@article {pmid39853846,
year = {2025},
author = {Moradi, F and Mokhtari, T},
title = {Role of NLRP3 Inflammasome in Chronic Pain and Alzheimer's Disease-A Review.},
journal = {Journal of biochemical and molecular toxicology},
volume = {39},
number = {2},
pages = {e70071},
doi = {10.1002/jbt.70071},
pmid = {39853846},
issn = {1099-0461},
support = {//This study was funded by the Faculty Development Grants from Hubei University of Medicine (No. 2023QDJZR) and partially supported by a grant from the National Institute of Environmental Health Sciences (NIEHS, R35ES030443)./ ; },
mesh = {*Alzheimer Disease/metabolism ; Humans ; *NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; *Inflammasomes/metabolism ; *Chronic Pain/metabolism/physiopathology ; Animals ; Microglia/metabolism/pathology ; },
abstract = {The coexistence of Alzheimer's disease (AD) and chronic pain (CP) in the elderly population has been extensively documented, and a growing body of evidence supports the potential interconnections between these two conditions. This comprehensive review explores the mechanisms by which CP may contribute to the development and progression of AD, with a particular focus on neuroinflammatory pathways and the role of microglia, as well as the activation of the NLR family pyrin domain containing 3 (NLRP3) inflammasome. The review proposes that prolonged pain processing in critical brain regions can dysregulate the activity of the NLRP3 inflammasome within microglia, leading to the overproduction of pro-inflammatory cytokines and excessive oxidative stress in these regions. This aberrant microglial response also results in localized neuroinflammation in brain areas crucial for cognitive function. Additionally, CP as a persistent physiological and psychological stressor may be associated with hypothalamic-pituitary-adrenal (HPA) axis dysfunction, systemic inflammation, disruption of the blood-brain barrier (BBB), and neuroinflammation. These pathophysiological changes can cause morphological and functional impairments in brain regions responsible for cognition, memory, and neurotransmitter production, potentially contributing to the development and progression of CP-associated AD. Resultant neuroinflammation can further promote amyloid-beta (Aβ) plaque deposition, a hallmark of AD pathology. Potential therapeutic interventions targeting these neuroinflammatory pathways, particularly through the regulation of microglial NLRP3 activation, hold promise for improving outcomes in individuals with comorbid CP and AD. However, further research is required to fully elucidate the complex interplay between these conditions and develop effective treatment strategies.},
}

*Alzheimer Disease/metabolism
Humans
*NLR Family, Pyrin Domain-Containing 3 Protein/metabolism
*Inflammasomes/metabolism
*Chronic Pain/metabolism/physiopathology
Animals
Microglia/metabolism/pathology

@article {pmid39853561,
year = {2025},
author = {Lee, HH and Chinnameyyappan, A and Feldman, OJ and Marotta, G and Survilla, K and Lanctôt, KL},
title = {Behavioral and Psychological Symptoms (BPSD) in Alzheimer's Disease (AD): Development and Treatment.},
journal = {Current topics in behavioral neurosciences},
volume = {},
number = {},
pages = {},
doi = {10.1007/7854_2024_566},
pmid = {39853561},
issn = {1866-3370},
abstract = {Behavioral and psychological symptoms of dementia (BPSD), such as agitation, apathy, and psychosis, are highly prevalent and have a significant impact on patients and their care partners. The neurobiology of BPSD involves a complex interplay of structural brain changes and alterations in the neurotransmitter system. Various genetic and plasma biomarkers have also been studied. Research in BPSD has been limited by heterogeneity in the diagnostic criteria and assessment tools. As such, there have been ongoing efforts to develop a gold-standard assessment tool and diagnostic criteria. Current practice guidelines recommend nonpharmacological therapies as first-line treatments. Pharmacological options are often used when there is an insufficient response to nonpharmacological strategies, but there can be serious adverse effects with existing pharmacological agents. This has resulted in growing efforts to develop novel therapeutics with more favorable tolerability profiles, with some showing promising results. Other biological therapies, such as neurostimulation, have also demonstrated positive results. As our understanding of BPSD evolves, ongoing research efforts in treatment of BPSD are warranted in order to enhance the quality of life for patients and their care partners.},
}

@article {pmid39853424,
year = {2025},
author = {Zavarella, M and Cecchetti, G and Rugarli, G and Ghirelli, A and Bottale, I and Orlandi, F and Spinelli, EG and Santangelo, R and Caso, F and Calloni, SF and Vezzulli, PQ and Falini, A and Magnani, G and Agosta, F and Filippi, M},
title = {Favorable long-term cognitive outcomes following recurrent ARIA linked to amyloid-lowering therapies: two cases.},
journal = {Journal of neurology},
volume = {272},
number = {2},
pages = {168},
pmid = {39853424},
issn = {1432-1459},
support = {Project Age-It: "Ageing Well in an Ageing Society"//Ministero dell'Università e della Ricerca/ ; },
mesh = {Humans ; *Cognitive Dysfunction/etiology/drug therapy ; *Antibodies, Monoclonal, Humanized/administration & dosage/adverse effects ; *Alzheimer Disease/drug therapy ; Aged ; Male ; Female ; Recurrence ; Positron-Emission Tomography ; Aged, 80 and over ; Disease Progression ; Follow-Up Studies ; },
abstract = {INTRODUCTION: The large-scale approval of anti-amyloid monoclonal antibodies for treating Alzheimer's disease (AD) has raised concerns about their safety due to treatment-emergent amyloid-related imaging abnormalities (ARIA).

METHODS: We present two cases of patients diagnosed with mild cognitive impairment due to AD who were enrolled in the GRADUATE I clinical trial. They received subcutaneous gantenerumab every two weeks during the study period.

RESULTS: Both patients experienced recurrent ARIA-Effusion/Edema type (ARIA-E). One developed symptomatic and severe ARIA, leading to hospitalization and study withdrawal. We report a long follow-up post-randomization (65 and 54 months), during which the adverse events did not appear to have a negative impact on disease progression. Additionally, one patient had a negative amyloid-PET over a year after treatment cessation.

DISCUSSION: These cases suggest that recurrent ARIA-E do not inevitably lead to accelerated progression, instead, may relate to possible long-term benefits. The mechanisms underlying these findings warrant further real-life evidence.},
}

Humans
*Cognitive Dysfunction/etiology/drug therapy
*Antibodies, Monoclonal, Humanized/administration & dosage/adverse effects
*Alzheimer Disease/drug therapy
Aged
Male
Female
Recurrence
Positron-Emission Tomography
Aged, 80 and over
Disease Progression
Follow-Up Studies

@article {pmid39852770,
year = {2025},
author = {Kala, S and Strutz, AG and Katt, ME},
title = {The Rise of Pluripotent Stem Cell-Derived Glia Models of Neuroinflammation.},
journal = {Neurology international},
volume = {17},
number = {1},
pages = {},
doi = {10.3390/neurolint17010006},
pmid = {39852770},
issn = {2035-8385},
support = {5P20GM109098-10/GF/NIH HHS/United States ; T32AG052375/GF/NIH HHS/United States ; },
abstract = {Neuroinflammation is a blanket term that describes the body's complex inflammatory response in the central nervous system (CNS). It encompasses a phenotype shift to a proinflammatory state, the release of cytokines, the recruitment of peripheral immune cells, and a wide variety of other processes. Neuroinflammation has been implicated in nearly every major CNS disease ranging from Alzheimer's disease to brain cancer. Understanding and modeling neuroinflammation is critical for the identification of novel therapeutic targets in the treatment of CNS diseases. Unfortunately, the translation of findings from non-human models has left much to be desired. This review systematically discusses the role of human pluripotent stem cell (hPSC)-derived glia and supporting cells within the CNS, including astrocytes, microglia, oligodendrocyte precursor cells, pericytes, and endothelial cells, to describe the state of the field and hope for future discoveries. hPSC-derived cells offer an expanded potential to study the pathobiology of neuroinflammation and immunomodulatory cascades that impact disease progression. While much progress has been made in the development of models, there is much left to explore in the application of these models to understand the complex inflammatory response in the CNS.},
}

