Qi, S and Wang, S and Tan, Y and Pan, C and Bi, X},
title = {Extracellular Matrix (ECM)-Regulated Molecular Switches: Tissue Inhibitors of Metalloproteinases in Synaptic Formation and Neuropathic Diseases.},
journal = {Cellular and molecular neurobiology},
volume = {45},
number = {1},
pages = {100},
pmid = {41201670},
issn = {1573-6830},
support = {32200636//National Natural Science Foundation of China/ ; KM202310025028//R&D Program of Beijing Municipal Education Commission/ ; },
mesh = {Humans ; *Extracellular Matrix/metabolism ; Animals ; *Synapses/metabolism ; *Tissue Inhibitor of Metalloproteinases/metabolism ; *Matrix Metalloproteinases/metabolism ; *Nervous System Diseases/metabolism ; Neuronal Plasticity/physiology ; },
abstract = {Synaptic formation, the cornerstone of neurological function, underpins complex behaviors and cognitive processes, with structural/functional aberrations implicated in neurodevelopmental disorders and neurodegenerative pathologies. Synaptogenesis involves dynamic interplay between cell adhesion molecules (CAMs) and extracellular matrix (ECM) components, which collectively regulate neuronal connectivity and plasticity. Matrix metalloproteinases (MMPs) and their endogenous inhibitors, tissue inhibitors of metalloproteinases (TIMPs), emerge as critical regulators of these processes through ECM remodeling and modulation of cell surface receptor signaling. This review synthesizes current understanding of ECM-TIMP-MMP axes in synaptic development, highlighting their dual roles in physiological plasticity and pathological disruption across neurodegenerative diseases (e.g., Alzheimer's disease, Parkinson's disease), neuro-oncological disorders, and neuroinflammatory conditions. By dissecting the context-dependent functions and therapeutic implications of TIMP family members in synaptic maintenance and disease progression, this work provides a conceptual framework for advancing TIMP-based neurotherapeutic strategies and a theoretical basis for future exploration of TIMP as a potential therapeutic target for neurological disorders.},
}

Humans
*Extracellular Matrix/metabolism
Animals
*Synapses/metabolism
*Tissue Inhibitor of Metalloproteinases/metabolism
*Matrix Metalloproteinases/metabolism
*Nervous System Diseases/metabolism
Neuronal Plasticity/physiology

@article {pmid41201576,
year = {2025},
author = {Zhao, B and Zhou, S and Wei, T and Xu, J and Geng, C and Wang, Z and Tang, Y},
title = {Lost in Space and Thought: Navigating the Cognitive Map in Alzheimer's Disease.},
journal = {Neuroscience bulletin},
volume = {},
number = {},
pages = {},
pmid = {41201576},
issn = {1995-8218},
abstract = {Spatial navigation is one of the brain's most fundamental abilities, enabling us to move through the world with ease. The seemingly effortless act of navigation depends on complex cognitive functions, with the cognitive map playing a central role. In individuals with Alzheimer's disease (AD) and mild cognitive impairment (MCI), however, this once intuitive ability becomes disoriented and impaired before the emergence of noticeable memory symptoms. AD pathology disrupts structural and functional disabilities in the brain's navigation system, resulting in cognitive map-based navigational difficulties. These deficits affect not only physical navigation but also extend into abstract, knowledge-based domains. In this review, we explore the role of cognitive map dysfunction in the navigation impairments seen in AD, synthesizing current evidence from studies of both spatial and non-spatial deficits. These insights may deepen our knowledge of how the brain navigates and also offer promising avenues for predictive biomarkers and targeted interventions.},
}

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

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

@article {pmid41201520,
year = {2025},
author = {Lv, H and Mao, N and Liu, A and Zhao, X and Zhu, B},
title = {Puerarin Alleviates High-fat High-sugar Diet-induced Alzheimer's Disease-like Pathology and Insulin Resistance in Mice by Inhibiting p35/CDK5-mediated Mitochondrial Fission.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {9},
pmid = {41201520},
issn = {1559-1182},
mesh = {Animals ; *Isoflavones/pharmacology/therapeutic use ; *Cyclin-Dependent Kinase 5/metabolism ; *Insulin Resistance/physiology ; *Alzheimer Disease/drug therapy/pathology/metabolism ; *Diet, High-Fat/adverse effects ; Humans ; Male ; *Mitochondrial Dynamics/drug effects ; Cell Line, Tumor ; Mice ; Mice, Inbred C57BL ; Amyloid beta-Peptides/metabolism ; Signal Transduction/drug effects ; Mitochondria/drug effects/metabolism ; Glucose ; },
abstract = {Puerarin has demonstrated protective effects against Alzheimer's disease (AD) and diabetes. This study aimed to explore the therapeutic potential and mechanistic basis of puerarin against high-fat high-sugar (HFHS) diet-induced AD-like pathology and insulin resistance, with a specific focus on p35/cyclin-dependent kinase 5 (CDK5) signaling. SH-SY5Y cells were cultured under high glucose (HG) conditions to induce AD-like pathology, and mice were fed with an HFHS diet to establish an AD model. Both models were treated with various concentrations of puerarin. The expression and activity of p35/CDK5 were examined by Western blot and kinase assays. Rescue experiments were conducted by transfecting SH-SY5Y cells with p35 overexpression plasmids. The protein levels of amyloid-beta (Aβ)42, amyloid precursor protein (APP), and phosphorylated-Tau were assessed by immunofluorescence. The protein levels in the insulin signal-related signaling pathway were examined. Mitochondrial dysfunction mediated by CDK5/dynamin-related protein 1 (DRP1) was determined. Additionally, cognitive function in mice was evaluated using behavioral tests, including the open field test, novel object recognition test, and Morris water maze. Insulin resistance in mice was assessed using biochemical assays. Puerarin inhibited HG-induced p35/CDK5 activation in SH-SY5Y cells. It also decreased the HG-induced upregulation of Aβ42, APP, and p-Tau in SH-SY5Y cells. Moreover, puerarin ameliorated HG-induced insulin resistance and mitochondrial dysfunction in SH-SY5Y cells, as evidenced by improved insulin signaling and restored mitochondrial ultrastructure. However, p35 overexpression abrogated these protective effects. In vivo, puerarin alleviated HFHS diet-induced cognitive impairment, Aβ deposition, and Tau phosphorylation in mice. Furthermore, puerarin ameliorated HFHS diet-induced insulin resistance and mitochondrial dysfunction in mice. Puerarin ameliorated HFHS diet-induced cognitive impairment, insulin resistance, and mitochondrial dysfunction by inhibiting p35/CDK5 activity. Our findings highlight the therapeutic potential of puerarin in the management of diet-induced AD.},
}

Animals
*Isoflavones/pharmacology/therapeutic use
*Cyclin-Dependent Kinase 5/metabolism
*Insulin Resistance/physiology
*Alzheimer Disease/drug therapy/pathology/metabolism
*Diet, High-Fat/adverse effects
Humans
Male
*Mitochondrial Dynamics/drug effects
Cell Line, Tumor
Mice
Mice, Inbred C57BL
Amyloid beta-Peptides/metabolism
Signal Transduction/drug effects
Mitochondria/drug effects/metabolism
Glucose

@article {pmid41201456,
year = {2025},
author = {Francia, M and Ramesh, N and Boltz, T and Bot, M and van der Flier, WM and Visser, PJ and van der Lee, S and Teunissen, CE and Pijnenburg, YA and den Braber, A and Olde Loohuis, L and Reus, LM and Tijms, BM and Ophoff, RA},
title = {Integrative analysis of cerebrospinal fluid biomarkers, metabolomics, and polygenic risk reveals novel metabolite associations with Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251389924},
doi = {10.1177/13872877251389924},
pmid = {41201456},
issn = {1875-8908},
abstract = {BackgroundCerebrospinal fluid (CSF) metabolomics offers an opportunity to investigate in vivo biological pathways impacted in the human brain by Alzheimer's disease (AD). While impairments in brain glucose metabolism and lipid homeostasis are implicated in AD, the underlying metabolic pathways remain unclear. Genotype information can also be leveraged to study associations between CSF metabolites and AD genetic risk.ObjectiveTo evaluate how CSF metabolomic profiles and genetic risk are associated with AD pathology as reflected by established CSF biomarkers (Aβ, P-Tau, and T-Tau).MethodsWe collected CSF mass spectrometry measurements of 678 metabolites and 4865 unnamed compounds, as well as genome-wide genotype data from 487 individuals in the Amsterdam Dementia cohort. Polygenic risk scores (PRS) for AD were calculated. Elastic net regression models were used to predict AD biomarker levels with CSF metabolites, and pathway enrichment analysis was performed to assess the metabolic pathways involved.Results98 CSF metabolites were found to be significantly correlated with P-Tau or T-Tau, but none with Aβ CSF levels. Elastic net regression models identified 42 and 34 metabolites predicting P-Tau and T-Tau, respectively, including novel associations with Anserine and Fucose. Pathway enrichment analysis implicated Pentose and Glucuronate Interconversions, Glycerophospholipid Metabolism, and ABC Transporters in AD pathology. PRS analysis highlighted four CSF phosphatidylcholines significantly associated with AD genetic risk.ConclusionsCSF metabolites demonstrate a lack of Aβ levels associations, contrasting with multiple significant findings for P-Tau and T-Tau. Novel associations with Anserine and Fucose may provide new insights into metabolic pathways impacted by AD pathology.},
}

