@article {pmid40642909,
year = {2025},
author = {Tan, Y and Yang, D and Ke, Z and Hu, Z and Song, W and Tang, L and Zhou, Z and Mo, Y and Huang, L and Xu, Y},
title = {The Effect of APOE ε4 Allele on Dynamic Local Spontaneous Brain Activity and Functional Integration in Alzheimer's Disease.},
journal = {Human brain mapping},
volume = {46},
number = {10},
pages = {e70269},
doi = {10.1002/hbm.70269},
pmid = {40642909},
issn = {1097-0193},
support = {82130036//National Natural Science Foundation of China/ ; ZDXK202216//Jiangsu Province Key Medical Discipline/ ; 2022ZD0211800//STI 2030 - Major Projects/ ; },
mesh = {Humans ; *Alzheimer Disease/physiopathology/genetics/diagnostic imaging/blood ; *Apolipoprotein E4/genetics ; Male ; Female ; Aged ; Magnetic Resonance Imaging ; Middle Aged ; Amyloid beta-Peptides/blood ; Alleles ; Aged, 80 and over ; *Brain/physiopathology/diagnostic imaging ; },
abstract = {The apolipoprotein E (APOE) ε4 allele is the most important genetic risk factor for sporadic Alzheimer's disease (AD), yet its mechanisms in AD pathology and cognitive decline remain unclear. Using a sliding-time window approach to directly quantify the instantaneous fluctuations of various local metrics based on continuous time series and calculate voxel-wise concordance of these metrics, we explored the impact of APOE ε4 on dynamic local brain activity and functional integration in AD, and its interrelations with plasma biomarkers and cognition. Results showed that APOE ε4 widely affected dALFF, dReHo, dGSCorr, and voxel-wise concordance. For AD patients, APOE ε4 carriers uniquely exhibited correlations between dALFF in the right angular gyrus/supramarginal gyrus and MoCA scores and orientation function, and between voxel-wise concordance in the right caudate nucleus (CAU) and general cognition, attention, language function, orientation function, plasma Aβ42. Critically, APOE ε4-related altered voxel-wise concordance in the right CAU mediated the relationship between plasma Aβ and language cognition in AD. Moreover, the combined model incorporating dynamic metrics, plasma AD biomarkers, and demographic data effectively distinguished AD from NC (AUC = 0.94, sensitivity = 87.69%, specificity = 86.84%). In conclusion, the APOE ε4 allele might play a pivotal role in modulating brain dynamic functional activities in AD, which may contribute to the association between Aβ pathology and cognitive decline. Our findings may provide imaging markers and targets for the diagnosis and treatment of AD.},
}

Humans
*Alzheimer Disease/physiopathology/genetics/diagnostic imaging/blood
*Apolipoprotein E4/genetics
Male
Female
Aged
Magnetic Resonance Imaging
Middle Aged
Amyloid beta-Peptides/blood
Alleles
Aged, 80 and over
*Brain/physiopathology/diagnostic imaging

@article {pmid40642529,
year = {2025},
author = {Lizcano, F and Sanabria, D and Aviles, E},
title = {Hormonal modulation, mitochondria and Alzheimer's prevention: the role of GLP-1 agonists and estrogens.},
journal = {Frontiers in molecular biosciences},
volume = {12},
number = {},
pages = {1622186},
pmid = {40642529},
issn = {2296-889X},
abstract = {Alzheimer's disease (AD) is the most prevalent cause of dementia worldwide, disproportionately affecting women and lacking effective disease-modifying therapies. While traditional approaches have focused on amyloid β (Aβ) plaques and tau pathology, emerging evidence highlights the role of metabolic dysfunction, mitochondrial impairment, and hormonal signaling in the pathogenesis of AD. Estrogens exert neuroprotective effects by modulating synaptic plasticity, enhancing mitochondrial bioenergetics, and reducing oxidative stress and inflammation. Similarly, glucagon-like peptide-1 receptor agonists (GLP-1RAs), initially developed for the treatment of type 2 diabetes, have demonstrated promising cognitive benefits, potentially mediated through improved insulin signaling, neuronal survival, and reduced β-amyloid (Aβ) and tau burden. This review explores the converging mechanisms through which estrogens and GLP-1RAs may act synergistically to prevent or delay the onset of AD. We examine the influence of sex differences in mitochondrial dynamics, estrogen receptor distribution, and GLP-1 signaling pathways, particularly within central nervous system regions implicated in AD. Preclinical studies using GLP-1-estrogen conjugates have shown enhanced metabolic and neuroprotective outcomes, accompanied by reduced systemic hormonal exposure, suggesting a viable therapeutic strategy. As the global prevalence of AD continues to rise, especially among postmenopausal women, dual agonism targeting estrogen and GLP-1 receptors may represent a novel, physiologically informed approach to prevention and intervention. Ongoing clinical trials and future research must consider sex-specific factors, receptor polymorphisms, and brain-region selectivity to optimize the translational potential of this combined strategy.},
}

@article {pmid40642320,
year = {2025},
author = {},
title = {Correction to "The HOPE4MCI study: AGB101 treatment slows progression of entorhinal cortex atrophy in APOE ε4 non-carriers with mild cognitive impairment due to Alzheimer's disease".},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {11},
number = {3},
pages = {e70131},
doi = {10.1002/trc2.70131},
pmid = {40642320},
issn = {2352-8737},
abstract = {[This corrects the article DOI: 10.1002/trc2.70004.].},
}

@article {pmid40642087,
year = {2025},
author = {Noor, F and Aslam, S and Piras, IS and Tremblay, C and Beach, TG and Serrano, GE},
title = {Integrative bioinformatics and machine learning approaches reveal oxidative stress and glucose metabolism related genes as therapeutic targets and drug candidates in Alzheimer's disease.},
journal = {Frontiers in immunology},
volume = {16},
number = {},
pages = {1572468},
pmid = {40642087},
issn = {1664-3224},
mesh = {Humans ; *Alzheimer Disease/genetics/metabolism/drug therapy ; *Oxidative Stress/genetics ; *Machine Learning ; *Glucose/metabolism ; *Computational Biology/methods ; Molecular Docking Simulation ; Gene Regulatory Networks ; Gene Expression Profiling ; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/genetics/metabolism ; },
abstract = {BACKGROUND: Alzheimer's disease (AD), the most common form of dementia, has treatments that slow but do not stop cognitive decline. Additional treatments are based on its pathogenic mechanisms are needed. Evidence has long highlighted oxidative stress and impaired glucose metabolism as crucial factors in AD pathogenesis. Therefore, in this study we aimed to find key AD pathogenic pathways combining genes involved in oxidative stress and glucose metabolism as well as potential small-molecule therapeutic agents.

METHODS: Using autopsy brain RNA sequencing data (GSE125583) derived from the Arizona Study of Aging and Brain and Body Donation Program, AD-related genes were identified via differential gene expression, pathway and coexpression analysis. Oxidative stress and glucose metabolism genes were correlated to pinpoint module genes. GSE173955 was used an independent dataset was used for validation, conducting molecular docking, assessing hub genes for AD, and integrating machine learning approaches.

RESULTS: We identified 13,982 differentially expressed genes (DEGs) in AD patients. Through WGCNA coexpression analysis, 1,068 genes were linked to AD-specific modules. Pearson's correlation analysis highlighted 99 genes involved in oxidative stress and glucose metabolism. Overlap analysis of DEGs, module genes, and these metabolic genes revealed 21 key overlapping targets. PPI network and receiving operating curve (ROC) curve analyses then identified AKT1 and PPARGC1A as diagnostic hub genes for AD. Machine learning-based virtual screening of small molecules identified various inhibitors and enhancers with drug-like potential targeting AKT1 (upregulated) and PPARGC1A (downregulated), respectively. Among others, the Random Forest model was the most reliable for predicting molecular activity. Molecular docking further validated the binding affinities of these small molecules (inhibitors/enhancers) to AKT1 and PPARGC1A.

CONCLUSION: This study identified AKT1 and PPARGC1A as potential therapeutic targets in AD. We discovered drug candidates with strong binding affinities, offering new avenues for effective AD treatment strategies.},
}

Humans
*Alzheimer Disease/genetics/metabolism/drug therapy
*Oxidative Stress/genetics
*Machine Learning
*Glucose/metabolism
*Computational Biology/methods
Molecular Docking Simulation
Gene Regulatory Networks
Gene Expression Profiling
Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/genetics/metabolism

@article {pmid40641595,
year = {2025},
author = {Delvenne, A and Gobom, J and Reus, LM and Dobricic, V and Ten Kate, M and Schindler, SE and Ramakers, I and Tijms, BM and Vandenberghe, R and Schaeverbeke, J and Martinez-Lage, P and Tainta, M and Teunissen, CE and Popp, J and Peyratout, G and Tsolaki, M and Freund-Levi, Y and Lovestone, S and Streffer, J and Barkhof, F and Bertram, L and Blennow, K and Zetterberg, H and Visser, PJ and Vos, SJB},
title = {Cerebrospinal fluid proteomic profiling of cognitively unimpaired individuals with suspected non-Alzheimer's disease pathophysiology.},
journal = {Brain communications},
volume = {7},
number = {4},
pages = {fcaf253},
pmid = {40641595},
issn = {2632-1297},
abstract = {Suspected non-Alzheimer's disease pathophysiology (SNAP) is a biomarker-based concept describing individuals with abnormal tau and/or neurodegeneration markers but normal amyloid levels. SNAP is common in individuals with normal cognition (NC), but its underlying pathophysiology is understudied, while being relevant for clinical trial design and treatment approaches. We aimed to investigate the pathophysiology of individuals with NC who are amyloid-negative and tau-positive (SNAP) through cerebrospinal fluid (CSF) proteomics. Two hundred and ninety-one individuals with NC were classified based on CSF amyloid β1-42 and phosphorylated tau 181, as amyloid-negative/tau-negative (controls), amyloid-negative/tau-positive (SNAP), amyloid-positive/tau-negative and amyloid-positive/tau-positive. We measured 3102 proteins in CSF using tandem mass tag proteomic analyses. We compared protein abundance between groups using analysis of covariance and identified enriched biological pathways using Gene Ontology. We also examined differences between groups in genetic risk for Alzheimer's disease, estimated using polygenic risk scores based on genome-wide association study data. SNAP individuals with NC showed mostly increased protein levels (n = 360) compared with controls, mainly associated with neuroplasticity, angiogenesis, and protein modification and degradation. The proteomic profile of SNAP was similar to that of amyloid-positive/tau-positive individuals, while distinct from amyloid-positive/tau-negative individuals, who showed mainly decreased proteins associated with neuroplasticity. Higher levels of amyloid β1-40 and amyloid β1-42 were observed in SNAP compared with the three other groups. Polygenic risk scores analyses showed no significant differences between SNAP, amyloid-positive/tau-negative, and amyloid-positive/tau-positive individuals, while SNAP showed some genetic differences from controls, which were driven by APOE. Individuals with NC and SNAP or amyloid-positive/tau-positive status showed similar CSF proteomic profiles, while amyloid-positive/tau-negative individuals showed a distinct CSF proteomic profile. This suggests that tau, rather than amyloid, might be the main driver of the proteomic profiles in SNAP and other amyloid/tau subgroups. This may have implications for future proteomic studies and clinical trial design, as these findings highlight the importance of considering tau status in future studies.},
}

@article {pmid40641055,
year = {2025},
author = {Le, W and Shen, L and Guo, T and Xie, F},
title = {Spotlight on Alzheimer's disease and related dementias research in East Asia.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {7},
pages = {e70479},
doi = {10.1002/alz.70479},
pmid = {40641055},
issn = {1552-5279},
mesh = {Humans ; *Alzheimer Disease/epidemiology/therapy/diagnosis ; Asia, Eastern/epidemiology ; *Dementia/epidemiology/therapy/diagnosis ; Biomarkers/blood ; *Biomedical Research ; Neuroimaging ; },
abstract = {With a burgeoning dementia burden driven by unique demographic, genetic, and socioeconomic factors of East Asia, the region has made significant investments in understanding disease mechanisms, developing biomarkers, and exploring therapeutic approaches. This collection highlights the current landscape of Alzheimer's disease and related dementias research in East Asia, including region-specific epidemiological insights, advances in plasma biomarkers and neuroimaging, and innovative diagnostic and treatment strategies. Despite progress, challenges such as limited access to advanced imaging, cultural barriers to autopsy, and disparities in healthcare persist.},
}

Humans
*Alzheimer Disease/epidemiology/therapy/diagnosis
Asia, Eastern/epidemiology
*Dementia/epidemiology/therapy/diagnosis
Biomarkers/blood
*Biomedical Research
Neuroimaging

@article {pmid40641016,
year = {2025},
author = {Dahiya, M and Yadav, M and Kumar, A and Goyal, C},
title = {Tau Pathology in Alzheimer's Disease: Bridging Molecular Mechanisms and Targeted Therapies.},
journal = {CNS & neurological disorders drug targets},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118715273376581250626003322},
pmid = {40641016},
issn = {1996-3181},
abstract = {Alzheimer's disease (AD), the leading cause of dementia, is characterized by β-amyloid (Aβ) plaques and neurofibrillary tangles of hyperphosphorylated tau. While Aβ-targeting therapies have been a primary focus of drug development, their long-term efficacy remains uncertain. Emerging evidence suggests that tauopathy is more closely linked to cognitive decline, positioning tau as a promising therapeutic target. Tauopathies, a group of neurodegenerative disorders marked by tau dysfunction and aggregation, were historically attributed to a toxic gain-of-function. However, clinical trials targeting tau have yielded limited success, likely due to the heterogeneity of tau pathology, variable patient responses, and suboptimal therapeutic strategies. Here, we underline the need for a refined understanding of tau biology to develop effective interventions. Advancing precision medicine approaches and identifying optimal tau species for therapeutic intervention could transform tau-targeting therapies into a cornerstone in managing tauopathies. By integrating insights from genetics, pathology, and translational research, future efforts may overcome current challenges and unlock novel treatment avenues, ultimately improving patient outcomes.},
}

@article {pmid40640892,
year = {2025},
author = {Noh, MY and Kwon, HS and Kwon, MS and Nahm, M and Jin, HK and Bae, JS and Kim, SH},
title = {Biomarkers and therapeutic strategies targeting microglia in neurodegenerative diseases: current status and future directions.},
journal = {Molecular neurodegeneration},
volume = {20},
number = {1},
pages = {82},
pmid = {40640892},
issn = {1750-1326},
support = {RS-2024-00348451//Korea Dementia Research Center/ ; },
mesh = {Humans ; *Microglia/metabolism ; *Neurodegenerative Diseases/metabolism/therapy ; *Biomarkers/metabolism ; Animals ; },
abstract = {Recent advances in our understanding of non-cell-autonomous mechanisms in neurodegenerative diseases (NDDs) have highlighted microglial dysfunction as a core driver of disease progression. Conditions such as Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), and frontotemporal dementia (FTD) share features of impaired microglial phagocytosis, chronic neuroinflammation, and metabolic dysregulation. These insights have prompted new therapeutic strategies targeting microglial function and emphasized the need for reliable biomarkers to monitor disease progression and treatment response. Well-established therapeutic targets, such as triggering receptor expressed on myeloid cells 2 (TREM2), progranulin (PGRN), and sortilin (SORT1), along with emerging candidates including LILRB4, P2Y6R, TAM receptors, and neuroinflammation-related markers, are discussed alongside novel blood, cerebrospinal fluid (CSF), and imaging biomarkers. Despite notable progress, many of these biomarkers remain restricted to preclinical studies and face translational challenges due to species-specific differences, lack of standardization, and clinical heterogeneity. Emerging technologies-including single-cell omics, spatial transcriptomics, and artificial intelligence (AI)-driven integration of multimodal data-offer new opportunities to align biomarker profiles with evolving disease states and improve patient stratification. Building on the model of companion diagnostics (CDx) in oncology, integrating multimodal biomarker strategies holds promise for guiding personalized interventions, improving clinical outcomes, and deepening our mechanistic understanding of microglial contributions across the neurodegenerative spectrum.},
}

Humans
*Microglia/metabolism
*Neurodegenerative Diseases/metabolism/therapy
*Biomarkers/metabolism
Animals

@article {pmid40640460,
year = {2025},
author = {Heimler, SR and Amick, KA and Bergstrom, J and Moliné, M and Mahapatra, G and Craft, S and Molina, AJA},
title = {Nervonic acid and 15-epi-PGA1 mediate systemic mitochondrial dysfunction in AD dementia.},
journal = {GeroScience},
volume = {},
number = {},
pages = {},
pmid = {40640460},
issn = {2509-2723},
support = {R01 AG054523/GF/NIH HHS/United States ; R01 AG061805/GF/NIH HHS/United States ; P30 AG068635/GF/NIH HHS/United States ; P30 AG 072947/GF/NIH HHS/United States ; },
abstract = {Systemic mitochondrial dysfunction is apparent in the pathophysiology of Alzheimer's disease (AD). However, the factors driving bioenergetic decline remain unclear. This study utilized serum samples from older adults with normal cognition, mild cognitive impairment, and dementia to identify circulating molecules that can drive mitochondrial dysfunction in the context of AD. We used mass spectrometry to measure the abundance of lipid metabolites and applied tiered selection criteria to identify candidate "mito-inhibitory" molecules. These criteria were based on correlations with (1) in vitro bioenergetic effects of whole serum samples on naïve cells, (2) the bioenergetic capacity of blood cells from the serum donor, and (3) cognition, as measured by the modified mini-mental state exam. Mito-inhibitory lipid candidates were validated by examining their bioenergetic effects on neurons, myoblasts, and fibroblasts in vitro. Our results indicate that nervonic acid and 15-epi Prostaglandin A1 (15-epi-PGA1) are elevated in participants with dementia compared to those with normal cognition. Importantly, both metabolites inhibited mitochondrial function across multiple cell types in vitro. High resolution respirometric analyses reveal that inhibitory effects from lipid treatment occur via broad inhibition of the electron transfer system (ETS) with no change in overall mitochondrial content. This study provides insights into the mechanisms underlying systemic bioenergetic decline associated with AD dementia. The identification of circulating factors that drive mitochondrial bioenergetic decline may inform the development of mitochondrial therapeutics for AD.},
}

@article {pmid40639970,
year = {2025},
author = {Franceschi, AM and Keir, G and Benzinger, TLS and Cogswell, PM and Ali, FZ and Petrella, JR and Prescott, JW and Whitlow, CT and Zaharchuk, G and Allen, JW and , },
title = {Clinical Role of Brain PET in Alzheimer Disease in the Era of Disease-Modifying Therapies.},
journal = {AJNR. American journal of neuroradiology},
volume = {},
number = {},
pages = {},
doi = {10.3174/ajnr.A8738},
pmid = {40639970},
issn = {1936-959X},
abstract = {Alzheimer disease (AD) is the leading cause of dementia, with an estimated 6.9 million Americans aged 65 and older living with Alzheimer dementia today, with this number projected to grow to 13.8 million by 2060. Amyloid and τ accumulation underpin our understanding of the pathophysiology of AD, with the abnormal accumulation of these proteins leading to neurodegeneration. With the recent approval of antiamyloid monoclonal antibody therapies for patients with early-stage Alzheimer disease by the Food and Drug Administration, there is renewed energy and focus on brain imaging for diagnosis, triage, and monitoring of patients with neurodegenerative disease. Furthermore, PET imaging of amyloid and τ has revolutionized our understanding of dementia progression and staging, and influences patient management in the clinical setting. We aim to update radiologists on the evolving role of amyloid and τ PET in clinical practice, emphasizing the need for standardized workflows and the integration of molecular imaging data with other disease biomarkers. We also discuss the clinical implications of amyloid and τ PET, including their impact on diagnosis and treatment decisions, as well as the challenges of reimbursement and workforce capacity. With recent shifts in the AD management landscape, it is crucial for radiologists to keep abreast of recent advances in clinical practice, thereby ensuring effective patient care.},
}

@article {pmid40639271,
year = {2025},
author = {Mao, Y and Zhang, L and Zhang, C and Qin, L and Liao, X and Zhao, L},
title = {The close relationship between trace elements (Cu, Fe, Zn, Se, Rb, Si, Cr, and V) and Alzheimer's disease: Research progress and insights.},
journal = {Journal of trace elements in medicine and biology : organ of the Society for Minerals and Trace Elements (GMS)},
volume = {90},
number = {},
pages = {127692},
doi = {10.1016/j.jtemb.2025.127692},
pmid = {40639271},
issn = {1878-3252},
abstract = {Alzheimer's disease (AD) is a typical neurodegenerative disorder primarily characterized by the deposition of β-amyloid (Aβ) plaques and the hyperphosphorylation of tau protein, leading to the formation of neurofibrillary tangles (NFTs). These pathological changes are closely associated with the imbalance of trace element homeostasis. Trace elements are extensively involved in fundamental physiological processes, including DNA synthesis, protein synthesis, energy metabolism, and enzymatic reactions, all of which are essential for cognitive function and brain development. This review summarizes the alterations in homeostasis and the biological roles of trace elements such as copper, iron, zinc, selenium, rubidium, silicon, chromium, and vanadium, as well as their relationship with the onset and progression of AD. Additionally, we discuss recent advancements in therapeutic strategies targeting the balance of trace element ions, including metal chelators, supplements, nanomedicines, and small-molecule drugs, to provide new perspectives for AD research and treatment.},
}

@article {pmid40638744,
year = {2025},
author = {Keil, SA and Jansson, D and Braun, M and Iliff, JJ},
title = {Glymphatic dysfunction in Alzheimer's disease: A critical appraisal.},
journal = {Science (New York, N.Y.)},
volume = {389},
number = {6756},
pages = {eadv8269},
doi = {10.1126/science.adv8269},
pmid = {40638744},
issn = {1095-9203},
mesh = {*Alzheimer Disease/physiopathology ; Humans ; *Glymphatic System/physiopathology ; Animals ; *Brain/physiopathology ; },
abstract = {Thirteen years after the initial publication defining the glymphatic system, we critically reappraise the role of its dysfunction in Alzheimer's disease (AD). Our understanding of glymphatic function and its involvement in the pathogenesis of AD derives primarily from correlative clinical data and rodent studies. A causal role for glymphatic dysfunction in AD has not yet been established in humans. We review current approaches to assess glymphatic function clinically, which capture different features of perivascular fluid dynamics or their results. The absence of clinically suitable imaging approaches to measuring glymphatic exchange in the human brain is an obstacle to evaluating whether glymphatic function is impaired in AD populations and to developing and evaluating therapeutics to modulate glymphatic function in the treatment and prevention of AD.},
}

*Alzheimer Disease/physiopathology
Humans
*Glymphatic System/physiopathology
Animals
*Brain/physiopathology

@article {pmid40637746,
year = {2025},
author = {Xu, D and Wu, J and Zhao, X and Shen, J and Lu, Z and Yang, Z},
title = {A bibliometric analysis of the current research status and hotspots regarding Aducanumab treatment for Alzheimer's disease.},
journal = {Naunyn-Schmiedeberg's archives of pharmacology},
volume = {},
number = {},
pages = {},
pmid = {40637746},
issn = {1432-1912},
abstract = {BACKGROUND: The prevalence of Alzheimer's disease is steadily increasing, and Aducanumab has garnered significant attention as a treatment since 2021. There is a growing body of research on Aducanumab and its relationship with Alzheimer's disease; however, there is currently a lack of bibliometric analysis regarding the use of Aducanumab in the treatment of Alzheimer's disease.

OBJECTIVE: This study employs bibliometric methods to analyze the current research landscape and hotspots surrounding Alzheimer's disease and Aducanumab, providing a reference for subsequent investigations in this field and the promotion of Aducanumab as a treatment for Alzheimer's disease.

METHODS: This study retrieved articles related to Alzheimer's disease and Aducanumab from the WOS core database, covering the period from the establishment of the database until Dec 31, 2024. After a rigorous selection process, analyses were conducted using GraphPad Prism 10, VOSviewer, and CiteSpace to obtain insights into publication and citation metrics, collaboration networks among countries, institutions, and authors, as well as clustering analysis of reference papers and keywords.

RESULTS: The number of articles regarding Aducanumab treatment for Alzheimer's disease has been increasing annually, with a notable surge occurring after 2021. The three countries with the highest publication output are the United States, the United Kingdom, and China. The leading institutions in terms of publication volume are Biogen, Harvard Medical School, and the University of California, San Francisco. The top three authors contributing to this body of work are Poul F. Høilund-Carlsen, Abass Alavi, and Mona-Elisabeth Revheim. The journals with the highest publication rates include Alzheimer's & Dementia, the International Journal of Molecular Sciences, and the Journal of Alzheimer's Disease. The most cited article is "Lecanemab in Early Alzheimer's Disease," authored by van Dyck CH et al., published in 2023 in the New England Journal of Medicine. The ten most frequently occurring keywords are Alzheimer's disease, Aducanumab, dementia, amyloid-beta, immunotherapy, tau, a-beta, mouse model, amyloid, and mild cognitive impairment. The keyword and cluster "pharmacokinetics" currently represent a research hotspot in this field.

CONCLUSION: This study employs bibliometric methods to reveal the publication trends related to Aducanumab in the context of Alzheimer's disease, examining collaborations among countries, regions, and authors, as well as recent research hotspots. It provides objective data that serves as a reference for scientific research and clinical practice concerning Aducanumab treatment for Alzheimer's disease.},
}

@article {pmid40637583,
year = {2025},
author = {Bonomi, CG and Motta, C and Di Donna, MG and Poli, M and Koch, G and Martorana, A},
title = {Rethinking dementia in the oldest old: Lessons to learn for the diagnosis and treatment of Alzheimer's disease.},
journal = {Neural regeneration research},
volume = {},
number = {},
pages = {},
doi = {10.4103/NRR.NRR-D-25-00312},
pmid = {40637583},
issn = {1673-5374},
}

@article {pmid40637522,
year = {2025},
author = {Nonino, F and Colosimo, C and Massacesi, L},
title = {[Lecanemab and Alzheimer-Perusini's disease: between therapeutic hopes and regulatory challenges.].},
journal = {Recenti progressi in medicina},
volume = {116},
number = {7-8},
pages = {407-410},
doi = {10.1701/4530.45309},
pmid = {40637522},
issn = {2038-1840},
mesh = {Humans ; *Alzheimer Disease/drug therapy/physiopathology ; *Amyloid beta-Peptides/metabolism/immunology ; *Antibodies, Monoclonal, Humanized/adverse effects/therapeutic use/administration & dosage ; Aged ; *Antibodies, Monoclonal/therapeutic use/adverse effects ; },
abstract = {Alzheimer-Perusini's disease (AD) represents a growing health crisis. The lack of effective disease-modifying treatments and its increasing prevalence in the elderly population contribute to a major burden for patients and their caregivers, challenging health systems globally. The accumulation of beta-amyloid protein (Aβ) within the brain tissue plays an important pathogenic role in the inflammatory and degenerative mechanisms leading to cognitive and functional impairment. In recent years monoclonal antibodies targeting (Aβ) have been developed and one of them (lecanemab) recently received marketing authorization by the European Medicines Agency (Ema). Although they represent an important innovation in the treatment of AD, their clinical net benefit is uncertain, due to modest efficacy and the threat of potentially severe side effects. Cost, mode od delivery and complexity of programs aimed at minimizing risks for people with AD may limit access to these therapies and pose equity issues within health systems.},
}

Humans
*Alzheimer Disease/drug therapy/physiopathology
*Amyloid beta-Peptides/metabolism/immunology
*Antibodies, Monoclonal, Humanized/adverse effects/therapeutic use/administration & dosage
Aged
*Antibodies, Monoclonal/therapeutic use/adverse effects

@article {pmid40636703,
year = {2025},
author = {Patricio-Martínez, A and Patricio, F and Macuil-Chapuli, E and Martínez-Juárez, EÁ and Flores-Díaz, S and Cedillo-Ramírez, ML and Limón, ID},
title = {The role of probiotics, prebiotics, and postbiotics: cellular and molecular pathways activated on glial cells in Alzheimer's disease.},
journal = {Frontiers in neuroscience},
volume = {19},
number = {},
pages = {1598011},
pmid = {40636703},
issn = {1662-4548},
abstract = {Supplementation with prebiotics and probiotics can modulate the intestinal microbiota, returning it to a more physiological state; therefore, they can be considered as a possible treatment in many prevalent conditions, including neurodegenerative diseases. Alzheimer's disease (AD) is the most common form of dementia, accounting for 60 to 70% of cases. The neuropathological features of AD include neuritic plaques (extracellular deposits of the beta-amyloid protein, Aβ), neurofibrillary tangles (resulting from hyperphosphorylation of the tau protein), a predominantly cholinergic synaptic decrease, and the presence of inflammatory markers, all these characteristics together trigger the neurodegenerative process and cognitive deterioration. The etiology of AD is multifactorial, however, in recent years evidence has been shown on the significant association between dysbiosis, neuroinflammation, and neurodegeneration. In the present review, we will discuss the role of gut microbiota in the pathogenesis of AD, as well as the underlying mechanisms that trigger the use of probiotics, prebiotics, and postbiotics in neuroinflammation. Our attention will focus on the cellular and molecular mechanisms triggered by astrocytes and microglia, cells involved in mediating neuroinflammation and neurodegeneration in AD.},
}

@article {pmid40636522,
year = {2025},
author = {Wang, J and Chen, Y and Chen, S and Mu, Z and Chen, J},
title = {How endothelial cell metabolism shapes blood-brain barrier integrity in neurodegeneration.},
journal = {Frontiers in molecular neuroscience},
volume = {18},
number = {},
pages = {1623321},
pmid = {40636522},
issn = {1662-5099},
abstract = {BACKGROUND/OBJECTIVE: Endothelial cells, a monolayer of cells adjacent to blood vessels, play a critical role in maintaining vascular function through metabolic pathways such as glycolysis, fatty acid, and amino acid metabolism. Recent studies have revealed their significant involvement in neurodegenerative diseases, although the underlying mechanisms remain unclear.