@article {pmid39851568,
year = {2025},
author = {Mooradian, AD and Haas, MJ},
title = {Role of Thyroid Hormone in Neurodegenerative Disorders of Older People.},
journal = {Cells},
volume = {14},
number = {2},
pages = {},
doi = {10.3390/cells14020140},
pmid = {39851568},
issn = {2073-4409},
mesh = {Humans ; *Thyroid Hormones/metabolism ; *Neurodegenerative Diseases/metabolism/pathology ; Animals ; Aged ; },
abstract = {Thyroid dysfunction is associated with a number of neuropsychiatric manifestations. Cognitive decline is a common feature of hypothyroidism and clinical or subclinical hyperthyroidism. In addition, there is a significant association between thyroid hormone (TH) levels and the degree of cognitive impairment in Parkinson's disease (PD). The pathophysiology of TH-related neurodegeneration include changes in the blood-brain barrier, increased cellular stress, altered processing of β-amyloid precursor protein and the effect of TH on neuronal cell viability. The neurotoxicity of TH is partially mediated by the thyroid hormone responsive protein (THRP). This protein is 83% homologous to mouse c-Abl-interacting protein-2 (Abi2), a c-Abl-modulating protein with tumor suppressor activity. In cell cultures, increasing THRP expression either with TH treatment or exogenously through transfecting neuronal or PC 12 cells causes cell necrosis. The expression of exogenous THRP in other cells such as the colonic epithelial cell line Caco-2 and the glial cell line U251 has no effect on cell viability. The effect of THRP on cell viability is not modulated by c-Abl tyrosine kinase. The causal relationship between specific biochemical perturbations in cerebral tissue and thyroid dysfunction remains to be elucidated.},
}

Humans
*Thyroid Hormones/metabolism
*Neurodegenerative Diseases/metabolism/pathology
Animals
Aged

@article {pmid39851526,
year = {2025},
author = {Chen, W and Kim, S and Kim, SY and Beheshtian, C and Kim, N and Shin, KH and Kim, RH and Kim, S and Park, NH},
title = {GV1001, hTERT Peptide Fragment, Prevents Doxorubicin-Induced Endothelial-to-Mesenchymal Transition in Human Endothelial Cells and Atherosclerosis in Mice.},
journal = {Cells},
volume = {14},
number = {2},
pages = {},
doi = {10.3390/cells14020098},
pmid = {39851526},
issn = {2073-4409},
support = {441902-19900//University of California System/ ; },
mesh = {*Doxorubicin/pharmacology/adverse effects ; Animals ; *Atherosclerosis/pathology/drug therapy ; Humans ; Mice ; *Epithelial-Mesenchymal Transition/drug effects ; *Telomerase/metabolism ; Mitochondria/drug effects/metabolism ; Reactive Oxygen Species/metabolism ; Endothelial Cells/drug effects/metabolism/pathology ; Human Umbilical Vein Endothelial Cells/drug effects/metabolism ; NF-kappa B/metabolism ; Mice, Inbred C57BL ; Male ; Disease Models, Animal ; Peptide Fragments/pharmacology ; },
abstract = {Doxorubicin is a highly effective anticancer agent, but its clinical use is restricted by severe side effects, including atherosclerosis and cardiomyopathy. These complications are partly attributed to doxorubicin's ability to induce endothelial-to-mesenchymal transition (EndMT) in vascular endothelial cells, a critical process in the initiation and progression of atherosclerosis and cardiomyopathy. GV1001, a multifunctional peptide with anti-inflammatory, anti-cancer, antioxidant, and anti-Alzheimer's properties, has demonstrated inhibition of EndMT. We investigated whether GV1001 could counteract doxorubicin-induced EndMT in endothelial cells and prevent atherosclerosis in a mouse model. The results revealed that GV1001 significantly suppressed EndMT induced by doxorubicin, likely through its protective effects on mitochondria. By mitigating mitochondrial damage, GV1001 reduced the accumulation of mitochondrial and cellular reactive oxygen species (ROS), repressed the activation of nuclear factor kappa B (NF-κB), and reduced the production of proinflammatory cytokines in endothelial cells. Additionally, GV1001 reduced systemic and vascular inflammation, lipid accumulation, and monocyte/macrophage infiltration within arterial walls in mice. In conclusion, GV1001 appears to prevent doxorubicin-induced atherosclerosis by safeguarding vascular endothelial cells from mitochondrial dysfunction, inflammation, and phenotypic changes. These findings suggest the potential of GV1001 as a therapeutic agent to mitigate the long-term cardiovascular side effects associated with doxorubicin treatment in humans.},
}

*Doxorubicin/pharmacology/adverse effects
Animals
*Atherosclerosis/pathology/drug therapy
Humans
Mice
*Epithelial-Mesenchymal Transition/drug effects
*Telomerase/metabolism
Mitochondria/drug effects/metabolism
Reactive Oxygen Species/metabolism
Endothelial Cells/drug effects/metabolism/pathology
Human Umbilical Vein Endothelial Cells/drug effects/metabolism
NF-kappa B/metabolism
Mice, Inbred C57BL
Male
Disease Models, Animal
Peptide Fragments/pharmacology

@article {pmid39851389,
year = {2024},
author = {Trinh, DQ and Mai, NH and Pham, TD},
title = {Insufficient Sleep and Alzheimer's Disease: Potential Approach for Therapeutic Treatment Methods.},
journal = {Brain sciences},
volume = {15},
number = {1},
pages = {},
doi = {10.3390/brainsci15010021},
pmid = {39851389},
issn = {2076-3425},
abstract = {The interaction between Alzheimer's disease (AD) and sleep deprivation has recently gained attention in the scientific literature, and recent advances suggest that AD epidemiology management should coincide with the management of sleeping disorders. This review focuses on the aspects of the mechanisms underlying the link between AD and insufficient sleep with progressing age. We also provide information which could serve as evidence for future treatments of AD from the early stages in connection with sleep disorder medication.},
}

@article {pmid39851253,
year = {2024},
author = {Sun, Y and Pang, X and Huang, X and Liu, D and Huang, J and Zheng, P and Wei, Y and Pang, C},
title = {Potential mechanisms of non-coding RNA regulation in Alzheimer's disease.},
journal = {Neural regeneration research},
volume = {},
number = {},
pages = {},
doi = {10.4103/NRR.NRR-D-24-00696},
pmid = {39851253},
issn = {1673-5374},
abstract = {Alzheimer's disease, a progressively degenerative neurological disorder, is the most common cause of dementia in the elderly. While its precise etiology remains unclear, researchers have identified diverse pathological characteristics and molecular pathways associated with its progression. Advances in scientific research have increasingly highlighted the crucial role of non-coding RNAs in the progression of Alzheimer's disease. These non-coding RNAs regulate several biological processes critical to the advancement of the disease, offering promising potential as therapeutic targets and diagnostic biomarkers. Therefore, this review aims to investigate the underlying mechanisms of Alzheimer's disease onset, with a particular focus on microRNAs, long non-coding RNAs, and circular RNAs associated with the disease. The review elucidates the potential pathogenic processes of Alzheimer's disease and provides a detailed description of the synthesis mechanisms of the three aforementioned non-coding RNAs. It comprehensively summarizes the various non-coding RNAs that have been identified to play key regulatory roles in Alzheimer's disease, as well as how these non-coding RNAs influence the disease's progression by regulating gene expression and protein functions. For example, miR-9 targets the UBE4B gene, promoting autophagy-mediated degradation of Tau protein, thereby reducing Tau accumulation and delaying Alzheimer's disease progression. Conversely, the long non-coding RNA BACE1-AS stabilizes BACE1 mRNA, promoting the generation of amyloid-[2] and accelerating Alzheimer's disease development. Additionally, circular RNAs play significant roles in regulating neuroinflammatory responses. By integrating insights from these regulatory mechanisms, there is potential to discover new therapeutic targets and potential biomarkers for early detection and management of Alzheimer's disease. This review aims to enhance the understanding of the relationship between Alzheimer's disease and non-coding RNAs, potentially paving the way for early detection and novel treatment strategies.},
}

@article {pmid39851113,
year = {2025},
author = {Mishra, AS and Vasantham, M and Ghosh, B and Malliappan, SP},
title = {Transforming Alzheimer's Treatment: Unveiling New Potential with Drug Repurposing Strategies.},
journal = {Current medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0109298673341391241231054936},
pmid = {39851113},
issn = {1875-533X},
abstract = {Alzheimer's disease (AD) remains a significant challenge in neurology, marked by progressive cognitive decline and neurodegeneration. Despite extensive research efforts, effective treatments are still lacking. Traditional drug discovery is often slow and costly, frequently resulting in limited success. Drug repurposing, which identifies new therapeutic uses for existing medications, has emerged as a promising approach to expedite AD treatment development. This review examines the potential of drug repurposing to transform AD therapy by utilizing the established safety profiles and known mechanisms of current drugs. We explore various repurposed drugs under investigation for AD, originally intended for cardiovascular, metabolic, and psychiatric conditions. Detailed discussions include how these drugs provide neuroprotective benefits by inhibiting amyloid-beta aggregation, reducing tau phosphorylation, and modulating neuroinflammation. Additionally, we emphasize the benefits of drug repurposing, such as shortened development timelines, lower costs, and increased chances of clinical success. By integrating current research findings, this review offers a thorough overview of the most promising repurposed drug candidates and their potential impact on AD treatment strategies. It stresses the importance of innovative approaches in AD research and calls for greater investment in drug repurposing initiatives. Through these strategies, we aim to accelerate the availability of effective treatments, providing renewed hope and a brighter future for those affected by this devastating disease.},
}