@article {pmid41201240,
year = {2025},
author = {Lee, CY and Shi, H and Ma, D and Beg, MF and Cao, J},
title = {Identification of Regions of Interest in Neuroimaging Data With Irregular Boundary Based on Semiparametric Transformation Models and Interval-Censored Outcomes.},
journal = {Statistics in medicine},
volume = {44},
number = {25-27},
pages = {e70309},
doi = {10.1002/sim.70309},
pmid = {41201240},
issn = {1097-0258},
support = {RGPIN-2023-04057//Natural Sciences and Engineering Research Council of Canada/ ; RGPIN-2021-02963//Natural Sciences and Engineering Research Council of Canada/ ; },
mesh = {Humans ; Alzheimer Disease/diagnostic imaging ; *Neuroimaging/methods/statistics & numerical data ; Computer Simulation ; *Models, Statistical ; Algorithms ; Disease Progression ; Likelihood Functions ; Brain/diagnostic imaging/pathology ; Magnetic Resonance Imaging ; Prognosis ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder that leads to memory loss, cognitive decline, and behavioral changes, without a known cure. Neuroimages are often collected alongside the covariates at baseline to forecast the prognosis of the patients. Identifying regions of interest within the neuroimages associated with disease progression is thus of significant clinical importance. One major complication in such analysis is that the domain of the brain area in neuroimages is irregular. Another complication is that the time to AD is interval-censored, as the event can only be observed between two revisit time points. To address these complications, we propose to model the imaging predictors via bivariate splines over triangulation and incorporate the imaging predictors in a flexible class of semiparametric transformation models. The regions of interest can then be identified by maximizing a penalized likelihood. A computationally efficient expectation-maximization algorithm is devised for parameter estimation. An extensive simulation study is conducted to evaluate the finite-sample performance of the proposed method. An illustration with the AD Neuroimaging Initiative dataset is provided.},
}

Humans
Alzheimer Disease/diagnostic imaging
*Neuroimaging/methods/statistics & numerical data
Computer Simulation
*Models, Statistical
Algorithms
Disease Progression
Likelihood Functions
Brain/diagnostic imaging/pathology
Magnetic Resonance Imaging
Prognosis

@article {pmid41201155,
year = {2025},
author = {Afxenti, S and Bourdakou, MM and Loizidou, EM and Zachariou, M and Lambrianides, A and Pantzaris, M and Spyrou, GM},
title = {Integrative analysis of proteomic and mri data reveals protein associations with brain imaging features in Alzheimer's disease.},
journal = {Expert review of proteomics},
volume = {},
number = {},
pages = {},
doi = {10.1080/14789450.2025.2584129},
pmid = {41201155},
issn = {1744-8387},
abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the leading cause of dementia worldwide. Despite extensive research, the complex molecular mechanisms underlying AD remain incompletely understood, limiting diagnostic and therapeutic advancements.

RESEARCH DESIGN AND METHODS: We presented an integrative, multi-layer computational framework to highlight proteins associated with AD-related brain changes using imaging, proteomic, genetic and network-based analyses. Utilizing data from the Alzheimer's Disease Neuroimaging Initiative (ADNI), we combined cerebrospinal fluid (CSF) proteomics with structural brain MRI features through a supervised multi-omics integration method.

RESULTS: This approach enabled the identification of key proteins linked to imaging traits. To contextualize these findings, proteins were mapped to their corresponding genes, investigated AD brain-imaging genetic associations through genome-wide association studies (GWAS) and applied network-based analyses. Proteins highlighted from both analyses were further verified in brain-specific databases to assess their functional roles, recurrence across studies, and spatial expression. Five proteins -APP, VGF, APOE, SCG3, and NCAN- were consistently associated with imaging-derived traits and are implicated in neurodegenerative mechanisms.

CONCLUSIONS: This study highlights the critical role of integrating imaging and proteomic data as part of the genotype-to-phenotype roadmap for AD, revealing molecular underpinnings of brain changes and offering a blueprint for the development of targeted therapeutic strategies.},
}

@article {pmid41201135,
year = {2025},
author = {Gai, K and Song, Y and Gao, D and Nie, Q and Luo, X and Xu, C and Cai, C and Smith, A and Li, X and Shi, W and Zhang, L and Sun, W and Lin, F},
title = {Advanced Stem Cell Therapy: 3D-Bioprinted Brain-Like Transplants for Alzheimer's Disease-Like Dementia.},
journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
volume = {},
number = {},
pages = {e10062},
doi = {10.1002/advs.202510062},
pmid = {41201135},
issn = {2198-3844},
support = {SQ2024YFB4600188//National Key Research and Development Program of China/ ; 52375295//National Natural Science Foundation of China/ ; },
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder that lacks effective treatments and urgently requires innovative therapeutic strategies. Although stem cell therapy has demonstrated efficacy in preclinical and clinical studies, it faces challenges such as low cell survival (<5%) and uncontrolled glial differentiation. This study aims to develop a 3D-bioprinted neural patch to enhance stem cell therapy for AD. The hypothesis is that a supportive bioengineered microenvironment would improve cell integration and neuronal differentiation, leading to functional recovery. A tri-component bioink (gelatin/alginate/fibrinogen) is created with tunable printability, biocompatibility, and biodegradation, establishing functional transplantation microenvironments for a 3D-printed human induced pluripotent stem cell (hiPSC)-derived neural progenitor cell (NPC) construct as a hippocampal patch. The system (TTBT) maintains NPC survival and promotes neuronal differentiation, neurite development, and calcium signaling in vitro. In AD-like rats, these constructs improved cell retention (3.41-fold over suspensions), enhanced neuron (79.21 ± 6.67% vs 65.08 ± 7.14%) and GABAergic neuron (29.85 ± 7.69% vs 15.93 ± 10.33%) differentiation, and restored long-term potentiation (LTP) to 97.89% ± 19.84% of healthy control levels. Behavioral tests also show memory improvement, particularly in the Morris water maze. This 3D-printed therapy not only holds potential for enhancing stem cell treatments but also addresses other 3D brain defects.},
}

@article {pmid41201009,
year = {2025},
author = {Chong Chie, JAK and Persohn, SA and Pandey, RS and Carter, GW and Simcox, OR and Salama, P and Territo, PR and , },
title = {Neurometabolic and vascular dysfunction as an early diagnostic for Alzheimer's disease and related dementias.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {11},
pages = {e70790},
doi = {10.1002/alz.70790},
pmid = {41201009},
issn = {1552-5279},
support = {//Initiative ADNI/ ; U01 AG024904/NH/NIH HHS/United States ; W81XWH-12-2-0012/NH/NIH HHS/United States ; T32AG071444/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *Alzheimer Disease/diagnosis/metabolism/diagnostic imaging ; Male ; Female ; Aged ; Retrospective Studies ; Early Diagnosis ; Disease Progression ; *Brain/metabolism/diagnostic imaging ; Biomarkers/metabolism ; Aged, 80 and over ; Neuroimaging ; },
abstract = {INTRODUCTION: Recent studies suggest that the brain undergoes anatomical and functional restructuring, resulting in neurometabolic and vascular dysregulation (MVD) prior to amyloid beta accumulation, which begins at an early age and leads to the onset of Alzheimer's disease (AD).

METHODS: Using a retrospective clinical population (n = 403) from the Alzheimer's Disease Neuroimaging Initiative, cerebral perfusion and metabolism changes across 59 brain regions were evaluated from clinical studies. Results were verified by transcriptomic signatures and clinical cognitive assessments.

RESULTS: Our findings suggest that disease progression follows a stage-dependent MVD pattern that can identify at-risk regions. Although each region progresses at a different pace, regions related to memory, cognition, and motor function showed significant early dysregulation. Importantly, these changes aligned with transcriptomic and cognitive signatures.

DISCUSSION: This study underscores that MVD in brain regions varies by sex and disease stage, making it a sensitive tool for early AD diagnosis. This approach could improve patient monitoring, stratification, and therapeutic testing.

HIGHLIGHTS: The potential of metabolic and vascular dysfunction as an early biomarker was assessed. An analytical method to assess dysregulation via imaging was developed. An analytical and graphical method to visualize the changes across disease spectrum was developed. Brain regions progress at different rates across Alzheimer's disease progression. Results were aligned with transcriptomics and cognitive signatures.},
}

Humans
*Alzheimer Disease/diagnosis/metabolism/diagnostic imaging
Male
Female
Aged
Retrospective Studies
Early Diagnosis
Disease Progression
*Brain/metabolism/diagnostic imaging
Biomarkers/metabolism
Aged, 80 and over
Neuroimaging

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

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

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

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

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

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

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

@article {pmid41200854,
year = {2025},
author = {Haque, SR and Ghosh, S and Banerjee, R and Maity, D},
title = {An Excited-State Intramolecular Proton Transfer Mechanism-Based Reactive Probe for Ratiometric Fluorescence Detection of Epinephrine in Live Cells.},
journal = {Chembiochem : a European journal of chemical biology},
volume = {},
number = {},
pages = {e202500631},
doi = {10.1002/cbic.202500631},
pmid = {41200854},
issn = {1439-7633},
support = {MLP0108//Council of Scientific and Industrial Research-Indian Institute of Chemical Technology/ ; SRG/2023/001243//Science and Engineering Research Board/ ; },
abstract = {Epinephrine (EPI), also known as adrenaline, is involved in various physiological processes of the sympathetic nervous system and may be linked to the progression of different serious diseases, including cancers, Alzheimer's, and Parkinson's diseases etc. There is an urgency in developing a fluorescence probe for the detection of EPI. An excited-state intramolecular proton transfer mechanism (ESIPT)-based reactive probe HBT-EPI has been successfully developed for ratiometric fluorescent detection of EPI in physiological conditions. EPI undergoes a cascade of nucleophilic attack at the carbonothioate site of the probe using the secondary amine and β-hydroxyl group to release the ESIPT-active 2-(2'-hydroxyphenyl) benzothiazole (HBT) fluorophore. Thus, a ratiometric fluorescence response is obtained. The probe is highly selective for EPI detection compared to other catecholamine-based neurotransmitters. A minimum of 1 µM of EPI can be easily detected using this probe. HBT-EPI has been successfully demonstrated for ratiometric fluorescence detection of EPI in live cells via confocal imaging.},
}