METHODS: By reviewing literature from the past decade, we summarized the metabolic alterations and functional changes of endothelial cells in neurological disorders.

RESULTS: In neurodegenerative diseases such as stroke, Alzheimer's disease, multiple sclerosis, and aging, metabolic dysregulation in cerebral vascular endothelial cells disrupts their normal function and is closely associated with blood-brain barrier impairment.

CONCLUSION: Aberrant endothelial cell metabolism compromises the integrity of the blood-brain barrier and exacerbates the pathological progression of neurodegenerative diseases. Our review further explores the therapeutic potential of targeting endothelial cell metabolism in various pathological contexts, aiming to provide novel insights for the prevention and treatment of related disorders.},
}

@article {pmid40636521,
year = {2025},
author = {Sharma, E and Mehta, D and Jadhav, N and Gujrati, G and Dhananya, S and Moorthy, M and Ramaswamy, G and Zhou, Y and Nair, S},
title = {Whole-genome sequencing shows modulation of neurodegenerative genes by Withania somnifera in human SK-N-SH cells.},
journal = {Frontiers in molecular neuroscience},
volume = {18},
number = {},
pages = {1512727},
pmid = {40636521},
issn = {1662-5099},
abstract = {BACKGROUND: Aging is driven by several primary and secondary hallmarks that manifest with age, of which neurodegenerative diseases are important manifestations. The ability to decelerate or reverse aging, and promote healthy aging, has garnered great interest in recent times. In traditional medicine, Withania somnifera (WS) or Ashwagandha has been recognized for its adaptogenic and rejuvenative effects.

METHODS: To investigate WS-modulated global gene expression profiles, we performed whole-genome sequencing of WS-treated human neuroblastoma SK-N-SH cells at different doses (50 and 100 μg/mL) and time points (3 h and 9 h) and validation by quantitative real-time PCR (qRT-PCR) and immunoblotting. Disease enrichment analysis for brain-related disorders was performed by DisGeNET.

RESULTS: Using differential gene expression analyses, we identified 19,945 WS-modulated genes. Of these, 2,403 and 177 genes were significantly (p ≤ 0.05) upregulated and downregulated, respectively, by WS treatment. Interestingly, different patterns of gene expression were exhibited in dose-dependent (9 upregulated, 1 downregulated, 100 μg/mL 3 h vs. 50 μg/mL 3 h; 21 upregulated, 86 downregulated, 100 μg/mL 9 h vs. 50 μg/mL 9 h) and temporal kinetics (210 upregulated, 6 downregulated, 50 μg/mL 9 h vs. 50 μg/mL 3 h; 8 upregulated, 49 downregulated, 100 μg/mL 9 h vs. 100 μg/mL 3 h). Furthermore, qRT-PCR experiments validated the RNA-seq results. WS-modulated genes were implicated in Alzheimer's disease, migraine, Parkinson's disease, bipolar disorder, cognition, stress, anxiety, forgetfulness, sleep disorders, and substance abuse among others.

CONCLUSION: Taken together, our transcriptomic profiling study revealed for the first time that WS may modulate key genes in neurodegenerative disorders with potential beneficial implications for brain-related disorders and healthy aging.},
}

@article {pmid40636063,
year = {2025},
author = {Armstrong, MJ and Grill, JD and Tropea, TF},
title = {It is time to share Alzheimer biomarker results in dementia with Lewy bodies.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {17},
number = {3},
pages = {e70144},
pmid = {40636063},
issn = {2352-8729},
abstract = {UNLABELLED: There are increasing calls for sharing individual biomarker results with participants in dementia research. No studies investigate returning Alzheimer's disease (AD) biomarker results to individuals with syndromic dementia with Lewy bodies (DLB) even though most of these individuals have both pathologies. This perspective argues that AD biomarkers are valid, interpretable, and actionable, particularly relating to expected prognosis and treatment effects, in people with DLB. Thus, there is an ethical imperative to study AD biomarker result sharing in these patients. This will require revising current disclosure practices. Areas of need include unique pre- and post-test education and careful assessment of the readiness to receive results and post-result responses in people with DLB given the frequency of neuropsychiatric symptoms in this group. Studying responses to sharing AD biomarkers in people with DLB will also inform other dementia settings (e.g., returning synuclein results to individuals with syndromic AD) and neurodegenerative diseases more broadly.

HIGHLIGHTS: There are increasing calls for biomarker result sharing in dementia research.No processes exist to guide result sharing in dementia with Lewy bodies (DLB).Alzheimer biomarker results in DLB are valid, interpretable, and actionable.Research is needed on the methods and effects of sharing with people with DLB.Research is needed for sharing evidence of co-pathology across neurodegenerations.},
}

@article {pmid40635533,
year = {2025},
author = {Tae, WS and Ham, BJ and Pyun, SB and Kim, BJ},
title = {Current Clinical Applications of Structural MRI in Neurological Disorders.},
journal = {Journal of clinical neurology (Seoul, Korea)},
volume = {21},
number = {4},
pages = {277-293},
doi = {10.3988/jcn.2025.0185},
pmid = {40635533},
issn = {1738-6586},
support = {2022R1F1A1074517/NRF/National Research Foundation of Korea/Korea ; RS-2023-00241730/NRF/National Research Foundation of Korea/Korea ; RS-2025-00515464/NRF/National Research Foundation of Korea/Korea ; },
abstract = {Structural magnetic resonance imaging (sMRI) plays a pivotal role in the evaluation of neurological disorders by providing high-resolution anatomical information. Recent advances in quantitative postprocessing techniques have expanded the utility of sMRI beyond visual assessments by enabling the detection of subtle morphological changes associated with various neurological and psychiatric conditions. This review summarizes current clinical applications of sMRI-based analysis, including brain volumetry, shape analysis, voxel-based morphometry (VBM), surface-based morphometry, source-based morphometry, and voxel-based lesion-symptom mapping (VLSM). Volumetric and shape-based analyses allow for assessments of region-specific atrophy and subregional morphological alterations, while VBM and surface-based morphometry provide complementary insights into tissue volumes and the architecture of the cortical surface. Source-based morphometry reveals network-level patterns of structural covariance, and VLSM directly correlates lesion locations with functional outcomes, particularly in stroke. It has been demonstrated that these methodologies are clinically relevant in conditions such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, epilepsy, and major depressive disorder. By quantifying structural brain alterations that are not readily detectable using conventional imaging methods, these tools improve diagnostic accuracy, support prognostication, and facilitate monitoring of treatment effects. This review highlights the growing integration of sMRI postprocessing techniques into clinical neurology.},
}

@article {pmid40635531,
year = {2025},
author = {Park, KH and Choi, SH and Shim, Y and Youn, YC and Yang, DW and Kim, S},
title = {Use of Amyloid Positron-Emission Tomography to Diagnose Alzheimer's Disease in Clinical Practice in South Korea: Expert Recommendations.},
journal = {Journal of clinical neurology (Seoul, Korea)},
volume = {21},
number = {4},
pages = {251-264},
doi = {10.3988/jcn.2025.0037},
pmid = {40635531},
issn = {1738-6586},
abstract = {Amyloid positron-emission tomography (PET) is the optimal method for detecting amyloid plaque deposition in patients experiencing cognitive decline, which is essential for diagnosing Alzheimer's disease. However, its clinical application globally has been restricted by the high cost, short radiotracer half-life, and significant accessibility challenges. In particular, the lack of treatment options following diagnosis has been considered the largest obstacle to using amyloid PET as a diagnostic tool. Consequently, the current appropriate-use recommendations for amyloid PET tend to support restricting its use. However, the relatively low cost and superior accessibility of amyloid PET in South Korea have resulted in it being used much more frequently in clinical settings than in other countries. The recent introduction of disease-modifying drugs has increased the importance and frequency of amyloid PET usage. Considering these circumstances, this article presents expert opinions on the appropriate use of amyloid PET in South Korea based on existing recommendations and survey results from dementia experts in South Korea.},
}

@article {pmid40635450,
year = {2025},
author = {Li, J and Li, Y and Wang, Z and Yao, Y and Yao, D and Chen, K and Xia, Y},
title = {Oxytocin Intervention Mitigates Pathological and Behavioral Impairments in APP/PS1 Mice Subjected to Early Social Isolation.},
journal = {CNS neuroscience & therapeutics},
volume = {31},
number = {7},
pages = {e70511},
doi = {10.1111/cns.70511},
pmid = {40635450},
issn = {1755-5949},
support = {2022ZD0208500//STI 2030-Major Project/ ; 2024YFHZ0359//Sichuan Province Science and Technology Support Program/ ; },
mesh = {Animals ; *Oxytocin/pharmacology/therapeutic use ; *Social Isolation/psychology ; Mice ; *Alzheimer Disease/pathology/psychology/drug therapy/genetics/metabolism ; Mice, Transgenic ; Male ; Presenilin-1/genetics ; Gastrointestinal Microbiome/drug effects ; Amyloid beta-Protein Precursor/genetics ; Mice, Inbred C57BL ; Anxiety/drug therapy ; Depression/drug therapy ; Receptors, Oxytocin/metabolism ; Disease Models, Animal ; },
abstract = {BACKGROUND: Neuropsychiatric symptoms, such as anxiety and depression, are prevalent during the prodromal phase of Alzheimer's disease (AD). Social isolation (SI) has been implicated as a potential exacerbating factor for emotional disturbances in AD pathogenesis. Despite the well-established role of oxytocin (OXT) in regulating social behavior and mental health, its function and mechanisms in alleviating AD-related psychiatric symptoms remain poorly understood.

MATERIALS AND METHODS: We utilized a 12-week SI model to assess its effects on anxiety, depression-like behaviors, and social cognition in early-stage AD mice. Through immunofluorescence, enzyme-linked immunosorbent assay, and 16S rDNA sequencing, we examined the changes in AD pathology and gut microbiota composition induced by SI, as well as the effects of OXT intervention.

RESULTS: Our findings revealed that SI markedly intensified anxiety-like behaviors, depression-like phenotypes, and social cognitive impairments in AD mice. Mechanistically, SI resulted in decreased OXT levels and upregulated OXT receptor expression while also exacerbating AD-related pathological features, including increased Aβ plaque deposition, aberrant microglial proliferation, and reduced PSD-95 expression in the prefrontal cortex. Furthermore, SI induced significant changes in gut microbiota composition. OXT intervention demonstrated therapeutic efficacy by mitigating behavioral deficits, alleviating AD-related pathological damage, and restoring gut microbiota homeostasis in SI AD mice.

CONCLUSION: These results underscore OXT as a promising therapeutic avenue for AD, offering novel insights into treatment strategies and identifying potential therapeutic targets through the restoration of gut homeostasis and mitigation of pathological processes.},
}

Animals
*Oxytocin/pharmacology/therapeutic use
*Social Isolation/psychology
Mice
*Alzheimer Disease/pathology/psychology/drug therapy/genetics/metabolism
Mice, Transgenic
Male
Presenilin-1/genetics
Gastrointestinal Microbiome/drug effects
Amyloid beta-Protein Precursor/genetics
Mice, Inbred C57BL
Anxiety/drug therapy
Depression/drug therapy
Receptors, Oxytocin/metabolism
Disease Models, Animal

@article {pmid40635217,
year = {2025},
author = {Guo, L and Lin, Y and Sun, B},
title = {Highly Efficient and Eco-friendly Synthesis and Bio-activities of 1,3-benzazoles as Cu (II) Chelators in Alzheimer's Disease Therapy.},
journal = {Current medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0109298673371011250612094752},
pmid = {40635217},
issn = {1875-533X},
abstract = {INTRODUCTION: Dyshomeostasis of Cu2+ and abnormal interactions between Cu2+ and β Amyloid peptide (Aβ) can promote Aβ aggregation and oxidative stress, which are considered to trigger Alzheimer's Disease (AD). Metal chelating therapy is a promising approach for the treatment of AD.

METHOD: In this study, 2-(2-hydroxyphenyl)benzazoles were synthesized via microwave irradiation promotion. Chelators inhibiting Cu2+-induced Aβ aggregation were determined through turbidity assay and BCA protein assay, while anti-oxidants were detected via HRP/Amplex red assay and fluorescent probe of DCFH-DA. Cell viability was measured by MTT assay.

RESULTS: The bio-activity for inhibiting Cu2+ induced-Aβ aggregation of chelators S-1, S-3, S-4, S-5, S-7, S-10, N-5, N-9, N-10 O-2, O-4, X-N-2 was better than that of CQ. The ability of the chelators (S-1, S-10, O-2, O-5, N-9, and X-N-2) to decrease the level of ROS in Aβ+Cu2+ treated SH-SY5Y cells was better than that of CQ. The ability to attenuate Aβ-mediated cytotoxicity in SH-SY5Y cells of S-10 (O-2, O-5, and N-9) was better than that of CQ.

CONCLUSION: After the evolution of the bio-activities for the treatment of AD in vitro, it was found that 4 chelators (S-10, O-2, O-5, and N-9) exhibited better bio-activities than CQ in all aspects.},
}

@article {pmid40635213,
year = {2025},
author = {A Shaldam, M and Carradori, S and Melfi, F and Guglielmi, P and Diomede, F and Piattelli, M and O Tawfik, H},
title = {Potential of MAO-B Inhibitors with Multi-Target Inhibition and Antioxidant Properties for the Treatment of Neurodegenerative Disorders.},
journal = {Mini reviews in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113895575392491250630195630},
pmid = {40635213},
issn = {1875-5607},
abstract = {Millions of people worldwide are affected by neurodegenerative disorders (NDs), which include a broad range of clinical ailments that affect the brain or peripheral nervous system, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease, etc. Neuronal cell death in NDs is often linked to oxidative stress; thus, antioxidant treatment can combat oxidative cell damage, and this strategy has been studied in neurodegenerative processes. Over the past 10 years, we have witnessed intense research activity on the biological potential of human monoamine oxidase (hMAO) inhibitors that have been associated with the prevention of oxidative stress and inflammation. These inhibitors have emerged as promising therapeutic agents, especially in the treatment of neurodegenerative diseases (NDs), where their core activity may help mitigate disease progression. An overview of the current state of numerous scaffolds, such as chromones, coumarins, chalcones, propargylamines, benzothiazoles, aminoisoquinolines, and the natural compounds, including ferulic acid, resveratrol, and chrysin, which combine antioxidant capability and hMAO inhibition is given in this review, with particular attention given to each scaffold's mechanism of action and structure-activity relationships (SARs), which are thoroughly discussed. Focusing on the dual mechanism of action, combining inhibition and antioxidant properties, as a potential therapy for neurodegenerative diseases, we have reviewed the different chemical classes of multi-targetdirected ligand (MTDL) inhibitors developed within this framework. Other central nervous system (CNS)-related enzymes, such as cholinesterases, carbonic anhydrases, and BACE-1, have also been explored as targets in the MTDL strategy. By understanding their biological activity, medicinal chemists can better comprehend biological activity and recommend more effective and specific ND treatments.},
}

@article {pmid40633621,
year = {2025},
author = {Limone, A and Di Napoli, C and De Rosa, G and Bagnoli, S and Izzo, A and Procaccini, C and Matarese, G and Nacmias, B and Lavecchia, A and Sarnataro, D},
title = {Modulation of mitochondrial quality control through autophagic pathway in familial Alzheimer's disease.},
journal = {Biochimica et biophysica acta. Molecular cell research},
volume = {},
number = {},
pages = {120019},
doi = {10.1016/j.bbamcr.2025.120019},
pmid = {40633621},
issn = {1879-2596},
abstract = {Autophagy is a highly conserved cellular catabolic process recognized as an essential pathway for the maintenance of cellular homeostasis. Growing evidence implicates autophagic dysfunction in the pathogenesis of several neurodegenerative disorders, including Alzheimer's disease (AD), thus its modulation might represent an interesting therapeutic tool. Searching for a compound that stimulates autophagic pathway, led us to identify the inhibitor of RPSA receptor, NSC47924. In this study, we show that, NSC47924 down-modulated Akt-mTOR-axis pathway, the master regulator of autophagy, which was abnormally hyperactivated in fibroblasts from genetic AD-affected patients. Consistently, by monitoring the conversion of LC3, we found that inhibition of RPSA enhanced and restored the compromised autophagic flux. Moreover, by qRT-PCR analysis we found that inhibitor treatment upregulated the expression of autophagy-linked genes. Importantly, AD-affected fibroblasts exhibited massive mitochondrial network fragmentation and mitophagy defects, which were restored through the stimulation of autophagy induced by RPSA inhibition. Consistent with an efficient elimination of dysfunctional mitochondria, we found that the turnover of both the mitophagy regulators PINK1 and Parkin and the autophagic receptors p62, NDP52, OPTN, was modulated, thus restoring a highly interconnected organelle's network. In addition, the improvement of mitochondrial morphology correlated with a functional recovery, as assessed by Seahorse analysis and mitochondrial ROS production evaluation. Collectively, our findings suggest that RPSA inhibition stimulates an autophagic pathway promoting the efficient removal of damaged mitochondria, favouring the recovery of cellular homeostasis, and counteracting crucial AD pathogenic mechanisms.},
}

@article {pmid40633409,
year = {2025},
author = {Khaliq, A and Ahmad, F and Rehman, HU and Alanazi, SA and Haleem, H and Junaid, K and Andrikopoulou, E},
title = {Revolutionizing medical imaging: A cutting-edge AI framework with vision transformers and perceiver IO for multi-disease diagnosis.},
journal = {Computational biology and chemistry},
volume = {119},
number = {},
pages = {108586},
doi = {10.1016/j.compbiolchem.2025.108586},
pmid = {40633409},
issn = {1476-928X},
abstract = {The integration of artificial intelligence in medical image classification has significantly advanced disease detection. However, traditional deep learning models face persistent challenges, including poor generalizability, high false-positive rates, and difficulties in distinguishing overlapping anatomical features, limiting their clinical utility. To address these limitations, this study proposes a hybrid framework combining Vision Transformers (ViT) and Perceiver IO, designed to enhance multi-disease classification accuracy. Vision Transformers leverage self-attention mechanisms to capture global dependencies in medical images, while Perceiver IO optimizes feature extraction for computational efficiency and precision. The framework is evaluated across three critical clinical domains: neurological disorders, including Stroke (tested on the Brain Stroke Prediction CT Scan Image Dataset) and Alzheimer's (analyzed via the Best Alzheimer MRI Dataset); skin diseases, covering Tinea (trained on the Skin Diseases Dataset) and Melanoma (augmented with dermoscopic images from the HAM10000/HAM10k dataset); and lung diseases, focusing on Lung Cancer (using the Lung Cancer Image Dataset) and Pneumonia (evaluated with the Pneumonia Dataset containing bacterial, viral, and normal X-ray cases). For neurological disorders, the model achieved 0.99 accuracy, 0.99 precision, 1.00 recall, 0.99 F1-score, demonstrating robust detection of structural brain abnormalities. In skin disease classification, it attained 0.95 accuracy, 0.93 precision, 0.97 recall, 0.95 F1-score, highlighting its ability to differentiate fine-grained textural patterns in lesions. For lung diseases, the framework achieved 0.98 accuracy, 0.97 precision, 1.00 recall, 0.98 F1-score, confirming its efficacy in identifying respiratory conditions. To bridge research and clinical practice, an AI-powered chatbot was developed for real-time analysis, enabling users to upload MRI, X-ray, or skin images for automated diagnosis with confidence scores and interpretable insights. This work represents the first application of ViT and Perceiver IO for these disease categories, outperforming conventional architectures in accuracy, computational efficiency, and clinical interpretability. The framework holds significant potential for early disease detection in healthcare settings, reducing diagnostic errors, and improving treatment outcomes for clinicians, radiologists, and patients. By addressing critical limitations of traditional models, such as overlapping feature confusion and false positives, this research advances the deployment of reliable AI tools in neurology, dermatology, and pulmonology.},
}

@article {pmid40633205,
year = {2025},
author = {Metzendorf, NG and Godec, A and Petrovic, A and Chourlia, A and Napoleone, A and Syvänen, S and Rofo, F and Hultqvist, G},
title = {Somatostatin therapy, neprilysin activation, and amyloid beta reduction: A novel approach for Alzheimer's treatment.},
journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie},
volume = {189},
number = {},
pages = {118325},
doi = {10.1016/j.biopha.2025.118325},
pmid = {40633205},
issn = {1950-6007},
abstract = {INTRODUCTION: Neprilysin is the primary enzyme responsible for the degradation of amyloid beta (Aβ), with its levels regulated by the hormone somatostatin (SST).

METHODS: We have developed a novel treatment mechanism for Alzheimer's disease (AD) by combining SST with a blood-brain barrier (BBB) transporter and a Fc fragment to extend its half-life. This treatment was tested in a murine AD model overexpressing amyloid precursor protein (APP) with the Arctic mutation in Aβ (APPArcSwe).

RESULTS: Our findings demonstrate a significant increase in neprilysin levels, which correlates with a reduction in various forms of Aβ, including membrane-bound and intracellular Aβ aggregates, as well as Aβ42 in insoluble aggregates.

DISCUSSION: These results suggest that neprilysin can effectively degrade Aβ with the Arctic mutation. Additionally, this treatment strategy successfully reduces both oligomeric and larger Aβ, aggregates, a challenge for other therapeutic approaches. This novel strategy holds promise as a potential therapeutic approach for AD.},
}

@article {pmid40632863,
year = {2025},
author = {Shao, L and Zhang, Y and Yang, Z and Shi, C and Yue, X and Li, C and Liu, Y and Fu, Z and Tang, C and Zhao, X and Han, M and Zhang, J and Sun, W and Yao, Z and Xi, K and Fang, Z and Wang, Z and Feng, F and Ma, C and Zhao, K and Zhang, Y and Ni, S and Jiang, X and Chen, C},
title = {Synthetic efferocytic receptor microglia enhances anti-inflammatory clearance of amyloid-β for AD treatment in mice.},
journal = {Science advances},
volume = {11},
number = {28},
pages = {eads6613},
doi = {10.1126/sciadv.ads6613},
pmid = {40632863},
issn = {2375-2548},
mesh = {Animals ; *Amyloid beta-Peptides/metabolism ; *Microglia/metabolism ; *Alzheimer Disease/metabolism/therapy/pathology ; Mice ; Disease Models, Animal ; Phagocytosis ; Humans ; Inflammation ; Nanoparticles/chemistry ; Anti-Inflammatory Agents ; Mice, Transgenic ; },
abstract = {Monoclonal antibody immunotherapy targeting the clearance of amyloid-β (Aβ) has shown promise in Alzheimer's disease (AD). However, current antibody treatments trigger Fc receptors and induce proinflammatory responses, in turn exacerbating neuronal damage. Here, we report a synthetic efferocytic receptor (SER) integrating Aβ-targeting scFv, efferocytosis receptor backbone based on TIM4 and downstream signal for microglia (MG) reprogramming, which enabled selective elimination of Aβ without inducing an inflammatory response. Specifically, our in-house-customized MG-editing mRNA lipid nanoparticles (MERLINs) efficiently introduced SER mRNA into MG to generate Aβ-specific SER-MG in situ. SER-MG exhibited robust Aβ-specific phagocytosis and stimulated anti-inflammatory efferocytosis typical signaling in vitro. In a mouse model of AD, SER expression in the MG markedly increased the clearance of Aβ and dampened inflammation, resulting in improved behavioral outcomes along with substantially reduced synapse elimination. Our findings establish that AD-associated aberrant MG can be in situ reprogrammed with SER for Aβ clearance in an anti-inflammatory manner, with broad application in other inflammation-related diseases.},
}

Animals
*Amyloid beta-Peptides/metabolism
*Microglia/metabolism
*Alzheimer Disease/metabolism/therapy/pathology
Mice
Disease Models, Animal
Phagocytosis
Humans
Inflammation
Nanoparticles/chemistry
Anti-Inflammatory Agents
Mice, Transgenic

@article {pmid40632335,
year = {2025},
author = {Banu, Z and Das, NR},
title = {In Vitro Assessment of Cholinesterase Inhibition and Neuroprotective Effects of Elaeocarpus angustifolius Blume Against Amyloid-Beta Peptide-Induced Toxicity in SH-SY5Y and BV-2 Cells.},
journal = {Neurochemical research},
volume = {50},
number = {4},
pages = {226},
pmid = {40632335},
issn = {1573-6903},
mesh = {*Amyloid beta-Peptides/toxicity ; Humans ; *Neuroprotective Agents/pharmacology/isolation & purification ; *Cholinesterase Inhibitors/pharmacology/isolation & purification ; Animals ; *Plant Extracts/pharmacology ; Mice ; Butyrylcholinesterase/metabolism ; Cell Survival/drug effects/physiology ; *Peptide Fragments/toxicity ; Acetylcholinesterase/metabolism ; Cell Line, Tumor ; Cell Line ; Dose-Response Relationship, Drug ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder primarily characterized by memory impairment and cognitive decline. Pathophysiological mechanisms contributing to AD include oxidative stress, increased acetylcholinesterase activity, neuroinflammation, and the accumulation of hyperphosphorylated tau proteins and amyloid-β (Aβ) plaques in the brain. The shortcomings of existing therapeutic approaches have necessitated the exploration of alternative treatment strategies. Elaeocarpus angustifolius Blume, traditionally used for neurological disorders, has been investigated for its neuroprotective potential through its alkaloid-rich fraction. This study evaluated the acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitory activities of E. angustifolius alkaloid-rich fraction (EAF) and its protective effects against Aβ1-42-induced cytotoxicity in human neuron-like SH-SY5Y cells and murine microglial BV-2 cells using the MTT assay. The results demonstrated that for AChE and BuChE, EAF showed significant inhibition with IC50 of 145.1 ± 4.782 µg/mL and 165.8 ± 1.10 µg/mL, respectively. In the MTT assay, EAF effectively mitigated Aβ1-42-induced cytotoxicity in a dose-dependent manner, with the highest dose (100 µg/mL) restoring viability from 67.91 to 75.31% in SH-SY5Y cells and from 60.29 to 76.01% in BV-2 cells. From these results, it is apparent that EAF has anticholinesterase and neuroprotective properties. However, further research on this may help decipher underlying mechanisms before establishing EAF as an effective alternative in treating AD.},
}

*Amyloid beta-Peptides/toxicity
Humans
*Neuroprotective Agents/pharmacology/isolation & purification
*Cholinesterase Inhibitors/pharmacology/isolation & purification
Animals
*Plant Extracts/pharmacology
Mice
Butyrylcholinesterase/metabolism
Cell Survival/drug effects/physiology
*Peptide Fragments/toxicity
Acetylcholinesterase/metabolism
Cell Line, Tumor
Cell Line
Dose-Response Relationship, Drug

@article {pmid40631238,
year = {2025},
author = {Brisendine, MH and Nieves-Esparcia, DQ and Willoughby, OS and Brown, JR and Braxton, DS and Henry, SN and McCoin, C and Thyfault, JP and Morris, JK and Poelzing, S and Grange, RW and Najt, CP and Drake, JC},
title = {Age-dependent remodeling of the sciatic proteome in 5xFAD mice can be attenuated by exercise or donepezil treatment to maintain neuromuscular function.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.07.01.662603},
pmid = {40631238},
issn = {2692-8205},
abstract = {UNLABELLED: Background: Alzheimer's disease (AD) progresses along a continuum for years to possibly decades prior to cognitive decline and clinical diagnosis. Preclinical AD is associated with neuromuscular dysfunction. We previously characterized early neuromuscular impairment prior to cognitive decline at 4 months of age in the 5xFAD mouse model of AD. However, the underlying cause(s) for peripheral nerve dysfunction leading to impaired skeletal muscle torque production are not understood, therefore limiting interventional capacity. We hypothesized that either voluntary wheel running or donepezil treatment, begun prior to neuromuscular decline, would delay manifestation of neuromuscular impairment in 5xFAD mice. Methods: Sciatic nerves from 5xFAD and wild-type (WT) mice were analyzed by tandem mass tag (TMT)-labeled proteomics at 3, 4, and 7 months to investigate proteome remodeling. Separate cohorts, using 3-month-old 5xFAD mice and WT littermates given voluntary wheel access for 4 weeks or treated with the acetylcholinesterase inhibitor donepezil to test if neuromuscular dysfunction could be attenuated. Afterwards, we assessed tibial nerve stimulated plantar flexion torque and sciatic nerve compound (motor) neuron action potential (CNAP) in-vivo at 4 months. Additionally, we performed TMT-labeled proteomics to ascertain the effect of exercise and donepezil treatments on sciatic proteome. Results: Sciatic nerves in 5xFAD mice exhibited proteomic remodeling from 3 to 4 months, particularly in pathways linked to mitochondrial turnover, calcium handling, lipid metabolism, and inflammation, coinciding with onset of neuromuscular dysfunction. Both exercise and donepezil attenuated in nerve-stimulated muscle torque and CNAP dysfunction. Both exercise and donepezil attenuated proteomic remodeling of the sciatic nerve involving mitochondrial-centric processes through both shared and independent mechanisms. Conclusions: Declines in neuromuscular function may be pre-clinical identifiers for AD that share pathway similarities with noted central effects of the pathology on the brain. Our findings highlight the importance of a systemic approach to AD pathology and importance of disease state in interventional efficacy.