@article {pmid39849525,
year = {2025},
author = {Lu, Y and Xu, Y and Zhou, L and Wang, S and Han, Y and Wang, K and Qin, C},
title = {Bone marrow mesenchymal stem cells derived cytokines associated with AKT/IAPs signaling ameliorate Alzheimer's disease development.},
journal = {Stem cell research & therapy},
volume = {16},
number = {1},
pages = {14},
pmid = {39849525},
issn = {1757-6512},
support = {2021-I2M-1-034, 2019-I2M-1-004//Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences/ ; 2022QNRC001//Young Elite Scientitsts Sponsorship Program by CAST/ ; 2023-PT180-01//the Non-Profit Central Research Institute Fund of the Chinese Academy of Medical Sciences/ ; },
mesh = {Animals ; *Alzheimer Disease/therapy/metabolism ; Mice ; *Mesenchymal Stem Cells/metabolism ; *Proto-Oncogene Proteins c-akt/metabolism ; *Cytokines/metabolism ; Female ; Signal Transduction ; Disease Models, Animal ; Mesenchymal Stem Cell Transplantation/methods ; Mice, Transgenic ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative condition affecting around 50 million people worldwide. Bone marrow-derived mesenchymal stem cells (BMMSCs) have emerged as a promising source for cellular therapy due to their ability to differentiate into multiple cell types and their paracrine effects. However, the direct injection of BMMSCs can lead to potential unpredictable impairments, prompting a renewed interest in their paracrine effects for AD treatment. The specific mechanism and central role of cytokines in this process have not been fully elucidated.

METHODS: Mouse BMMSCs were isolated, validated, and then transplanted intracerebrally into APP/PS1 female mice. The behavioral tests, including open-field test, novel object recognition test, and Morris water maze were performed, followed by β-amyloidosis plaque and neuron apoptosis analyses. Then the tissue RNA sequencing and mBMMSC cytokine analysis were performed. A cytokine antibody array for BMMSCs and the brain slice models were performed with AD model tissues were used to elucidate the molecular mechanisms. Finally, APP/PS1 mice were administrated with cytokine mixture for cognitive recovery.

RESULTS: Our results demonstrated that BMMSCs significantly improved cognitive function, reduced beta-amyloid plaque deposition, and decreased apoptotic neurons through the activation of the AKT signaling pathway. Using a cytokine antibody array, we identified three highly expressed AKT pathway regulated neuroprotective factors in BMMSCs: IGF1, VEGF, and Periostin2. These cytokines were found to upregulate inhibitors of apoptosis family proteins (IAPs) and suppress Caspase-3 activity in brain slices induced with beta amyloidosis (Aβ), okadaic acid (OA), and lipopolysaccharide (LPS). When injection of this cytokine mixture to APP/PS1 mice also resulted in a mitigation of cognitive impairment.

CONCLUSIONS: These findings suggest that the secretory factors IGF1, VEGF, and Periostin2 derived from BMMSCs play a crucial role in neuroprotection by modulating the AKT/IAPs pathway to restore neuronal function. These cytokine sets could be a potential therapeutic strategy for AD and lay the groundwork for promising clinical applications.},
}

Animals
*Alzheimer Disease/therapy/metabolism
Mice
*Mesenchymal Stem Cells/metabolism
*Proto-Oncogene Proteins c-akt/metabolism
*Cytokines/metabolism
Female
Signal Transduction
Disease Models, Animal
Mesenchymal Stem Cell Transplantation/methods
Mice, Transgenic

@article {pmid39848035,
year = {2025},
author = {Azam, U and Naseer, MM and Rochais, C},
title = {Analysis of skeletal diversity of multi-target directed ligands (MTDLs) targeting Alzheimer's disease.},
journal = {European journal of medicinal chemistry},
volume = {286},
number = {},
pages = {117277},
doi = {10.1016/j.ejmech.2025.117277},
pmid = {39848035},
issn = {1768-3254},
abstract = {Alzheimer's disease (AD) remains a significant healthcare challenge, necessitating innovative therapeutic approaches to address its complex and multifactorial nature. Traditional drug discovery strategies targeting single molecular targets are not sufficient for the effective treatment of AD. In recent years, MTDLs have emerged as promising candidates for AD therapy, aiming to simultaneously modulate multiple pathological targets. Among the various strategies employed in MTDL design, pharmacophore hybridization offers a versatile approach to integrate diverse pharmacophoric features within a single molecular scaffold. This strategy provides access to a wide array of chemical space for the design and development of novel therapeutic agents. This review, therefore, provides a comprehensive overview of skeletal diversity exhibited by MTDLs designed recently for AD therapy based on pharmacophore hybridization approach. A diverse range of pharmacophoric elements and core scaffolds hybridized to construct MTDLs that has the potential to target multiple pathological features of AD including amyloid-beta aggregation, tau protein hyperphosphorylation, cholinergic dysfunction, oxidative stress, and neuroinflammation are discussed. Through the comprehensive analysis and integration of structural insights of key biomolecular targets, this review aims to enhance optimization efforts in MTDL design, ultimately striving towards a comprehensive cure for the multifaceted pathophysiology of the disease.},
}

@article {pmid39846361,
year = {2025},
author = {Wang, SJ and Wei, LC and Chiu, HJ},
title = {Comment on "Delirium event and associated treatment modifications among older adults with Alzheimer's disease: An interrupted time-series analysis of Medicare data".},
journal = {Pharmacotherapy},
volume = {45},
number = {1},
pages = {70},
doi = {10.1002/phar.4636},
pmid = {39846361},
issn = {1875-9114},
}

@article {pmid39846360,
year = {2025},
author = {Aparasu, RR and Talwar, A},
title = {Response to comment on "Delirium event and associated treatment modifications among older adults with Alzheimer's disease: An interrupted time-series analysis of Medicare data".},
journal = {Pharmacotherapy},
volume = {45},
number = {1},
pages = {71},
doi = {10.1002/phar.4637},
pmid = {39846360},
issn = {1875-9114},
}

@article {pmid39846055,
year = {2025},
author = {Wei, S and Yang, W and Wang, E and Wang, S and Li, Y},
title = {A 3D decoupling Alzheimer's disease prediction network based on structural MRI.},
journal = {Health information science and systems},
volume = {13},
number = {1},
pages = {17},
pmid = {39846055},
issn = {2047-2501},
abstract = {PURPOSE: This paper aims to develop a three-dimensional (3D) Alzheimer's disease (AD) prediction method, thereby bettering current predictive methods, which struggle to fully harness the potential of structural magnetic resonance imaging (sMRI) data.

METHODS: Traditional convolutional neural networks encounter pressing difficulties in accurately focusing on the AD lesion structure. To address this issue, a 3D decoupling, self-attention network for AD prediction is proposed. Firstly, a multi-scale decoupling block is designed to enhance the network's ability to extract fine-grained features by segregating convolutional channels. Subsequently, a self-attention block is constructed to extract and adaptively fuse features from three directions (sagittal, coronal and axial), so that more attention is geared towards brain lesion areas. Finally, a clustering loss function is introduced and combined with the cross-entropy loss to form a joint loss function for enhancing the network's ability to discriminate between different sample types.

RESULTS: The accuracy of our model is 0.985 for the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset and 0.963 for the Australian Imaging, Biomarker & Lifestyle (AIBL) dataset, both of which are higher than the classification accuracy of similar tasks in this category. This demonstrates that our model can accurately distinguish between normal control (NC) and Alzheimer's Disease (AD), as well as between stable mild cognitive impairment (sMCI) and progressive mild cognitive impairment (pMCI).

CONCLUSION: The proposed AD prediction network exhibits competitive performance when compared with state-of-the-art methods. The proposed model successfully addresses the challenges of dealing with 3D sMRI image data and the limitations stemming from inadequate information in 2D sections, advancing the utility of predictive methods for AD diagnosis and treatment.},
}

@article {pmid39845447,
year = {2024},
author = {Zhao, Y and Qiu, C and Lin, P and Yang, M and Huang, L and Zhao, Z and Wu, X and Zhou, D},
title = {Decreased prefrontal activation during verbal fluency task after repetitive transcranial magnetic stimulation treatment for depression in Alzheimer's disease: a functional near-infrared spectroscopy study.},
journal = {Frontiers in aging neuroscience},
volume = {16},
number = {},
pages = {1460853},
pmid = {39845447},
issn = {1663-4365},
abstract = {BACKGROUND: Studies have shown the clinical effects of repetitive transcranial magnetic stimulation (rTMS) on depression in Alzheimer's disease (AD). However, the underlying mechanisms remain poorly understood. The measurement of brain activation links neurobiological and functional aspects but is challenging in patients with dementia. This study investigated the influence of rTMS on cortical activation in patients with AD and depressive symptoms, measured using functional near-infrared spectroscopy (fNIRS) during a verbal fluency task.