@article {pmid41200797,
year = {2025},
author = {},
title = {Correction to "Age and sex are associated with Alzheimer's disease neuropathology in Down syndrome".},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {11},
pages = {e70914},
doi = {10.1002/alz.70914},
pmid = {41200797},
issn = {1552-5279},
}

@article {pmid41200794,
year = {2025},
author = {Udeh-Momoh, CT and Aliwa, B and Atwoli, L and Blackmon, K and Bosire, E and Gitau, S and Kaleli, H and Kamanda, C and Khakali, L and Maina, R and Mativo, P and Mbugua, S and Merali, Z and Muchungi, K and Njogu, N and Nyankira, D and Okech, V and Ondieki, A and Onyancha, C and Onyango, SO and Shah, J and Shah, S and Smith, C and Sokhi, D and Waa, S and Gregory, S and Hill-Jarrett, TG and Kafetsouli, D and Mielke, MM and Muniz-Terrera, G and Solomon, A and Thesen, T and Tsoy, E and Yasoda-Mohan, A and Yokoyama, JS and Watermeyer, TJ},
title = {Identifying sex- and gender-specific endocrinological, lifestyle, psychosocial, and socio-cultural targets for Alzheimer's disease prevention in Africans: The Female Brain Health and Endocrine Research in Africa (FemBER-Africa) project.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {11},
pages = {e70887},
doi = {10.1002/alz.70887},
pmid = {41200794},
issn = {1552-5279},
support = {SAGA23/ALZ/Alzheimer's Association/United States ; SAGA23-1141999/ALZ/Alzheimer's Association/United States ; },
mesh = {Humans ; *Alzheimer Disease/prevention & control ; Female ; *Life Style ; Male ; Brain/diagnostic imaging ; Biomarkers ; Risk Factors ; Africa ; Sex Factors ; Aged ; African People ; },
abstract = {Dementia rates are rising globally, with the burden increasing most rapidly in low- to middle-income countries. Despite this, research into Alzheimer's disease and related dementias (ADRD) among African populations remains limited, with existing models based on Western cohorts that overlook sex-, gender-, and ancestry-specific factors. The Female Brain Health and Endocrine Research in Africa (FemBER-Africa) project, hosted at the Brain and Mind Institute, Aga Khan University, Kenya, will establish a deeply phenotyped cohort of 250 African individuals across the ADRD spectrum. It will assess sex-specific risk factors linked to ethnicity, lifestyle, and endocrinological variables using fluid-based biomarkers (blood and saliva), neuroimaging (magnetic resonance imaging and positron emission tomography), and culturally adapted cognitive tests. By comparing data with Western and diasporic cohorts, the study aims to identify ancestry-specific and shared mechanisms driving ADRD risk and progression. The findings will support targeted, culturally relevant prevention and intervention strategies, addressing the underrepresentation of African populations in global dementia research. HIGHLIGHTS: By 2030, > 78 million individuals are expected to have dementia, with the highest burden among women in low- to middle-income countries. Despite this, African populations remain underrepresented in Alzheimer's disease and related dementias (ADRD) research. Existing ADRD risk models fail to account for the unique influence of sex, gender, and ancestry on dementia risk. Female-specific reproductive and hormonal factors, including menopause transition and hormone therapy use, are poorly integrated into current models. The Female Brain Health and Endocrine Research in Africa (FemBER-Africa) project is the first large-scale study to examine sex- or gender-specific and endocrine contributors to ADRD in an African population, using advanced diagnostic, biomarker, and culturally adapted cognitive assessments. The study will assess how biological (hormonal, metabolic), lifestyle (physical activity, diet), and socio-cultural (education, health-care access) factors interact to influence ADRD risk in African women. Insights from FemBER-Africa will inform the development of sex- and gender-specific, culturally adapted ADRD prevention strategies, enhancing the precision and equity of dementia mitigation efforts globally.},
}

Humans
*Alzheimer Disease/prevention & control
Female
*Life Style
Male
Brain/diagnostic imaging
Biomarkers
Risk Factors
Africa
Sex Factors
Aged
African People

@article {pmid41200792,
year = {2025},
author = {Rosado, AM and Vizcarra, JC and Sharma, SRR and Keene, CD and White, CL and Kim, A and Forrest, SL and Kovacs, GG and Chuah, CN and Flanagan, ME and Pearce, TM and Dugger, BN and Gutman, DA},
title = {Digital neuropathology of neurodegenerative disorders: Foundations, research advances, and future directions.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {11},
pages = {e70775},
doi = {10.1002/alz.70775},
pmid = {41200792},
issn = {1552-5279},
support = {T32AG087922/NH/NIH HHS/United States ; K08AG065463/NH/NIH HHS/United States ; R21AG066012/NH/NIH HHS/United States ; R01AG062517/NH/NIH HHS/United States ; R01AG072080/NH/NIH HHS/United States ; R01AG059689/NH/NIH HHS/United States ; RF1AG072080/NH/NIH HHS/United States ; U24NS133949/NH/NIH HHS/United States ; U24NS133945/NH/NIH HHS/United States ; P30AG072972/NH/NIH HHS/United States ; P30AG066546/NH/NIH HHS/United States ; //Chan Zuckerberg Initiative DAF, an advise fund of Silicon Valley Community Foundation/ ; },
mesh = {Humans ; *Neurodegenerative Diseases/pathology ; *Neuropathology/methods/trends ; Machine Learning ; Alzheimer Disease/pathology ; *Image Processing, Computer-Assisted/methods ; },
abstract = {A neuropathology examination after death remains the gold standard for differentiating between Alzheimer disease (AD) and AD and related dementias (ADRD). Increasing interest and familiarity with digital imaging highlights recent shifts to modernize pathology workflows by leveraging technology that automates imaging and analysis. This review provides an overview of digital pathology technologies and their associated infrastructure, available open-source and proprietary digital pathology software, relevant background on neurodegenerative histopathological features, and computational research. It further examines recent developments in digital pathology in neurodegenerative disease research with an emphasis on machine learning. We discuss evidence supporting how recently developed technologies and methodologies can enhance our understanding of histopathologic features of neurodegeneration and correlations of histopathologic features with cognitive performance and age at death. Finally, we review potential directions for neurodegenerative disease digital pathology research given trends in technological infrastructure development and other digital pathology research. HIGHLIGHTS: Provides a historical summary of digital pathology with respect to neuropathology. Examines key digital pathology technologies. Explores digital pathology applications in neurodegenerative disease and their contribution to research. Discusses the future of digital neuropathology.},
}

Humans
*Neurodegenerative Diseases/pathology
*Neuropathology/methods/trends
Machine Learning
Alzheimer Disease/pathology
*Image Processing, Computer-Assisted/methods

@article {pmid41200791,
year = {2025},
author = {Sarwar, MR and Cross, AJ and Godbee, K and Geethadevi, GM and Magin, P and Tullipan, M and Baker, AL and Bonevski, B and Ward, SA and Mahal, A and Versace, V and Bell, JS and Mc Namara, K and O'Reilly, SL and Thomas, D and Manias, E and Anstey, KJ and Varnfield, M and Jayasena, R and Elliott, RA and Lee, CY and Hernan, A and van den Bosch, D and Ferreira, C and George, J},
title = {Identifying dementia risk profiles for targeted interventions: A latent class analysis of at-risk middle-aged Australians.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {11},
pages = {e70888},
doi = {10.1002/alz.70888},
pmid = {41200791},
issn = {1552-5279},
support = {GNT1171851//National Health and Medical Research Council/ ; },
mesh = {Humans ; Female ; Male ; Middle Aged ; Latent Class Analysis ; *Dementia/epidemiology/prevention & control ; Cross-Sectional Studies ; Australia/epidemiology ; Risk Factors ; Australasian People ; },
abstract = {INTRODUCTION: This study aimed to identify distinct dementia risk profiles in middle-aged adults with two or more potential dementia risk factors, to inform targeted prevention strategies.

METHODS: Cross-sectional analysis of baseline sociodemographic, clinical, and dementia-risk data from the HAPPI MIND trial. Dementia risk was assessed using the Australian National University Alzheimer's Disease Risk Index. Risk profiles were identified using latent class analysis (LCA).

RESULTS: Among 403 participants (mean age 56.4 ± 5.7 years, 62.5% female), the median number of dementia risk factors was 5.0; hyperlipidaemia (92.5%), low cognitive activity (72.5%), obesity (57.6%), and hypertension (52.7%) were the most prevalent. Several risk factors showed significant positive correlations. LCA identified three distinct classes: 1-High Cardiometabolic Burden; 2-High Behavioural and Psychosocial Risk; and 3-Low Risk with Healthy Behaviours.

DISCUSSION: The identified latent classes highlight heterogeneity of dementia risk profile in midlife. Tailored, multidomain interventions addressing each group's specific needs may improve dementia risk profiles and support broader health outcomes.