GRAPHICAL ABSTRACT: Created in Biorender.},
}

@article {pmid40630923,
year = {2025},
author = {Pascuzzo, R and Palesi, F and Wan, YM and Cazzaniga, FA},
title = {Editorial: A comprehensive look at biomarkers in neurodegenerative diseases: from early diagnosis to treatment response assessment.},
journal = {Frontiers in aging neuroscience},
volume = {17},
number = {},
pages = {1642793},
pmid = {40630923},
issn = {1663-4365},
}

@article {pmid40630916,
year = {2025},
author = {Huang, X and Ji, Q and Tong, T and Cai, L and Elmadhoun, O and Zeng, Y and Geng, X and Ding, Y},
title = {Evaluating the safety and feasibility of remote ischemic conditioning for slowing cognitive decline in mild Alzheimer's dementia.},
journal = {Frontiers in neurology},
volume = {16},
number = {},
pages = {1592829},
pmid = {40630916},
issn = {1664-2295},
abstract = {OBJECTIVE: Alzheimer's disease (AD) is characterized by complex pathological mechanisms involving neuroinflammation, oxidative stress, and vascular dysfunction. Remote Ischemic Conditioning (RIC) has shown potential in addressing these pathways by improving cerebral blood flow, reducing oxidative stress, and modulating inflammatory responses. This protocol focuses on evaluating the safety, feasibility, and preliminary efficacy of RIC as a multi-target intervention for delaying cognitive decline in patients with mild Alzheimer's dementia, aiming to improve cognitive outcomes and overall quality of life.

METHODS AND EXPECTED RESULTS: This study is a randomized, controlled, single-center, prospective clinical trial designed to evaluate the safety, feasibility, and preliminary efficacy of RIC in patients with mild Alzheimer's dementia. Eligible participants will be recruited and randomly assigned to either the RIC group or a control group receiving sham RIC, with 20 patients in each group. Participants will receive either RIC or sham RIC once daily over a 3-month period. Outcome measures will assess cognitive function, psychological well-being, and inflammatory and neurodegenerative biomarkers. Psychiatric adverse events will be monitored throughout the treatment using the Hamilton Anxiety Rating Scale (HAMA) and the Hamilton Depression Rating Scale (HAMD-17). Cognitive function and daily living abilities will be evaluated at baseline, 3 months, 6 months, and 12 months post-treatment using the Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), Clinical Dementia Rating (CDR), and the Activities of Daily Living (ADL) scales. In addition, blood samples will be collected at each time point to measure plasma biomarkers of β-amyloid species and serum inflammatory cytokines to assess potential changes in cognitive decline, disease progression, and inflammation. The primary endpoint is safety, with the expectation that RIC will not increase psychiatric adverse events as reflected in HAMA and HAMD-17 scores. Primary efficacy endpoints include improvements in MMSE, MoCA, CDR, and ADL scores, indicating potential cognitive benefits and enhanced daily functioning. Secondary endpoints will analyze biomarkers to evaluate disease progression and inflammation levels before and after treatment.

CONCLUSION: This trial aims to determine the safety, feasibility, and potential effectiveness of RIC as a multi-target intervention for mild Alzheimer's dementia by integrating cognitive and neuropsychological assessments with biological markers, providing a foundation for future studies.},
}

@article {pmid40630497,
year = {2025},
author = {Stites, SD and Schumann, R and Kuz, C and Harkins, K and Largent, E and Krieger, A and Sankar, P and Zuelsdorff, M},
title = {Are Knowledge and Interpersonal Contact Cures for Alzheimer's Stigma? Data From Caregivers Offer Clues.},
journal = {Stigma and health},
volume = {10},
number = {2},
pages = {199-213},
pmid = {40630497},
issn = {2376-6972},
abstract = {Research on caregivers suggests interpersonal contact with persons with Alzheimer's disease (AD) and higher disease-oriented knowledge may heighten AD stigma, though these same mechanisms are often employed in anti-stigma campaigns. If we better understand associations among caregiver experience, interpersonal contact, AD knowledge and AD stigma, we can develop improved ways of reducing stigma and avoid unintended consequences. In a factorial design experiment, 2,371 participants read a vignette describing a fictional person; the vignette varied on clinical symptom stage, AD biomarker result, and treatment availability. Multivariable analyses assessed effects of caregiver experience, interpersonal contact, and different domains of disease-oriented knowledge on modified Family Stigma in Alzheimer's Disease Scale (FS-ADS) outcomes. Interaction analyses tested how clinical features may modify those associations. AD caregiver experience was associated with higher reactions on 6 of 7 FS-ADS domains. Disease-oriented knowledge, independent of content domain, did not substantially affect those associations. However, knowledge of caregiving, treatment, and life impact associated with lower FS-ADS scores, and knowledge about disease course and risk factors associated with higher reactions on FS-ADS domains. Knowledge of treatment modified reactions to symptoms and treatment availability. Knowledge of disease course modified reactions to a biomarker result. AD caregiver experience and interpersonal contact did not modify associations between clinical characteristics and FS-ADS domains. Distinct associations among different domains of AD knowledge and stigma outcomes should be considered when developing anti-stigma campaigns. Failure to do so risks worsening rather than alleviating AD stigma.},
}

@article {pmid40629890,
year = {2025},
author = {Loring, DW and Hermann, BP and Meador, KJ and Lah, JJ and Goldstein, FC and Bilder, RM},
title = {Would a rose by any other name smell as sweet? Complexity, context, and consequences of neuropsychology performance labels.},
journal = {The Clinical neuropsychologist},
volume = {},
number = {},
pages = {1-9},
doi = {10.1080/13854046.2025.2529530},
pmid = {40629890},
issn = {1744-4144},
abstract = {Objective: The American Academy of Clinical Neuropsychology (AACN) has proposed standardized performance labels to enhance consistency in neuropsychological reporting. While valuable in forensic and medicolegal contexts, these guidelines may limit interpretive flexibility and clinical relevance in diverse practice settings. This manuscript examines the contextual appropriateness of AACN labels across diverse clinical and research settings, highlighting the need for diagnostic flexibility over rigid adherence to normative descriptors. Methods: We reviewed the historical and conceptual underpinnings of neuropsychological assessment, focusing on Ward Halstead's distinction between "biological" and "psychometric" intelligence. This framework was used to explore how interpretive models shape clinical reasoning and test interpretation. Special attention was given to the implications of score labeling in multidisciplinary team settings (e.g. dementia diagnosis, epilepsy surgery and within large-scale research initiatives, including Alzheimer's Disease Research Centers (ADRCs). Conclusions: Although AACN performance labels support greater transparency and consistency in select contexts, their universal implementation may obscure meaningful cognitive patterns and diminish diagnostic precision. Labels such as "below average" may fail to capture clinically meaningful decline in high-functioning individuals or obscure clinically relevant cognitive patterns critical for diagnosis and treatment planning. We argue for a context-sensitive approach to score interpretation that allows flexible, informed use of descriptors aligned with specific referral questions and clinical goals. Neuropsychological assessment is most effective when guided by integrative clinical reasoning rather than uncritical application of standardized labeling conventions.},
}

@article {pmid40629265,
year = {2025},
author = {Wang, J and Liu, C and Dai, Y and Mei, C and Wang, G and Wang, Y and Huang, T and Zhan, J and Cheng, J},
title = {Efficacy of music therapy as a non-pharmacological measure to support alzheimer's disease patients: a systematic review.},
journal = {BMC geriatrics},
volume = {25},
number = {1},
pages = {508},
pmid = {40629265},
issn = {1471-2318},
support = {S202410488180X,202310488043X//Key Laboratory Open Fund of Ministry of Education College Student Innovation and Entrepreneurship Project/ ; OHIC2024G07, OHIC2024Z04//Occupational Hazard Identification and control Key laboratory of Hubei Province open fund/ ; 2023KF002//Ministry of Education/ ; WJ2023M107//Health Commission of Hubei Province scientific research project/ ; },
mesh = {Humans ; *Music Therapy/methods ; *Alzheimer Disease/therapy/psychology ; Quality of Life/psychology ; Treatment Outcome ; Cognitive Dysfunction/therapy/psychology ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is a degenerative disease of the central nervous system characterized by progressive memory degradation and language and behavior disorders. Apart from curative pharmacological therapies, music therapy (MT) has been diffusely used as an efficient and economical non-pharmacological treatment for AD patients in recent years.

METHODS: Three databases (PubMed, Web of Science and PsycINFO) were searched to analyse the efficacy of MT in patients with AD. Keywords included "Alzheimer's disease", "AD", "Mild Cognitive Impairment", "MCI", "music" and "music therapy".

RESULTS: Literatures between January 2013 and January 2023 were selected, with 42 literatures included in the study, which highlights the beneficial impact of MT on cognition (memory, attention, language), behavioural and psychological symptoms (anxiety, depression and agitation), quality of life, self-esteem and physical pain in AD patients.

CONCLUSION: MT is a promising non-pharmacological treatment approach for individuals living with AD. However, further evidences from prospective, randomised, blinded, uniform, and rigorous method-logical investigations in this field are required to conclusively validate MT's impact on this disease. PROSPERO REGISTRATION NUMBER: CRD420251034039.},
}

Humans
*Music Therapy/methods
*Alzheimer Disease/therapy/psychology
Quality of Life/psychology
Treatment Outcome
Cognitive Dysfunction/therapy/psychology

@article {pmid40628581,
year = {2025},
author = {Amano, T and Inoue, M and Dixit, S and Tarafder, A},
title = {Ethnoracial Disparities in Advance Care Planning Among People With Alzheimer's Disease and Related Dementias.},
journal = {The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jagp.2025.06.006},
pmid = {40628581},
issn = {1545-7214},
abstract = {OBJECTIVES: This study aims to investigate racial/ethnic variations in advance care planning (ACP) among people with Alzheimer's disease and related dementias (ADRD) and identify race/ethnicity-specific correlates of ACP.

METHODS: The study used data from four waves of the Health and Retirement Study (HRS, 2012-2018). We included 5,420 observations with dementia, which was estimated using the machine-learning based Gianattasio-Power algorithm. Five types of engagement in ACP were measured: durable power of attorney, living will, future treatment discussion, limiting medical treatment, and number of ACP engaged. Besides ethnoracial identity, potential correlates of ACP were selected based on the literature. Regression analyses with subgroup analyses by race/ethnicity were performed.

RESULTS: Ethnoracial identity was significantly associated with the likelihood of ACP engagement. The association between ethnoracial identity and the number of ACP engagement was significant after adjusting for covariates. Non-Hispanic Black (Risk Ratio [RR] = 0.670, 95% Confidence Interval [CI] = [0.607, 0.740]) and Hispanic (RR= 0.597, 95% CI = [0.518, 0.688]) individuals with ADRD engaged in fewer ACP than non-Hispanic White counterparts. Factors such as gender, marital status, household wealth and income, number of ADL difficulty, number of health conditions, self-rated health, and nursing home residency were differentially associated with the number of ACP engagement among three ethnoracial groups.

CONCLUSIONS: The prevalence of engagement in ACP varies across ethnoracial groups. Non-Hispanic Black and Hispanic individuals are less likely to engage in various aspects of ACP than their non-Hispanic white counterparts. Race/ethnicity-specific correlates of ACP should be considered to develop equitable strategies that promote ACP among diverse populations.},
}

@article {pmid40627107,
year = {2025},
author = {Mushtaq, T and Hameed, H and Cláudia Paiva-Santos, A and Tariq, U and Hameed, A},
title = {Exosome-Mediated Delivery of Amyloid Beta Modulators: A Potential Therapeutic Strategy for Alzheimer's Disease.},
journal = {Molecular neurobiology},
volume = {},
number = {},
pages = {},
pmid = {40627107},
issn = {1559-1182},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the deposition of amyloid-beta (Aβ) plaques and tau protein abnormalities, disrupting synaptic function and causing progressive cognitive decline. However, significant efforts in research are still hampered by current treatments, which are limited by poor penetration of the BBB and non-specific effects. Recent developments in nanotechnology and drug delivery have found exosomes as innovative carriers targeting Aβ. They have identified a novel approach to treating the underlying pathology of AD. Exosomes are naturally occurring extracellular vesicles with several unique advantages. They are biocompatible, can cross the BBB, and can be engineered to deliver therapeutic agents with precision. These agents range from small interfering RNA (siRNA), peptides, or drugs designed to either inhibit Aβ aggregation, enhance its clearance, or regulate the genes involved in its production. Among these agents, neural-derived exosomes offer great promise as they naturally attract neuronal tissue and, therefore, increase the specificity of the treatment. In preclinical studies, such therapies have proven encouraging by demonstrating reduced Aβ accumulation, a decrease in neuroinflammation, and cognitive improvement in models of AD. However, translation into clinical application faces some challenges, such as development of scalable methods of exosome production, drug loading efficiency, stability, and safety upon administration. The present review takes an outlook toward the growing area of targeting Aβ pathology via exosomes with potential benefits, recent breakthroughs, and open challenges. Harnessed therapy from exosomes can create groundbreaking-therapies in treating AD that hope for millions to come out from this devastator disease.},
}

@article {pmid40626308,
year = {2025},
author = {Aktary, N and Jeong, Y and Oh, S and Shin, Y and Sung, Y and Rahman, M and Ramos Santiago, L and Choi, J and Song, HG and Nurkolis, F and Ribeiro, RIMA and Park, MN and Kim, B},
title = {Unveiling the therapeutic potential of natural products in Alzheimer's disease: insights from in vitro, in vivo, and clinical studies.},
journal = {Frontiers in pharmacology},
volume = {16},
number = {},
pages = {1601712},
pmid = {40626308},
issn = {1663-9812},
abstract = {Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder described as progressive cognitive decline and neuronal dysfunction, affecting millions globally. While current pharmacological treatments provide symptomatic relief and modestly slow disease progression, they fail to address the underlying pathophysiology and are often accompanied by severe adverse effects. This underscores the urgent need for innovative, multi-target therapeutic strategies that can effectively step in AD's complex pathogenesis. Emerging evidence highlights the therapeutic potential of natural products, particularly herbal medicines, as versatile modulators of key pathogenic processes in AD. These compounds exert neuroprotective effects by mitigating oxidative stress, suppressing neuroinflammation, inhibiting tau hyperphosphorylation, and reducing amyloid-beta aggregation. Additionally, they strengthen synaptic plasticity and stabilize mitochondrial function, offering a holistic approach to disease control. This comprehensive review synthesizes findings from network pharmacology, in vitro and in vivo studies, and clinical trials to evaluate the role of natural products in AD treatment. Advances in bioinformatics and systems biology facilitate the mapping of intricate protein-protein interactions, the identification of potential biomarkers, and the clarification of molecular mechanisms underlying AD progression. Integrating phytochemicals with conventional AD medications may improve therapeutic efficacy through synergistic mechanisms; however, pharmacokinetic interactions and safety considerations must be rigorously assessed. Notably, clinical trials investigating compounds such as curcumin, resveratrol, and ginsenosides suggest promising adjunctive benefits when incorporated into established treatment regimens. Furthermore, the convergence of herbal therapeutics with modern pharmacology presents an avenue for customized and integrative AD management. This review also emphasizes advancements in experimental models, including brain organoids and transgenic animals, which serve as crucial platforms for mechanistic studies and therapeutic validation. Ongoing trials on plant-derived compounds continue to pave the way for translational applications, reinforcing the viability of natural product-based interventions. By advocating a multidisciplinary framework that merges traditional medicine, modern pharmacology, and precision medicine, this work contributes to reshaping the AD landscape of therapy. It provides a roadmap for future research, fostering novel treatment paradigms that prioritize efficacy, safety, and sustainability in combating this disastrous disorder.},
}

@article {pmid40625312,
year = {2025},
author = {Hsieh, SW and Hsiao, CY and Yang, YH and Hsieh, HM},
title = {Healthcare related costs associated with donepezil use in patients with very mild dementia due to Alzheimer's disease: A retrospective observational study.},
journal = {Journal of Alzheimer's disease reports},
volume = {9},
number = {},
pages = {25424823251356233},
pmid = {40625312},
issn = {2542-4823},
abstract = {BACKGROUND: The cost-effectiveness of Donepezil in mild to severe Alzheimer's disease (AD) has been widely studied, but research on very mild dementia (VMD) remains limited.

OBJECTIVE: This retrospective observational study evaluated the efficacy of Donepezil in patients with VMD in two hospitals in southern Taiwan between 2011 and 2019.

METHODS: We recruited 909 VMD patients with a Clinical Dementia Rating (CDR) of 0.5 and used propensity score matching to create two groups: 352 receiving Donepezil and 352 not. Demographic data, Mini-Mental State Examination (MMSE), and healthcare costs were analyzed over 1-year and 3-year periods.

RESULTS: At baseline, Donepezil treatment was associated with lower inpatient, outpatient, and overall healthcare costs. After 1 year, outpatient drug costs increased, while inpatient drug costs decreased, leading to higher overall healthcare drug costs. Over 3 years, outpatient drug continued to rise, while inpatient drug costs remained stable, leading to higher overall healthcare drug costs. Donepezil users had significantly more outpatient visits, but inpatient admissions were unaffected. Patients receiving Donepezil were older and had lower MMSE; male gender, Parkinsonism, chronic lung disease, and liver disease were less common in this group.

CONCLUSIONS: Although Donepezil users initially had lower healthcare costs, overall healthcare drug costs increased in the Donepezil group at both the 1-year and 3-year follow-ups, while inpatient drug costs were only reduced in the short term.},
}

@article {pmid40625063,
year = {2025},
author = {Kiviniemi, V and Helakari, H and Raitamaa, L and Huotari, N and Rajna, Z and Järvelä, M and Elabasy, A and Tuunanen, J and Poltojainen, V and Väyrynen, T and Tuovinen, T and Kananen, J and Korhonen, V},
title = {Ultrafast Imaging of Physiological Brain Pulsations With Magnetic Resonance Encephalography-From Noise to Predictive Clinical Biomarker.},
journal = {NMR in biomedicine},
volume = {38},
number = {8},
pages = {e70092},
doi = {10.1002/nbm.70092},
pmid = {40625063},
issn = {1099-1492},
support = {2022-120//EU JPND/ ; 2017-2021//Jane & Aatos Erkko Foundation/ ; 210043//Jane & Aatos Erkko Foundation/ ; 275342//Research Council of Finland/ ; 338599//Research Council of Finland/ ; 314497//Aivosäätiö TERVA/ ; //Uniogs Oulu Doctoral Program/ ; //Pohjois-Suomen Terveydenhuollon Tukisäätiö/ ; //The Finnish Medical Foundation/ ; //Finnish Neurological Foundation/ ; //Finnish Government Funding for Research/OUH/ ; //Orion Research Foundation/ ; //Medical Research Center (MRC)-OUH/ ; //Maire Taponen Foundation/ ; //The Finnish Brain Foundation/ ; //Instrumentarium Science Foundation/ ; //The University of Oulu Scholarship Foundation/ ; //Emil Aaltonen Foundation/ ; //Suorsa Foundation/ ; },
mesh = {Humans ; *Brain/physiology ; *Magnetic Resonance Imaging/methods ; Biomarkers/metabolism ; Animals ; },
abstract = {Over the past decade, novel in vivo imaging techniques have revealed that physiological pulsations drive the transport of brain solutes and that impairment of fluid flow precedes certain neuropathologies. Although the pioneering investigations on brain solute transport mechanisms mainly employed imaging of exogenous tracers, novel advanced ultrafast functional MRI sequences enable critical sampling of propagating physiological pulsations driving the brain fluids devoid of aliased mixing of signals. In this review, we summarize the emerging magnetic resonance encephalography (MREG) technique, beginning with a historical perspective and physiological background of the phenomena of brain pulsatility as measured in the parenchyma and cerebrospinal fluid (CSF). We give a detailed account of how functional contrast mechanisms evident in the T2(*)-weighted MREG signal enable the simultaneous mapping of three distinct physiological signals. Our narrative review continues with an account of signal analysis and methodological considerations arising from 12 years of experience in ultrafast brain scanning. Our review concludes with a presentation of how sleep-related physiological changes in the driving pulsations influence solute transport in a healthy brain and our perspective on the potential of these pulsations as emerging biomarkers for predictive, diagnostic, and treatment monitoring in the context of Alzheimer's disease and other central nervous system (CNS) conditions.},
}

Humans
*Brain/physiology
*Magnetic Resonance Imaging/methods
Biomarkers/metabolism
Animals

@article {pmid40624595,
year = {2025},
author = {Price, D and Cramer, J and Rogers, CB and Prajapati, P and Shakhashiro, Y and Nelson, PT and Wang, WX},
title = {Immunoelectron microscopy and biochemical studies using three anti-tau antibodies in human brains: associations between pTau and ribosomes.},
journal = {Acta neuropathologica communications},
volume = {13},
number = {1},
pages = {150},
pmid = {40624595},
issn = {2051-5960},
support = {P20GM103436/NH/NIH HHS/United States ; P30 AG072946/NH/NIH HHS/United States ; },
mesh = {Humans ; *tau Proteins/metabolism/immunology ; Microscopy, Immunoelectron/methods ; *Brain/metabolism/pathology/ultrastructure ; *Neurofibrillary Tangles/metabolism/pathology/ultrastructure ; *Ribosomes/metabolism/ultrastructure/pathology ; Aged ; Female ; Male ; Aged, 80 and over ; *Alzheimer Disease/pathology/metabolism ; Middle Aged ; Antibodies ; },
abstract = {The hallmark neuropathological lesions of Alzheimer's disease (AD) are extracellular amyloid-beta (Aβ) plaque deposits and intracellular Tau neurofibrillary tangles (NFTs). Identifying the intracellular localization of early pathologic changes can enhance our understanding of disease mechanisms and stimulate new approaches in diagnosis and treatment. Despite extensive biochemical studies of AD-related protein aggregates, there have been relatively few studies recently in terms of transmission electron microscopy of proteinaceous lesions in human brains across a range of disease severity. Here we performed immunoelectron microscope studies used three anti-Tau antibodies (MC-1, AT8, and PHF-1) on short post-mortem interval (PMI) human brain tissues obtained from the University of Kentucky Alzheimer's Disease Research Center (UK-ADRC) autopsy cohort, along with corresponding biochemical and immunofluorescent studies. Although these three antibodies have been reported to label different phases of NFT formation, in our hands they all tended to stain pathologic structures along a continuum that included pretangles and mature NFTs. Immunoelectron microscopy studies, augmented by serial sectioning, revealed that all three Tau antibodies recognize both granular and fibrillary structures in pretangles and early-stage NFTs. Phosphorylated Tau (pTau) immunoreactivity often exhibited a peri-nuclear distribution. The pTau was frequently found localized to ribosomes, either free within the cytoplasm or attached to the endoplasmic reticulum (ER). This observation aligns with previous descriptions, but the enhanced ultrastructural preservation provided improved resolution. Subcellular fractionation and Western blot analyses confirmed the enrichment of pTau in the ER fractions in AD brains. Interestingly, total Tau (including non-phosphorylated Tau) did not preferentially co-purify with the ER in non-AD brains. Immunofluorescent staining revealed that pTau immunoreactivity evolved from cytoplasmic granules in pretangles, with an intracytoplasmic distribution that overlapped complementarily with ribosome and ER markers. Our results suggest that biochemical associations between pTau with ribosomes and ER are a common phenomenon in human aged brains.},
}

Humans
*tau Proteins/metabolism/immunology
Microscopy, Immunoelectron/methods
*Brain/metabolism/pathology/ultrastructure
*Neurofibrillary Tangles/metabolism/pathology/ultrastructure
*Ribosomes/metabolism/ultrastructure/pathology
Aged
Female
Male
Aged, 80 and over
*Alzheimer Disease/pathology/metabolism
Middle Aged
Antibodies

@article {pmid40624486,
year = {2025},
author = {Wang, Y and Yu, Q and Chen, B and Zhou, J and Li, Z and Liao, W and Liu, J and Yang, A},
title = {Two cases of Amyloid-Related Imaging Abnormalities (ARIA) following lecanemab treatment for alzheimer's disease and a literature review.},
journal = {BMC neurology},
volume = {25},
number = {1},
pages = {281},
pmid = {40624486},
issn = {1471-2377},
abstract = {OBJECTIVE: To investigate the imaging characteristics and management strategies of amyloid-related imaging abnormalities (ARIA) in Alzheimer's disease (AD) patients treated with lecanemab.