METHODS: In this randomized, double-blind study, patients with AD and depression received either active rTMS (n = 17) or sham-rTMS (n = 16). Patients received 4 weeks of bilateral standard rTMS (1 Hz rTMS delivered to the right dorsolateral prefrontal cortex (DLPFC) and 10-Hz rTMS delivered to the left DLPFC).

RESULTS: No significant changes were found in the Mini-Mental State Examination (MMSE) and Modified Barthel Index (MBI); however, significant changes were found for the 17-item Hamilton Depression Rating Scale (HAMD-17) and the depression score of the Neuropsychiatric Inventory (NPI-depression; p < 0.05). The results showed a decrease in the concentration of oxygenated hemoglobin, as measured with fNIRS, from baseline to week 4 in CH41 (in right DLPFC; p = 0.0047, FDR-corrected). There was a negative correlation between the improvement in HAMD-17 severity in these patients and reduced oxygenated hemodynamic response of CH41 (r = - 0.504, p = 0.039).

CONCLUSION: The results indicated a positive effect of rTMS on depression in patients with AD. The underlying cortical changes were imaged using fNIRS. Prefrontal activation measured by fNIRS is a potential biomarker for monitoring the response of patients with depression in AD to rTMS treatment.},
}

@article {pmid39844773,
year = {2025},
author = {Xie, Y and Liu, J and Hou, Z and Wang, H and Liu, K and Chen, X and Fan, Z and Li, D and Li, C and Pan, Y and Zhao, Y and Zhu, Y and Hu, B},
title = {CD4-Derived Double-Negative T Cells Ameliorate Alzheimer's Disease-Like Phenotypes in the 5×FAD Mouse Model.},
journal = {CNS neuroscience & therapeutics},
volume = {31},
number = {1},
pages = {e70187},
doi = {10.1111/cns.70187},
pmid = {39844773},
issn = {1755-5949},
support = {2021YFA1101400//National Key Research and Development Program of China/ ; ZDBS-LY-SM024//Basic Frontier Science Research Program of CAS/ ; XDA 046205//Strategic Priority Research Program of CAS/ ; },
mesh = {Animals ; *Alzheimer Disease/therapy ; Mice ; *Disease Models, Animal ; *Mice, Transgenic ; *CD4-Positive T-Lymphocytes ; Phenotype ; Mice, Inbred C57BL ; Male ; Maze Learning/physiology ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is a debilitating neurodegenerative disorder that is difficult to predict and is typically diagnosed only after symptoms manifest. Recently, CD4[+] T cell-derived double-negative T (DNT) cells have shown strong immuno-regulatory properties in both in vitro and in vivo neuronal inflammation studies. However, the effectiveness of DNT cells in treating on AD are not yet fully understood.

OBJECTIVE: This study's aims were three-fold, to (1) evaluate the efficacy of CD4[+] T cell-derived DNT cells treatment on AD mice, (2) understand how DNT treatment make changes in different cell types of 5FAD mice, (3) identify the side effects of DNT treatment.

METHODS: We performed tail vein injection of transformed and amplified CD4[+] T cell-derived DNT cells into 5 × FAD mice, while using WT mice and saline injection 5FAD mice as controls. DNT suspensions or NaCl alone were administered to 5 × FAD mice at the 6 months of age. For intravenous injection (n = 10 for both DNT and control injections), 5 × FAD mice were injected with a total of 5 × 10[6] DNT cells suspended in 200 μL of 0.9% NaCl or 0.9% NaCl alone via the lateral tail vein. Behavioral tests and pathology tests were carried out 30 days after cell transplantation.

RESULTS: Through qualitative analysis, we identified 6 main themes. DNT from young wild-type mice enhance the capability of spatial learning and memory in AD mice. DNT cell treatment rejuvenates the microglial function. DNT cell treatment improves the state of oligodendrocytes. DNT cell treatment finetunes the activation of the immune system. DNT cell treatment improves the synaptic plasticity and increases the complexity of neurons. DNT cell treatment reduces the density of amyloid Beta plaques deposition in the cortex and hippocampus of 5 × FAD mice.

DISCUSSION: The findings from this study reveal that DNT treatment improved spatial memory and learning abilities, reduced Aβ deposition, and enhanced synaptic plasticity, contrasting with previous reports on thymus-derived DNT cells. Additionally, CD4[+] T cell-derived DNT therapy exhibited anti-inflammatory effects and modulated microglial function, promoting a neuroprotective environment. Notably, DNT treatment also reduced tau pathology by decreasing levels of abnormally phosphorylated tau. These findings suggest that CD4[+] T cell-derived DNT cells hold therapeutic potential for AD, effectively targeting both Aβ and tau pathologies.},
}

Animals
*Alzheimer Disease/therapy
Mice
*Disease Models, Animal
*Mice, Transgenic
*CD4-Positive T-Lymphocytes
Phenotype
Mice, Inbred C57BL
Male
Maze Learning/physiology

@article {pmid39843406,
year = {2025},
author = {Islam, MR and Al-Imran, MIK and Zehravi, M and Sweilam, SH and Mortuza, MR and Gupta, JK and Shanmugarajan, TS and Devi, K and Tummala, T and Alshehri, MA and Rajagopal, K and Asiri, M and Ahmad, I and Emran, TB},
title = {Targeting signaling pathways in neurodegenerative diseases: Quercetin's cellular and molecular mechanisms for neuroprotection.},
journal = {Animal models and experimental medicine},
volume = {},
number = {},
pages = {},
doi = {10.1002/ame2.12551},
pmid = {39843406},
issn = {2576-2095},
abstract = {BACKGROUND: Neurodegenerative diseases (NDs), including Alzheimer's disease, Parkinson's disease, and Huntington's disease, are complex and challenging due to their intricate pathophysiology and limited treatment options.

METHODS: This review systematically sourced articles related to neurodegenerative diseases, neurodegeneration, quercetin, and clinical studies from primary medical databases, including Scopus, PubMed, and Web of Science.

RESULTS: Recent studies have included quercetin to impact the cellular and molecular pathways involved in neurodegeneration. Quercetin, a flavonoid abundant in vegetables and fruits, is gaining attention for its antioxidant, anti-inflammatory, and antiapoptotic properties. It regulates signaling pathways such as nuclear factor-κB (NF-κB), sirtuins, and phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt). These pathways are essential for cellular survival, inflammation regulation, and apoptosis. Preclinical and clinical studies have shown that quercetin improves symptoms and pathology in neurodegenerative models, indicating promising outcomes.

CONCLUSIONS: The study explores the potential of incorporating laboratory research into practical medical treatment, focusing on quercetin's neuroprotective effects on NDs and its optimal dosage.},
}

@article {pmid39843000,
year = {2024},
author = {Almasi, E and Heidarianpour, A and Keshvari, M},
title = {The interactive effects of different exercises and hawthorn consumption on the pain threshold of TMT-induced Alzheimer male rats.},
journal = {The journal of physiological sciences : JPS},
volume = {74},
number = {1},
pages = {36},
doi = {10.1186/s12576-024-00925-4},
pmid = {39843000},
issn = {1880-6562},
mesh = {Animals ; Male ; *Alzheimer Disease/physiopathology/therapy/chemically induced ; Rats ; *Pain Threshold/drug effects ; *Physical Conditioning, Animal/physiology ; *Crataegus ; *Plant Extracts/pharmacology ; Swimming ; Disease Models, Animal ; Rats, Sprague-Dawley ; },
abstract = {Exercise increases the pain threshold in healthy people. However, the pain threshold modulation effect of exercise and hawthorn is unclear because of its potential benefits in people with persistent pain, including those with Alzheimer's disease. Accordingly, after the induction of Alzheimer's disease by trimethyl chloride, male rats with Alzheimer's disease were subjected to a 12-week training regimen consisting of resistance training, swimming endurance exercises, and combined exercises. In addition, hawthorn extract was orally administered to the rats. Then, their pain threshold was evaluated using three Tail-flick, Hot-plate, and Formalin tests. Our results showed that Alzheimer's decreased the pain threshold in all three behavioral tests. Combined exercise with hawthorn consumption had the most statistically significant effect on Alzheimer's male rats' pain threshold in all three experiments. A combination of swimming endurance and resistance exercises with hawthorn consumption may modulate hyperalgesia in Alzheimer's rats. Future studies need to determine the effects of these factors on the treatment and/or management of painful conditions. GRAPHICAL ABSTRACT.},
}