HIGHLIGHTS: Middle-aged Australians who participated in the HAPPI MIND dementia risk reduction trial had a median of five modifiable risk factors. Significant positive correlations were observed between behavioral and clinical risk factors, such as depression, along with poor diet, social isolation, and smoking. Latent class analysis revealed three distinct profiles: High Cardiometabolic Burden; High Behavioral and Psychosocial Risk; and Low Risk with Healthy Behaviors. The findings suggest there is a need for personalized, multidomain prevention strategies tailored to individual risk profiles in primary care.},
}

Humans
Female
Male
Middle Aged
Latent Class Analysis
*Dementia/epidemiology/prevention & control
Cross-Sectional Studies
Australia/epidemiology
Risk Factors
Australasian People

@article {pmid41200514,
year = {2025},
author = {Iyer, AK and Moutinho, M and Ayata, P and Karahan, H},
title = {Editorial: Myeloid cells as active players in human neurodegenerative diseases.},
journal = {Frontiers in neuroscience},
volume = {19},
number = {},
pages = {1712394},
pmid = {41200514},
issn = {1662-4548},
}

@article {pmid41200502,
year = {2025},
author = {Chiyanika, C and Chan, NY and Liu, W and Au, LWC and Chen, W and Liu, C and Chen, S and Leung, EYL and Ho, CL and Cai, Y and Ko, H and Chen, Q and Chu, W and Mok, VCT and Abrigo, J},
title = {Comparative analysis of PET and multiparametric MRI biomarkers in Alzheimer's disease continuum cohort.},
journal = {Journal of Alzheimer's disease reports},
volume = {9},
number = {},
pages = {25424823251394399},
pmid = {41200502},
issn = {2542-4823},
abstract = {BACKGROUND: Non-invasive biomarkers are key to early Alzheimer's disease (AD) detection. Multiparametric MRI and advanced imaging offer promising, accessible tools for identifying AD-related changes, supporting timely diagnosis and intervention.

OBJECTIVE: To assess how accurately multiparametric MRI biomarkers identify AD using Aβ-PET imaging as the reference, and to evaluate whether MRI metrics in AD-related brain regions can distinguish between Aβ-positive and Aβ-negative subjects across the AD continuum.

METHODS: In this exploratory retrospective study, 44 subjects aged 50-80 years were classified based on their PET and MRI biomarkers following the NIA-AA 2024 framework. MRI metrics included selected regional brain volumes (T1-weighted), mean diffusivity and fractional anisotropy (DTI-MD, DTI-FA), quantitative susceptibility mapping (QSM), and T1rho imaging. These were compared with amyloid load, and diagnostic performance was assessed using area-under-the-curve (AUC) analysis.

RESULTS: 25 subjects were Aβ+ (AD continuum), while 19 were Aβ- (controls). Volumes of the hippocampus, thalamus, amygdala, cingulate, putamen, and corpus callosum and DTI-MD in the hippocampus, corpus callosum, cuneus, and cingulate showed optimal diagnostic performance (AUC ≥ 0.80), with hippocampal volume and hippocampal DTI-MD showing AUCs > 0.90, (both p < 0.05). Combining hippocampal volumetry and hippocampal DTI-MD (AUC = 0.95, p < 0.001) improved diagnostic accuracy by 2.1% compared to using either biomarker alone. LASSO logistic regression analysis showed that amyloid positivity was significantly associated with hippocampal volume (p < 0.001).

CONCLUSIONS: Hippocampal volumetry and hippocampal DTI-MD may be superior and more sensitive imaging biomarkers for AD. Their combined use could improve diagnostic accuracy and enhance early AD detection.},
}

@article {pmid41200274,
year = {2025},
author = {Chowdhury, SR and Katari, V and Sen, D and Mondal, P},
title = {Editorial: Current chemical approaches in combating neuroinflammation in Alzheimer's disease (AD).},
journal = {Frontiers in aging neuroscience},
volume = {17},
number = {},
pages = {1712601},
pmid = {41200274},
issn = {1663-4365},
}

@article {pmid41200152,
year = {2025},
author = {Wang, W and Feng, Z and Shu, L and Hu, Y and Chen, Y and Zhang, B and Huang, H},
title = {Bridging prion biology and Alzheimer's disease: from pathogenic seeds to precision therapeutics.},
journal = {Frontiers in molecular neuroscience},
volume = {18},
number = {},
pages = {1660151},
pmid = {41200152},
issn = {1662-5099},
abstract = {Alzheimer's disease (AD) is characterized by the pathological aggregation of amyloid-beta (Aβ) and tau proteins, which display self-templating propagation reminiscent of the prion protein (PrP [Sc]). Despite these similarities, distinct structural heterogeneities and host interaction mechanisms offer unique avenues for disease-modifying therapies. This review comprehensively synthesizes recent advancements addressing: (1) the conformational commonalities and strain-specificities shared between Aβ/tau and PrP [Sc] ; (2) the spatiotemporal dissemination patterns of pathogenic seeds within neural networks; and (3) the development of biomarkers and therapeutic strategies rooted in prion theory. By integrating insights from prion biology with AD pathogenesis, we propose a comprehensive "conformation-propagation-microenvironment" framework for precision intervention, thereby offering a novel paradigm to surmount current therapeutic limitations.},
}

@article {pmid41200107,
year = {2025},
author = {Ghadami, S and Dellinger, K},
title = {Developing and optimizing a biocompatible tauopathy model using extracellular vesicle-mediated gene delivery.},
journal = {Frontiers in medicine},
volume = {12},
number = {},
pages = {1672046},
pmid = {41200107},
issn = {2296-858X},
abstract = {INTRODUCTION: Tauopathy models are essential in vitro systems for investigating tau-targeted therapies and advancing Alzheimer's disease research. Extracellular vesicles (EVs), owing to their high biocompatibility, low toxicity, and reduced immunogenicity, represent promising carriers for gene delivery and disease modeling.

METHODS: We investigated the potential of EVs as a delivery system for the human four-repeat tau isoform lacking N-terminal sequences (4R0N) and enhanced green fluorescent protein (EGFP) into Neuro-2a cells. EV-mediated transfection efficiency was compared with conventional methods, including lentiviral and chemical (lipofectamine and polyethyleneimine, PEI) approaches. Response surface methodology (RSM) was used to optimize EV-mediated delivery parameters.

RESULTS: EVs successfully delivered large plasmid DNA into Neuro-2a cells, resulting in detectable tau and EGFP expression. Optimization via RSM further improved gene delivery efficiency and reproducibility compared to unoptimized EV preparations and conventional transfection methods.

DISCUSSION: These findings demonstrate that EVs can serve as a robust and biocompatible platform for tau gene delivery, providing a promising alternative to traditional transfection strategies for generating physiologically relevant tauopathy models.},
}

@article {pmid41199994,
year = {2025},
author = {Rajamani, G and Naqvi, S and Sharma, A},
title = {Structure-activity relationship of GSK-3β inhibitors: insight into drug design for Alzheimer's disease.},
journal = {RSC medicinal chemistry},
volume = {},
number = {},
pages = {},
pmid = {41199994},
issn = {2632-8682},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder characterised by cognitive impairment, memory loss, and decline in thinking and learning skills. The exact pathophysiology of the disease is still unknown; however, theories such as tau hyperphosphorylation, amyloid-β (Aβ) aggregation, and cholinergic dysfunction explain its pathogenesis. A few available drugs provide only symptomatic relief, while recently approved monoclonal antibody-based drugs target aggregated amyloid beta clearance. Extensive research is ongoing for drug development targeting various pathways, where one of the targets is glycogen synthase kinase (GSK-3β). GSK-3β plays diverse roles in physiological functions, and its dysregulation may lead to pathological conditions such as Alzheimer's disease (AD). GSK-3β comprises serine and threonine residues, is responsible for phosphorylation of the tau protein, and activates the amyloid precursor protein (APP) to synthesise Aβ. Consequently, the abnormal functioning of GSK-3β leads to hyperphosphorylation of the tau protein, and the formation of Aβ plaques eventually leads to neurofibrillary tangles. To develop GSK-3β inhibitors, one must know the requirements of crucial structural features in drug candidates to act at the active site for interaction. This review focuses on the latest pool of GSK-3β inhibitors and their design strategy, structure-activity relationship (SAR), molecular docking, and permeability across the brain layers. This broad review collection may benefit readers by providing the structural requirements to develop new GSK-3β inhibitors for treating AD.},
}

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

@article {pmid41199715,
year = {2025},
author = {Ko, H and Mok, VCT and Shi, L and Abrigo, J and Lam, BYK and Lee, ATC},
title = {Magnetic resonance imaging-based machine learning to detect mild cognitive impairment associated with Alzheimer's disease: abridged secondary publication.},
journal = {Hong Kong medical journal = Xianggang yi xue za zhi},
volume = {31 Suppl 7},
number = {5},
pages = {22-24},
pmid = {41199715},
issn = {1024-2708},
}

@article {pmid41199607,
year = {2025},
author = {Bae, JS},
title = {Vaccine trends: a narrative review.},
journal = {Journal of Yeungnam medical science},
volume = {42},
number = {},
pages = {71},
doi = {10.12701/jyms.2025.42.71},
pmid = {41199607},
issn = {2799-8010},
abstract = {Vaccination has played a central role in the historical and modern fight against infectious diseases. This review explores the evolution of infectious disease perception from ancient humoral theories to the modern "One Health" framework, reflecting the integration of environmental, animal, and human health. Vaccines have not only reduced morbidity and mortality but have also provided profound economic and developmental benefits across societies. Climate change, antimicrobial resistance, and the rapid emergence of new infectious threats have prompted innovations in vaccine technologies, including messenger RNA, DNA, viral vector, and nanoparticle-based platforms. These advances support personalized vaccine strategies, such as vaccinomics, and extend their application to noncommunicable diseases, including cancer and Alzheimer disease. Despite their success, vaccines face challenges including global access disparities, waning immunity, pathogen evolution, and vaccine hesitancy. Nonetheless, vaccination remains a cornerstone of global health security, with strong returns on investment and crucial roles in socioeconomic stabilization during pandemics. Future vaccine strategies must integrate technological innovation with equitable access and public trust, for instance, through global initiatives like the Coalition for Epidemic Preparedness Innovations and the World Health Organization COVID-19 Vaccines Global Access, and the establishment of regional manufacturing hubs to effectively respond to unpredictable threats like "Disease X."},
}