METHODS: We report two clinical cases of ARIA following lecanemab treatment and analyze the imaging features, risk factors, and management strategies of ARIA based on the latest literature.

RESULTS: The occurrence of ARIA is associated with risk factors such as advanced age, ApoE ε4 carrier status, cerebral amyloid angiopathy (CAA), and a history of cerebrovascular disease.

CONCLUSION: During lecanemab treatment for AD, it is essential to fully understand the mechanisms, imaging characteristics, and management strategies of ARIA. Close monitoring of clinical symptoms and imaging changes is crucial for the timely detection and appropriate management of ARIA.},
}

@article {pmid40622958,
year = {2025},
author = {Zhai, C and Cai, J and Du, M and Fei, Y and Wu, Q},
title = {Assessing Microglial Phagocytosis of Myelin Debris in vitro Under Repeated Magnetic Stimulation.},
journal = {Journal of visualized experiments : JoVE},
volume = {},
number = {220},
pages = {},
doi = {10.3791/67642},
pmid = {40622958},
issn = {1940-087X},
mesh = {*Microglia/cytology/physiology/metabolism ; *Phagocytosis/physiology ; *Myelin Sheath/metabolism ; Animals ; Coculture Techniques/methods ; Mice ; },
abstract = {Microglia, the resident phagocytes of the central nervous system (CNS), play a pivotal role in maintaining CNS integrity and homeostasis by removing damaged cells, cellular debris, and myelin remnants. The accumulation of myelin debris is implicated in a range of CNS disorders, including multiple sclerosis, Alzheimer's disease, traumatic brain injury, and spinal cord injury. The presence of myelin debris not only exacerbates neuroinflammation but also hampers the regenerative potential of myelin. Therefore, enhancing the ability of microglia to clear myelin debris through phagocytosis represents a promising therapeutic strategy. Magnetic stimulation has emerged as an innovative treatment modality for CNS diseases, with growing evidence suggesting its potential to promote microglial phagocytosis and support CNS recovery. To further elucidate the effects of magnetic stimulation on microglial clearance of myelin debris, we designed an in vitro experiment involving the co-culture of microglia and myelin debris. The co-culture was subjected to repetitive magnetic stimulation to assess its impact on microglial phagocytic activity in the context of CNS pathology.},
}

*Microglia/cytology/physiology/metabolism
*Phagocytosis/physiology
*Myelin Sheath/metabolism
Animals
Coculture Techniques/methods
Mice

@article {pmid40622710,
year = {2025},
author = {Cai, Y and Fang, L and Yang, J and Zhou, X and Liu, L and Li, A and Sun, P and Lan, G and He, Z and Zhu, Y and Zhang, L and Jiang, M and Yu, X and Liu, Z and Guo, T and , },
title = {Higher Educational Attainment and Accelerated Tau Accumulation in Alzheimer Disease.},
journal = {JAMA neurology},
volume = {},
number = {},
pages = {},
doi = {10.1001/jamaneurol.2025.1801},
pmid = {40622710},
issn = {2168-6157},
abstract = {IMPORTANCE: The impact of educational attainment (EA) on longitudinal tau accumulation remains largely underexplored.

OBJECTIVE: To investigate the association of EA with tau accumulation in Alzheimer disease (AD).

This cohort study used 3 independent samples: the Alzheimer's Disease Neuroimaging Initiative (ADNI; October 2015-July 2022, mean follow-up: 3.0 years), Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease study (A4; 2014-2022, mean follow-up: 4.7 years), and Greater-Bay-Area Healthy Aging Brain Study (GHABS; July 2021-August 2024, mean interval from plasma collection to tau positron emission tomography [PET]: 1.0 years). The ADNI and GHABS represent Northern American and Southern Chinese populations, respectively. A4 is a multicenter trial. Participants with amyloid β (Aβ) and subsequent tau PET were included from ADNI, A4, and GHABS, and a subset had plasma phosphorylated tau (p-tau) 217 (p-tau217) and resting-state functional magnetic resonance imaging (RS-fMRI) data. Data were analyzed from July 2022 to January 2025.

EXPOSURES: EA, Aβ-PET, tau-PET, plasma p-tau217, and RS-fMRI.

MAIN OUTCOMES AND MEASURES: Participants were classified as high EA and low EA based on median years of EA. Longitudinal tau changes were compared across Aβ-PET positivity and EA groups. Interactions of EA status with Aβ burden, entorhinal tau, and plasma p-tau217 on tau accumulation were investigated in Aβ-positive (Aβ+) individuals. Connectivity-associated tau spread was compared across different Aβ/EA groups. Whether or not Aβ-targeting treatment attenuated tau accumulation in Aβ+ high-EA individuals was also evaluated.

RESULTS: This study included 887 participants: 377 from ADNI (mean [SD] age, 73.3 [7.2] years; 191 female [50.7%]), 395 from A4 (mean [SD] age, 71.9 [4.8] years; 223 female [56.5%]), and 115 from GHABS (mean [SD] years, 66.0 [7.4] years; 76 female [66.1%]). In the Aβ-negative group, high-EA individuals exhibited slower tau accumulation than low-EA individuals (right middle temporal gyrus: estimate = -0.002; 95% CI, -0.003 to -0.0002; P = .03). Conversely, higher EA in the Aβ+ group was correlated with accelerated tau accumulation (left middle temporal gyrus: estimate = 0.003; 95% CI, 0.0003-0.005; P = .03) and stronger Aβ-associated (left visual region: estimate = 0.38; 95% CI, 0.11-0.65; P = .006), entorhinal tau-associated (left middle temporal gyrus: estimate = 0.35; 95% CI, 0.08-0.63; P = .01), and plasma p-tau217-associated tau accumulation (left inferior temporal gyrus: estimate = 0.46; 95% CI, 0.02-0.90; P = .04), as well as increased connectivity-associated tau spread compared with lower EA (estimate = 0.33; 95% CI, 0.003-0.67; P = .048). Aβ-targeting treatment appeared to mitigate plasma p-tau217-associated tau accumulation in patients with AD and higher EA (estimate = -0.52; 95% CI, -0.80 to -0.24; P < .001).

CONCLUSIONS AND RELEVANCE: Results of this cohort study suggest that higher EA was associated with faster tau accumulation and spread in Aβ+ individuals, highlighting the importance of Aβ clearance in mitigating tau progression in patients with AD and higher EA.},
}

@article {pmid40621927,
year = {2025},
author = {Shiqing, Y and Xinjie, L and Xiaotong, Z and Jiayan, C and Jiahai, L and Xiaodong, C and Yongliang, L and Xiang, L},
title = {Clostridium butyricum enhances cognitive function in APP/PS1 mice by modulating neuropathology and regulating acetic acid levels in the gut microbiota.},
journal = {Microbiology spectrum},
volume = {},
number = {},
pages = {e0017825},
doi = {10.1128/spectrum.00178-25},
pmid = {40621927},
issn = {2165-0497},
abstract = {The amyloid deposition-to-cognitive impairment pathway is crucial in Alzheimer's disease (AD) pathogenesis, with gut microbes influencing its development. Our study evaluated Clostridium butyricum MIYAIRI 588 (CBM588) as a potential AD treatment. In APP/PS1 mice, CBM588 improved cognitive function and alleviated colonic tissue pathology by modulating tight junction proteins (upregulating Claudin 1, ZO-1, and Occludin) and reducing inflammatory cytokines (IL-6, IL-1β, and TNF-α mRNA). It also reduced Aβ plaque deposition in the brain, regulated the JNK/CDK5/GSK-3β pathway to inhibit Tau hyperphosphorylation, and maintained neuronal integrity by downregulating Bax/Bcl-2 and inflammatory cytokines, thereby inhibiting apoptosis. While not altering the overall gut flora structure, CBM588 increased acetate-producing bacteria and decreased pro-inflammatory genera, reducing lipopolysaccharide levels. It also elevated short-chain fatty acids, particularly acetate, in colonic feces and brain tissue. Sodium acetate further inhibited BV2 cell apoptosis by suppressing JAK/STAT signaling and reducing Aβ and p-Tau expressions. In conclusion, CBM588 holds great potential as a novel probiotic for AD control.IMPORTANCEThe current study underscores the pivotal role of gut microbiota modulation in the treatment of Alzheimer's disease(AD). Our comprehensive evaluation of CBM588 demonstrates its remarkable potential to ameliorate cognitive impairment in APP/PS1 mice by modulating gut microbiota composition, upregulating short-chain fatty acids, particularly acetate, and mitigating neuroinflammation. These findings not only provide novel insights into the gut-brain axis in AD but also offer a promising therapeutic strategy, highlighting the importance of targeting gut microbiota in future AD research and interventions.},
}

@article {pmid40621876,
year = {2025},
author = {Wu, CY and Chen, L and Dickson, JR and Zhang, B and Arnold, SE and Dodge, HH},
title = {Synthetic control methods for n-of-1 and parallel-group trials in Alzheimer's disease: A proof-of-concept study using the I-CONECT.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {7},
pages = {e70460},
doi = {10.1002/alz.70460},
pmid = {40621876},
issn = {1552-5279},
support = {R01AG051628/AG/NIA NIH HHS/United States ; R01AG056102/AG/NIA NIH HHS/United States ; K01AG088184/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *Alzheimer Disease/drug therapy/therapy ; Proof of Concept Study ; Male ; Female ; *Research Design ; Aged ; Treatment Outcome ; Reproducibility of Results ; },
abstract = {INTRODUCTION: With the advent of Alzheimer's disease (AD)-modifying and symptomatic treatments of demonstrated efficacy, enrolling participants as concurrent placebo controls in trials can become increasingly difficult. Synthetic controls have been proposed as a viable alternative to concurrent control groups, but their feasibility and reliability remain untested in AD studies.

METHODS: I-CONECT trial, which evaluates conversational interactions on cognition, was used to test synthetic control methods. Data from the National Alzheimer's Coordinating Center-Uniform Data Set was used to create synthetic-controls for I-CONECT participants using two methods: 1) case mapping and 2) case modeling. Efficacy estimates were compared between original versus synthetic-controlled trials.

RESULTS: In parallel-group designs, treatment effect sizes for the primary outcome were closely aligned between the original trial (β = 1.67) and synthetic control analyses (β = 1.40-1.65). For n-of-1 designs, the two methods showed high agreement in identifying treatment responders (Kappa = 0.75-0.82).

DISCUSSION: Synthetic control methods are feasible and reliable to create alternative controls in AD studies.

CLINICAL TRIAL REGISTRATION: NCT02871921.

HIGHLIGHTS: Synthetic control methods are feasible and suitable for evaluating treatment effects in various trial designs such as n-of-1, single-arm, and parallel groups. Synthetic control methods can help replicate early-phase Alzheimer's trials, informing go/no-go decisions for larger-scale studies. The choice of similarity algorithms is critical as it affects the quality of historical case mapping. The National Alzheimer's Coordinating Center-Uniform Data Set (NACC-UDS) provided an ideal pool for identifying historical cases with similar demographic, biological, and social characteristics to participants in trials, enabling the creation of synthetic control groups for Alzheimer's clinical research.},
}

Humans
*Alzheimer Disease/drug therapy/therapy
Proof of Concept Study
Male
Female
*Research Design
Aged
Treatment Outcome
Reproducibility of Results

@article {pmid40621760,
year = {2025},
author = {Rathee, S and Pandey, V and Soni, S and Sen, D and Jain, SK},
title = {Comprehending Alzheimer's Disease: Molecular Mechanisms and Treatment Strategies.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050368798250626075628},
pmid = {40621760},
issn = {1875-5828},
abstract = {Alzheimer's disease (AD) is a complex neurodegenerative disorder and a growing global health challenge, driven by increasing life expectancy and an aging population. This review provides a comprehensive exploration of AD pathophysiology, integrating current hypotheses such as the amyloid cascade, tau protein pathology, cholinergic dysfunction, neuroinflammation, vascular contributions, and potential infection-related mechanisms. The multifactorial etiology of AD, encompassing genetic predispositions and environmental factors, underscores its intricate nature. This study delves into the diagnostic advancements, including the identification and utilization of biomarkers for early detection and disease monitoring. Therapeutic approaches are critically evaluated, highlighting anti-amyloid and anti-tau strategies, alongside emerging innovations in stem cell therapy and nanobiotechnology. A detailed examination of clinical trials offers insights into the achievements and setbacks of translating research into effective treatments. By synthesizing epidemiological trends, molecular mechanisms, and therapeutic developments, this review aims to advance our understanding of AD and foster collaborative efforts to develop transformative solutions. It emphasizes the urgency of addressing this multifaceted disease, presenting a nuanced perspective on its complexity while illuminating future directions for research and clinical practice.},
}

@article {pmid40621512,
year = {2025},
author = {Yi, Y and Deng, X},
title = {Efficacy of donepezil combined with rehabilitation training in the treatment of Alzheimer's disease.},
journal = {Pakistan journal of medical sciences},
volume = {41},
number = {6},
pages = {1612-1617},
pmid = {40621512},
issn = {1682-024X},
abstract = {OBJECTIVE: To examine the efficacy of donepezil combined with rehabilitation training for treating Alzheimer's disease (AD) and its impact on nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF).

METHODS: This single center retrospective analysis was conducted at the First Affiliated Hospital of Chongqing Medical and Pharmaceutical College and included 184 patients with AD treated between January 2022 to May 2024. Of them, 92 patients who received donepezil combined with rehabilitation training (combined group) were matched in a 1:1 ratio with a cohort that received donepezil alone (donepezil group). The treatment efficacy, cognitive function, ability to engage in daily living activity before and after the treatment, serum NGF and BDNF levels, and incidence of adverse reactions were compared between the two groups.

RESULTS: The total efficacy of patients in the combined group was higher than that of the donepezil group (P<0.05). After the treatment, mini-mental state examination (MMSE) and activity of daily living (ADL) scores of patients in the combined group were significantly higher than in the donepezil group (P<0.05). In contrast, the combined treatment method was associated with considerably lower Alzheimer's disease assessment scale-cognitive subscale (ADAS-Cog) scores (P<0.05). Patients who received the combined treatment had significantly higher serum NGF and BDNF levels than those treated by donepezil alone (P<0.05).

CONCLUSIONS: Compared with donepezil alone, the combination of donepezil and rehabilitation training is associated with significantly improved therapeutic effects and better serum NGF and BDNF levels.},
}

@article {pmid40621323,
year = {2025},
author = {Chundu, UC and Thiriveedhi, SR and Bhatti, C and Mupparaju, JS and Otinashvili, N and Gelishvili, E},
title = {A Systematic Review of the Efficacy and Safety of Anti-amyloid Monoclonal Antibodies in Alzheimer's Disease.},
journal = {Cureus},
volume = {17},
number = {6},
pages = {e85377},
pmid = {40621323},
issn = {2168-8184},
abstract = {Monoclonal antibody (mAb) therapies targeting amyloid-beta (Aβ) plaques have gained prominence over the past decade as potential disease-modifying treatments for Alzheimer's disease (AD), leading to major regulatory approvals and global debate. Nonetheless, the central question persists: does this emerging therapy have a justified role in the treatment protocol for AD? This systematic review evaluates the efficacy and safety of these agents across phase II and III clinical trials conducted in the past decade (2014-2024), aligning with the timeline when disease-modifying therapies gained momentum. A systematic search was performed across PubMed and the Cochrane Library to identify phase II and III randomized controlled trials (RCTs) conducted between January 2014 and December 2024. The inclusion criteria focused on studies that evaluated cognitive outcomes using scales such as the Clinical Dementia Rating-Sum of Boxes (CDR-SB), Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), and Mini-Mental State Examination (MMSE). Additionally, trials assessing biomarkers, including CSF measures and PET imaging, were included. Safety outcomes, particularly amyloid-related imaging abnormalities (ARIA), were also systematically analyzed. Due to heterogeneity in outcome measures, a narrative synthesis was conducted. Sixteen RCTs met the inclusion criteria. Lecanemab reduced amyloid burden with 81% of patients achieving amyloid-negative PET scans (Clarity AD trial) and showed a 27% reduction in cognitive decline on the ADCOMS scale. While statistically significant, the 27% ADCOMS (Alzheimer's Disease Composite Score) reduction warrants comparison to MCID (minimal clinically important difference) thresholds (e.g., ~0.5-1.0 points for CDR-SB in early AD) to assess real-world impact. Donanemab demonstrated 76% plaque clearance and a 35% slowing in cognitive decline in early AD patients. Aducanumab showed dose-dependent effects on plaque clearance but had inconsistent cognitive outcomes and higher ARIA rates. Recent mAb trials provide promising evidence for disease modification in early AD stages, particularly with lecanemab and donanemab. However, variability in cognitive outcomes and safety concerns warrant cautious interpretation and long-term validation.},
}

@article {pmid40620970,
year = {2025},
author = {Chatzipieris, FP and Kokkalis, A and Georgiou, N and Petsas, E and Apostolou, EV and Vougioukalakis, GC and Mavromoustakos, T},
title = {New Prospects in the Inhibition of Monoamine Oxidase‑B (MAO-B) Utilizing Propargylamine Derivatives for the Treatment of Alzheimer's Disease: A Review.},
journal = {ACS omega},
volume = {10},
number = {25},
pages = {26208-26232},
pmid = {40620970},
issn = {2470-1343},
abstract = {It is well-known that monoamine oxidase (MAO) plays a pivotal role in neurodegeneration and the inhibition of this enzyme can manifest antidepressant properties as well as have a positive impact in Alzheimer's and Parkinson's diseases. MAO has two isoforms: MAO-A and MAO-B. The main hMAO-B inhibitors used for the treatment of Alzheimer's and Parkinson's diseases, encompass a terminal triple bond in their structure, which provides their potency. Recently, a new class of inhibitors has emerged, bearing the carbon-carbon triple bond not necessarily at the end of the chain. In this review, the structure and physiological function of the MAO enzymes is discussed, the general synthetic procedures of propargylamines, as well as their mechanism of inhibition. Moreover, it is highlighted the current development and discovery of potential hMAO-B inhibitors from propargylamine scaffolds, showcasing their structure-activity relationships (SARs) with the enzyme. Conformational relationships' analysis is performed as well. Induced fit docking is performed, also, to the most potent compounds revealed in order to assess their binding energy and interactions with the enzyme. Finally, molecules which do not contain a propargylamine moiety in their structure were studied and compared against a known hMAO-B inhibitor, deprenyl. From the superimposition results of these molecules with deprenyl, as well as the interactions of the molecules with the amino acids of the active site of hMAO-B, it appears that these compounds have several similarities with deprenyl, opening new paths for the creation of novel molecules against Alzheimer's disease (AD).},
}

@article {pmid40620684,
year = {2025},
author = {Chen, P and Wang, F and Ling, B and Zhu, Y and Lin, H and Huang, J and Wang, X},
title = {Mesenchymal Stem Cell-Derived Extracellular Vesicles: Emerging Therapies for Neurodegenerative Diseases.},
journal = {International journal of nanomedicine},
volume = {20},
number = {},
pages = {8547-8565},
pmid = {40620684},
issn = {1178-2013},
mesh = {Humans ; *Extracellular Vesicles/transplantation/metabolism ; *Neurodegenerative Diseases/therapy ; *Mesenchymal Stem Cells/cytology/metabolism ; Animals ; Mesenchymal Stem Cell Transplantation ; },
abstract = {Neurodegenerative diseases are a group of chronic diseases characterized by a gradual loss of neurons that worsens over time and dysfunction. These diseases are extremely harmful, not only affecting the physical health of the patients, but also having a serious impact on their quality of life. They mainly include Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), Amyotrophic lateral sclerosis (ALS), etc. Their pathogenesis is complex, and it is difficult for the existing treatments to effectively slow down the progression of the disease. In recent years, Mesenchymal Stem Cells (MSCs) have received widespread attention for their anti-inflammatory, immunomodulatory and neuroprotective properties. In this context, MSC-derived Extracellular Vesicles (MSC-EVs) have demonstrated unique therapeutic potential as a cell-free therapeutic strategy. MSC-EVs are rich in bioactive substances such as proteins, lipids, mRNAs and miRNAs, which can pass through the blood-brain barrier and be targeted to the diseased area to regulate neuronal survival, synaptic plasticity and neuroinflammatory responses. In addition, compared with stem cell therapy, MSC-EVs have the advantages of low immunogenicity, easy storage and transportation, and avoiding ethical controversies. However, their clinical application still faces challenges: standardized isolation and purification techniques have not been unified, vesicle loading efficiency and targeting need to be further optimized, and long-term safety needs to be systematically evaluated. This review focuses on the role of MSC-EVs in the development of neurological diseases and explores their possible dual roles, both favorable and unfavorable, in the context of neurological diseases. In addition, this review provides a review of current studies on EVs as potential biomarkers for the diagnosis and treatment of neurodegenerative diseases and provides a comprehensive review of the prospects and challenges of MSC-EVs in clinical applications.},
}

Humans
*Extracellular Vesicles/transplantation/metabolism
*Neurodegenerative Diseases/therapy
*Mesenchymal Stem Cells/cytology/metabolism
Animals
Mesenchymal Stem Cell Transplantation

@article {pmid40620322,
year = {2025},
author = {Zarei, M and Sabetkasaei, M and Mozafari, M and Zaeri, S},
title = {The expanding role of semaglutide: beyond glycemic control.},
journal = {Journal of diabetes and metabolic disorders},
volume = {24},
number = {2},
pages = {160},
pmid = {40620322},
issn = {2251-6581},
abstract = {Semaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1RA), has transformed the treatment landscape for type 2 diabetes and obesity due to its robust efficacy and wide-ranging therapeutic benefits. This review outlines semaglutide's diverse mechanisms of action, including its roles in glucose homeostasis, weight reduction, and cardiovascular protection. Data from the SUSTAIN and PIONEER clinical trials demonstrate significant reductions in HbA1c, body weight, and major adverse cardiovascular events (MACE), firmly establishing semaglutide as a key agent in diabetes management. The STEP trials further highlight its exceptional effectiveness in weight control, with participants achieving up to 20% weight loss alongside improvements in obesity-related comorbidities. Moreover, ongoing studies such as the FOCUS trial are investigating its impact on microvascular complications. Beyond glycemic control, semaglutide exhibits renoprotective, anti-inflammatory, and potential hepatoprotective effects. Emerging evidence also supports its expanding role in the management of non-alcoholic fatty liver disease (NAFLD), heart failure, polycystic ovary syndrome (PCOS), obstructive sleep apnea (OSA), alcohol use disorder (AUD), and Alzheimer's disease. While gastrointestinal side effects are the most commonly reported adverse events, long-term studies affirm its overall safety and tolerability. The availability of both subcutaneous and oral formulations further enhances treatment adherence and accessibility. As a result, semaglutide has emerged as a cornerstone therapy for a broad spectrum of metabolic, cardiovascular, and neuroendocrine disorders. Future research should continue to explore its therapeutic potential in under-studied populations, including individuals with non-diabetic cardiovascular disease and hepatic fibrosis.},
}

@article {pmid40619807,
year = {2025},
author = {Demirsoy, İ},
title = {Tau Pathology in the Medial Temporal Lobe and Neocortex: Implications for Cognitive Unimpaired in Cognitively Unimpaired Older Adults.},
journal = {Balkan medical journal},
volume = {42},
number = {4},
pages = {329-338},
doi = {10.4274/balkanmedj.galenos.2025.2025-2-93},
pmid = {40619807},
issn = {2146-3131},
mesh = {Humans ; Female ; Male ; Aged ; *Neocortex/physiopathology/pathology ; *Temporal Lobe/physiopathology/pathology ; Aged, 80 and over ; *tau Proteins/analysis ; Retrospective Studies ; Positron-Emission Tomography/methods ; *Cognition/physiology ; Alzheimer Disease/physiopathology ; Neuropsychological Tests ; },
abstract = {BACKGROUND: The accumulation of proteins such as amyloid-beta and tau, which disrupt normal cellular processes, characterizes Alzheimer's disease (AD). Cognitive decline is strongly linked to tau pathology, which initially manifests in the medial temporal lobe (MTL).

AIMS: To investigated the association between cognitive performance and regional tau accumulation, as measured by positron emission tomography (PET) imaging, in cognitively normal older adults. Understanding this relationship is critical for early intervention before noticeable cognitive decline emerges.

STUDY DESIGN: Retrospective study.

METHODS: Tau PET scans were conducted on 440 participants enrolled in the anti-amyloid treatment in asymptomatic Alzheimer's (A4) study. The participants, aged 65-85, were cognitively unimpaired and had complete demographic and genetic profiles. Tau levels in the MTL and temporal neocortex (NEO) was quantified using composite metrics. Cognitive function was evaluated using the preclinical Alzheimer's cognitive composite (PACC) and its individual components. Multiple linear regression models were applied to determine the associations between tau burden and cognitive outcomes, including interaction terms to evaluate the moderating roles of sex and apolipoprotein E (APOE)-ε4 genotype.

RESULTS: The average participant age was 71.8 years (standard deviation = 4.84), with females comprising 58% of the sample. Greater tau accumulation in both tauMTL and tauNEO regions was significantly associated with lower cognitive scores. Specifically, reduced PACC scores (p < 0.001) corresponded with higher tau levels in both regions, primarily influenced by declines in Delayed Logical Memory and Free and Cued Selective Reminding test scores. Additionally, tauNEO levels were modestly linked to Mini-Mental State Examination scores. The effects of sex and APOE-ε4 status were minimal.