Animals
Male
*Alzheimer Disease/physiopathology/therapy/chemically induced
Rats
*Pain Threshold/drug effects
*Physical Conditioning, Animal/physiology
*Crataegus
*Plant Extracts/pharmacology
Swimming
Disease Models, Animal
Rats, Sprague-Dawley

@article {pmid39842814,
year = {2025},
author = {Ma, YN and Xia, Y and Karako, K and Song, P and Tang, W and Hu, X},
title = {Serum proteomics reveals early biomarkers of Alzheimer's disease: The dual role of APOE-ε4.},
journal = {Bioscience trends},
volume = {},
number = {},
pages = {},
doi = {10.5582/bst.2024.01365},
pmid = {39842814},
issn = {1881-7823},
abstract = {Alzheimer's disease (AD), the leading cause of dementia, significantly impacts global public health, with cases expected to exceed 150 million by 2050. Late-onset Alzheimer's disease (LOAD), predominantly influenced by the APOE-ε4 allele, exhibits complex pathogenesis involving amyloid-β (Aβ) plaques, neurofibrillary tangles (NFTs), neuroinflammation, and blood-brain barrier (BBB) disruption. Proteomics has emerged as a pivotal technology in uncovering molecular mechanisms and identifying biomarkers for early diagnosis and intervention in AD. This paper reviews the genetic and molecular roles of APOE-ε4 in the pathology of AD, including its effects on Aβ aggregation, tau phosphorylation, neuroinflammation, and BBB integrity. Additionally, it highlights recent advances in serum proteomics, revealing APOE-ε4-dependent and independent protein signatures with potential as early biomarkers for AD. Despite technological progress, challenges such as population diversity, standardization, and distinguishing AD-specific biomarkers remain. Directions for future research emphasize multicenter longitudinal studies, multi-omics integration, and the clinical translation of proteomic findings to enable early detection of AD and personalized treatment strategies. Proteomics advances in AD research hold the promise of improving patient outcomes and reducing the global disease burden.},
}

@article {pmid39842570,
year = {2025},
author = {Raj, V and Raorane, CJ and Shastri, D and Kim, JH and Lee, S},
title = {Sulfonic acid functionalized β-amyloid peptide aggregation inhibitors and antioxidant agents for the treatment of Alzheimer's disease: Combining machine learning, computational, in vitro and in vivo approaches.},
journal = {International journal of biological macromolecules},
volume = {},
number = {},
pages = {140142},
doi = {10.1016/j.ijbiomac.2025.140142},
pmid = {39842570},
issn = {1879-0003},
abstract = {Alzheimer's disease (AD) is characterized as a neurodegenerative disorder that is caused by plaque formation by accumulating β-amyloid (Aβ), leading to neurocognitive function and impaired mental development. Thus, targeting Aβ represents a promising target for the development of therapeutics in AD management. Several functionalized sulfonic acid molecules have been reported, including tramiprosate prodrug, which is currently in clinical trial III and exhibits a good response in mild to moderate AD patients. Therefore, expanding upon this approach, we hypothesized that the sulfonic acid functionalized aromatic class molecule might demonstrate a good inhibitory effect against β-amyloid aggregation, leading to a decrease in the progression burden of AD. We used computational and in vitro approaches to establish effective compounds. As a result, three potent hit molecules were selected based on binding score as well as availability. In the case of safety profile of compounds, in vitro using human neuroblastoma SH-SY5Y cells and in vivo using C. elegans was performed at doses up to 500 μM; no difference in viability was exhibited between control and treatment groups. However, H2O2-induced ROS stress was significantly reduced in neuroblastoma cells after treatment. The AFM and ThT-embedded β-amyloid1-42 kinetic studies confirmed B-PEA-MBSA and H-HPA-NSA potency. H-HPA-NSA arrested elongation phase of Aβ aggregation in kinetic study at a lower concentration (10 μM), while B-PEA-MBSA reduced the intensity of stationary phase at a dose of 100 μM. Thus, based on the outcomes, it can be suggested that B-PEA-MBSA and H-HPA-NSA can prevent β-amyloid aggregation with mild to moderate AD.},
}

@article {pmid39841316,
year = {2025},
author = {Hussain, A and Jairajpuri, DS and Anwar, S and Choudhury, A and Hawwal, MF and Firdous, A and Alajmi, MF and Hassan, MI},
title = {Apigenin-mediated MARK4 inhibition: a novel approach in advancing Alzheimer's disease therapeutics.},
journal = {Molecular diversity},
volume = {},
number = {},
pages = {},
pmid = {39841316},
issn = {1573-501X},
support = {RSPD2023R980//King Saud University/ ; Grant No. 3-69/2020-CCRUM/Tech//Central Council for Research in Unani Medicine/ ; },
abstract = {Apigenin, a dietary flavonoid with notable anti-cancer properties, has emerged as a promising candidate for the treatment of neurodegenerative disorders, particularly Alzheimer's disease (AD). While extensively studied for its ability to modulate key molecular pathways in cancers, apigenin also exerts neuroprotective effects by reducing neuroinflammation, protecting neurons from oxidative stress, and enhancing neuronal survival and synaptic plasticity. This dual functionality makes apigenin an intriguing therapeutic option for diseases like AD, where kinase dysregulation plays a central role. In this study, we focus on Microtubule Affinity-Regulating Kinase 4 (MARK4), a key enzyme implicated in tauopathies associated with AD, as well as in cancer progression. Through in silico analysis, we explore the interaction between apigenin and MARK4, revealing significant structural changes within the kinase domain upon ligand binding. These computational findings were confirmed via experimental assays using purified recombinant MARK4, where apigenin demonstrated potent inhibition with an IC50 value of 2.39 µM. Fluorescence binding assays further confirmed a strong binding affinity (Ka = 10[8] M[-1]), indicating that apigenin efficiently occupies the MARK4 active site, thereby suppressing its enzymatic activity. These results position apigenin as a potent inhibitor of MARK4, offering a dual therapeutic advantage-both as an anti-cancer agent and as a neuroprotective compound for the potential treatment of AD. This study opens new avenues for the development of apigenin-based therapeutics targeting kinase dysregulation in cancer and neurodegeneration.},
}

@article {pmid39840612,
year = {2025},
author = {Saks, DG and Sachdev, PS},
title = {Monogenic causes of cerebral small vessel disease- models for vascular cognitive impairment and dementia?.},
journal = {Current opinion in psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1097/YCO.0000000000000978},
pmid = {39840612},
issn = {1473-6578},
abstract = {PURPOSE OF REVIEW: Recent advancements in molecular biomarkers and therapeutic options for Alzheimer's disease have brought into focus the need for greater progress in the second most common cause of dementia, vascular cognitive impairment and dementia (VCID). We examine how the study of monogenic causes of VCID has contributed to the understanding of its pathophysiology and potential biomarker and treatment research.

RECENT FINDINGS: It is widely accepted that conditions which disrupt the cerebral small vessels contribute to vascular pathologies including stroke and cerebral microbleeds, ultimately leading to vascular cognitive impairment and dementia. Among these conditions are a range of monogenic small vessel diseases (SVDs) such as CADASIL, CARASIL, Fabry disease and COL4A-related disorders.

SUMMARY: This review indicates the importance of furthering research into monogenic SVDs in order to gain insight into the pathomechanisms of VCID more broadly. Monogenic conditions are easier to model than sporadic VCID and can serve as a guide for identifying biomarkers for diagnosis, monitoring and intervention outcomes.},
}

@article {pmid39840140,
year = {2024},
author = {Ashraf, F and Rasool, FK and Uddin, MMN and Siddiq, MA and Mustafa, MS},
title = {Targeting Beta-Amyloid Protein with Monoclonal Antibodies: A New Hope for Alzheimer's Treatment.},
journal = {Annals of neurosciences},
volume = {31},
number = {4},
pages = {243-245},
pmid = {39840140},
issn = {0972-7531},
}