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

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

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

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

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

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

@article {pmid41199342,
year = {2025},
author = {Liu, Y and Sobue, A and Sahara, N and Isobe, M and Tanaka, R and Zhu, Y and Zhu, W and Matsuzaki, T and Yamanaka, K and Yamada, K and Mizoguchi, H},
title = {Abnormal behaviors and glial responses in an animal model of tau pathology.},
journal = {Molecular brain},
volume = {18},
number = {1},
pages = {83},
pmid = {41199342},
issn = {1756-6606},
support = {JPMJSP2125//JST SPRING/ ; JP24wm0425014//AMED, Japan/ ; 22K19749; 23K27360; 23H02669 (2023)//Japan Society for the Promotion of Science (JSPS) KAKENHI, Japan/ ; },
mesh = {Animals ; *Neuroglia/pathology/metabolism ; Disease Models, Animal ; *Behavior, Animal ; *Tauopathies/pathology/genetics/physiopathology ; Mice, Transgenic ; *tau Proteins/metabolism ; Mice ; Humans ; Male ; Gene Expression Regulation ; },
abstract = {Tau hyperphosphorylation has been considered a major contributor to neurodegeneration in Alzheimer's disease (AD) and frontotemporal dementia, and related tauopathies have gained prominence in the development of therapies for these conditions. Glial responses are key features of AD and frontotemporal dementia, and are associated with neuroinflammation. Numerous transgenic mouse models that recapitulate critical AD-like pathology and cognitive impairment have been developed to examine pathogenic mechanisms and evaluate therapeutic approaches targeting tau and glial reactivity. Glial reactivity and neuroinflammation coincide with tau hyperphosphorylation, which induces behavioral impairment; however, the specific correlation between glial cell activation and abnormal behavior remains unknown. In this study, we investigated changes in glial cell gene expressions related to abnormal behaviors in rTg4510 mice, which phenocopy the tau pathology, neuroinflammation, and neurodegeneration observed in human tauopathies. Both 4- and 6-month-old rTg4510 mice displayed significantly impaired nest-building behavior compared with control mice. Paired association learning was also impaired in 4-month-old rTg4510 mice. Moreover, rTg4510 mice of both age groups exhibited abnormal exploratory behavior, and these mice spent a longer time in the open arms of the plus-maze test than control mice. Using a magnetic-activated cell-sorting technique, we analyzed glial cell gene expressions related to neuroinflammation, phagocytosis, and amyloid synthesis in the prefrontal cortex of rTg4510 mice. Regression analysis of glial gene expressions and behavioral tests revealed that various glial reactivities were associated with behavioral abnormalities. Our findings suggest specific genetic characteristics of glial cells that may lead to abnormal behavior in rTg4510 mice.},
}

Animals
*Neuroglia/pathology/metabolism
Disease Models, Animal
*Behavior, Animal
*Tauopathies/pathology/genetics/physiopathology
Mice, Transgenic
*tau Proteins/metabolism
Mice
Humans
Male
Gene Expression Regulation

@article {pmid41199341,
year = {2025},
author = {Luo, H and Marron Fernandez de Velasco, E and Kim, J and Yang, P and Mermelstein, P and Bonventre, JV and Cooke, PS and Wickman, K},
title = {Membrane-associated estrogen receptor α prevents the amyloid β-induced suppression of GIRK channel activity in hippocampal neurons from female mice.},
journal = {Biology of sex differences},
volume = {16},
number = {1},
pages = {90},
pmid = {41199341},
issn = {2042-6410},
support = {DA048742/NH/NIH HHS/United States ; },
mesh = {Animals ; *G Protein-Coupled Inwardly-Rectifying Potassium Channels/metabolism ; Female ; *Hippocampus/metabolism/cytology ; *Amyloid beta-Peptides/pharmacology/metabolism ; *Neurons/metabolism/drug effects ; Male ; *Estrogen Receptor alpha/metabolism ; Mice ; *Sex Characteristics ; Mice, Inbred C57BL ; Receptor, Metabotropic Glutamate 5/metabolism ; },
abstract = {BACKGROUND: Amyloid β oligomers (oAβ) are a key pathogenic driver in Alzheimer's Disease (AD). Neuronal G protein-gated inwardly rectifying K[+] (GIRK/Kir3) channels are important regulators of neuronal excitability and prominent somatodendritic effectors for inhibitory G protein-coupled receptors, including the γ-aminobutyric acid type B receptor (GABABR). We previously reported a male-specific suppression of GIRK channel activity in hippocampal (HPC) neurons evoked by oAβ in in vitro, ex vivo, and in vivo mouse models of AD, and showed that this adaptation correlated with synaptic and cognitive impairment. Using pharmacological approaches, we showed that this adaptation is mediated by co-activation of cellular prion protein (PrP[C]) and metabotropic glutamate receptor 5 (mGluR5) and requires activation of cytosolic phospholipase A2 α (cPLA2α). However, the mechanisms underlying the sex specificity was unknown. Given the clinical context that females exhibit a 2-fold higher incidence of AD than males, and the loss of neuroprotective estrogen by menopause contributes to the sex differences in AD, we postulated that estrogen-associated resilience underlies this sex dimorphism of oAβ action.

METHODS: To examine the strength of GIRK-dependent signaling in HPC neurons, we performed electrophysiology in primary HPC cultures from neonatal male and female mice and then measured whole-cell currents evoked by the direct-acting GIRK channel agonist ML297 and the GABABR-selective agonist baclofen. We used an array of genetic and pharmacological approaches to investigate the molecular mechanism(s) underlying the vulnerability and resilience of GIRK channel activity to oAβ in male and female HPC neurons, respectively.

RESULTS: We found that resilience to the oAβ-induced and PrP[C]/mGluR5-dependent suppression of GIRK channel activity in female HPC neurons is conferred by membrane-associated estrogen receptor α (mERα) and caveolin 1 (Cav1). When this resilience factor is blocked or absent, oAβ suppresses GIRK channel activity in female HPC neurons via the same PrP[C]-mGluR5-cPLA2α signaling pathway identified previously in male neurons.

CONCLUSION: As estrogen levels decline with aging and menopause, the protective influence of mERα/Cav1 may diminish, unmasking the oAβ-induced suppression of GIRK channel activity and exacerbating disease progression in females. While amyloid β plaques (Aβ) are notable hallmarks of Alzheimer's Disease (AD), cognitive impairment in the early stages of the disease tracks more closely with the level of soluble Aβ oligomers (oAβ) in the brain. oAβ promotes cognitive deficits by disrupting the balance of excitatory and inhibitory influences on neurons in brain regions important for learning and memory such as the hippocampus, but the underlying molecular targets of oAβ and its pathogenic mechanisms are not fully understood. We recently demonstrated that oAβ weakens the activity of a prominent inhibitory influence on neuronal excitability (the GIRK channel) in the hippocampus of male but not female mice. This sexually dimorphic effect of oAβ was interesting and unexpected given that women are twice as likely to develop AD than men, and because disease progression is more aggressive in women. In this study, we investigated the mechanisms underlying the resilience of GIRK channels in female hippocampal neurons to oAβ. We found that resilience is conferred by estrogen and one of its receptors. When the influence of this receptor is diminished using pharmacological or genetic interventions, oAβ weakens GIRK channel activity in female and male neurons to a similar degree, and via the same mechanism. We speculate that with the onset of menopause, the protective influence of estrogen on GIRK channel activity in the hippocampus begins to wane. This, combined with other female-specific effects of oAβ on neuronal activity, contributes to the increased incidence and severity of AD in females.},
}

Animals
*G Protein-Coupled Inwardly-Rectifying Potassium Channels/metabolism
Female
*Hippocampus/metabolism/cytology
*Amyloid beta-Peptides/pharmacology/metabolism
*Neurons/metabolism/drug effects
Male
*Estrogen Receptor alpha/metabolism
Mice
*Sex Characteristics
Mice, Inbred C57BL
Receptor, Metabotropic Glutamate 5/metabolism

@article {pmid41199115,
year = {2025},
author = {},
title = {Correction to "Comparison of plasma p-tau217/Aβ42, p-tau217, and Aβ42/Aβ40 biomarkers by race to detect Alzheimer's disease".},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {11},
pages = {e70913},
doi = {10.1002/alz.70913},
pmid = {41199115},
issn = {1552-5279},
}

@article {pmid41199071,
year = {2025},
author = {Zhang, L and Ma, Y and Fang, H and Gong, Y and Li, C and Meng, H and Song, J and Lu, X and Zhang, H and Niu, Q and Wang, L},
title = {Aluminum Exposure Leads to Aβ Deposition via the ciRs-7 Pathway.},
journal = {Biological trace element research},
volume = {},
number = {},
pages = {},
pmid = {41199071},
issn = {1559-0720},
support = {03201250//PhD Start-up Foundation of Shanxi Medical University/ ; 202203021222377//The Natural Science Foundation of Shanxi Province/ ; },
abstract = {Aluminum, a ubiquitous environmental neurotoxin, has been implicated in the pathogenesis of neurodegenerative disorders, including Alzheimer's disease (AD). While Aβ deposition is a hallmark of AD progression, the molecular mechanisms underlying aluminum-induced Aβ aggregation remain incompletely understood. This study examines the role of the ciRs-7-miR-7-UBE2A axis in aluminum-induced Aβ deposition. Healthy male SD rats and PC12 cells were stratified into groups based on aluminum maltolate exposure levels to establish an in vivo and in vitro neurotoxicity model. Hippocampal aluminum content, along with the expression levels of ciRs-7, miR-7, UBE2A, and Aβ1-42, were systematically analyzed. The results demonstrated a dose-dependent decrease in ciRs-7 and UBE2A expression with escalating aluminum exposure, accompanied by concurrent upregulation of miR-7 and Aβ1-42 accumulation. Conversely, ciRs-7 overexpression reversed these pathological trends. Mechanistically, aluminum exposure downregulates ciRs-7 in the hippocampus, thereby derepressing miR-7 activity, which suppresses UBE2A expression and ultimately promotes Aβ deposition. These results identify a novel circRNA-dependent mechanism in aluminum neurotoxicity, suggesting therapeutic targets for AD intervention.},
}