CONCLUSION: Elevated tau deposition in the MTL and NEO is associated with diminished cognitive function, particularly in memory and processing speed domains. Notably, tau accumulation in the MTL showed a strong association with poorer outcomes on memory-related cognitive measures. The limited influence of sex and APOE-ε4 genotype highlights tau pathology as a key contributor to early cognitive decline in preclinical AD.},
}

Humans
Female
Male
Aged
*Neocortex/physiopathology/pathology
*Temporal Lobe/physiopathology/pathology
Aged, 80 and over
*tau Proteins/analysis
Retrospective Studies
Positron-Emission Tomography/methods
*Cognition/physiology
Alzheimer Disease/physiopathology
Neuropsychological Tests

@article {pmid40619654,
year = {2025},
author = {Jaitawat, DPS and Singh, I and Chauhan, SB},
title = {Next-Generation Phospholipid Nanocomplexes for Precision Neurotherapeutics: Harnessing Endogenous Blood-Brain Barrier Transport Mechanisms to Revolutionize the Treatment of Neurodegenerative Diseases.},
journal = {Recent advances in drug delivery and formulation},
volume = {},
number = {},
pages = {},
doi = {10.2174/0126673878361646250623062415},
pmid = {40619654},
issn = {2667-3886},
abstract = {The treatment of neurodegenerative illnesses remains a substantial problem due to the blood-brain barrier's restrictive nature, which restricts therapeutic agent penetration. Phospholipid Nanocomplexes (PNCs) have emerged as next-generation neurotherapeutics, utilizing natural BBB transport pathways to improve drug delivery. These nanocarriers, with lipid-based architectures, allow for receptor-mediated transcytosis, lipid raft-mediated transport, and adsorptive-mediated endocytosis, resulting in precise and sustained drug release inside the central nervous system. Recent preclinical and clinical studies have shown that PNC-based formulations of neurotrophic factors, antioxidants, and gene-silencing therapies significantly improve neuronal survival, cognitive function, and neuroprotection in conditions like Alzheimer's Disease (AD), Parkinson's Disease (PD), Glioblastoma (GBM), and multiple sclerosis. Despite the positive outcomes, issues such as scalability, long-term safety, and regulatory approval remain. This study critically assesses the present status of PNC-based neurotherapeutics, emphasizing their benefits over traditional therapies, analyzing the most recent clinical trial outcomes, and assessing difficulties and future prospects. To improve PNC effectiveness, the potential for artificial intelligence-driven medication design, multifunctionalized nanocarriers, and hybrid biomaterial methods is investigated. As biocompatible and patientspecific nanomedicine advances, PNCs represent a breakthrough approach to precision neuroscience, providing tailored, efficient, and safer therapies for neurodegenerative diseases.},
}

@article {pmid40619622,
year = {2025},
author = {Campbell, JL},
title = {Exploring Interprofessional Collaboration and Patient-Centered Care for People Living With Dementia.},
journal = {Home healthcare now},
volume = {43},
number = {4},
pages = {197-205},
pmid = {40619622},
issn = {2374-4537},
mesh = {Humans ; *Patient-Centered Care/organization & administration ; *Dementia/therapy/nursing ; Caregivers/psychology ; *Interprofessional Relations ; *Cooperative Behavior ; Quality of Life ; Patient Care Team/organization & administration ; *Home Care Services/organization & administration ; },
abstract = {Alzheimer's disease and other dementias are expected to affect millions of individuals in the coming decades, placing a growing burden on healthcare systems, families, and caregivers. Current approaches to dementia care are often fragmented, marked by poor coordination and limited communication among healthcare providers. This lack of integration contributes to delayed diagnoses, inadequate treatment, and heightened caregiver stress. This article emphasizes the critical role of inter-professional collaboration (IPC) in addressing these challenges and improving outcomes for people living with dementia (PLWD). Effective IPC involves coordinated efforts among physicians, nurse practitioners, nurses, home health aides, therapists, and social workers to deliver comprehensive, patient-centered care that meets the complex cognitive, physical, and psychosocial needs of PLWD. By implementing an organized, multidisciplinary approach, healthcare systems can not only improve quality of care but also reduce caregiver burden and improve the quality of life for individuals affected by dementia.},
}

Humans
*Patient-Centered Care/organization & administration
*Dementia/therapy/nursing
Caregivers/psychology
*Interprofessional Relations
*Cooperative Behavior
Quality of Life
Patient Care Team/organization & administration
*Home Care Services/organization & administration

@article {pmid40619245,
year = {2025},
author = {Sueyoshi, M and Harada, K and Okawa, M and Matsuhara, T and Ando, M and Araki, R and Minote, Y and Ishihara, K and Shimohama, S and Takata, K},
title = {Stimulation of α7 Nicotinic Acetylcholine Receptors by PNU282987 Demonstrates Efferocytosis-Like Activation and Neuroprotection in Human Models of Microglia and Cholinergic Neurons under the Pathophysiological Conditions of Alzheimer's Disease.},
journal = {Biological & pharmaceutical bulletin},
volume = {48},
number = {7},
pages = {972-985},
doi = {10.1248/bpb.b25-00308},
pmid = {40619245},
issn = {1347-5215},
mesh = {*alpha7 Nicotinic Acetylcholine Receptor/agonists/metabolism ; *Microglia/drug effects/metabolism ; *Alzheimer Disease/drug therapy/metabolism ; *Benzamides/pharmacology/therapeutic use ; Animals ; Humans ; Amyloid beta-Peptides/metabolism ; Phagocytosis/drug effects ; Mice ; *Cholinergic Neurons/drug effects/metabolism ; *Bridged Bicyclo Compounds/pharmacology ; *Neuroprotective Agents/pharmacology/therapeutic use ; Male ; Induced Pluripotent Stem Cells/drug effects ; Disease Models, Animal ; Mice, Inbred C57BL ; *Nicotinic Agonists/pharmacology ; Efferocytosis ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-β (Aβ) peptide accumulation, leading to neuroinflammation and neurodegeneration. In early AD stages, neurodegeneration of basal forebrain cholinergic neurons occurs. Microglia, which are brain immune cells, contribute to Aβ clearance and neuroinflammation. This study investigated the therapeutic effects of PNU282987, a selective full agonist of α7 nicotinic acetylcholine receptor (nAChR), using human models of microglia (hiMacs) and basal forebrain cholinergic neurons (hiBFChNs), both differentiated from human induced pluripotent stem cells (hiPSCs). Our findings indicated that PNU282987 markedly enhanced Aβ phagocytosis by microglia and extracellular Aβ clearance. Furthermore, PNU282987 injection reduced Aβ accumulation in the brain of a mouse model. Treatment of hiMacs with PNU282987 upregulated the expressions of efferocytosis-related genes, such as ASAP2, OSM, and THBD. Efferocytosis-like activation by PNU282987 in hiMacs was further suggested by an increased release of the anti-inflammatory cytokine interleukin-10 (IL-10), along with suppression of the pro-inflammatory cytokine IL-1β produced from microglia with Aβ treatment. This indicates a transformation from Aβ-induced inflammatory phagocytosis to an efferocytosis-like anti-inflammatory phagocytosis. PNU282987 also exerted direct neuroprotective effects on hiBFChNs against Aβ and tumor necrosis factor-α. Furthermore, PNU282987 changed the extracellular contents released from Aβ-treated hiMacs and attenuated the neurotoxicity. These results suggest that α7 nAChR stimulation by PNU282987 enhances the therapeutic effects against AD by promoting Aβ clearance with anti-neuroinflammatory regulation in the microglia and providing direct protection to neurons, thereby addressing the inflammatory and neurodegenerative aspects of AD.},
}

*alpha7 Nicotinic Acetylcholine Receptor/agonists/metabolism
*Microglia/drug effects/metabolism
*Alzheimer Disease/drug therapy/metabolism
*Benzamides/pharmacology/therapeutic use
Animals
Humans
Amyloid beta-Peptides/metabolism
Phagocytosis/drug effects
Mice
*Cholinergic Neurons/drug effects/metabolism
*Bridged Bicyclo Compounds/pharmacology
*Neuroprotective Agents/pharmacology/therapeutic use
Male
Induced Pluripotent Stem Cells/drug effects
Disease Models, Animal
Mice, Inbred C57BL
*Nicotinic Agonists/pharmacology
Efferocytosis

@article {pmid40618273,
year = {2025},
author = {Huang, Y and Chen, Y and He, Z and Lu, W and Lai, H and Wang, Y and Wang, J},
title = {MicroRNA and Alzheimer's disease: Diagnostic biomarkers and potential therapeutic targets.},
journal = {Neural regeneration research},
volume = {},
number = {},
pages = {},
doi = {10.4103/NRR.NRR-D-25-00002},
pmid = {40618273},
issn = {1673-5374},
abstract = {MicroRNAs (miRNAs), small non-coding RNAs ranging from 19 to 25 nucleotides in length, are key regulators of gene expression that function primarily by inhibiting the translation of target mRNAs. Recent studies have suggested that miRNAs play important roles in regulating key aspects in the pathology of Alzheimer's disease, including the modulation and accumulation of amyloid-beta and tau proteins. Moreover, miRNAs have been implicated in the regulation of neuroinflammation through various inflammatory pathways, notably the nuclear factor kappa B signaling cascade. Additional emerging evidence has shown that miRNAs regulate synaptic growth and maturation, and they perform promising roles in regulating neuronal death and development. miRNAs also offer a novel avenue for direct reprogramming of neurons, representing a promising strategy for Alzheimer's disease treatment. The regulation of miRNA biogenesis and the post-transcriptional modifications of miRNAs are critical factors in Alzheimer's disease pathology, influencing miRNA activity and disease progression. In this review, we comprehensively explore the role of different miRNAs in regulating various pathological processes associated with Alzheimer's disease, focusing primarily on four representative miRNAs: miR-9, miR-29, miR-126, and miR-146a for further exploration. We also discuss the influence of miRNA biogenesis on Alzheimer's disease, emphasizing how dysregulation of miRNA processing may contribute to the disease. Additionally, we highlight the potential of miRNAs as both diagnostic biomarkers and therapeutic targets in Alzheimer's disease, along with promising vector delivery strategies aimed at improving clinical outcomes. Finally, we discuss the challenges and limitations associated with the use of miRNAs in the diagnosis and treatment of Alzheimer's disease. By reviewing the current clinical applications of miRNAs as biomarkers and therapeutic agents, we aim to provide insights that will inform future research and development in this promising field.},
}

@article {pmid40618175,
year = {2025},
author = {Chen, W and Liao, Y and Shi, X and Su, F and Kong, H and Fang, Y and Zheng, Y and Zhou, J and Liu, G and Zhou, X and Yao, X and Ashford, CB and Li, F and Yang, L and Bergeron, MF and Ashford, JW and Zhang, X and Pei, Z},
title = {Predicting brain amyloid load with digital and blood-based biomarkers.},
journal = {Alzheimer's research & therapy},
volume = {17},
number = {1},
pages = {149},
pmid = {40618175},
issn = {1758-9193},
support = {82071255,82271266,82271448,82401672//National Natural Science Foundation of China/ ; 82071255,82271266,82271448,82401672//National Natural Science Foundation of China/ ; 82071255,82271266,82271448,82401672//National Natural Science Foundation of China/ ; 82071255,82271266,82271448,82401672//National Natural Science Foundation of China/ ; 2020B1212060017//Guangdong Provincial Key Laboratory of Diagnosis and Treatment of Major Neurological Diseases/ ; 2020B1212060017//Guangdong Provincial Key Laboratory of Diagnosis and Treatment of Major Neurological Diseases/ ; 2020B1212060017//Guangdong Provincial Key Laboratory of Diagnosis and Treatment of Major Neurological Diseases/ ; 2020B1212060017//Guangdong Provincial Key Laboratory of Diagnosis and Treatment of Major Neurological Diseases/ ; 2020B1212060017//Guangdong Provincial Key Laboratory of Diagnosis and Treatment of Major Neurological Diseases/ ; 2020B1212060017//Guangdong Provincial Key Laboratory of Diagnosis and Treatment of Major Neurological Diseases/ ; 2020B1212060017//Guangdong Provincial Key Laboratory of Diagnosis and Treatment of Major Neurological Diseases/ ; 2020B1111170002//Guangdong Provincial Clinical Research Center for Neurological Diseases/ ; 2020B1111170002//Guangdong Provincial Clinical Research Center for Neurological Diseases/ ; 2020B1111170002//Guangdong Provincial Clinical Research Center for Neurological Diseases/ ; 2020B1111170002//Guangdong Provincial Clinical Research Center for Neurological Diseases/ ; 2020B1111170002//Guangdong Provincial Clinical Research Center for Neurological Diseases/ ; 2020B1111170002//Guangdong Provincial Clinical Research Center for Neurological Diseases/ ; 2020B1111170002//Guangdong Provincial Clinical Research Center for Neurological Diseases/ ; 2015B050501003 and 2020A0505020004//Southern China International Joint Research Center for Early Intervention and Functional Rehabilitation of Neurological Diseases/ ; 2015B050501003 and 2020A0505020004//Southern China International Joint Research Center for Early Intervention and Functional Rehabilitation of Neurological Diseases/ ; 2015B050501003 and 2020A0505020004//Southern China International Joint Research Center for Early Intervention and Functional Rehabilitation of Neurological Diseases/ ; 2015B050501003 and 2020A0505020004//Southern China International Joint Research Center for Early Intervention and Functional Rehabilitation of Neurological Diseases/ ; 2015B050501003 and 2020A0505020004//Southern China International Joint Research Center for Early Intervention and Functional Rehabilitation of Neurological Diseases/ ; 2015B050501003 and 2020A0505020004//Southern China International Joint Research Center for Early Intervention and Functional Rehabilitation of Neurological Diseases/ ; 2015B050501003 and 2020A0505020004//Southern China International Joint Research Center for Early Intervention and Functional Rehabilitation of Neurological Diseases/ ; 201604020010//Guangdong Provincial Engineering Center for Major Neurological Disease Treatment, Guangdong Provincial Translational Medicine Innovation Platform for Diagnosis and Treatment of Major Neurological Disease, Guangzhou Clinical Research and Translational Center for Major Neurological Diseases/ ; 201604020010//Guangdong Provincial Engineering Center for Major Neurological Disease Treatment, Guangdong Provincial Translational Medicine Innovation Platform for Diagnosis and Treatment of Major Neurological Disease, Guangzhou Clinical Research and Translational Center for Major Neurological Diseases/ ; 201604020010//Guangdong Provincial Engineering Center for Major Neurological Disease Treatment, Guangdong Provincial Translational Medicine Innovation Platform for Diagnosis and Treatment of Major Neurological Disease, Guangzhou Clinical Research and Translational Center for Major Neurological Diseases/ ; 201604020010//Guangdong Provincial Engineering Center for Major Neurological Disease Treatment, Guangdong Provincial Translational Medicine Innovation Platform for Diagnosis and Treatment of Major Neurological Disease, Guangzhou Clinical Research and Translational Center for Major Neurological Diseases/ ; 201604020010//Guangdong Provincial Engineering Center for Major Neurological Disease Treatment, Guangdong Provincial Translational Medicine Innovation Platform for Diagnosis and Treatment of Major Neurological Disease, Guangzhou Clinical Research and Translational Center for Major Neurological Diseases/ ; 201604020010//Guangdong Provincial Engineering Center for Major Neurological Disease Treatment, Guangdong Provincial Translational Medicine Innovation Platform for Diagnosis and Treatment of Major Neurological Disease, Guangzhou Clinical Research and Translational Center for Major Neurological Diseases/ ; 201604020010//Guangdong Provincial Engineering Center for Major Neurological Disease Treatment, Guangdong Provincial Translational Medicine Innovation Platform for Diagnosis and Treatment of Major Neurological Disease, Guangzhou Clinical Research and Translational Center for Major Neurological Diseases/ ; 2019QN01Y139//Young Talent Recruitment Project of Guangdong/ ; ZDSYS20220606100803007//Shenzhen Key Laboratory for Systems Medicine in Inflammatory Diseases/ ; 2022YFA1104904//National Key Research and Development Program of China/ ; },
mesh = {Humans ; *Amyloid beta-Peptides/blood/metabolism ; Biomarkers/blood ; Male ; Female ; Aged ; *Alzheimer Disease/blood/diagnosis/diagnostic imaging/metabolism ; *Brain/metabolism/diagnostic imaging ; Positron-Emission Tomography ; tau Proteins/blood ; Aged, 80 and over ; Machine Learning ; Peptide Fragments/blood ; Middle Aged ; Neuropsychological Tests ; Cognitive Dysfunction/blood/diagnosis ; Glial Fibrillary Acidic Protein/blood ; },
abstract = {BACKGROUND: With the recent approval of anti-β-amyloid (Aβ) treatment for Alzheimer's disease (AD), a demand has emerged for scalable, convenient and accurate estimations of brain Aβ burden for the detection of AD that would enable timely, accurate and reliable diagnosis in one's primary care physician's (PCPs) office as called for recently by World Health Organization (WHO).

METHODS: MemTrax, a 2-minute online memory test, was selected as the digital biomarker of cognitive impairment, and blood-based biomarkers (BBMs) including Aβ42, Aβ40, P-tau181, GFAP and NfL were used to estimate AD-related metrics in different groups of elderly individuals (n = 349) for comparison with Aβ PET scans of brain Aβ burden. The correlations between MemTrax, MoCA, BBMs and brain Aβ burden, expressed in centiloid (CL) values, were analyzed for predicting CL value alone or in combinations using machine-learning (ML).

RESULTS: Both MemTrax and the MoCA were able to differentiate Aβ status similarly. Integration of MemTrax and BBMs using ML, however, significantly improved the AUCs (over the same with MoCA) for differentiating Aβ status. MemTrax and p-Tau181/Aβ42 composite showed the strongest relationship with CL value among other BBMs. Most importantly, regression analyses of MemTrax and p-Tau181/Aβ42 aptly predicted CL values.

CONCLUSION: The combination of MemTrax and BBMs provides an accurate, convenient, non-invasive, cost-effective and scalable way to estimate Aβ load, which provides an opportunity for mass screening and timely and accurate diagnosis of AD. Our findings could also facilitate more effective AD clinical management in the PCPs office worldwide for more equitable access to current standard of care.},
}

Humans
*Amyloid beta-Peptides/blood/metabolism
Biomarkers/blood
Male
Female
Aged
*Alzheimer Disease/blood/diagnosis/diagnostic imaging/metabolism
*Brain/metabolism/diagnostic imaging
Positron-Emission Tomography
tau Proteins/blood
Aged, 80 and over
Machine Learning
Peptide Fragments/blood
Middle Aged
Neuropsychological Tests
Cognitive Dysfunction/blood/diagnosis
Glial Fibrillary Acidic Protein/blood

@article {pmid40616751,
year = {2025},
author = {Wei, X and Liu, X and Ban, Y and Li, J and Huang, R},
title = {Silencing NRBP1 Gene with shRNA Improves Cognitive Function and Pathological Features in AD Rat Model.},
journal = {Biochemical genetics},
volume = {},
number = {},
pages = {},
pmid = {40616751},
issn = {1573-4927},
support = {NO.2023D01C150//National Natural Science Foundation of Xinjiang Uyghur Autonomous Region/ ; },
abstract = {Alzheimer's disease (AD) is a prevalent neurodegenerative condition in the elderly, characterized by complex pathogenesis, and a current absence of specific treatment. This study aimed to investigate the effectiveness of silencing the NRBP1 gene using siRNA technology to improve cognitive function and pathological features in an AD rat model. An AD rat model was induced by intraperitoneal injections of D-galactose and oral AlCl3 administration over 90 days, thus replicating early-stage AD pathology. The rats were randomly assigned to the Blank control (Blank), AD model (AD), AD model + shRNA negative control (AD + Neg), and AD model + NRBP1-shRNA groups (AD + shRNA), initiating experiments at 30, 60, and 90 days.Cognitive function was assessed through the Morris water maze test, revealing that rats in the AD + shRNA group showed significantly reduced latency, swim time, swim distance, and crossing times compared to the AD and AD + Neg groups (P < 0.05), with no significant difference from the Blank group. Thioflavin-S fluorescence staining demonstrated a significant reduction in the number, average area, and burden of plaques in the hippocampal tissue of the AD + shRNA group compared to the AD and AD + Neg groups (P < 0.05). ELISA assays confirmed a notable decrease in Aβ1-42 levels in the hippocampal tissue of the AD + shRNA group compared to the AD and AD + Neg groups (P < 0.05). Fluorescence quantitative PCR analysis revealed a significant downregulation of NRBP1 gene expression in the hippocampal tissue of the AD + shRNA group (P < 0.05).In conclusion, using siRNA to silence the NRBP1 gene demonstrates potential in enhancing cognitive function and reducing pathological features in an AD rat model. This provides preliminary evidence that justifies further investigation into its mechanistic and therapeutic implications.},
}

@article {pmid40616321,
year = {2025},
author = {Zhao, NN and Yu, T and Zhou, CM and Si, HX and Hao, YF and Li, C and Wang, H and Du, Y and Zhang, W},
title = {FK506 reverses neuropathology and cognitive impairment in APPswe/PS1dE9 mice.},
journal = {Neurological research},
volume = {},
number = {},
pages = {1-11},
doi = {10.1080/01616412.2025.2528156},
pmid = {40616321},
issn = {1743-1328},
abstract = {BACKGROUND: Alzheimer's disease (AD), a chronic and progressive neurodegenerative disease, is the most common cause of dementia. An important pathological basis for AD lesions is the excessive generation and deposition of β-amyloid (Aβ) caused by increased expression of the β-secretase, known as the β-site amyloid precursor protein cleaving enzyme 1 (BACE1). Effective suppression of the BACE1 overexpression has become a key AD treatment. Nuclear factor of activated T cells (NFAT) is a key transcription factor that regulates the expression of BACE1 in AD lesions, while Calcineurin (CaN) is a key regulatory protein that affects the transcription function of NFAT. Several lines of evidence have indicated that FK506 may promote the Aβ degradation via upregulation of the matrix metalloproteinase-9 (MMP-9) expression, which is associated with reduction of Aβ plaque deposition in the cerebral cortex and hippocampus.

METHODS: In this study, behavioral, histological, and biochemical methods were used to investigate the key role and molecular mechanisms of CaN inhibitor FK506 in cognitive dysfunction, regulation of BACE1 expression, and Aβ production in APPswe/PS1dE9 transgenic mice. Results The results indicate that FK506 inhibits NFAT1 levels in the cerebral cortex and hippocampus, thereby reducing the expression of BACE1 and mediating APP processing towards non-amyloidosis pathways, significantly reducing Aβ overproduction, which in turn saved cognitive deficits in APPswe/PS1dE9 transgenic mice. In addition, FK506 treatment had no significant effect on the expression of a disintegrin and metalloprotease (ADAM10) in α - secretase.

CONCLUSIONS: FK506 rescues cognitive deficits in APPswe/PS1dE9 mice by reducing Aβ production and deposition in the brain.},
}

@article {pmid40616254,
year = {2025},
author = {Bleibtreu, E and Riese, F},
title = {Cost of Psychiatric Inpatient Treatment for Dementia in Switzerland: A Case-Level Analysis of Billing Data.},
journal = {International journal of geriatric psychiatry},
volume = {40},
number = {7},
pages = {e70122},
doi = {10.1002/gps.70122},
pmid = {40616254},
issn = {1099-1166},
mesh = {Humans ; Switzerland ; *Dementia/economics/therapy ; Male ; Female ; Aged ; *Hospital Costs/statistics & numerical data ; Aged, 80 and over ; *Hospitalization/economics ; Length of Stay/economics ; *Hospitals, Psychiatric/economics ; },
abstract = {OBJECTIVE: The objective of this study was to investigate the cost of care for patients with a primary diagnosis of dementia in Swiss hospitals under the new TARPSY reimbursement system.

METHODS: We used a dataset of the Swiss hospital reimbursement system TARPSY from 2016 to 2019, including all relevant remuneration variables at the patient level, to investigate hospital costs. Costs were analyzed by geographic location and hospital type. Homogeneity coefficients were used to analyze case cost homogeneity.

RESULTS: We identified 7090 cases in the TARPSY database who were treated in Swiss hospitals under the primary diagnosis of dementia from 2016 to 2019. Of these, 6747 cases were included in our analysis. The total case costs and daily costs increased from 2016 to 2019, whereas the length of stay decreased. The average total case cost in 2019 was CHF 34,917 (σ = 32,926), corresponding to a daily cost of CHF 946 (σ = 373.44). Patients were treated for an average of 39.7 (σ = 32.40) days. In 2019, the total costs billed according to TARPSY for 57,939 days of hospital care for dementia as the primary diagnosis were CHF 51.3 million. The case costs differed by region and hospital type. Overall, cost homogeneity for total case cost as a proxy for the quality of the cost calculation was "satisfactory, sufficient" and did not show a clear trend towards improvement during the introduction of TARPSY.

DISCUSSION: Our analysis provides reliable, case-level cost data for dementia hospital treatment in Switzerland. The total cost of dementia treatment in psychiatric hospitals appears to be much lower than previous estimates had indicated. When correcting for changes in accounting practices, total case costs only increased modestly from 2016 to 2019.},
}

Humans
Switzerland
*Dementia/economics/therapy
Male
Female
Aged
*Hospital Costs/statistics & numerical data
Aged, 80 and over
*Hospitalization/economics
Length of Stay/economics
*Hospitals, Psychiatric/economics

@article {pmid40616109,
year = {2025},
author = {Kawai, R and Kazui, H and Ueba, T and Nakamura, N and Minami, M and Nakajima, M and Yamada, S and Kishima, H and Kanemoto, H and Iseki, C and Mori, E},
title = {Characteristics of patients with idiopathic normal pressure hydrocephalus for whom neurosurgeons hesitate to perform shunt surgery: a nationwide hospital-based survey in Japan.},
journal = {Fluids and barriers of the CNS},
volume = {22},
number = {1},
pages = {69},
pmid = {40616109},
issn = {2045-8118},
support = {JPMH22GB1002//the MHLW Research on Dementia Program/ ; },
mesh = {Humans ; *Hydrocephalus, Normal Pressure/surgery/epidemiology ; Japan/epidemiology ; Aged, 80 and over ; Female ; Male ; *Cerebrospinal Fluid Shunts/statistics & numerical data ; *Neurosurgeons/statistics & numerical data ; Aged ; Surveys and Questionnaires ; *Practice Patterns, Physicians'/statistics & numerical data ; *Neurosurgical Procedures/statistics & numerical data ; },
abstract = {BACKGROUND: There is no consensus regarding the indications for shunt surgery in patients with idiopathic normal pressure hydrocephalus (iNPH) aged ≥ 85 years or in those with severe physical or mental comorbidities. This nationwide study investigates the current approaches of neurosurgeons regarding iNPH treatment and surgical indications.

METHODS: A questionnaire, developed in collaboration with neurosurgeons and dementia specialists, was distributed to 1,220 facilities from October 10, 2023. Responses were collected through December 11, 2023 and analyzed to assess current practices and factors influencing surgical decisions.

RESULTS: In total, 656 facilities (53.8%) responded. Of them, 30 (4.6%) had a policy of not performing shunt surgery at their own facility and referred patients to other appropriate facilities, and 139 (21.2%) did not perform any shunt surgeries in 2022. The most common number of shunt surgeries performed in 2022 was 1-5 surgeries per facility, accounting for 257 facilities (57.1%). Regarding age-related indications for shunt surgery, 159 facilities (35.3%) reported no age restrictions, whereas 155 facilities (57.8%) among the 268 facilities considering age (59.6%) responded that patients aged ≥ 90 years were not indicated for shunt surgery. Among 450 facilities that performed shunt surgeries in 2022, hesitations resulting from comorbidities were reported as follows: cerebrovascular disease (10.0%), orthopedic disease (11.5%), dialysis (29.8%), Parkinson's syndrome (19.5%), Alzheimer's disease (AD) (42.7%), schizophrenia (44.2%), absence of disproportionately enlarged subarachnoid space hydrocephalus (DESH) (41.5%), and insufficient care or institutionalization (56.0%). Logistic regression analyses showed that the number of shunt surgeries performed in 2022 was significant predictor of age ≥ 90 years, cerebrovascular disease, Parkinson's syndrome, AD, no DESH, and insufficient care or institutionalization. Significant predictors for dialysis, AD, and schizophrenia included the presence of collaborating internal medicine facilities. For dialysis and AD, the classification of facilities and having a qualified dementia specialist were significant predictors, respectively.

CONCLUSIONS: A number of Japanese neurosurgeons hesitate to perform shunt surgery in patients with iNPH aged ≥ 90 years, with comorbid AD or schizophrenia, lacking DESH findings, or having insufficient care support or are institutionalized. Multidisciplinary collaboration with internal medicine, including neurology and psychiatry, may help expand appropriate surgical indications for these patients.},
}

Humans
*Hydrocephalus, Normal Pressure/surgery/epidemiology
Japan/epidemiology
Aged, 80 and over
Female
Male
*Cerebrospinal Fluid Shunts/statistics & numerical data
*Neurosurgeons/statistics & numerical data
Aged
Surveys and Questionnaires
*Practice Patterns, Physicians'/statistics & numerical data
*Neurosurgical Procedures/statistics & numerical data

@article {pmid40615880,
year = {2025},
author = {Faridar, A and Gamez, N and Li, D and Wang, Y and Boradia, R and Thome, AD and Zhao, W and Beers, DR and Thonhoff, JR and Nakawah, MO and Román, GC and Volpi, JJ and Toledo, JB and George, M and Davis, CS and Pascual, B and Grundman, M and Masdeu, JC and Appel, SH},
title = {Low-dose interleukin-2 in patients with mild to moderate Alzheimer's disease: a randomized clinical trial.},
journal = {Alzheimer's research & therapy},
volume = {17},
number = {1},
pages = {146},
pmid = {40615880},
issn = {1758-9193},
support = {PTCG-21-1818034/ALZ/Alzheimer's Association/United States ; R01AG077685/NH/NIH HHS/United States ; R01AG077685/NH/NIH HHS/United States ; },
mesh = {Humans ; *Alzheimer Disease/drug therapy/cerebrospinal fluid ; *Interleukin-2/administration & dosage/therapeutic use ; Male ; Female ; Double-Blind Method ; Aged ; *T-Lymphocytes, Regulatory/drug effects ; Middle Aged ; Aged, 80 and over ; Treatment Outcome ; Biomarkers/cerebrospinal fluid/blood ; Dose-Response Relationship, Drug ; },
abstract = {BACKGROUND: We previously documented that regulatory T cells (Tregs) immunomodulatory mechanisms are compromised in Alzheimer's disease (AD), shifting the immune system toward a pro-inflammatory response. However, Tregs are a potentially restorable therapeutic target in AD. In this study, we evaluated the safety and efficacy of two dosing frequencies of low-dose Interleukin-2 (IL-2) in expanding Tregs to modify disease progression in AD individuals.