@article {pmid39839307,
year = {2024},
author = {He, J and Xu, P and Xu, T and Yu, H and Wang, L and Chen, R and Zhang, K and Yao, Y and Xie, Y and Yang, Q and Wu, W and Sun, D and Wu, D},
title = {Therapeutic potential of hydrogen-rich water in zebrafish model of Alzheimer's disease: targeting oxidative stress, inflammation, and the gut-brain axis.},
journal = {Frontiers in aging neuroscience},
volume = {16},
number = {},
pages = {1515092},
pmid = {39839307},
issn = {1663-4365},
abstract = {Alzheimer's disease (AD) is a complex neurodegenerative disorder, with amyloid-beta (Aβ) aggregation playing a key role in its pathogenesis. Aβ-induced oxidative stress leads to neuronal damage, mitochondrial dysfunction, and apoptosis, making antioxidative strategies promising for AD treatment. This study investigates the effects of hydrogen-rich water (HRW) in a zebrafish AD model. Zebrafish were exposed to aluminum chloride to induce AD-like pathology and then treated with HRW using a nanobubble device. Behavioral assays, ELISA, Hematoxylin-eosin (H&E) staining, and reactive oxygen species (ROS) and neutrophil fluorescence labeling were employed to assess HRW's impact. Additionally, 16S rRNA sequencing analyzed HRW's effect on gut microbiota. HRW can significantly improve cognitive impairment and depression-like behavior in zebrafish AD model, reduce Aβ deposition (p < 0.0001), regulate liver Soluble epoxide hydrolase (sEH) levels (p < 0.05), reduce neuroinflammation, and reduce oxidative stress. Furthermore, HRW reduced the number of harmful bacteria linked to AD pathology by restoring the balance of microbiota in the gut. These findings suggest that HRW has potential as a therapeutic strategy for AD by targeting oxidative stress, inflammation, and gut-brain axis modulation.},
}

@article {pmid39839126,
year = {2024},
author = {Liu, B and Sun, H and Zhao, Q and Li, L and Tian, R and Lui, S and Zhu, H},
title = {Plastic but not progressive changes in cognitive function and hippocampal volume in an adolescent with bipolar disorder: a case report.},
journal = {Frontiers in psychiatry},
volume = {15},
number = {},
pages = {1507333},
pmid = {39839126},
issn = {1664-0640},
abstract = {Bipolar disorder (BD) is a prevalent mood disorder characterized by alternating episodes of depression and mania, often accompanied by varying degrees of cognitive impairment. Cognitive impairments often serve as indicators of a bleak prognosis or the likelihood of progressing to dementia. Additionally, some studies suggest that individuals diagnosed with BD may undergo a decline in hippocampal volume. However, the potential for reversibility of these changes, particularly in adolescents, remains unclear. We present an intriguing case involving an 18-year-old male student who experiences concurrent occurrences of both BD and mild cognitive impairment (MCI), accompanied by a subtle reduction in hippocampal volume. Initially, the individual exhibited impaired general cognitive function, as indicated by an IQ score of 80 on the Standard Raven's Progressive Matrices test, and demonstrated slightly reduced bilateral hippocampal volume compared to the normative reference, as determined through quantitative structural magnetic resonance imaging (qsMRI). The deposition profiles of amyloid beta (Aβ) peptide in the brain were not identified with 18F-AV45 PET/MRI. Following six months of combined psychopharmacological treatment and cognitive behavioral therapy, the individual's psychopathological symptoms improved significantly, leading to a restoration of his IQ score to 116 and normalization of hippocampal volume. This case suggests that the hippocampal volume reduction and cognitive impairment seen in some adolescents with BD may demonstrate greater plasticity compared to neurodegenerative conditions such as Alzheimer's disease (AD). These findings highlight the potential importance of early intervention in young BD patients with cognitive impairments.},
}

@article {pmid39839078,
year = {2025},
author = {Underwood, BR and Lourida, I and Gong, J and Tamburin, S and Tang, EYH and Sidhom, E and Tai, XY and Betts, MJ and Ranson, JM and Zachariou, M and Olaleye, OE and Das, S and Oxtoby, NP and Chen, S and Llewellyn, DJ and , },
title = {Data-driven discovery of associations between prescribed drugs and dementia risk: A systematic review.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {11},
number = {1},
pages = {e70037},
pmid = {39839078},
issn = {2352-8737},
abstract = {ABSTRACT: Recent clinical trials on slowing dementia progression have led to renewed focus on finding safer, more effective treatments. One approach to identify plausible candidates is to assess whether existing medications for other conditions may affect dementia risk. We conducted a systematic review to identify studies adopting a data-driven approach to investigate the association between a wide range of prescribed medications and dementia risk. We included 14 studies using administrative or medical records data for more than 130 million individuals and 1 million dementia cases. Despite inconsistencies in identifying specific drugs that may modify Alzheimer's or dementia risk, some themes emerged for drug classes with biological plausibility. Antimicrobials, vaccinations, and anti-inflammatories were associated with reduced risk, while diabetes drugs, vitamins and supplements, and antipsychotics were associated with increased risk. We found conflicting evidence for antihypertensives and antidepressants. Drug repurposing for use in dementia is an urgent priority. Our findings offer a basis for prioritizing candidates and exploring underlying mechanisms.

HIGHLIGHTS: ·We present a systematic review of studies reporting association between drugs prescribed for other conditions and risk of dementia including 139 million people and 1 million cases of dementia.·Our work supports some previously reported associations, for example, showing decreased risk of dementia with drugs to treat inflammatory disease and increased risk with antipsychotic treatment.·Antimicrobial treatment was perhaps more surprisingly associated with decreased risk, supportive of recent increased interest in this potential therapeutic avenue.·Our work should help prioritize drugs for entry into adaptive platform trials in Alzheimer's disease and will serve as a useful resource for those investigating drugs or classes of drugs and risk of dementia.},
}

@article {pmid39838927,
year = {2025},
author = {Wang, Z and Sun, Y and Bai, Z and Li, M and Kong, D and Wu, G},
title = {Mitochondria-Related Genome-Wide Mendelian Randomization Identifies Putatively Causal Genes for Neurodegenerative Diseases.},
journal = {Movement disorders : official journal of the Movement Disorder Society},
volume = {},
number = {},
pages = {},
doi = {10.1002/mds.30123},
pmid = {39838927},
issn = {1531-8257},
support = {SDQLQN2021-01//Qilu Young Scholars Program of Shandong University/ ; 202306352//Taishan Scholar Foundation of Shandong Province/ ; },
abstract = {BACKGROUND: Mitochondrial dysfunction is increasingly recognized as a key factor in neurodegenerative diseases (NDDs), underscoring the therapeutic potential of targeting mitochondria-related genes. This study aimed to identify novel biomarkers and drug targets for these diseases through a comprehensive analysis that integrated genome-wide Mendelian randomization (MR) with genes associated with mitochondrial function.

METHODS: Using existing publicly available genome-wide association studies (GWAS) summary statistics and comprehensive data on 1136 mitochondria-related genes, we initially identified a subset of genes related to mitochondrial function that exhibited significant associations with NDDs. We then conducted colocalization and summary-data-based Mendelian randomization (SMR) analyses using expression quantitative trait loci (eQTL) to validate the causal role of these candidate genes. Additionally, we assessed the druggability of the encoded proteins to prioritize potential therapeutic targets for further exploration.

RESULTS: Genetically predicted levels of 10 genes were found to be significantly associated with the risk of NDDs. Elevated DMPK and LACTB2 levels were associated with increased Alzheimer's disease risk. Higher expression of NDUFAF2, BCKDK, and MALSU1, along with lower TTC19, raised Parkinson's disease risk. Higher ACLY levels were associated with both amyotrophic lateral sclerosis and multiple sclerosis (MS) risks, while decreased MCL1, TOP3A, and VWA8 levels raised MS risk. These genes primarily impact mitochondrial function and energy metabolism. Notably, several druggable protein targets identified are being explored for potential NDDs treatment.

CONCLUSIONS: This data-driven MR study demonstrated the causal role of mitochondrial dysfunction in NDDs. Additionally, this study identified candidate genes that could serve as potential pharmacological targets for the prevention and treatment of NDDs. © 2025 International Parkinson and Movement Disorder Society.},
}

@article {pmid39838674,
year = {2025},
author = {Cheng, M and Gao, Y and Wu, Y and Zhang, L and Xu, B and Lu, X},
title = {Plasmalogens Activate AKT/mTOR Signaling to Attenuate Reactive Oxygen Species Production in Spinal Cord Injury.},
journal = {Current gene therapy},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115665232330349241225074627},
pmid = {39838674},
issn = {1875-5631},
abstract = {BACKGROUND: Plasmalogens, the primary phospholipids in the brain, possess intrinsic antioxidant properties and are crucial components of the myelin sheath surrounding neuronal axons. While their neuroprotective effects have been demonstrated in Alzheimer's disease, their potential benefits in spinal cord injury remain unexplored. This study investigates the reparative effects of plasmalogens on spinal cord injury and the underlying mechanisms.

METHODS: In vitro, we developed dorsal root ganglion (DRG) and RAW 264.7 cell models under high-reactive oxygen species (ROS) conditions to assess ROS levels, neuronal damage, and inflammatory microenvironment changes before and after plasmalogen application. In vivo, we used a complete mouse spinal cord transection model to evaluate changes in ROS levels, neuronal demyelination, and apoptosis following plasmalogen treatment. Additionally, we assessed sensory and motor function recovery and investigated the regulatory effects of plasmalogens on the AKT/mTOR signaling pathway.