@article {pmid41198987,
year = {2025},
author = {Xu, WL and Chen, L and Fan, HH and Codd, GA and Giesy, JP and Guo, YM and Hilborn, ED and Sedan, D and Andrinolo, D and Chatterjee, S and Wang, HJ and Liu, Y and Wu, QH and He, J and Dai, SM and Xu, LL and Xiao, SM and Liu, YQ and Yang, R and Chen, J and Xie, P},
title = {Novel insights into cyanobacterial (microcystins) neurotoxicity in rats: hepatic encephalopathy.},
journal = {Archives of toxicology},
volume = {},
number = {},
pages = {},
pmid = {41198987},
issn = {1432-0738},
support = {31770555//National Natural Science Foundation of China/ ; 42367038//National Natural Science Foundation of China/ ; 31901186//National Natural Science Foundation of China/ ; },
abstract = {Microcystis, a commonly occurring genus of bloom-forming cyanobacteria, can produce numerous secondary metabolites, including microcystins (MCs), which are hepatotoxic and neurotoxic to humans and animals. However, the mechanisms of cyanobacterial neurotoxicity associated with MCs have not yet been clarified. This study reports the first observations of hepatic encephalopathy (HE) after exposure to Microcystis bloom extracts (MEs), which contained MCs. Mechanisms of toxicity were studied in rats exposed to MEs by use of a single intraperitoneal injection of 80 μg MC-LR equivalents/kg, body mass. Abnormal serum biochemical markers of hepatic functions and histopathological damage of liver and cerebral cortex were observed. Specifically, Alzheimer type II astrocytes, histological markers of HE, were observed. Motor impairment and significantly increased concentrations of ammonia in serum, increased activities of glutamine synthetase, and concentrations of glutamine in the cerebral cortex were detected, which indicated occurrence of HE. Mechanisms of HE, including ammonia poisoning, oxidative stress and inflammation, were confirmed by real-time quantitative PCR and transcriptomics. Also, transcriptomics revealed that zinc ions dyshomeostasis and ferroptosis are involved in the development of HE. This study presents novel insights into neurotoxic symptoms in human poisonings caused by Microcystis, links neurotoxicity in the brain to the liver, i.e., the liver-brain axis, and provides a new perspective on the multi-organ toxicity of Microcystis and a basis for developing treatments.},
}

@article {pmid41198899,
year = {2025},
author = {Ferrari-Souza, JP and Povala, G and Rahmouni, N and Bellaver, B and Ferreira, PCL and De Bastiani, MA and Leffa, DT and Lussier, FZ and Aguzzoli, CS and Brum, WS and Carello-Collar, G and Borelli, WV and Therriault, J and Macedo, AC and Servaes, S and Stevenson, J and Pola, I and Gauthier, S and Souza, DO and Schilling, LP and Lourenco, MV and Triana-Baltzer, G and Kolb, HC and Benedet, AL and Ashton, NJ and Tudorascu, DL and Zetterberg, H and Blennow, K and Johnson, SC and Pascoal, TA and Rosa-Neto, P and Zimmer, ER},
title = {Microglia modulate Aβ-dependent astrocyte reactivity in Alzheimer's disease.},
journal = {Nature neuroscience},
volume = {},
number = {},
pages = {},
pmid = {41198899},
issn = {1546-1726},
support = {AARGD-21-850670, AACSFD-22-928689, AARFD-23-1148735, and BFECAA2024/ALZ/Alzheimer's Association/United States ; 24AARFD-1243899/ALZ/Alzheimer's Association/United States ; AARFD-22-974627/ALZ/Alzheimer's Association/United States ; AARFD-22-923814/ALZ/Alzheimer's Association/United States ; AARFD-23-1148735/ALZ/Alzheimer's Association/United States ; 24AACSF-1200375/ALZ/Alzheimer's Association/United States ; AACSF-D 22-928689/ALZ/Alzheimer's Association/United States ; ADSF-21-831376-C, ADSF-21-831381-C, ADSF-21-831377-C, and ADSF-24-1284328-C/ALZ/Alzheimer's Association/United States ; ZEN-21-848495 and SG-23-1038904 QC/ALZ/Alzheimer's Association/United States ; NIRG-12-92090 and NIRP-12-259245/ALZ/Alzheimer's Association/United States ; 200691/2021-0//Ministry of Science, Technology and Innovation | Conselho Nacional de Desenvolvimento Científico e Tecnológico (National Council for Scientific and Technological Development)/ ; 2023-00356, 2022-01018 and 2019-02397//Vetenskapsrådet (Swedish Research Council)/ ; 2017-00915 and 2022-00732//Vetenskapsrådet (Swedish Research Council)/ ; 201809-2016862//Alzheimer's Drug Discovery Foundation (ADDF)/ ; RDAPB-201809-2016615//Alzheimer's Drug Discovery Foundation (ADDF)/ ; JPND2021-00694//EU Joint Programme - Neurodegenerative Disease Research (Programi i Përbashkët i BE-së për Kërkimet mbi Sëmundjet Neuro-degjeneruese)/ ; JPND2019-466-236//EU Joint Programme - Neurodegenerative Disease Research (Programi i Përbashkët i BE-së për Kërkimet mbi Sëmundjet Neuro-degjeneruese)/ ; R01AG068398//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; AG027161, AG021155, and AG062715//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; R01AG075336 and R01AG073267//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; 2020-VICO-279314 and 2024-VICO-356138//Fonds de Recherche du Québec - Santé (Fonds de la recherche en sante du Quebec)/ ; MOP-11-51-31; RFN 152985, 159815, and 162303//Gouvernement du Canada | Canadian Institutes of Health Research (Instituts de Recherche en Santé du Canada)/ ; },
abstract = {Experimental evidence suggests that activated microglia induce astrocyte reactivity in neurodegenerative disorders, such as Alzheimer's disease (AD). In this study, we investigated the association between microglial activation and amyloid-β (Aβ) with reactive astrogliosis in individuals across the AD spectrum. We examined 101 individuals using positron emission tomography radiotracers to assess Aβ deposition ([[18]F]AZD4694), tau aggregation ([[18]F]MK-6240) and microglial activation ([[11]C]PBR28), along with plasma biomarkers for astrocyte reactivity (GFAP) and tau phosphorylation (p-tau217). We further evaluated 251 individuals with cerebrospinal fluid levels of the microglial marker sTREM2. We found that Aβ pathology was associated with astrocyte reactivity across cortical brain regions only in the presence of microglial activation. The microglia-dependent effects of Aβ on astrocyte reactivity were further related to cognitive impairment through tau phosphorylation and aggregation. Our results suggest that microglial activation plays a key role in Aβ-related astrocyte reactivity, which, in turn, contributes to downstream pathological features of AD.},
}

@article {pmid41198777,
year = {2025},
author = {Koca, S and Kiris, I and Sahin, S and Karsidag, S and Cinar, N and Baykal, AT},
title = {Proteomic signatures and mitochondrial dysfunctions in peripheral T cells reveal novel ınsights into Alzheimer's disease.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {38897},
pmid = {41198777},
issn = {2045-2322},
support = {216S605//Türkiye Bilimsel ve Teknolojik Araştırma Kurumu/ ; },
mesh = {Humans ; *Alzheimer Disease/metabolism/pathology/immunology ; *Mitochondria/metabolism/pathology ; *Proteomics/methods ; Male ; Female ; Aged ; *CD4-Positive T-Lymphocytes/metabolism ; *CD8-Positive T-Lymphocytes/metabolism ; *Proteome/metabolism ; Membrane Potential, Mitochondrial ; Aged, 80 and over ; Tandem Mass Spectrometry ; B-Lymphocytes/metabolism ; },
abstract = {Alzheimer's disease (AD) exhibits progressive cognitive decline and recent scientific studies hint to the peripheral immune system as a contributor. In this study, we isolated peripheral immune cells including CD4 + and CD8 + T cells, CD14 + monocytes and CD19 + B cells from AD patients and age-matched controls via fluorescence-activated cell sorting. Label-free LC-MS/MS-based proteomic expression analysis within each cell type, comparing AD and control groups independently, 387 significantly altered proteins were identified in CD4 + and 121 in CD8 + T cells. Bioinformatic analysis uncovered distinct, cell-type-specific signatures: CD4 + cells showed dysregulation in ribosomal and RNA-binding proteins linked to neurodegeneration and oxidative stress while CD8 + cells showed elevated glycolytic enzyme expression and hyperpolarized mitochondrial membrane potential. Furthermore, mitochondrial functional assays, JC-1 and MitoSOX Red, further supported cell-type-dependent differences in mitochondrial activity. These findings may suggest that peripheral T cells have unique proteomic and functional alterations in AD, implicating mitochondrial dysfunction as a potential contributor to disease pathology.},
}

Humans
*Alzheimer Disease/metabolism/pathology/immunology
*Mitochondria/metabolism/pathology
*Proteomics/methods
Male
Female
Aged
*CD4-Positive T-Lymphocytes/metabolism
*CD8-Positive T-Lymphocytes/metabolism
*Proteome/metabolism
Membrane Potential, Mitochondrial
Aged, 80 and over
Tandem Mass Spectrometry
B-Lymphocytes/metabolism