METHODS: In this phase 2a, randomized, double-blind, placebo-controlled study, 38 participants were assigned to receive subcutaneous IL-2 (10^6 IU/day) for five days, administered either every 4 weeks (IL-2 q4wks) or every 2 weeks (IL-2 q2wks), versus placebo, for 21 weeks, followed by 9 weeks of observation. The primary endpoints were the incidence and severity of adverse events. For the secondary endpoints, changes in Treg numbers and suppressive functions were evaluated. Exploratory endpoints included changes in plasma inflammatory mediators, CSF AD-related biomarkers, and clinical scales.

RESULTS: Of the 38 participants, 9 received IL-2 q4wks, 10 received IL-2 q2wks, and 19 received placebo. All participants completed the trial with no serious adverse events or deaths. Both IL-2 dosing regimens increased Treg numbers and suppressive function, but IL-2 q4wks treatment exhibited superiority in enhancing Treg percentage and Foxp3 mean fluorescent intensity. In longitudinal analysis of 45 inflammatory mediators, IL-2 q4wks administration demonstrated greater efficacy in alleviating the plasma inflammatory mediators CCL2, CCL11, and IL-15, while enhancing IL-4 and CCL13 levels. A significant improvement in CSF Aβ42 levels (p = 0.045 vs. placebo) on Day 148 was observed following IL-2 q4wks administration, compared to placebo. While CSF NfL increased by 217 pg/ml in placebo recipients, it remained stable in the IL-2 q4wks group (p = 0.060, IL-2 q4wks vs. placebo). The adjusted mean change from baseline in the ADAS-cog score at week 22 indicated a trend toward slower clinical progression in IL-2 q4wks recipients compared to placebo (p = 0.061).

CONCLUSIONS: The IL-2 immunotherapeutic strategy was safe and well-tolerated. IL-2 q4wks effectively expanded Treg populations, leading to modification in inflammatory mediators and CSF Aβ42 levels, while also showing promising trends on clinical scales. These findings provide a foundation for further investigation of low-dose IL-2 as a potential treatment for Alzheimer's Disease.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT06096090, Registration Date: 10-17-2023.},
}

Humans
*Alzheimer Disease/drug therapy/cerebrospinal fluid
*Interleukin-2/administration & dosage/therapeutic use
Male
Female
Double-Blind Method
Aged
*T-Lymphocytes, Regulatory/drug effects
Middle Aged
Aged, 80 and over
Treatment Outcome
Biomarkers/cerebrospinal fluid/blood
Dose-Response Relationship, Drug

@article {pmid40614979,
year = {2025},
author = {Xu, C and Shen, P and Li, Q and Ong, SS and Qian, Y and Song, Y and Xu, T},
title = {Combination of electroacupuncture and Liqi Yangyin formula treatment alleviates cognitive impairment and constipation in D-gal-induced mice via modulation of the brain-gut axis.},
journal = {Brain research bulletin},
volume = {},
number = {},
pages = {111451},
doi = {10.1016/j.brainresbull.2025.111451},
pmid = {40614979},
issn = {1873-2747},
abstract = {Mild cognitive impairment (MCI), a precursor to Alzheimer's disease, and constipation, a common gastrointestinal complaint in older adults, frequently co-occur and have been increasingly linked through the gut-brain axis. Emerging evidence suggests that disruptions in gut microbiota and intestinal function may contribute to cognitive decline. However, effective therapeutic strategies that simultaneously address both conditions remain limited. This study investigated the effects of electroacupuncture (EA) combined with the Liqi Yangyin (LQYY) formula on cognitive function and constipation in a D-galactose (D-gal)-induced mouse model of MCI. Forty-five C57BL/6 mice were randomized into five groups: control, D-gal model, EA, EA+LQYY, and donepezil groups. Behavioural tests, including the Y-maze and Morris water maze, were used to assess cognitive performance. Meanwhile, gastrointestinal (GI) transit rate, fecal water content, and histological analysis were conducted to evaluate constipation-related parameters. Intestinal barrier function was assessed via Occludin and ZO-1 protein expression, and levels of 5-hydroxytryptamine (5-HT) and amyloid-beta (Aβ42) were measured in the colon, serum, and hippocampus. Results showed that EA+LQYY significantly improved cognitive performance and alleviated constipation compared to the model group, with superior efficacy to EA alone or donepezil. Mechanistically, EA+LQYY restored intestinal barrier integrity (via upregulation of Occludin and ZO-1), increased 5-HT levels in the gut, serum, and hippocampus, and reduced Aβ42 deposition in the colon, serum, and hippocampus across tissues. These findings suggest that EA+LQYY modulates the gut-brain axis through multi-target mechanisms, offering a promising integrative therapy for MCI and associated constipation. Future studies should explore specific molecular pathways and long-term clinical efficacy to further validate its therapeutic potential.},
}

@article {pmid40614917,
year = {2025},
author = {Ribeiro, R and Leite, FHA and Mendes, GO and Georgia de F T Barbosa, F and Cavalcante, SFA and Franca, TCC and Dos Santos, MC and Veiga-Junior, VF},
title = {Computational investigation of hardwickiic acid-derived amides using molecular docking and prediction of ADME/Tox properties as potential of cholinesterase inhibitors.},
journal = {Chemico-biological interactions},
volume = {},
number = {},
pages = {111631},
doi = {10.1016/j.cbi.2025.111631},
pmid = {40614917},
issn = {1872-7786},
abstract = {This study is a theoretical investigation of amides derived from hardwickiic acid (HA) as potential inhibitors of human acetyl- and butyryl-cholinesterase (hAChE and hBChE) and as drug candidates against Alzheimer's Disease (AD). Twelve compounds were prepared and geometrically optimized using GaussView 5.0.8 and the DFT method with the B3LYP/6-31G basis set to visualize molecular electrostatic potential (MEP) maps and frontier orbitals (HOMO and LUMO). In addition, pharmacokinetic and toxicological properties were studied using the online servers PreADMET and SwissADME. Molecular docking was performed against crystal structures of hAChE and hBChE prepared with the biopolymer module in SYBYL-X 2.0, previously validated. The results revealed similar profiles in surface maps and molecular orbitals for the amide substituent group. Pharmacokinetic predictions demonstrated that all 12 HA amide derivatives showed significant values for blood-brain barrier (BBB) penetration, classifying them as active in the central nervous system (CNS), a crucial pathway for AD treatment. Intermolecular interactions between the compounds and targets suggest that the benzyl amide derivative I had the highest affinity toward the hAChE binding site (-10.1 kcal/mol), while the hydroxy amide derivative L showed the highest affinity for the hBChE binding site (-9.7 kcal/mol). These findings can inform future enzymatic assays of HA amide derivatives against AChE and BChE.},
}

@article {pmid40614664,
year = {2025},
author = {Matar, S and Gomaa, RA and Essawy, A and El Wakil, A},
title = {Human placental extract (HPE) counteracts diabetic brain neurodegeneration by targeting PI3K/mTOR/GSK3β signaling and modulates hippocampal apoptosis and regeneration.},
journal = {Tissue & cell},
volume = {96},
number = {},
pages = {103033},
doi = {10.1016/j.tice.2025.103033},
pmid = {40614664},
issn = {1532-3072},
abstract = {OBJECTIVE: Diabetes mellitus (DM) is closely associated with neurodegeneration, predominantly through impaired insulin signaling and inflammation-driven neuronal cell death. This study aimed to evaluate the neuroprotective effects of human placental extract (HPE) on hippocampal integrity and neurogenesis in a streptozotocin (STZ)-induced diabetic rat model.

METHODS: Male rats were randomly assigned into four groups: control, HPE, STZ, and STZ + HPE. Apoptosis was assessed via flow cytometry using Annexin V-FITC/PI staining, while ELISA measured hippocampal levels of PI3K, mTOR, and GSK3β. Histological and ultrastructural changes were analyzed using toluidine blue staining and transmission electron microscopy (TEM), and immunohistochemical markers GFAP, Ki67, and caspase-3 were used to evaluate astrocyte activation, cell proliferation, and neuronal apoptosis, respectively.

RESULTS: STZ significantly increased early and late apoptotic cells (4.30 ± 0.15 % and 16.21 ± 0.08 %) and necrosis (3.28 ± 0.58 %) while reducing viable cells to 76.05 ± 0.84 %, compared to controls (93.16 ± 0.29 %). HPE treatment of diabetic rats significantly reversed these changes (p < 0.001). Moreover, STZ downregulated PI3K (31.46 ± 2.25 pg/mg) and mTOR (1.59 ± 0.10 ng/mg), while upregulating GSK3β (3.65 ± 0.12 ng/mg). HPE treatment restored PI3K (41.28 ± 2.49 pg/mg), mTOR (2.24 ± 0.15 ng/mg), and reduced GSK3β (2.74 ± 0.28 ng/mg). Histologically, STZ caused degeneration of pyramidal neurons, irregular nuclear membranes, and cytoplasmic vacuolation in the CA3 region, which were ameliorated by HPE. GFAP immunoreactivity, markedly declined in diabetic rats, was augmented following HPE treatment, indicating attenuation of reactive astrogliosis. Additionally, HPE restored Ki67-positive proliferative cells in the CA3 region, reversing the diabetes-induced decline in hippocampal neurogenesis. Caspase-3 immunostaining showed elevated apoptosis in STZ rats, which was significantly reduced by HPE, restoring levels comparable to those of controls and confirming its anti-apoptotic effect.

CONCLUSIONS: HPE significantly mitigates STZ-induced hippocampal damage by restoring insulin signaling (PI3K/mTOR/GSK3β pathway), suppressing apoptosis and inflammation, and promoting neurogenesis. The combined effects on both caspase-3-mediated apoptosis and Ki67-driven proliferation highlight HPE's dual role in neuroprotection and regeneration. These findings support the therapeutic potential of HPE in managing diabetes-associated neurodegenerative changes.},
}

@article {pmid40614624,
year = {2025},
author = {Li, ZH and Liu, HM and Fan, ZY and Pang, W and Cheng, LP},
title = {Design, synthesis and evaluation of vanillin derivatives as dual-target inhibitors for the treatment of Alzheimer's disease.},
journal = {Bioorganic & medicinal chemistry},
volume = {129},
number = {},
pages = {118296},
doi = {10.1016/j.bmc.2025.118296},
pmid = {40614624},
issn = {1464-3391},
abstract = {The purpose of this study is to develop more effective therapeutic agents to slow or prevent Alzheimer's progression. A lead compound ZINC4372573 was identified by using molecular docking and molecular dynamics simulation techniques. A series of novel vanillin derivatives were designed and synthesized as dual inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). The in vitro assay results show that compound 4c exhibits the most potent inhibitory activity against both AChE and BuChE, with IC50 values of 0.18 μM and 7.61 μM, respectively. This performance is superior to the positive control drug galantamine (AChE IC50 = 3.65 μM; BuChE IC50 = 15.29 μM). Molecular docking study reveals that the good activity of 4c may be attributed to the preferable docking mode, robust intermolecular interactions (including π-π stacking and hydrogen bonding), and the superior binding properties of the indole ring. Cytotoxicity test for compound 4c was further performed by CCK-8 method, with results indicating a favorable safety profile. In addition, antioxidant test for 4c reveals its notable antioxidant activity. These findings suggest that 4c holds potential as a promising dual AChE/BuChE inhibitor for the development of novel therapeutic agents targeting Alzheimer's disease. Subsequent investigations will prioritize comprehensive evaluation of in vivo therapeutic efficacy and pharmacokinetic characterization, thereby facilitating translational development toward clinical applications.},
}

@article {pmid40614596,
year = {2025},
author = {Xiong, L and Yu, Q and Chen, L and Deng, Y and Ai, Q and Xu, X and Meng, Z and Chen, F and Zhao, X and Wei, J and Yu, H},
title = {Curcumin analogue C66 ameliorates the pathology of Alzheimer's disease through suppression of JNK signaling pathway.},
journal = {International immunopharmacology},
volume = {162},
number = {},
pages = {115156},
doi = {10.1016/j.intimp.2025.115156},
pmid = {40614596},
issn = {1878-1705},
abstract = {Oxidative stress and neuroinflammation are two key pathological features in the early stage of Alzheimer's disease (AD), and they promote each other to further drive the progression of AD. Therefore, the development of therapeutic agents with dual anti-inflammatory and antioxidant properties represents a promising strategy for AD treatment. C66, a synthetic derivative of curcumin, protected PC12 cells and primary neurons from oxidative damage caused by Aβ. In addition, C66 alleviated Aβ-induced excessive inflammatory response in BV2 cells. Further results showed that C66 reduced neuroinflammation and neuronal apoptosis, ultimately improved cognitive decline in APPswe/PSEN1dE9 (APP/PS1) double transgenic AD mice. Importantly, C66 exhibited superior improved properties in APP/PS1 mice compared with the clinical control drug donepezil. Mechanistically, we indicated that C66 conferred its neuroprotective effects by inhibiting c-Jun N-terminal kinase (JNK) pathway. The result was further confirmed by using SP600125, a specific JNK inhibitor. Together, our findings suggest that C66 is expected to be further developed as a drug candidate for AD therapy.},
}

@article {pmid40612575,
year = {2025},
author = {Alsubai, S and Ojo, S and Nathaniel, TI and Ayari, M and Baili, J and Almadhor, A and Al Hejaili, A},
title = {Transfer deep learning and explainable AI framework for brain tumor and Alzheimer's detection across multiple datasets.},
journal = {Frontiers in medicine},
volume = {12},
number = {},
pages = {1618550},
pmid = {40612575},
issn = {2296-858X},
abstract = {INTRODUCTION: The pressing need for accurate diagnostic tools in the medical field, particularly for diseases such as brain tumors and Alzheimer's, poses significant challenges to timely and effective treatment.

METHODS: This study presents a novel approach to MRI image classification by integrating transfer learning with Explainable AI (XAI) techniques. The proposed method utilizes a hybrid CNN-VGG16 model, which leverages pre-trained features from the VGG16 architecture to enhance classification performance across three distinct MRI datasets: brain tumor classification, Alzheimer's disease detection, and a third dataset of brain tumors. A comprehensive preprocessing pipeline ensures optimal input quality and variability, including image normalization, resizing, and data augmentation.

RESULTS: The model achieves accuracy rates of 94% on the brain tumor dataset, 81% on the augmented Alzheimer dataset, and 93% on the third dataset, underscoring its capability to differentiate various neurological conditions. Furthermore, the integration of SHapley Additive exPlanations (SHAP) provides a transparent view of the model's decision-making process, allowing clinicians to understand which regions of the MRI scans contribute to the classification outcomes.

DISCUSSION: This research demonstrates the potential of combining advanced deep learning techniques with explainability to improve diagnostic accuracy and trust in AI applications within healthcare.},
}

@article {pmid40612293,
year = {2025},
author = {Bayleyegn Derso, T and Mengistu, BA and Demessie, Y and Fenta, MD and Getnet, K},
title = {Neural stem cells in adult neurogenesis and their therapeutic applications in neurodegenerative disorders: a concise review.},
journal = {Frontiers in molecular medicine},
volume = {5},
number = {},
pages = {1569717},
pmid = {40612293},
issn = {2674-0095},
abstract = {The idea of using stem cell therapy to treat neurodegenerative diseases has undergone significant change over the years and has made significant progress recently. Neurotrophins, growth factors, and transcription factors regulate neural stem cell proliferation and differentiation. Disruption of these regulatory mechanisms, including negative feedback, can contribute to neurodegenerative diseases. Contemporary research highlights a growing global concern regarding diverse neurodegenerative disorders affecting both humans and animals. These conditions arise from neuronal cell death, axonal regeneration failure, and impairment of neuronal structure. Current pharmacological treatments primarily offer symptomatic relief without altering disease progression. Consequently, researchers are investigating innovative therapeutic strategies, with neural stem cell therapy emerging as a promising avenue. Adult neural stem cells, embryonic neural stem cells, and induced pluripotent stem cells represent potential cell sources, although challenges such as ethical considerations and technical limitations remain. The therapeutic application of neural stem cells holds significant promise for addressing neurodegenerative diseases, including Alzheimer's disease, stroke, amyotrophic lateral sclerosis, spinal cord injury, and multiple sclerosis. Neural stem cell therapy aims to replenish lost neurons and promote neural regeneration in these conditions. While clinical trials have demonstrated some success in improving cognitive and motor functions in individuals with neurodegenerative impairments, challenges such as immunological rejection, the identification of compatible cell sources, ethical concerns, treatment efficacy, and potential side effects necessitate thorough investigation before widespread clinical implementation. Despite these challenges, neural stem cell-based therapy offers substantial potential for revolutionizing the treatment of neurodegenerative diseases and central nervous system injuries. This paper, therefore, explores adult neurogenesis and the therapeutic potential of neural stem cells within the dynamic field of neurodegenerative disorders.},
}

@article {pmid40611874,
year = {2025},
author = {Tjandra, D and Irwin, C and Migrino, RQ and Giordani, B and Wiens, J},
title = {Estimated Effects of Comorbidities on Risk of All-cause Dementia in Patients with Mild Cognitive Impairment.},
journal = {Sage open aging},
volume = {11},
number = {},
pages = {30495334251347053},
pmid = {40611874},
issn = {3049-5334},
abstract = {INTRODUCTION: Estimating the effects of comorbidities on risk of all-cause dementia (ACD) could potentially better inform prevention strategies and identify novel risk factors compared to more common post-hoc analyses from predictive modeling.

METHODS: In a retrospective cohort study of patients with mild cognitive impairment (MCI) from US Veterans Affairs Medical Centers between 2009 and 2021, we used machine learning techniques from the treatment effect estimation literature to estimate individualized effects of 25 comorbidities (e.g., hypertension) on ACD risk within 10 years of MCI diagnosis. Age and healthcare utilization were adjusted for using exact matching.

RESULTS: After matching, of 19,797 MCI patients, 6,767 (34.18%) experienced ACD onset. Dyslipidemia (percentage point increase of ACD risk range across different treatment effect estimation techniques = 0.009-0.044), hypertension (range = 0.007-0.043), and diabetes (range = 0.007-0.191) consistently had non-zero average effects.

DISCUSSION: Our findings support known associations between dyslipidemia, hypertension, and diabetes that increase the risk of ACD in MCI patients, demonstrating the potential for these approaches to identify novel risk factors.},
}

@article {pmid40611675,
year = {2025},
author = {Shan, G and Zhang, Y and Wang, G and Wu, SS and Ding, AA},
title = {Closed-form confidence intervals for saved time using summary statistics in Alzheimer's disease studies.},
journal = {Statistical methods in medical research},
volume = {},
number = {},
pages = {9622802251348796},
doi = {10.1177/09622802251348796},
pmid = {40611675},
issn = {1477-0334},
abstract = {Saved time is used in Alzheimer's disease (AD) trials as an easy interpretation of the treatment benefit to communicate with patients, family members, and caregivers. The projection approach is frequently applied to estimate saved time and its confidence interval (CI) by using the placebo or treatment disease progression curves. The estimated standard error of saved time by using these existing methods does not account for the correlation between outcomes. In addition, there was no closed-form CI for researchers to use in practice. To fill this critical gap, we derive the closed-form CI for saved time estimated from the placebo or treatment disease progression curves. We compare them with regard to coverage probability and interval width under various disease progression patterns that are commonly observed in AD symptomatic therapy and disease-modifying therapy trials. Data from the phase 3 donanemab trials are used to illustrate the application of the new CI methods.},
}

@article {pmid40611368,
year = {2025},
author = {Wyman-Chick, KA and Chrenka, EAB and Kane, JPM and Barrett, MJ and Miller, MJ and Schousboe, JT and Werner, AM and Rossom, RC},
title = {Utilization Patterns and Clinical Factors Associated With Hospitalization in Early-Stage Dementia With Lewy Bodies.},
journal = {International journal of geriatric psychiatry},
volume = {40},
number = {7},
pages = {e70125},
doi = {10.1002/gps.70125},
pmid = {40611368},
issn = {1099-1166},
support = {R21AG074368/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *Lewy Body Disease/therapy/epidemiology ; Male ; Female ; *Hospitalization/statistics & numerical data ; Aged ; *Emergency Service, Hospital/statistics & numerical data ; Aged, 80 and over ; Alzheimer Disease/therapy/epidemiology ; United States/epidemiology ; Case-Control Studies ; Middle Aged ; Dementia, Vascular/therapy/epidemiology ; },
abstract = {OBJECTIVES: Characterize patterns of hospitalization and emergency department (ED) visits in early-stage dementia with Lewy bodies (DLB).

METHODS: We analyzed electronic health records and claims data from a U.S. healthcare system up to 3 years before/after initial diagnosis of DLB (n = 175), Alzheimer's disease (AD, n = 2478), or vascular dementia (VD, n = 513). Controls were randomly matched 3:1 with the DLB group on sex/age (n = 525). Generalized linear models were used to compare rates and types of utilization between diagnosis group with adjustment for patient characteristics.

RESULTS: Patients with DLB had significantly greater rates of hospitalization and ED visits compared to patients with AD (Incidence Rate Ratio (IRR): 1.46, 95% CI 1.24, 1.73, IRR: 1.46, 95% CI 1.29, 1.77, respectively) and controls (IRR: 1.77, 95% CI 1.46, 2.14, IRR: 2.21, 95% CI 1.82, 2.69, respectively) and ED visits compared to those with VD (IRR: 1.24, 95% CI 1.03, 1.50). Patients with DLB were over 50% more likely to have a hospitalization associated with falls compared to those with AD and VD (OR: 1.75, 95% CI 1.16, 2.62 OR: 1.56, 95% CI: 1.01, 2.48, respectively). Compared to patients with AD, DLB patients were found to have 2.9-time higher likelihood of experiencing at least one hospitalization (Odds Ratio: 2.89. 95% CI: 1.17, 6.45).

CONCLUSIONS: Patients with DLB were substantially more likely to utilize ED services than patients with AD, VD, or controls, and more likely to experience hospitalizations compared to AD and control groups. Fall prevention and psychiatric treatment may be particularly important in reducing hospitalizations in early-stage DLB.},
}

Humans
*Lewy Body Disease/therapy/epidemiology
Male
Female
*Hospitalization/statistics & numerical data
Aged
*Emergency Service, Hospital/statistics & numerical data
Aged, 80 and over
Alzheimer Disease/therapy/epidemiology
United States/epidemiology
Case-Control Studies
Middle Aged
Dementia, Vascular/therapy/epidemiology

@article {pmid40610846,
year = {2025},
author = {Tahami Monfared, AA and Barrows, S and Fox, L and Herbel, B and Herring, WL and Krumbach, A and Zhang, Q},
title = {Societal Costs and Efficiency of Subcutaneous versus Intravenous Lecanemab in Early Alzheimer's Disease: A U.S. Cost Comparison Model.},
journal = {Neurology and therapy},
volume = {},
number = {},
pages = {},
pmid = {40610846},
issn = {2193-8253},
abstract = {INTRODUCTION: Intravenous (IV) therapies often impose significant burdens and costs on payers, providers, patients, and caregivers. A fixed-dose subcutaneous (SC) formulation may enhance convenience, improve outcomes, and reduce societal costs compared with weight-based IV dosing. This study estimated the relative societal value and cost implications of IV versus SC lecanemab administration for early Alzheimer's disease (AD) in the USA.

METHODS: A targeted literature review identified outcomes related to IV and SC modes of administration across therapeutic areas to inform and parameterize a cost-comparison model. The model incorporated direct treatment costs; economic value of administration time for providers, patients, and caregivers; and quality-of-life (QOL) impacts for patients and caregivers. Costs were estimated from a societal perspective over 4 years, including a per-patient head-to-head analysis and a population-level assessment accounting for population size, current treatment rates, and SC uptake. Scenario analyses evaluated the impact of key inputs and assumptions on study findings.

RESULTS: SC lecanemab was estimated to yield per-patient savings of $72,891-$80,925 over 4 years compared with IV administration, corresponding to annual savings of $18,223-$20,231 at willingness-to-pay thresholds of $150,000 and $200,000 per quality-adjusted life-year gained, respectively. Savings stemmed from a $40,638 reduction in treatment costs, $8151 decrease in administration time costs, and $24,102-$32,136 reduction in QOL-related costs. At the population level, assuming current treatment rates and 49.4% SC uptake, total savings of $3.16-$3.71 billion were projected over 4 years. Sensitivity analyses indicated per-patient savings varied based on site of care, IV drug wastage, and caregiver disutilities, while population-level savings were sensitive to treatment rates and SC uptake.