RESULTS: In high-ROS cell models, plasmalogens protected DRG neurons (TUJ-1) from axonal damage and modulated the proinflammatory/anti-inflammatory balance in RAW 264.7 cells. In vivo, plasmalogens significantly reduced ROS levels, improved the immune microenvironment, decreased the proinflammatory (iNOS)/anti-inflammatory (ARG-1) ratio, lowered neuronal (TUJ-1) apoptosis (Caspase-3, BAX), and reduced axonal degeneration while promoting myelin (MBP) regeneration, indicating a neuroprotective effect. These findings are linked to the activation of the AKT/mTOR signaling pathway.

CONCLUSION: Plasmalogens reduce ROS levels and regulate inflammation-induced damage, contributing to neuroprotection. This study reveals that plasmalogens promote remyelination, reduce axonal degeneration and neuronal apoptosis, and-used here for the first time in spinal cord injury repair- may protect neurons by reducing ROS levels and activating the AKT/mTOR signaling pathway.},
}

@article {pmid39838656,
year = {2025},
author = {Xie, D and Cai, Z and Mao, J and Qu, X and Cao, L and Zhou, J},
title = {High-prediction QSAR Modeling Study Based on the Efficacy of a Novel 6-hydroxybenzothiazole-2-carboxamide Targeted Monoamine Oxidase B in the Treatment of Neurodegenerative Diseases.},
journal = {Medicinal chemistry (Shariqah (United Arab Emirates))},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115734064364749250102024805},
pmid = {39838656},
issn = {1875-6638},
abstract = {BACKGROUND: Neurodegenerative diseases are a group of disorders characterized by progressive neuronal degeneration and death, of which Alzheimer's disease and Parkinson's disease are the most common. These diseases are closely associated with increased expression of monoamine oxidase B (MAO-B), an important enzyme that regulates neurotransmitter concentration, and its overactivity leads to oxidative stress and neurotoxicity, accelerating the progression of neurodegenerative diseases. Therefore, the development of effective MAO-B inhibitors is important for the treatment of neurodegenerative diseases.

OBJECTIVE: This study aims to improve the prediction of the efficacy of novel 6-hydroxybenzothiazole- 2-carboxamide compounds in inhibiting MAO-B by improving the quantitative constitutive effect relationship (QSAR) modeling and to provide a theoretical basis for the discovery of novel neuroprotective drugs.

METHODS: The study first optimized the structures of 36 compounds using the heuristic method (HM) in CODESSA software to construct linear QSAR models. Subsequently, key descriptors were screened by using the gene expression programming (GEP) technique to generate nonlinear QSAR models and validate them.

RESULTS: The R², F-value, and R²cv of the linear model were 0.5724, 10.3752, and 0.4557, respectively, whereas the nonlinear model constructed by the GEP algorithm showed higher prediction accuracies by achieving R² values of 0.89 and 0.82, and mean squared errors (MSE) of 0.0799 and 0.1215 for the training and test sets, respectively. In addition, molecular docking experiments confirmed that the novel compound 31 was tightly bound to the MAO-B active site with significant inhibitory activity.

CONCLUSION: In this study, we successfully improved the prediction ability of the efficacy of novel 6-hydroxybenzothiazole-2-carboxamide compounds to inhibit MAO-B by improving the QSAR model. This not only provides new drug candidates for the treatment of neurodegenerative diseases, but also provides important theoretical guidance for subsequent drug design and development, which can help accelerate the process of new drug discovery and reduce the disease burden of patients.},
}

@article {pmid39838483,
year = {2025},
author = {Clemmensen, FK and Gramkow, MH and Simonsen, AH and Ashton, NJ and Huber, H and Blennow, K and Zetterberg, H and Waldemar, G and Hasselbalch, SG and Frederiksen, KS},
title = {Short-term variability of Alzheimer's disease plasma biomarkers in a mixed memory clinic cohort.},
journal = {Alzheimer's research & therapy},
volume = {17},
number = {1},
pages = {26},
pmid = {39838483},
issn = {1758-9193},
mesh = {Humans ; *Alzheimer Disease/blood/diagnosis ; *Biomarkers/blood ; Female ; Male ; Aged ; *Amyloid beta-Peptides/blood ; *tau Proteins/blood ; Cohort Studies ; Middle Aged ; Peptide Fragments/blood ; Aged, 80 and over ; Glial Fibrillary Acidic Protein/blood ; Neurofilament Proteins/blood ; },
abstract = {BACKGROUND: For clinical implementation of Alzheimer's disease (AD) blood-based biomarkers (BBMs), knowledge of short-term variability, is crucial to ensure safe and correct biomarker interpretation, i.e., to capture changes or treatment effects that lie beyond that of expected short-term variability and considered clinically relevant. In this study we investigated short-term intra- and inter-individual variability of AD biomarkers in the intended use population, memory clinic patients.

METHODS: In a consecutive sample of memory clinic patients (AD n = 27, non-AD n = 20), blood samples were collected on three separate days within a period of 36 days and analysed for plasma Aβ40, Aβ42, p-tau181, p-tau217, p-tau231, T-tau, neurofilament light (NfL), and glial fibrillary acidic protein (GFAP). We measured intra- and inter-individual variability and explored if the variability could be affected by confounding factors. Secondly, we established the minimum change required to detect a difference between two given blood samples that exceeds intra-individual variability and analytical variation (reference change value, RCV). Finally, we tested if classification accuracy varied across the three visits.

RESULTS: Intra-individual variability ranged from ~ 3% (Aβ42/40) to ~ 12% (T-tau). Inter-individual variability ranged from ~ 7% (Aβ40) to ~ 39% (NfL). Adjusting the models for time, eGFR, Hba1c, and BMI did not affect the variation. RCV was lowest for Aβ42/Aβ40 (- ~ 15%/ + ~ 17%) and highest in p-tau181 (- ~ 30/ + ~ 42%). No variation in classification accuracies was found across visits.

CONCLUSION: We found low intra-individual variability, robust to various factors, appropriate to capture individual changes in AD BBMs, while moderate inter-individual variability may give rise to caution in diagnostic contexts. High RCVs may pose challenges for AD BBMs with low fold changes and consequently, short-term variability is important to take into consideration when, e.g., estimating intervention effect and longitudinal changes of AD BBM levels.

TRIAL REGISTRATION: Clinicaltrials.gov (NCT05175664), date of registration 2021-12-01.},
}

Humans
*Alzheimer Disease/blood/diagnosis
*Biomarkers/blood
Female
Male
Aged
*Amyloid beta-Peptides/blood
*tau Proteins/blood
Cohort Studies
Middle Aged
Peptide Fragments/blood
Aged, 80 and over
Glial Fibrillary Acidic Protein/blood
Neurofilament Proteins/blood

@article {pmid39838434,
year = {2025},
author = {Kimura, N and Sasaki, K and Masuda, T and Ataka, T and Matsumoto, M and Kitamura, M and Nakamura, Y and Matsubara, E},
title = {Machine learning models for dementia screening to classify brain amyloid positivity on positron emission tomography using blood markers and demographic characteristics: a retrospective observational study.},
journal = {Alzheimer's research & therapy},
volume = {17},
number = {1},
pages = {25},
pmid = {39838434},
issn = {1758-9193},
mesh = {Humans ; Male ; Female ; Retrospective Studies ; Aged ; *Machine Learning ; *Positron-Emission Tomography/methods ; *Brain/diagnostic imaging/metabolism ; Biomarkers/blood ; Amyloid beta-Peptides/blood/metabolism ; Cognitive Dysfunction/blood/diagnostic imaging/diagnosis ; Aged, 80 and over ; Alzheimer Disease/blood/diagnostic imaging ; Dementia/blood/diagnostic imaging/diagnosis ; Middle Aged ; },
abstract = {BACKGROUND: Intracerebral amyloid β (Aβ) accumulation is considered the initial observable event in the pathological process of Alzheimer's disease (AD). Efficient screening for amyloid pathology is critical for identifying patients for early treatment. This study developed machine learning models to classify positron emission tomography (PET) Aβ-positivity in participants with preclinical and prodromal AD using data accessible to primary care physicians.

METHODS: This retrospective observational study assessed the classification performance of combinations of demographic characteristics, routine blood test results, and cognitive test scores to classify PET Aβ-positivity using machine learning. Participants with mild cognitive impairment (MCI) or normal cognitive function who visited Oita University Hospital or had participated in the USUKI study and met the study eligibility criteria were included. The primary endpoint was assessment of the classification performance of the presence or absence of intracerebral Aβ accumulation using five machine learning models (i.e., five combinations of variables), each constructed with three classification algorithms, resulting in a total of 15 patterns. L2-regularized logistic regression, and kernel Support Vector Machine (SVM) and Elastic Net algorithms were used to construct the classification models using 34 pre-selected variables (12 demographic characteristics, 11 blood test results, 11 cognitive test results).