@article {pmid41198665,
year = {2025},
author = {Hill, SA and Bravo-Ferrer, I and Čiulkinytė, A and Pérez Ramos, N and Rossetti, I and Colvin, C and Beltran-Lobo, P and Parra-Pérez, C and Emelianova, K and Dando, O and Geary, B and Nirujogi, RS and Alessi, DR and Lee, DY and Lee, YB and Díaz Castro, B},
title = {Molecular profiling of brain endothelial cell to astrocyte endfoot communication in mouse and human.},
journal = {Nature communications},
volume = {16},
number = {1},
pages = {9750},
pmid = {41198665},
issn = {2041-1723},
support = {RGS\R1\231330//Royal Society/ ; 609/ALZS_/Alzheimer's Society/United Kingdom ; 663/ALZS_/Alzheimer's Society/United Kingdom ; 218493/Z/19/Z//Wellcome Trust (Wellcome)/ ; ARUK-ECRBF2023B-005//Alzheimer's Research UK (ARUK)/ ; MC_UU_00018/1//RCUK | Medical Research Council (MRC)/ ; },
mesh = {Animals ; *Astrocytes/metabolism/cytology ; Humans ; *Endothelial Cells/metabolism ; Mice ; *Blood-Brain Barrier/metabolism/cytology ; *Brain/metabolism/cytology ; *Cell Communication ; Alzheimer Disease/metabolism/pathology ; Male ; Multiple Sclerosis/metabolism/pathology ; Lipopolysaccharides ; Mice, Inbred C57BL ; Female ; Proteome/metabolism ; },
abstract = {Our understanding of how the body communicates with the brain to coordinate their functions is remarkably limited. At the blood-brain barrier (BBB), brain endothelial cells (BECs) are ideally positioned to mediate signaling between blood and brain parenchyma via direct communication with astrocyte perivascular processes (endfeet). We develop a method to define the mouse in vivo astrocyte endfoot proteome, which in combination with BEC-specific RNA-seq, reveal BEC to astrocyte endfoot ligand-receptor pairs that are modulated when mice are exposed to a peripheral inflammatory insult with lipopolysaccharide. We show that over 80% of these mouse BEC-endfoot ligand-receptor pairs are also found in the human BBB, with a subset of them differentially expressed in human multiple sclerosis or Alzheimer's disease compared to healthy individuals. Our findings reveal dynamic BEC-endfoot communication pathways that are relevant to human physiology and provide methodology and datasets for the translational study of BEC-astrocyte crosstalk in health and disease.},
}

Animals
*Astrocytes/metabolism/cytology
Humans
*Endothelial Cells/metabolism
Mice
*Blood-Brain Barrier/metabolism/cytology
*Brain/metabolism/cytology
*Cell Communication
Alzheimer Disease/metabolism/pathology
Male
Multiple Sclerosis/metabolism/pathology
Lipopolysaccharides
Mice, Inbred C57BL
Female
Proteome/metabolism

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

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

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

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

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

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

@article {pmid41198606,
year = {2025},
author = {Loi, KJ and Radtke, N and Kiriluk, C and Noureldein, MH and Feldman, EL and Bakulski, KM and Chen, KS},
title = {Shared genes and pathways in dementia: Insights from genome-wide association studies.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {11},
pages = {e70845},
doi = {10.1002/alz.70845},
pmid = {41198606},
issn = {1552-5279},
support = {K99AG081390/AG/NIA NIH HHS/United States ; U01AG057562/AG/NIA NIH HHS/United States ; P30 AG072931/AG/NIA NIH HHS/United States ; 1K08AG084902/AG/NIA NIH HHS/United States ; AACSF-22-970586/ALZ/Alzheimer's Association/United States ; //Robert E. Nederlander Sr. Program for Alzheimer's Research/ ; //Robert and Katherine Jacobs Environmental Health Initiative/ ; //Andrea and Lawrence A. Wolfe Brain Health Initiative/ ; //Frank L. and Helen Gofrank Foundation Research Program in AD and Brain Health/ ; //Richard and Jane Manoogian Foundation/ ; //Sinai Medical Staff Foundation/ ; //Frances and Kenneth Eisenberg Emerging Scholar Program/ ; //NeuroNetwork for Emerging Therapies/ ; },
mesh = {Humans ; *Genome-Wide Association Study ; *Dementia/genetics ; *Genetic Predisposition to Disease/genetics ; Alzheimer Disease/genetics ; },
abstract = {Dementia, a collective term for neurodegenerative disorders marked by cognitive decline, affects millions worldwide, and is expected to rise significantly in prevalence. Genome-wide association studies (GWASs), as highlighted in this review, have revolutionized our understanding of dementia by identifying contributing genetic loci and pathways, including for Alzheimer's disease, vascular dementia, frontotemporal lobar dementia, and Lewy body dementia. This review critically analyzes published findings to shed insight on shared genes and pathways, encompassing lipid metabolism, immune responses, lysosomal mechanisms, and ionic homeostasis, which underlie neurodegeneration in dementia. We discuss methodological advances, challenges posed by genetic heterogeneity and population diversity, and the utility of polygenic risk scores in disease prediction. Furthermore, the importance of integrating tissue-specific expression data and non-European ancestral study cohorts is emphasized. Finally, this review outlines the next steps for advancing dementia research through GWASs and genetic insights. HIGHLIGHTS: Genome-wide association studies (GWASs) provide insight into the complex genetic architecture underlying dementia. Synthesizing GWASs across dementia subtypes highlights shared mechanisms. Identifying shared pathways may guide therapeutic development. Limitations exist and future GWASs may benefit from use of diverse populations.},
}

Humans
*Genome-Wide Association Study
*Dementia/genetics
*Genetic Predisposition to Disease/genetics
Alzheimer Disease/genetics

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

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

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

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

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

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

@article {pmid41198597,
year = {2025},
author = {Maioli, S and Nalvarte, I and Ankarcrona, M and Schultzberg, M and Zuloaga, KL and Goikolea, J and Visser, PJ and De Strooper, B and Winblad, B and Pizzo, P and Williams, PA and Rodriguez-Rodriguez, P and Naia, L},
title = {Bioenergetics and lipid metabolism in Alzheimer's disease: From cell biology to systemic health.},
journal = {Journal of internal medicine},
volume = {},
number = {},
pages = {},
doi = {10.1111/joim.70036},
pmid = {41198597},
issn = {1365-2796},
support = {//King Gustaf V:s and Queen Victoria's Foundation, Gun och Bertil Stohnes Stiftelse, Stiftelsen Gamla Tjänarinnor/ ; //Gun och Bertil Stohnes Stiftelse/ ; //Dementia Foundation/ ; NS110749//National Institutes of Health (NIH) research/ ; FO2024-0153-HK-50//the Swedish Brain Foundation/ ; 2024-0287//the Swedish Brain Foundation/ ; //Margaretha af Ugglas Foundation/ ; PRIN2022943TH9//Italian Ministry of University and Scientific Research/ ; PRIN P20225R4Y5//Italian Ministry of University and Scientific Research/ ; //European Union, NextGeneration EU/ ; //Cure Alzheimer's Fund (USA)/ ; //Italian Ministry of Research, NRRP-National Recovery and Resilience Plan grant, National Centre of Research 'Development of gene therapy and drugs with RNA technology', spoke 3 'Neurodegenerative Diseases/ ; //Ulla and Ingemar Dahlberg Foundation/ ; 2024-03440//Swedish Research Council/ ; 2023-02054//Swedish Research Council/ ; 2024-03577//Swedish Research Council/ ; 2022-00799//Swedish Research Council/ ; 2323-02503//Swedish Research Council/ ; //Strategic Research Program in Neuroscience-StratNeuro/ ; AF-1012350//Swedish Alzheimer Foundation/ ; AF-1011030//Swedish Alzheimer Foundation/ ; //Leif Lundblad Family and others/ ; },
abstract = {Alzheimer's disease (AD) is a complex neurodegenerative disorder characterized by progressive cognitive decline. Although amyloid-β and tau pathologies remain central to our understanding of AD, growing evidence suggests that disrupted lipid metabolism and impaired bioenergetics are closely linked to these hallmark features. Genetic, lipidomic and functional studies point to alterations in cholesterol, phospholipids and polyunsaturated fatty acids, which can influence mitochondrial function, organelle communication and glial responses. These processes are further modulated by apolipoprotein E (APOE) genotype, sex differences and systemic metabolic states such as obesity and diabetes, contributing to neuroinflammation and cognitive decline. Although findings are sometimes conflicting, an emerging theme is that lipid and energy metabolisms are central to how genetic and environmental risk factors shape AD pathogenesis. This integrated perspective highlights lipid and bioenergetic pathways as promising therapeutic targets, where metabolic modulators, lipid-directed interventions and lifestyle strategies may complement amyloid-based therapies and offer opportunities for precision approaches, particularly in women and APOE ε4 carriers.},
}