CONCLUSION: Subcutaneous lecanemab administration potentially offers substantial societal savings by lowering treatment costs, minimizing time demands, and relieving QOL burdens for patients and caregivers. These findings underscore the potential value of SC formulations in improving treatment delivery and alleviating AD economic impact; however, real-world data in AD are needed to further contextualize this comparison.},
}

@article {pmid40610268,
year = {2025},
author = {Sun, M and Mi, W},
title = {Microglial insulin resistance drives neurodegeneration.},
journal = {Trends in endocrinology and metabolism: TEM},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.tem.2025.06.006},
pmid = {40610268},
issn = {1879-3061},
abstract = {Brain insulin resistance (BIR) contributes to neurodegenerative diseases such as Alzheimer's disease (AD). Recently, Chen et al. revealed that microglial insulin signaling loss drives neuroinflammation and amyloid-β (Aβ) accumulation, promoting AD progression. These findings provide insights for the prevention and treatment of AD and cognitive disorders.},
}

@article {pmid40610071,
year = {2025},
author = {Selvaraj, C and Vijayalakshmi, P and Desai, D and Manoharan, J},
title = {Proteostasis imbalance: Unraveling protein aggregation in neurodegenerative diseases and emerging therapeutic strategies.},
journal = {Advances in protein chemistry and structural biology},
volume = {146},
number = {},
pages = {1-34},
doi = {10.1016/bs.apcsb.2024.11.008},
pmid = {40610071},
issn = {1876-1631},
mesh = {Humans ; *Proteostasis ; *Neurodegenerative Diseases/metabolism/therapy/pathology ; Animals ; Autophagy ; *Protein Aggregation, Pathological/metabolism/therapy/pathology ; *Protein Aggregates ; },
abstract = {Neurodegenerative diseases such as Alzheimer's, Parkinson's, Huntington's, and ALS are defined by the accumulation of misfolded and aggregated proteins, which impair cellular function and result in progressive neuronal death. This chapter examines the critical function of proteostasis-cellular protein homeostasis-in sustaining neuronal health and its disruption as a key factor in disease progression. Proteostasis is upheld by a complex array of mechanisms, which encompass molecular chaperones, the ubiquitin-proteasome system, autophagy-lysosomal pathways, and mitochondrial quality control. Impairment of these systems leads to protein misfolding and aggregation, resulting in toxic cellular environments that promote neurodegeneration. Novel therapeutic approaches focus on restoring proteostasis through the enhancement of cellular protein folding, degradation, and clearance mechanisms. This encompasses small molecule chaperones, gene therapy, RNA-based treatments, immunotherapy, autophagy inducers, and stem cell-based approaches, each addressing distinct components of the proteostasis network to mitigate or prevent disease progression. While these therapies show potential, challenges persist, such as possible side effects, selective targeting, and the efficacy of blood-brain barrier penetration. Personalized medicine and combination therapies customized to specific disease profiles are increasingly recognized for their potential to improve efficacy and safety. This chapter consolidates recent developments in therapies aimed at proteostasis, addresses the challenges encountered in clinical applications, and outlines potential future directions for transformative treatments. Ongoing research indicates that proteostasis modulation may significantly alter the course of neurodegenerative disease treatment, potentially enhancing patient outcomes and quality of life.},
}

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

@article {pmid40609789,
year = {2025},
author = {Kurkela, M and Dvořáková, L and Koivisto, H and Uusitalo, M and Kursula, P and Kettunen, M and Gröhn, O and Tanila, H and Koivunen, P},
title = {Targeting HIF-P4H-2 in APP/PS1 Alzheimer's mouse model improves glucose metabolism, reduces dystrophic neurites and maintains exploratory activity.},
journal = {The Journal of biological chemistry},
volume = {},
number = {},
pages = {110432},
doi = {10.1016/j.jbc.2025.110432},
pmid = {40609789},
issn = {1083-351X},
abstract = {Alzheimer's disease (AD) is the most common cause of dementia with limited treatment options. We asked whether activation of the hypoxia-inducible factor (HIF) pathway via genetic deficiency of HIF prolyl 4-hydoxylase-2 (HIF-P4H-2/PHD2/EGLN1) could be an AD disease modifying therapy using transgenic APP/PS1 female mice. At 12 months of age, APP/PS1/Hif-p4h-2[gt/gt] mice had 20% less cortical amyloid-β (Aβ) and less dystrophic neurites around amyloid plaques compared to APP/PS1 mice used as controls. Compared to controls, APP/PS1/Hif-p4h-2[gt/gt] mice were leaner, had better glucose tolerance and insulin sensitivity and higher expression levels of a HIF target, glucose transporter 1, in brain. These changes associated with lesser Aβ toxicity in APP/PS1/Hif-p4h-2[gt/gt] mice linking indices of neurodegeneration with HIF-P4H-2-deficiency-mediated amelioration on brain and systemic glucose metabolism. In open field and dark-light tests, APP/PS1/Hif-p4h-2[gt/gt] mice maintained their behavior during aging whereas controls showed a change by 60-80% in exploratory activity and anxiety parameters from 6 to 12 months. Maintenance of behavior associated with cortical Hif-p4h-2 mRNA downregulation, lesser Aβ toxicity and lower white adipose tissue inflammation in APP/PS1/Hif-p4h-2[gt/gt] mice. Altogether, these data connect activation of the HIF pathway via HIF-P4H-2 deficiency to neuroprotection in the APP/PS1 Alzheimer's mouse model.},
}

@article {pmid40609065,
year = {2025},
author = {Zissimopoulos, J and Thunell, J and Jacobson, M and Haye, S and Tysinger, B and Ferido, P and Joyce, G},
title = {Real-World Evidence of Brexpiprazole Use and 6-Month Mortality, Hospitalization, and Emergency Department Visits Among Persons With Dementia.},
journal = {Neurology},
volume = {105},
number = {3},
pages = {e213717},
doi = {10.1212/WNL.0000000000213717},
pmid = {40609065},
issn = {1526-632X},
mesh = {Humans ; Male ; Female ; Aged ; *Thiophenes/adverse effects/therapeutic use ; *Dementia/mortality/drug therapy ; Aged, 80 and over ; *Emergency Service, Hospital/statistics & numerical data ; *Hospitalization/statistics & numerical data ; United States/epidemiology ; *Quinolones/adverse effects/therapeutic use ; *Antipsychotic Agents/adverse effects/therapeutic use ; Aripiprazole/therapeutic use/adverse effects ; Medicare ; Emergency Room Visits ; },
abstract = {BACKGROUND AND OBJECTIVES: Alzheimer disease and other dementias are accompanied by depression and agitation and other behavioral and neuropsychiatric symptoms. In 2023, brexpiprazole became the first antipsychotic approved by the US Food and Drug Administration to treat agitation in persons with Alzheimer disease, but, like all atypical antipsychotics, it includes a black box warning of an increased risk of mortality among persons with dementia. This study provides real-world evidence of mortality in a heterogeneous sample of brexpiprazole users to understand effects in the population.

METHODS: We used a 100% sample of Medicare claims data Parts A, B, and D from 2014 to 2023. Our sample was limited to beneficiaries with diagnosed dementia, who were continuously enrolled for at least 2 years and were new users of the atypical antipsychotics brexpiprazole or aripiprazole in a given year. We used matching and logistic regression to estimate the relationship between incident use of brexpiprazole, compared with aripiprazole, and mortality, emergency department (ED) visits, and hospitalization within 6 months.

RESULTS: Among the 41,871 beneficiaries with dementia, 71.7% of brexpiprazole and 69.7% of aripiprazole users were women with a mean age of 75.7 and 78.0 years, respectively. Among persons living with dementia (PLWD), 6-month mortality was statistically lower among new users of brexpiprazole based on estimates from logistic regression and a matched sample of new users of brexpiprazole or aripiprazole (OR 0.49, [95% CI 0.37-0.65]).There was no statistical difference between the incident use of brexpiprazole and aripiprazole use for ED visits or hospitalization within 6 months of use initiation. Adjustment for potential unobserved confounding used two-stage least squares estimation and found no statistically significant differences in six-month mortality, ED visits, or hospitalizations between the 2 groups.

DISCUSSION: Brexpiprazole use is not associated with differential mortality risk compared with aripiprazole use among PLWD. Brexpiprazole offers a treatment option which is important given the heterogeneity of effects of antipsychotics on persons. A two-stage least squares method is used to eliminate bias on estimates because of observed and unobserved differences between the 2 groups, but the small sample size is a limitation.

CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that brexpiprazole does not increase the risk of mortality at 6 months compared with aripiprazole in PLWD.},
}

Humans
Male
Female
Aged
*Thiophenes/adverse effects/therapeutic use
*Dementia/mortality/drug therapy
Aged, 80 and over
*Emergency Service, Hospital/statistics & numerical data
*Hospitalization/statistics & numerical data
United States/epidemiology
*Quinolones/adverse effects/therapeutic use
*Antipsychotic Agents/adverse effects/therapeutic use
Aripiprazole/therapeutic use/adverse effects
Medicare
Emergency Room Visits

@article {pmid40608230,
year = {2025},
author = {Guleria, M and Malhan, A and Teli, G and Bisht, N and Jain, SK},
title = {Design strategies, structural insights, and biological potential of amyloid-beta inhibitors in Alzheimer's disease.},
journal = {Molecular diversity},
volume = {},
number = {},
pages = {},
pmid = {40608230},
issn = {1573-501X},
abstract = {Alzheimer's disease (AD) is an insidious neurodegenerative condition characterized by dementia, cognitive decline, and eventual mortality. The pathogenesis of AD is complex, influenced by multiple factors including neurotransmitter deficiencies, particularly acetylcholine (ACh) and the dysregulation of mental homeostasis, reactive oxygen species (ROS), and amyloid-beta (Aβ) peptide accumulation. The latter is firmly linked to the formation of neurofibrillary tangles (NFTs) and amyloid plaques in the cortical and hippocampal regions, which are hallmarks of the disease pathology. Recent advancements in therapeutic strategies have focused on inhibiting the amyloid-beta peptide, a key contributor to AD progression. This study explores the development of novel amyloid-beta inhibitors and their biological activities, focusing on the synthesis of radiolabeled compounds used in the diagnosis and treatment of Alzheimer's disease. Additionally, we explore the roles of crucial enzymes such as Electrophorus electricus acetylcholinesterase (eeAChE), human acetylcholinesterase (hAChE), and human butyrylcholinesterase (hBuChE) in the disease's neurochemical landscape. The goal of this review is to furnish the scientific community with insight into the design of innovative amyloid imaging agents. These agents are based on diverse scaffolds including flavone, pyrimidine, benzimidazole, imidazole, pyridine, pyrrole, quinoline, indanone, acridine, and peptide-based derivatives, serving as core structures for further research and development. This comprehensive evaluation not only elucidates the molecular underpinnings of AD but also propels forward the quest for efficacious diagnostic and therapeutic tools.},
}

@article {pmid40607399,
year = {2025},
author = {Lin, S and Zhan, Y and Wang, R and Pei, J},
title = {Decoding neuroinflammation in Alzheimer's disease: a multi-omics and AI-driven perspective for precision medicine.},
journal = {Frontiers in immunology},
volume = {16},
number = {},
pages = {1616899},
pmid = {40607399},
issn = {1664-3224},
mesh = {Humans ; *Alzheimer Disease/genetics/metabolism/diagnosis/immunology/etiology/therapy ; *Precision Medicine/methods ; *Neuroinflammatory Diseases/genetics ; Single-Cell Analysis ; Animals ; *Artificial Intelligence ; Biomarkers ; Microglia/metabolism/immunology ; Multiomics ; },
abstract = {Alzheimer's disease (AD) is a common neurodegenerative disease, which is characterized by β-amyloid (Aβ) deposition, Tau hyperphosphorylation, synaptic dysfunction and chronic neuroinflammation. Despite significant advances in research in recent years, effective therapeutic options remain limited. The development of single-cell RNA sequencing (scRNA-seq) has made it possible to analyze cellular heterogeneity in AD brain tissues at high resolution, breaking through the limitation of signal averaging in traditional large-scale tissue analysis. This technology has led to the discovery of novel disease-associated cell subsets, such as pro-inflammatory microglia and reactive astrocytes, and the identification of key molecular markers linked to disease progression. Integrating scRNA-seq with AI-driven analytics and multi-omics platforms further enhances our ability to decode the intricate immune-inflammatory networks underlying AD. This strategy is expected to achieve accurate classification and early diagnosis of AD subtypes, and promote the development of individualized treatment strategies based on individual molecular and immune characteristics.},
}

Humans
*Alzheimer Disease/genetics/metabolism/diagnosis/immunology/etiology/therapy
*Precision Medicine/methods
*Neuroinflammatory Diseases/genetics
Single-Cell Analysis
Animals
*Artificial Intelligence
Biomarkers
Microglia/metabolism/immunology
Multiomics

@article {pmid40604812,
year = {2025},
author = {Wang, YC and Huang, LY and Yan-Fu, and Xiong, SY and Wang, ZT and Tan, CC and Tan, L},
title = {Cerebrospinal fluid sTREM2 mediates the associations of α-synuclein with tau pathology in older adults without dementia: two population-based study.},
journal = {Journal of translational medicine},
volume = {23},
number = {1},
pages = {731},
pmid = {40604812},
issn = {1479-5876},
support = {82271475//National Natural Science Foundation of China/ ; },
abstract = {BACKGROUND: The role of microglial activation by α-synuclein in Alzheimer’s disease (AD) remains unclear. This study aimed to evaluate the role of soluble triggering receptor expressed on myeloid cells 2 (sTREM2) in regulating the relationship between α-synuclein and tau pathology in cerebrospinal fluid (CSF).

METHODS: A total of 989 participants were included in the CABLE (Chinese Alzheimer’s Biomarker and LifestylE) study. Multiple linear regression analyses were performed to assess the associations of CSF α-synuclein and sTREM2 with tau pathology. Causal mediation analyses with 10,000 bootstrap iterations were conducted to investigate the mediating effect of sTREM2 on the relationship between α-synuclein and tau pathology. Additionally, subgroup analyses were performed based on APOE ε4 carrier status. The same analytical method was applied to the ADNI (Alzheimer’s Disease Neuroimaging Initiative) cohort for validation. Furthermore, Cox proportional hazards models were employed to evaluate the longitudinal association between α-synuclein levels and the risk of AD in the ADNI cohort. Causal mediation analysis further evaluated the mediating role of tau pathology in the relationship between α-synuclein and the risk of AD.

RESULTS: In CABLE, elevated levels of α-synuclein were significantly associated with increased levels of sTREM2 (p < 0.001), p-tau181 (p < 0.001), and T-tau (p < 0.001). The relationship between α-synuclein and tau pathology was partially mediated by sTREM2, with mediation rates of 4.8% and 6.3%, respectively. Further subgroup analysis revealed that this mediating relationship was present only in APOE ε4 non-carriers. The CABLE findings were validated in the ADNI, with the proportion of mediators ranging from 17.1 to 18.8%. Additionally, higher levels of α-synuclein were linked to an increased risk of AD (hazard ratio = 2. 137, p = 0.006). The relationship between α-synuclein levels and the risk of AD was mediated by p-tau181 but not T-tau, with a mediation rate of 67.6%.

CONCLUSIONS: Overall, activated microglia partially mediate the α-synuclein-tau pathology association, while p-tau181 further mediates the relationship between α-synuclein and AD risk. Thus, targeting the CSF α-synuclein-microglia-tau pathological pathway provides new insights into the prevention and treatment of AD.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12967-025-06729-3.},
}

@article {pmid40604480,
year = {2025},
author = {Finger, E and Moses, A},
title = {As The River Flows: A Case Report of Post Obstructive Diuresis.},
journal = {BMC nephrology},
volume = {26},
number = {1},
pages = {341},
pmid = {40604480},
issn = {1471-2369},
mesh = {Humans ; Male ; Aged ; *Diuresis/physiology ; *Ureteral Obstruction/complications ; },
abstract = {BACKGROUND: Post obstructive diuresis (PObD) is a medical complication that occurs after a period of urinary obstruction. It is defined as a prolonged production of urine of at least 200 cc/hour for two consecutive hours or over 3 L of urine production over a 24-hour period following relief of urinary retention or an obstructive uropathy. Physiologic PObD lasts for 24 h while pathologic PObD lasts for over more than a 48-hour period and can lead to massive electrolyte deficiencies as well as the possibility of hypotension and consequent shock. The typical pathophysiology of pathologic PObD involves medullary washout from urinary retention and tubular injury, downregulation of sodium transport receptors in the thick ascending loop of Henle, a reduction in the glomerular filtration rate (GFR), and a poor response to antidiuretic hormone (ADH). Guidelines on the treatment of PObD rely on the regulation of fluid maintenance, however, they do not definitively describe how to manage contributive factors to the pathology. We discuss the case of a patient who developed severe PObD with a tailored approach to treating the underlying pathophysiologic mechanisms contributing to pathologic PObD while utilizing markers to guide patient management.

CASE PRESENTATION: A 79-year-old male with a past medical history of severe aortic stenosis, coronary artery disease, hyperlipidemia and mild Alzheimer's disease presented with invasive bladder cancer and consequent obstructive uropathy. An ileal conduit was created. Massive urinary diuresis occurred for more than 48 h once the obstruction was relieved and subsequently, our patient went into shock. Nephrology was consulted and a treatment plan was initiated that targeted appropriate fluid administration to overcome the massive diuresis while also focusing on improving the medullary gradient and response to anti-diuretic hormone. Our patient's condition improved after our multifaceted therapeutic approach.

CONCLUSION: This case report highlights the importance of maintaining appropriate fluid administration to treat fluid loss while avoiding augmentation of the diuresis. We also demonstrate the significance of a treatment plan that targets the pathophysiological mechanisms contributing to PObD to help treat our patient's condition.},
}

Humans
Male
Aged
*Diuresis/physiology
*Ureteral Obstruction/complications

@article {pmid40604347,
year = {2025},
author = {Falgàs, N and Maure-Blesa, L and Ances, B and Flores-Aguilar, L and Hartley, S and Hassenstab, J and Iulita, MF and Janicki, M and Koenig, K and Lao, P and Levin, J and McDade, E and Meijer, L and Rafii, MS and Snyder, HM and Sánchez-Valle, R and Fortea, J and , and Arriola Infante, J and Balasa, M and Barroeta, I and Barthelemy R, N and Bejanin, A and Benejam, B and Bosch, B and Bradshaw, A and Carmona-Iragui, M and Cohen, A and Comas Albertí, A and Csincsik, L and Cuello, AC and Del Hoyo Soriano, L and Dijkstra, J and Edwards, N and Giménez, S and Gonzalez-Ortiz, F and Gordon, B and Gutiérrez Fernández, S and Handen, B and Jacob, C and Johnson, E and Johansson, C and Lladó, A and Lleó, A and Morabito, S and Morcillo-Nieto, AO and Montoliu-Gaya, L and Okafor, M and Pérez-Millan, A and Potier, MC and Ringman, J and Rodríguez-Baz, Í and Rubenstein, E and Ryan, NS and Strydom, A and Vaqué-Alcázar, L and Vermunt, L and Videla Toro, L and Zaman, S},
title = {Genetically determined Alzheimer's disease research advances: The Down Syndrome & Autosomal Dominant Alzheimer's Disease 2024 Conference.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {7},
pages = {e70309},
doi = {10.1002/alz.70309},
pmid = {40604347},
issn = {1552-5279},
support = {GBHI_ALZ-18-543740//Global Brain Health Institute/ ; /AG/NIA NIH HHS/United States ; //UK Dementia Research Institute/ ; //Fundación Pasqual Maragall/ ; AARG-22-923680/ALZ/Alzheimer's Association/United States ; DYRK-DOWN//Agence Nationale de la Recherche/ ; 2326 - GRT-2024A//Fondation Jérôme Lejeune/ ; JR22/00014//Instituto de Salud Carlos III/ ; CD23/00235//Instituto de Salud Carlos III/ ; CM22/00052//Instituto de Salud Carlos III/ ; CM22/00219//Instituto de Salud Carlos III/ ; CM21/00243//Instituto de Salud Carlos III/ ; CP20/00038//Instituto de Salud Carlos III/ ; CP24/00112//Instituto de Salud Carlos III/ ; CM23/00291//Instituto de Salud Carlos III/ ; //Ministerio de Ciencias Innovación y Universidades/ ; //Fondos FEDER/ ; //UK Medical Research Council, UK NIHR UCLH Biomedical Research Centre, Dominantly Inherited Alzheimer Network/ ; GO-DS21//Agence Nationale de la Recherche (ANR), France 2030, Bpifrance, European Union's Horizon 2020 research and innovation program/ ; 190138295//European Innovation Council (EIC), Accelerator Program/ ; //Alzheimer's Association ISTAART Conference Support Award/ ; //Fundación Catalana del Síndrome de Down (FCSD)/ ; },
mesh = {Humans ; *Alzheimer Disease/genetics/therapy ; *Down Syndrome/genetics/complications ; Biomarkers ; *Biomedical Research ; Congresses as Topic ; },
abstract = {INTRODUCTION: The Down syndrome-associated Alzheimer's disease (DSAD) autosomal dominant Alzheimer's disease (ADAD) 2024 Conference in Barcelona, convened under an Alzheimer's Association International Society to Advance Alzheimer's Research and Treatment (ISTAART) grant through the Down syndrome and Alzheimer's disease (AD) Professional Interest Area (PIA), brought together global researchers to foster collaboration and knowledge exchange between the fields of DSAD and ADAD.

METHODS: This article provides a synthesis review of the conference proceedings, summarizing key discussions on biomarkers, natural history models, clinical trials, and ethical considerations in anti-amyloid therapies.

RESULTS: A total of 211 attendees from 16 countries joined the meeting. Global researchers presented on disease mechanisms, therapeutic developments, and patient care strategies. Discussions focused on challenges and opportunities unique to DSAD and ADAD. Experts emphasized the urgent need for tailored clinical trials for ADAD and DSAD and debated the safety and efficacy of anti-amyloid treatments. Ethical considerations highlighted equitable access to therapies and the crucial role of patient and caregiver involvement.

DISCUSSION: The conference highlighted the importance of inclusive research and collaboration across the genetic forms of AD.

HIGHLIGHTS: Biomarker research and natural history models developed in Down syndrome-associated Alzheimer's disease (DSAD) and autosomal dominant Alzheimer's disease (ADAD) enable the prediction of disease progression not only for DSAD and ADAD, but also for sporadic Alzheimer's disease (AD). -Collaboration and knowledge exchange among researchers across these genetic forms of AD will accelerate our understanding of the pathophysiology and advance preventive trials in DSAD and ADAD. -Tailored clinical trials for DSAD are urgently needed to address specific safety and efficacy concerns. -Inclusive research practices are crucial for advancing treatments and understanding of DSAD and ADAD.},
}

Humans
*Alzheimer Disease/genetics/therapy
*Down Syndrome/genetics/complications
Biomarkers
*Biomedical Research
Congresses as Topic

@article {pmid40604203,
year = {2025},
author = {Choi, J and Jeong, H and Ramalingam, M and Hwang, J and Kim, SJ and Kim, BC and Jeong, HS and Jang, S},
title = {Therapeutic effects of miR-937-3p by targeting NTN1 expression and regulating apoptosis in an Aβ-induced neuronal cell death.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {23611},
pmid = {40604203},
issn = {2045-2322},
support = {RS-2020-KH088567//Korea Health Industry Development Institute/Republic of Korea ; NRF-2021R1I1A3060435//National Research Foundation of Korea/ ; NRF-2020R1F1A1076616//National Research Foundation of Korea/ ; },
mesh = {*MicroRNAs/genetics/metabolism ; *Apoptosis/drug effects/genetics ; *Neurons/metabolism/drug effects/pathology ; Humans ; *Netrin-1/genetics/metabolism ; *Amyloid beta-Peptides/metabolism/toxicity ; *Alzheimer Disease/genetics/metabolism/pathology ; Gene Expression Regulation ; Animals ; Myeloid Cell Leukemia Sequence 1 Protein/metabolism/genetics ; },
abstract = {MicroRNAs (miRNAs) have multiple functions that regulate gene expression in various species. Few studies have explored the effects of miRNAs on the pathogenesis of Alzheimer's disease (AD); however, the potential neuroprotective effects of miRNAs on AD, particularly by targeting neuronal markers, remain unclear. In this study, we suggested potential neuroprotective roles for miR-937-3p in an in vitro AD model, which has not been extensively studied. Our biological analysis confirmed that miR-937-3p participated in neuronal protection and differentiation. We selected miR-937-3p as a novel candidate and identified Netrin1 (NTN1), an axon guidance regulator, as its target gene via qPCR analysis and luciferase assay. Additionally, FACS analysis revealed a reduction in apoptosis levels in Aβ-treated cells following treatment with the miR-937-3p-I. Western blot analysis showed that the expression of Mcl-1, an anti-apoptotic marker, increased with miR-937-3p-I treatment in an in vitro AD model. Interestingly, the levels of pro-caspase 7, pro-caspase 3, and pro-PARP, which are usually downregulated when their cleaved forms are upregulated, were found to increase with miR-937-3p-I treatment. The expression levels of neuronal markers such as NeuN, NFH, Tuj1, SYP, and MAP2 were enhanced by miR-937-3p-I treatment in the in vitro AD model. Therefore, miR-937-3p inhibition might play a therapeutic and neuroprotective role in AD by promoting NTN1 expression and repressing the apoptotic pathway.},
}

*MicroRNAs/genetics/metabolism
*Apoptosis/drug effects/genetics
*Neurons/metabolism/drug effects/pathology
Humans
*Netrin-1/genetics/metabolism
*Amyloid beta-Peptides/metabolism/toxicity
*Alzheimer Disease/genetics/metabolism/pathology
Gene Expression Regulation
Animals
Myeloid Cell Leukemia Sequence 1 Protein/metabolism/genetics

@article {pmid36945637,
year = {2025},
author = {Iannitelli, AF and Hassanein, L and Tish, MM and Mulvey, B and Blankenship, HE and Korukonda, A and Liles, LC and Sharpe, AL and Pare, JF and Villalba, R and Segal, A and Sloan, SA and Martinowich, K and Dougherty, JD and McCann, KE and Smith, Y and Beckstead, MJ and Weinshenker, D},
title = {Tyrosinase-induced neuromelanin accumulation triggers rapid dysregulation and degeneration of the mouse locus coeruleus.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2023.03.07.530845},
pmid = {36945637},
issn = {2692-8205},
support = {P51 OD011132/OD/NIH HHS/United States ; T32 ES012870/ES/NIEHS NIH HHS/United States ; RF1 AG061175/AG/NIA NIH HHS/United States ; F99 NS129168/NS/NINDS NIH HHS/United States ; UL1 TR002378/TR/NCATS NIH HHS/United States ; RF1 AG079199/AG/NIA NIH HHS/United States ; },
abstract = {UNLABELLED: The locus coeruleus (LC), the major source of norepinephrine (NE) in the brain, is among the earliest site of pathology in both Alzheimer's disease (AD) and Parkinson's disease (PD), and it undergoes catastrophic degeneration later in both disorders. Dysregulation of the LC is thought to contribute to prodromal symptoms of AD and PD such as anxiety and sleep disturbances, while frank LC loss promotes cognitive decline. However, the mechanisms responsible for its selective vulnerability are unknown. It has been suggested that neuromelanin (NM) pigment contributes to LC susceptibility, but causal relationships have been difficult to test because rodents do not naturally produce NM. Here, we report that viral-mediated expression of human tyrosinase induced pigmentation in mouse LC neurons that recapitulated key features of natural primate NM. One week of NM accumulation resulted in LC neuron hyperactivity, reduced tissue NE levels, transcriptional changes, and anxiety-like behavior. By 6-10 weeks, NM accumulation was associated with severe LC neuron neurodegeneration and microglial engulfment of the pigment granules, while the anxiety-like behavior abated. These phenotypes are reminiscent of LC dysfunction and cell death in AD and PD, validating this model for studying the consequences of NM accumulation in the LC as it relates to neurodegenerative disease.

SIGNIFICANCE STATEMENT: Alzheimer's disease (AD) and Parkinson's disease (PD) are two of the most common neurodegenerative diseases worldwide. Because therapies that cure or even prevent their progression are lacking, research is focused on the identifying earliest signs of disease as targets for diagnosis and treatment. The locus coeruleus (LC), the main source of the neurotransmitter n norepinephrine (NE) in the brain, is one of the first brain regions affected in both AD and PD. LC dysregulation promotes prodromal AD and PD symptoms, while its degeneration accelerates disease progression. Here we identify neuromelanin (NM) pigment as a LC vulnerability factor that induces neuronal hyperactivity followed by cell death. Approaches that mitigate NM accumulation and toxicity may target the earliest phases of neurodegenerative disease.},
}

@article {pmid40603917,
year = {2025},
author = {Roshanfekr, A and Moeini, Z and Golmohammadi, F and Balalaie, S and Seyedarabi, A},
title = {Antioxidative effects of phytoaromatic compounds on the cysteine of the SKCGS peptide as a critical aggregation domain of tau.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {23206},
pmid = {40603917},
issn = {2045-2322},
abstract = {Cysteine residues play a crucial role in maintaining the structural and functional integrity of proteins, but they are highly susceptible to oxidative modifications. These modifications can contribute to disorders such as Alzheimer's disease (AD). In tau protein, the SKCGS sequence, especially the cysteine residue at position C-322, is particularly vulnerable to oxidative stress (OS). This vulnerability promotes tau fibrillation and aggregation, both in vitro and in vivo. This study evaluated the antioxidative effects of cinnamaldehyde (Cin), phenylethyl alcohol (PEA), and the common crude spices (cinnamon, rose, saffron, and cardamom) on the SKCGS peptide of the tau protein (in solution and aroma forms), with a focus on their ability to prevent oxidative damage. We adopted a novel approach using aromatherapy that utilizes the aromatic and volatile properties of natural compounds. By combining biochemical assessments with molecular docking studies, we aimed to provide a comprehensive understanding of the protective mechanisms of the natural phytoaromatic compounds used in this study. The antioxidative potential of these compounds was assessed using the DPPH assay; thiol levels measured via DTNB and mBBr assays; and binding interactions evaluated through molecular docking. The DPPH assay confirmed the antioxidative activity of all tested compounds. DTNB and mBBr assays showed that the phytoaromatic compounds significantly preserved free thiol content in the SKCGS peptide under oxidative conditions (p < 0.05). Molecular docking predicted favorable binding interactions between the phytoaromatic compounds and the cysteine residue in the SKCGS sequence, suggesting a protective mechanism against OS. The data presented provided strong evidence supporting the idea that phytoaromatic compounds could be promising candidates for developing innovative treatment approaches for AD. The encouraging results from this study justify further exploration of phytoaromatic compounds as therapeutic agents for AD. This research opens up new avenues for creating effective treatments to address one of the most significant challenges in neurodegenerative medicine.},
}

@article {pmid40603911,
year = {2025},
author = {Zhou, J and Wei, Y and Li, X and Zhou, W and Tao, R and Hua, Y and Liu, H},
title = {A deep learning model for early diagnosis of alzheimer's disease combined with 3D CNN and video Swin transformer.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {23311},
pmid = {40603911},
issn = {2045-2322},
support = {20232BAB202025//Natural Science Foundation of Jiangxi Province/ ; },
abstract = {Alzheimer's disease (AD) constitutes a neurodegenerative disorder predominantly observed in the geriatric population. If AD can be diagnosed early, both in terms of prevention and treatment, it is very beneficial to patients. Therefore, our team proposed a novel deep learning model named 3D-CNN-VSwinFormer. The model consists of two components: the first part is a 3D CNN equipped with a 3D Convolutional Block Attention Module (3D CBAM) module, and the second part involves a fine-tuned Video Swin Transformer. Our investigation extracts features from subject-level 3D Magnetic resonance imaging (MRI) data, retaining only a single 3D MRI image per participant. This method circumvents data leakage and addresses the issue of 2D slices failing to capture global spatial information. We utilized the ADNI dataset to validate our proposed model. In differentiating between AD patients and cognitively normal (CN) individuals, we achieved accuracy and AUC values of 92.92% and 0.9660, respectively. Compared to other studies on AD and CN recognition, our model yielded superior results, enhancing the efficiency of AD diagnosis.},
}

@article {pmid40603012,
year = {2025},
author = {Kato, D},
title = {Impact of Sex Differences in Oligodendrocytes and Their Progenitor Cells on the Pathophysiology of Neuropsychiatric Disorders.},
journal = {Journal of Nippon Medical School = Nippon Ika Daigaku zasshi},
volume = {92},
number = {3},
pages = {226-233},
doi = {10.1272/jnms.JNMS.2025_92-306},
pmid = {40603012},
issn = {1347-3409},
mesh = {Humans ; *Oligodendroglia/pathology/physiology/metabolism ; *Sex Characteristics ; Female ; Male ; Animals ; Cell Differentiation/genetics ; *Mental Disorders/physiopathology/pathology/etiology ; Cell Proliferation/genetics ; *Oligodendrocyte Precursor Cells/pathology/physiology/metabolism ; Myelin Sheath/metabolism ; Multiple Sclerosis/physiopathology/pathology ; Autism Spectrum Disorder/physiopathology ; Alzheimer Disease/physiopathology/pathology ; Cell Movement ; Gene Expression ; },
abstract = {Neuropsychiatric disorders such as multiple sclerosis, Alzheimer's disease, and autism spectrum disorder exhibit significant sex differences in prevalence, progression, and response to treatment. Emerging evidence suggests that oligodendrocytes (OLs) and oligodendrocyte precursor cells (OPCs) play pivotal roles in these pathologies via mechanisms involving neuroinflammation, energy metabolism, and hormonal modulation, resulting in distinct functional outcomes. Specifically, female OPCs display higher proliferative and migratory capacities, whereas male OPCs are more prone to differentiation and myelination, thus contributing to robust myelin integrity. Dysregulation of these cells disrupts myelination and exacerbates disease progression. Addressing sex-specific gene expression in OPCs and OLs is therefore considered crucial for the development of targeted therapeutic strategies. This review highlights the significance of sex differences in the proliferation and differentiation of OPCs, as well as gene expression changes in OPCs and OLs, and emphasizes their contribution to the pathophysiology of neuropsychiatric disorders. Improved understanding of these differences is vital for advancing personalized sex-specific treatments and improving the clinical outcomes of neuropsychiatric disorders.},
}

Humans
*Oligodendroglia/pathology/physiology/metabolism
*Sex Characteristics
Female
Male
Animals
Cell Differentiation/genetics
*Mental Disorders/physiopathology/pathology/etiology
Cell Proliferation/genetics
*Oligodendrocyte Precursor Cells/pathology/physiology/metabolism
Myelin Sheath/metabolism
Multiple Sclerosis/physiopathology/pathology
Autism Spectrum Disorder/physiopathology
Alzheimer Disease/physiopathology/pathology
Cell Movement
Gene Expression

@article {pmid40602675,
year = {2025},
author = {Markowicz-Piasecka, M and Laitinen, T and Huttunen, KM},
title = {Optimizing the Structure of Repurposed Metformin Can Improve Anti-cholinesterase and Anti-amyloidogenic Effects.},
journal = {European journal of pharmacology},
volume = {},
number = {},
pages = {177886},
doi = {10.1016/j.ejphar.2025.177886},
pmid = {40602675},
issn = {1879-0712},
abstract = {Alzheimer's disease (AD) and diabetes mellitus (DM) share common pathological features, including insulin resistance, oxidative stress, and inflammation, suggesting AD may be considered a brain-specific form of DM. Metformin, a widely used antidiabetic drug, has shown neuroprotective effects potentially beneficial in AD by modulating insulin signaling, reducing inflammation, and inhibiting beta-amyloid (Aβ) aggregation. However, its hydrophilic nature limits brain permeability, prompting the synthesis of metformin derivatives to enhance pharmacokinetic properties. This study investigates a series of sulfonamide derivatives of metformin for their cholinesterase (ChE) inhibition using human acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), anti-Aβ aggregation using thioflavin T fluorescence assay in vitro, and antioxidative properties in human umbilical endothelial cells (HUVEC) and astrocytes. In vitro assays revealed that studied derivatives exhibit selective inhibitory activity against BChE over AChE. Additionally, certain derivatives demonstrated a synergistic effect with donepezil in AChE inhibition. The derivatives effectively inhibited also Aβ aggregation at both early and late stages, which may reduce Aβ plaque formation. Furthermore, the antioxidative properties of these derivatives were validated in cell-based assays, showing protective effects against oxidative stress in HUVEC and astrocytes. Thus, these findings suggest that metformin derivatives could serve as a dual-action therapy for AD by targeting both cholinergic and amyloidogenic pathways while providing antioxidative support. Future studies may focus on refining these compounds to optimize therapeutic potential in AD treatment, presenting a promising approach for repurposing antidiabetic drugs to address neurodegenerative disease mechanisms.},
}

@article {pmid40600688,
year = {2025},
author = {Fortea, J and Ferrer-Picón, E},
title = {An overview of the rivastigmine 13.3 mg/24h transdermal patch as a treatment option for Alzheimer's disease.},
journal = {Expert review of neurotherapeutics},
volume = {},
number = {},
pages = {},
doi = {10.1080/14737175.2025.2527211},
pmid = {40600688},
issn = {1744-8360},
abstract = {INTRODUCTION: Rivastigmine, a cholinesterase inhibitor, was first approved for the treatment of Alzheimer's disease (AD) dementia more than 20 years ago. Initially available as an oral formulation, a transdermal system was subsequently developed with the aim of improving tolerability while providing similar efficacy. Transdermal rivastigmine is approved for the treatment of severe AD as well as mild-to-moderate AD.

AREAS COVERED: Herein, the authors review randomized clinical trials, meta-analyses, and post-marketing observational studies involving the rivastigmine 13.3 mg/24 h patch for the treatment of patients with AD.

EXPERT OPINION: Cholinesterase inhibitors are a mainstay of the symptomatic treatment of patients with AD. Rivastigmine is available as oral and transdermal formulations, with the latter providing improved tolerability and convenience while maintaining efficacy. The high-dose 13.3 mg/24 h patch might offer benefits for some patients compared to the lower dose patch (4.6 mg/24 h) in patients with mild-to-moderate or severe AD, showing improvements in daily functioning and global clinical status on top of the cognitive benefits. The ability to titrate up to a dose of 13.3 mg/24 h provides an option for patients with severe AD or with an inadequate response to lower doses of rivastigmine.},
}

@article {pmid40600563,
year = {2025},
author = {Tripathi, S and Sharma, Y and Kumar, D},
title = {Harnessing Nature's Bounty: The Neuroprotective Potential of Phytoconstituents and Nanotechnology in Neurodegenerative Disease Therapeutics.},
journal = {CNS & neurological disorders drug targets},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118715273370166250610152453},
pmid = {40600563},
issn = {1996-3181},
abstract = {Investigations into the bioactive components of plant-based natural products indicate promising therapeutic potential for neurodegenerative diseases (NDs), including Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD). The loss and dysfunction of neurons characterize these disorders. Effective therapeutic guidelines are still elusive despite advances in our comprehension of NDs, in part because of unanswered questions about the safety and efficacy of natural therapies. On the other hand, preclinical models have shown that natural products-such as fruits, vegetables, nuts, herbs, and phytoconstituents found in freshwater and marine flora-have neuroprotective effects. These substances have the ability to work through a variety of pathways, halting cell death and reinstating neuronal activity. According to recent research, adding these phytoconstituents to nanocarriers, such as nanoparticles, can improve their selectivity and stability, possibly boosting the effectiveness of treatment. By making these agents more specific to target sites, nanotechnology presents a promising treatment option for NDs. Clinical trials assessing the efficacy of these natural compounds in treating neurological conditions are becoming more common as research advances, underscoring their potential as neuroprotective drugs. This study primarily focuses on the therapeutic efficacy of specific natural compounds and their bioactive components, which exhibit neuroprotective benefits in conditions associated with undiagnosed depression. Several preclinical models have demonstrated better results when natural derivatives are used, which has led to an increase in the use of natural therapies for treating NDs. Overall, despite ongoing difficulties, natural products have a great deal of promise for treating and preventing NDs; however, more research is needed to determine safe and effective treatment modalities.},
}

@article {pmid40600562,
year = {2025},
author = {Ye, JX and Wu, JY and Zhu, M and Ai, L and Huang, Q},
title = {Elucidating the Role of Gardeniae Fructus and Scutellariae Radix Herb Pair in Alzheimer's Disease via Network Pharmacology: Emphasis on Oxidative Stress, and the PI3K/Akt Pathway.},
journal = {Current pharmaceutical biotechnology},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113892010326797250422095516},
pmid = {40600562},
issn = {1873-4316},
abstract = {BACKGROUND: The combination of Gardeniae Fructus (ZZ) and Scutellariae Radix (HQ) is a traditional Chinese medicine used for Alzheimer's disease (AD). However, the molecular mechanisms underlying its anti-dementia effects, particularly its multi-component synergy and pathway modulation, remain poorly understood.

OBJECTIVE: Our study employed an integrated systems pharmacology approach to mechanistically decode the anti-AD properties of ZZ-HQ, combining network pharmacology predictions, molecular docking simulations, and experimental validation to identify critical bioactive components, molecular targets, and therapeutic pathways.

METHODS: A comprehensive network pharmacology analysis was performed to identify bioactive compounds within the ZZ-HQ complex and their potential protein targets associated with AD. Molecular docking was utilized to predict and assess the binding interactions between key bioactive compounds and AD-related protein targets. Experimental validation focused on baicalin, a major active compound in the ZZ-HQ complex, evaluating its effects on cell viability, apoptosis regulation, oxidative stress reduction, and the activation of the PI3K/Akt signaling pathway.

RESULTS: Fifty-four bioactive compounds were identified in the ZZ-HQ complex, interacting with 258 AD-associated proteins. Key compounds, such as baicalein and norwogonin, demonstrated strong binding affinities with pivotal proteins, including SRC and PIK3R1. Experimental studies further confirmed that baicalin significantly improved cell viability by activating the PI3K/Akt pathway, reducing apoptosis, and alleviating oxidative stress.

CONCLUSION: Our study uncovered the therapeutic potential of the ZZ-HQ combination in addressing AD through multi-target mechanisms, particularly via modulation of the PI3K/Akt pathway and oxidative stress. These findings provide a scientific basis for the pharmacological effects of ZZ-HQ and offer valuable insights for further research on its potential application in AD treatment.},
}

@article {pmid40600553,
year = {2025},
author = {Zhu, Y and Jin, X and Liu, J},
title = {Investigating the Biomarkers for Alzheimer's Disease: Insights from Microarray Analysis, Mendelian Randomization, and Experimental Validation.},
journal = {Current medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0109298673366495250527055016},
pmid = {40600553},
issn = {1875-533X},
abstract = {BACKGROUND: Alzheimer's disease (AD) is the most common cause of dementia worldwide, with a steadily increasing prevalence. However, the mechanisms underlying AD remain unclear, and current treatments have only limited efficacy.

OBJECTIVE: This study aimed to identify potential biomarker genes for AD and to explore the underlying mechanisms by integrating microarray analysis, Mendelian randomization (MR), and experimental validation.

METHODS: AD-related microarray datasets were downloaded from the Gene Expression Omnibus database. Differential expression analysis identified differentially expressed genes (DEGs) between AD and control samples. Summary-level data from genomewide association studies on AD were integrated with expression quantitative trait loci data to identify genes with potential causal relationships with AD using MR. The intersections between DEGs and causal genes were identified as hub genes. Functional analysis was performed to explore underlying mechanisms. Quantitative real-time PCR was applied to validate the expression of hub genes in clinical samples.

RESULTS: Differential expression analysis identified 312 DEGs, whereas MR identified 202 genes with causal effects on AD. The intersection of these two sets identified four hub genes: FCRLB, MT2A, PFKFB3, and SRGN. Functional analysis indicated significant associations between AD and immune-related pathways. Correlation analysis revealed significant connections between hub genes and immune cells in AD. The expression of MT2A, PFKFB3, and SRGN was significantly upregulated, whereas FCRLB was downregulated in clinical AD samples compared with controls.

CONCLUSION: The integration of microarray analysis, MR, and experimental validation identified and validated four potential biomarker genes with causal effects on AD, namely FCRLB, MT2A, PFKFB3, and SRGN. Functional analysis indicated a pivotal role of the immune microenvironment in AD. These findings offer insights into the molecular mechanisms of AD and have implications for improving its diagnosis and treatment strategies.},
}

@article {pmid40600550,
year = {2025},
author = {Hasan, U and Jain, H and Ali, R},
title = {Advancing Amyloid Aggregation Research: A Focus on Innovative Therapies, Molecular Modeling and Nano-Delivery Systems in Alzheimer's Disease.},
journal = {Current drug targets},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113894501388678250618070927},
pmid = {40600550},
issn = {1873-5592},
abstract = {INTRODUCTION: Alzheimer's disease (AD), the most common form of dementia, is a major global health issue. Its complex pathology, including amyloid-beta (Aβ) aggregation, leads to neuronal damage and cognitive decline. Since Aβ plays a major role in AD, therapies targeting its production, aggregation, and clearance are being actively explored. This review discusses recent advances in gene therapy, enzyme inhibitors, molecular modeling, and nano-delivery systems aimed at modifying AD progression, highlighting their potential and challenges.

METHODS: This review compiles findings on BACE1 and γ-secretase inhibitors, gene therapies that modify amyloid metabolism, and combination therapies. Studies have been selected based on their focus on Aβ regulation and their impact on disease progression, cognitive function, and breakthroughs in diagnostics, molecular modeling, and drug delivery for neurodegenerative conditions.

RESULTS: BACE1 inhibitors, such as verubecestat, and γ-secretase inhibitors, shows potential, however, they face significant challenges related to BBB penetration and adverse effects. Gene therapies using AAV vectors and CRISPR/Cas9 technologies are promising, particularly for individuals genetically predisposed to these diseases. Combination therapies targeting amyloid, tau, and neuro-inflammation have emerged as effective approaches. Advancements in PET, SPECT, MRI, small molecule probes, molecular modeling, and nano-particle-based drug delivery are improving diagnostic and treatment options.

DISCUSSION: The findings emphasize the multifactorial complexity of amyloid disorders and the limitations of mono-therapies. While certain agents demonstrated efficacy in early disease stages, most treatments have failed in advanced phases due to poor central nervous system (CNS) bioavailability, adverse effects, or insufficient target engagement. Novel delivery systems, combination therapies, and computational design approaches offer enhanced translational potential. However, challenges such as immune responses, delivery efficiency, and off-target effects continue to pose significant barriers.

CONCLUSION: Aβ-targeted therapies, including enzyme inhibitors and gene therapies, hold promise, though challenges such as BBB penetration and toxicity still remain. Combination therapies, along with advancements in diagnostics and drug delivery technology, are essential for finding effective treatments for Alzheimer's, Parkinson's, and other neurodegenerative diseases. Future research should prioritize overcoming the persistent barriers to BBB penetration, enhancing therapeutic selectivity, and refining drug delivery systems to enable more precise, targeted interventions, to ultimately reduce the progression of disease at the molecular level.},
}

@article {pmid40600356,
year = {2025},
author = {Hardy, J},
title = {Milestone Review: The History of Molecular Genetics Analysis of Alzheimer's Disease.},
journal = {Journal of neurochemistry},
volume = {169},
number = {7},
pages = {e70148},
doi = {10.1111/jnc.70148},
pmid = {40600356},
issn = {1471-4159},
mesh = {*Alzheimer Disease/genetics/history ; Humans ; History, 20th Century ; History, 21st Century ; Amyloid beta-Protein Precursor/genetics ; *Molecular Biology/history ; Animals ; Mutation/genetics ; Genome-Wide Association Study ; Genetic Predisposition to Disease/genetics ; },
abstract = {Alzheimer research has been driven by genetic findings: from the 1990s until about 2005, by the identification of amyloid precursor protein (APP) and presenilin (PSEN) mutations, leading to the formulation of the amyloid hypothesis, and then from ~2007 by genome-wide studies which have led to the increasing appreciation of the importance of microglial insufficiency in the disease pathogenesis. These genome findings have led not only to key mechanistic insights but also to progress in the use of genetic data to predict those at high risk of the disease so that earlier treatment becomes more practical. In this review I will outline these developments and attempts to synthesise the findings into a coherent single view of the disease.},
}

*Alzheimer Disease/genetics/history
Humans
History, 20th Century
History, 21st Century
Amyloid beta-Protein Precursor/genetics
*Molecular Biology/history
Animals
Mutation/genetics
Genome-Wide Association Study
Genetic Predisposition to Disease/genetics

@article {pmid40600330,
year = {2025},
author = {Comert Onder, F and Ural, K and Onder, A and Ozpolat, B and Ay, M},
title = {New and potential boron-containing compounds for treatment of Alzheimer's disease and cancers.},
journal = {Future medicinal chemistry},
volume = {},
number = {},
pages = {1-13},
doi = {10.1080/17568919.2025.2525065},
pmid = {40600330},
issn = {1756-8927},
abstract = {AIM: In this study, new boron-containing carbamate compounds were synthesized and evaluated as potential acetylcholinesterase (AChE) inhibitors by in vitro and in silico analyses.

MATERIALS & METHODS: The structures were characterized by spectroscopic analysis including [1]H NMR, [13]C NMR, [11]B NMR, and MS. The purities of the compounds were determined by HPLC analysis. In vitro and in silico analyses were performed.

RESULTS: Based on our findings, compounds (1-4) demonstrated more potent AChE inhibitory activity compared to tacrine, which is an FDA-approved AChE inhibitor. Compound 4 had the highest inhibitory activity with an IC50 of 37.87 ± 0.96 nM and was more effective than tacrine (74.23 ± 0.83 nM). Compounds 1, 2, and 3, respectively, showed 1.78-, 1.73-, and 1.58-fold more potent enzyme inhibition activity compared to tacrine. The strong interactions with critical residues in the binding pocket of AChE were identified between protein and the compounds. Furthermore, compound 4 exerted an antiproliferative activity against various human cancer cell lines (32.91 ± 4.92 µM in HT29 and 42.38 ± 2.73 µM in MCF-7).

CONCLUSION: Our study indicates the discovery of new boron-containing AChE inhibitors as potential candidates for the treatment of Alzheimer's disease and cancer.},
}

@article {pmid40600183,
year = {2025},
author = {Fu, X and Cai, H and Quan, S and Ren, Z and Xu, Y and Jia, L},
title = {Immune cells in Alzheimer's disease: insights into pathogenesis and potential therapeutic targets.},
journal = {Medical review (2021)},
volume = {5},
number = {3},
pages = {179-202},
pmid = {40600183},
issn = {2749-9642},
abstract = {Alzheimer's disease (AD) is a chronic neurodegenerative disorder for which there are currently no effective treatment options. Increasing evidence suggests that AD is a systemic disease closely associated with the immune system, not merely a central nervous system (CNS) disorder. Immune cells play crucial roles in the onset and progression of AD. Microglia and astrocytes are the primary inflammatory cells in the brain that can sensitively detect changes in the internal environment and transform into different phenotypes to exert differing effects at various stages of AD. Peripheral immune cells, such as T cells, B cells, monocytes/macrophages, and neutrophils can also be recruited to the CNS to mediate the inflammatory response in AD. As such, investigating the role of immune cells in AD is particularly important for elucidating its specific pathogenesis. This review primarily discusses the roles of central innate immune cells, peripheral immune cells, and the interactions between central and peripheral immune cells in the development of neuroinflammation in AD. Furthermore, we listed clinical trials targeting AD-associated neuroinflammation, which may represent a promising direction for developing effective treatments for AD in the future.},
}

@article {pmid40600167,
year = {2025},
author = {Aremu, SA},
title = {Alternative splicing and the aging brain in AfrAbia: New frontiers in dementia research.},
journal = {IBRO neuroscience reports},
volume = {19},
number = {},
pages = {101-109},
pmid = {40600167},
issn = {2667-2421},
abstract = {AfrAbia (Sub-Saharan Africa and Arab world), is undergoing a significant demographic shift characterized by increased longevity and rising dementia rates. Despite this, molecular insights into brain aging in these regions, especially in RNA processing pathways like alternative splicing (AS), are virtually absent. AS promotes transcriptomic and proteomic complexity and is pivotal for brain function, with its dysregulation connected to neurodegenerative diseases such as Alzheimer's disease (AD), frontotemporal dementia (FTD), and Parkinson's disease (PD). However, current knowledge is overwhelmingly derived from Western populations, limiting global applicability. This perspective synthesizes the mechanisms and regulatory elements of AS, its role in aging and neurodegeneration, and emerging biomarkers and therapeutic strategies. Special attention is paid to ancestry-associated splicing variants and fluid biomarker development in AfrAbian cohorts. We argue for inclusive, population-specific molecular studies to bridge disparities in dementia diagnosis, treatment, and prevention.},
}

@article {pmid40600046,
year = {2025},
author = {Kishor Kumar Reddy, C and Ahmed, HI and Mohzary, M and Monika Singh, T and Shuaib, M and Alam, S and Alnami, HM},
title = {AlzheimerViT: harnessing lightweight vision transformer architecture for proactive Alzheimer's screening.},
journal = {Frontiers in medicine},
volume = {12},
number = {},
pages = {1568312},
pmid = {40600046},
issn = {2296-858X},
abstract = {BACKGROUND: Alzheimer's is a disease in the human brain characterized by gradual memory loss, confusion, and alterations in behavior. It is a complex and continuously degenerative disorder of the nervous system, which still has early detection and diagnosis as challenges to overcome. The disease causes significant damage in individuals suffering from the disorder as they progressively lose cognitive ability. Its diagnosis and management depend primarily on the ability to diagnose early to initiate proper intervention. Unfortunately, this remains a difficult feat, given the resemblance of early signs of the disease with symptoms associated with normal aging and other disorders involving cognition. While clinical tests have their limitations, brain imaging such as MRI can provide detailed insights into changes in the brain. Deep learning techniques, mainly when applied to MRI data, have proven helpful in the early detection of Alzheimer's Disease.

METHODS: In the proposed study, a lightweight, self-attention-based vision transformer (ViT) is employed to predict Alzheimer's disease using MRI images from the OASIS-3 dataset. Data pre-processing and augmentation techniques have been added to strengthen the model's generalization ability and enhance model performance, which is visualized using Grad-Cam.

RESULTS: The proposed model achieves exceptional results with an accuracy of 98.57%, approximate precision of 98.7%, Recall of about 98.47%, and specificity of 98.67%. It also achieves a Kappa Score of 97.2% and an AUC ROC Score of 99%.

CONCLUSION: This paper, along with comprehensive data pre-processing and augmentation, represents one of the major steps toward achieving more robust and clinically applicable models for Alzheimer's disease prediction. The proposed study indicates that deep learning models have the potential to enhance the diagnosis of Alzheimer's disease. By integrating Deep learning techniques with careful data processing, more reliable early detection models can be developed, which in turn leads to better treatment outcomes.},
}

@article {pmid40600033,
year = {2025},
author = {Pandey, P and Bhatia Khan, S and Pruthi, J and Albalawi, E and Algarni, A and Almusharraf, A},
title = {GAN-enhanced deep learning for improved Alzheimer's disease classification and longitudinal brain change analysis.},
journal = {Frontiers in medicine},
volume = {12},
number = {},
pages = {1587026},
pmid = {40600033},
issn = {2296-858X},
abstract = {Alzheimer's disease (AD) is commonly defined by a progressive decline in cognitive functions and memory. Early detection is crucial to mitigate the devastating impacts of AD, which can significantly impair a person's quality of life. Traditional methods for diagnosing AD, while still in use, often involve time-consuming processes that are prone to errors and inefficiencies. These manual techniques are limited in their ability to handle the vast amount of data associated with the disease, leading to slower diagnosis and potential misclassification. Advancements in artificial intelligence (AI), specifically machine learning (ML) and deep learning (DL), offer promising solutions to these challenges. AI techniques can process large datasets with high accuracy, significantly improving the speed and precision of AD detection. However, despite these advancements, issues such as limited accuracy, computational complexity, and the risk of overfitting still pose challenges in the field of AD classification. To address these challenges, the proposed study integrates deep learning architectures, particularly ResNet101 and long short-term memory (LSTM) networks, to enhance both feature extraction and classification of AD. The ResNet101 model is augmented with innovative layers such as the pattern descriptor parsing operation (PDPO) and the detection convolutional kernel layer (DCK), which are designed to extract the most relevant features from datasets such as ADNI and OASIS. These features are then processed through the LSTM model, which classifies individuals into categories such as cognitively normal (CN), mild cognitive impairment (MCI), and Alzheimer's disease (AD). Another key aspect of the research is the use of generative adversarial networks (GANs) to identify the progressive or non-progressive nature of AD. By employing both a generator and a discriminator, the GAN model detects whether the AD state is advancing. If the original and predicted classes align, AD is deemed non-progressive; if they differ, the disease is progressing. This innovative approach provides a nuanced view of AD, which could lead to more precise and personalized treatment plans. The numerical outcome obtained by the proposed model for ADNI dataset is 0.9931, and for OASIS dataset, the accuracy gained by the model is 0.9985. Ultimately, this research aims to offer significant contributions to the medical field, helping healthcare professionals diagnose AD more accurately and efficiently, thus improving patient outcomes. Furthermore, brain simulation models are integrated into this framework to provide deeper insights into the underlying neural mechanisms of AD. These brain simulation models help visualize and predict how AD may evolve in different regions of the brain, enhancing both diagnosis and treatment planning.},
}