@article {pmid41198595,
year = {2025},
author = {Russ, KA and Lacy, K and Dage, JL and Foroud, T},
title = {The National Centralized Repository for Alzheimer's Disease and Related Dementia's Biomarker Assay Laboratory: A Resource for the Alzheimer's Disease Research Community.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {11},
pages = {e70774},
doi = {10.1002/alz.70774},
pmid = {41198595},
issn = {1552-5279},
support = {U24AG021886/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *Biomarkers/blood/cerebrospinal fluid ; *Alzheimer Disease/diagnosis/blood ; United States ; *Dementia/diagnosis ; Biomedical Research ; *Laboratories ; },
abstract = {Developments in Alzheimer's disease blood-based biomarkers research have provided critical information as to their use in early detection and assessments of progression in patients. The National Centralized Repository for Alzheimer's Disease and Related Dementias (NCRAD) Biomarker Assay Laboratory (BAL) was developed to provide expertise and access to robust and reliable research-use-only biomarkers (not for medical decision making) for the Alzheimer's disease and related dementias (ADRD) research community. The NCRAD BAL is a quality-focused laboratory delivering biomarker data through the use of highly standardized procedures and highly automated instrumentation with the goal of limiting pre-analytical variability while preparing samples for analysis, including limiting lot-to-lot variability of the assays. As biomarkers become United States Food and Drug Administration (FDA) -approved and move into use in CLIA labs, the NCRAD BAL will bring forward new platforms and assays reflecting the most current research-use-only biomarkers to support the research mandate of the ADRD research community. HIGHLIGHTS: The National Centralized Repository for Alzheimer's Disease and Related Dementias (NCRAD) has developed a Biomarker Assay Laboratory to support research of robust and reliable fluid biomarkers for Alzheimer's disease and neurodegeneration. NCRAD supports Alzheimer's Disease Research Centers by providing biomarker analyses on samples with clinical and imaging data through the National Institute on Aging (NIA) -funded Alzheimer's Disease Center Fluid Biomarker Initiative. The NCRAD Biomarker Assay Laboratory focuses on decreasing variability that will affect study results by utilizing highly standardized and automated procedures, strict monitoring of control measures, and controlling for lot-to-lot and instrument-to-instrument variability.},
}

Humans
*Biomarkers/blood/cerebrospinal fluid
*Alzheimer Disease/diagnosis/blood
United States
*Dementia/diagnosis
Biomedical Research
*Laboratories

@article {pmid41198537,
year = {2025},
author = {Zudeh, G and Sossai, S and Angelini, J and Stocco, G and Lucafò, M},
title = {Pharmacological Modulation of NLRP3: From Therapy Personalization to Innovative Drugs.},
journal = {Frontiers in bioscience (Landmark edition)},
volume = {30},
number = {10},
pages = {39537},
doi = {10.31083/FBL39537},
pmid = {41198537},
issn = {2768-6698},
support = {RC 15/23//Italian Ministry of Health/ ; },
mesh = {*NLR Family, Pyrin Domain-Containing 3 Protein/genetics/metabolism/antagonists & inhibitors ; Humans ; Inflammasomes/metabolism/genetics/drug effects ; *Precision Medicine/methods ; Epigenesis, Genetic ; DNA Methylation ; Animals ; Inflammation/drug therapy ; },
abstract = {The nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (NLRP3) inflammasome is a multiprotein complex fundamental for the secretion of pro-inflammatory cytokines during the innate immune response. NLRP3 dysregulation is implicated in the pathogenesis of several diseases, such as inflammatory bowel disease, arthritis, cancer, Alzheimer's disease, and type 2 diabetes. The pharmacological modulation of NLRP3 by several compounds, which are fully described in this review, represents an important strategy to regulate inflammatory processes. Moreover, NLRP3 is also involved in drug-related adverse reactions, and its pharmacological modulation represents a rapid strategy to mitigate such adverse effects, as reported in this study. NLRP3 inflammasome activation is tightly regulated by post-transcriptional modifications and epigenetic factors, such as long non-coding RNAs (lncRNAs) and DNA methylation, as well as other interacting regulators. Recently, different studies have revealed the importance of NLRP3 levels in predicting drug response. In particular, the methylation of the NLRP3 promoter, which is associated with the inflammasome expression level, emerged as a new promising pharmacoepigenetic biomarker for the glucocorticoid therapy response in several inflammatory disease conditions.},
}

*NLR Family, Pyrin Domain-Containing 3 Protein/genetics/metabolism/antagonists & inhibitors
Humans
Inflammasomes/metabolism/genetics/drug effects
*Precision Medicine/methods
Epigenesis, Genetic
DNA Methylation
Animals
Inflammation/drug therapy

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

@article {pmid41198459,
year = {2025},
author = {Zhao, H and Li, F and Xu, S and Du, Y and Chen, P and Wei, J and Hao, K and Liu, X and Liu, H},
title = {Restoration neurite growth by removing the blockage of endosome trafficking in Alzheimer-like mice.},
journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics},
volume = {},
number = {},
pages = {e00777},
doi = {10.1016/j.neurot.2025.e00777},
pmid = {41198459},
issn = {1878-7479},
abstract = {Synaptic loss is strongly associated with cognitive decline in Alzheimer's disease (AD). Endosomal trafficking dysfunction, observed in AD brains, impairs neurite growth. Because endosomal trafficking is essential for synaptic development, we selected LMTK1, a negative regulator of Rab11/RE pathway, for this study, given its upregulation in AD models. Clinical genomic data from the ADNI (Alzheimer's Disease Neuroimaging Initiative) database were analyzed to evaluate the relationship between LMTK1 and AD. Two AD mouse models, 3xTg and SAMP8, were examined for neurite outgrowth, synaptic density, LMTK1 expression, and recycling endosomes (RE) transport. LMTK1 knockdown was achieved using AAV. The Morris water maze, Golgi staining, immunofluorescence, and electrophysiology experiments were used to assess cognitive function, neurite outgrowth, synaptic density, RE transport, long-term potentiation (LTP), and synaptic transmission. The mechanism of LMTK1 in regulating RE transport was examined through co-immunoprecipitation, proteomics, and point mutation experiments. This study shows that phosphorylated LMTK1 activates TBC1D9B, which deactivates Rab11a and may suppress Rab11a[+] endosome trafficking and neurite growth. Clinical genomics data from the ADNI database support LMTK1's involvement in cognition in AD and possibly in glucose hypometabolism related to synaptic dysfunction. Knocking down LMTK1 improves neurite atrophy and synaptic density loss, likely by enhancing Rab11[+] endosome transport. Restoration of neurite morphology, hippocampal LTP, and cognitive function in AD mice suggest that inhibiting LMTK1 could represent a novel therapy for promoting neurite growth in AD. Hyperphosphorylation of LMTK1 may induce RE transport dysfunction, leading to neurite atrophy in AD mice. Therefore, targeting LMTK1 may offer a promising therapeutic approach for AD therapy.},
}

@article {pmid41198246,
year = {2025},
author = {Chen, M and Xue, M and Li, Y and Huang, W and Liu, L and Chen, Y and Chen, Y and Huang, F and Tu, S and Tang, J and Liu, J and Hu, J},
title = {Convolutional Neural Network-Self-Attention Mechanism Enhanced Near-Infrared: Non-Invasive Breakthrough for Alzheimer's Disease Versus Vascular Dementia.},
journal = {Journal of biophotonics},
volume = {},
number = {},
pages = {e202500383},
doi = {10.1002/jbio.202500383},
pmid = {41198246},
issn = {1864-0648},
support = {62565003//National Natural Science Foundation of China/ ; 12464028//National Natural Science Foundation of China/ ; 62005056//National Natural Science Foundation of China/ ; 2022GXNSFDA080006//Natural Science Foundation of Guangxi Province/ ; },
abstract = {Alzheimer's disease (AD) and vascular dementia (VaD) are two common forms of dementia. Differentiating between them is challenging due to the lack of clear clinical and auxiliary test differences. In this study, we developed a novel diagnostic method combining near-infrared spectroscopy with a convolutional neural network and self-attention mechanism (CNN-SAM). The CNN-SAM model, which integrates the self-attention mechanism to highlight important spectral features, outperformed other models with 99.3% accuracy. Data pre-processing, feature extraction, and parameter optimization further enhanced the model's performance. Visualization using the self-attention mechanism revealed key spectral bands at 1364 and 1484 nm as crucial for distinguishing AD and VaD. This approach offers a rapid, non-invasive, and accurate method for the diagnosis of AD and VaD, potentially advancing clinical practice.},
}

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

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

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

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

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

@article {pmid41197937,
year = {2025},
author = {Yuan, J and Zhang, J and Zhang, H and Tu, Y and Li, M},
title = {Propofol induces mitochondrial dysfunction in hippocampal neurons and postoperative cognitive dysfunction in male 3xTg-AD mice by blocking ESRRG-mediated HSD11B2 transcription.},
journal = {Brain research},
volume = {},
number = {},
pages = {150035},
doi = {10.1016/j.brainres.2025.150035},
pmid = {41197937},
issn = {1872-6240},
abstract = {Cognitive dysfunction is a severe issue of Alzheimer's disease (AD). This study explores the molecular mechanisms underlying propofol-induced postoperative cognitive dysfunction (POCD) in AD mice. Triple transgenic AD (3xTg-AD) male mice or control C57/BL6J mice were subjected to propofol anesthesia and abdominal surgery for modeling. AAV-mediated gene intervention was performed on male 3xTg-AD mice prior to propofol anesthesia. Reduced estrogen-related receptor gamma (ESRRG) and hydroxysteroid 11-beta dehydrogenase 2 (HSD11B2) expression was found in the hippocampus of male 3xTg-AD mice. ESRRG overexpression mitigated POCD and hippocampal mitochondrial dysfunction in male 3xTg-AD mice exposed to propofol. This was evidenced by shorter escape latencies, longer target quadrant times, increased platform crossings, reduced malondialdehyde and mitochondrial reactive oxygen species, decreased cytosolic cytochrome C and phosphorylated dynamin-related protein 1 (p-DRP1), and higher mitochondrial membrane potential, though these effects were reversed by HSD11B2 knockdown. In vitro, propofol lowered HT22 cell mitochondrial membrane potential and elevated cytochrome C and p-DRP1, but ESRRG overexpression countered these changes. Ultimately, propofol disrupts ESRRG-mediated HSD11B2 transcription, driving mitochondrial dysfunction and POCD in male 3xTg-AD mice.},
}

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

@article {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