RESULTS: Data from 262 records (260 unique participants) were analyzed. The mean (standard deviation [SD]) participant age was 73.8 (7.8) years. Using L2-regularized logistic regression, the mean receiver operating characteristic (ROC) area under the curve (AUC) (SD) in Model 0 (basic demographic characteristics) was 0.67 (0.01). Classification performance was similar in Model 1 (basic demographic characteristics and Mini Mental State Examination [MMSE] subscores) and Model 2 (demographic characteristics and blood test results) with a cross-validated mean ROC AUC (SD) of 0.70 (0.01) for both. Model 3 (demographic characteristics, blood test results, MMSE subscores) and Model 4 (Model 3 and ApoE4 phenotype) showed improved performance with a mean ROC AUC (SD) of 0.73 (0.01) and 0.76 (0.01), respectively. In models using blood test results, thyroid-stimulating hormone and mean corpuscular volume tended to be the largest contributors to classification. Classification performances were similar using the SVM and Elastic Net algorithms.

CONCLUSIONS: The machine learning models used in this study were useful for classifying PET Aβ-positivity using data from routine physician visits.

TRIAL REGISTRATION: UMIN Clinical Trials Registry (UMIN000051776, registered on 31/08/2023).},
}

Humans
Male
Female
Retrospective Studies
Aged
*Machine Learning
*Positron-Emission Tomography/methods
*Brain/diagnostic imaging/metabolism
Biomarkers/blood
Amyloid beta-Peptides/blood/metabolism
Cognitive Dysfunction/blood/diagnostic imaging/diagnosis
Aged, 80 and over
Alzheimer Disease/blood/diagnostic imaging
Dementia/blood/diagnostic imaging/diagnosis
Middle Aged

@article {pmid39838228,
year = {2025},
author = {Hou, Q and Li, Y},
title = {Dual inhibition of AChE and MAO-B in Alzheimer's disease: machine learning approaches and model interpretations.},
journal = {Molecular diversity},
volume = {},
number = {},
pages = {},
pmid = {39838228},
issn = {1573-501X},
support = {2021YFA1500300//National Key Research and Development Program of China/ ; 22275027//National Natural Science Foundation of China/ ; },
abstract = {Alzheimer's disease (AD) is one of the most prevalent neurodegenerative diseases. Given the multifactorial pathophysiology of AD, monotargeted agents can only alleviate symptoms but not cure AD. Acetylcholinesterase (AChE) and Monoamine oxidase B (MAO-B) are two key targets in the treatment of AD, molecules that inhibiting both targets are considered promising avenue to develop more effective AD therapies. In the present work, a dual inhibition dataset containing 449 molecules was established, based on which five machine learning algorithms (KNN, SVM, RF, GBDT, and LGBM) four fingerprints (MACCS, ECFP4, RDKitFP, PubChemFP) and DRAGON descriptors were combined to develop 25 classification models in which GBDT paired with ECFP4 and RF paired with PubchemFP achieved the same best performance across multiple metrics (Accuracy = 0.92, F1 Score = 0.94, MCC = 0.81). Moreover, based on the curated bioactivity datasets of AChE and MAO-B, regression models were developed to predict pIC50 values. For the AChE inhibition task, GBDT demonstrated the best performance (RMSE = 0.683, MAE = 0.500, R[2] = 0.721). The SVM algorithm emerged as the most effective for MAO-B inhibition (RMSE = 0.668, MAE = 0.507, R[2] = 0.675). The SHAP algorithm was used to interpret the optimal models, identifying and analyzing the key substructures and properties for both dual-target and single-target inhibitors. Moreover, molecules docking process provided potential mechanism and Structure-Activity Relationships (SAR) of dual-target inhibition further.},
}

@article {pmid39837459,
year = {2025},
author = {Yang, MX and Wang, ZR and Zhang, YL and Zhang, ZN and Li, YL and Wang, R and Su, Q and Guo, JH},
title = {Albumin antagonizes Alzheimer's disease-related Tau pathology and enhances cognitive performance by inhibiting aberrant Tau aggregation.},
journal = {Experimental neurology},
volume = {},
number = {},
pages = {115155},
doi = {10.1016/j.expneurol.2025.115155},
pmid = {39837459},
issn = {1090-2430},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder primarily characterized by cognitive impairment, for which effective treatments remain lacking. Albumin (ALB) is an essential carrier protein found in various body fluids, playing crucial roles in anti-inflammatory processes, antioxidation, and signal transduction. Recent research indicates that ALB may play a significant role in the development and progression of AD, though its specific function is not yet fully understood. In this study, we observed a link between serum ALB levels and cognitive performance in the elderly. Administration of ALB intranasally was shown to enhance learning and memory in MAPT/P301S transgenic mice, markedly decreasing hyperphosphorylation of Tau protein and reducing neuronal apoptosis. In a neuronal cell model overexpressing Tau, ALB administration in vitro attenuated Tau-induced toxicity and reduced the production of phosphorylated Tau. Additionally, co-incubation of Tau with ALB significantly reduced the formation of neurofibrillary tangles. These results suggest that ALB improves AD-related cognitive function by preventing the pathological aggregation of Tau and reducing its abnormal phosphorylation. Furthermore, ALB's neuroprotective effect helps prevent neuronal apoptosis in the cortex and hippocampus, providing potential targets for AD prevention and treatment.},
}

@article {pmid39835706,
year = {2025},
author = {Cacabelos, R and Martínez-Iglesias, O and Cacabelos, N and Carrera, J and Rodríguez, D and Naidoo, V},
title = {The impact of genetic variability on Alzheimer's therapies: obstacles for pharmacogenetic progress.},
journal = {Expert opinion on drug metabolism & toxicology},
volume = {},
number = {},
pages = {1-28},
doi = {10.1080/17425255.2024.2433626},
pmid = {39835706},
issn = {1744-7607},
abstract = {INTRODUCTION: Genetic load influences the therapeutic response to conventional drugs in Alzheimer's disease (AD). Pharmacogenetics (PGx) is the best option to reduce drug-drug interactions and adverse drug reactions in patients undergoing polypharmacy regimens. However, there are important limitations that make it difficult to incorporate pharmacogenetics into routine clinical practice.

AREAS COVERED: This article analyzes the pharmacogenetic apparatus made up of pathogenic, mechanistic, metabolic, transporter, and pleiotropic genes responsible for the efficacy and safety of pharmacological treatment, the impact of genetic load on the outcome of multifactorial treatments, and practical aspects for the effective use of PGx.

EXPERT OPINION: Over 120 genes are closely associated with AD. There is an accumulation of cerebrovascular (CVn) and neurodegenerative (ADn) genes in AD. APOE-4 carriers accumulate more deleterious genetic load related to other CVn and ADn genes, develop the disease earlier, and are at a biological disadvantage compared to APOE-4 non-carriers. CYP2D6-PMs and APOE-4 carriers are the worst responders to anti-dementia drugs. Some limitations hinder the implementation of PGx in clinical practice, including lack of pharmacogenetic information for many drugs, low number of genes in PGx screening protocols, and educational deficiencies in the medical community regarding PGx and genomic medicine.},
}

@article {pmid39835563,
year = {2025},
author = {Kushwaha, SK and Ashawat, MS and Arora, R and Baldi, A},
title = {Auranofin-loaded PLGA Nanoparticles for Neuroprotection against Aluminium-induced Alzheimer's Disease.},
journal = {Current pharmaceutical design},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113816128336703241202182209},
pmid = {39835563},
issn = {1873-4286},
abstract = {AIM: The aim of the current study was to explore nano-formulation for effective neuroprotection by auranofin.

BACKGROUND: Currently, the treatment options for various CNS disorders, particularly neurodegenerative disorders, are greatly constrained. A significant obstacle in this pursuit is the blood-brain barrier, a shielding covering that hinders the route of numerous biochemical treatments into the brain. To overcome this problem, nanoformulation- based approaches are gaining interest, increasing the compound's BBB penetrability.

OBJECTIVE: The objective of this study was to evaluate whether nanoparticles fabricated from poly(lactic-co-glycolic acid) encapsulated with auranofin could oppose aluminium chloride-induced Alzheimer's disease.

METHOD: Auranofin-encapsulated PLGA nanoparticles were prepared, and their particle size, Entrapment Efficiency (EE), distribution of particles, morphological surface charge, and structural characteristics were characterized. During the in vivo study, rats were orally administered AlCl3 at 100 mg/kg for 21 days. Meanwhile, auranofin and auranofin nanoparticles were orally administered at doses of 5 and 10 mg/kg and 2.5 and 5 mg/kg, respectively, within 2 weeks. After the course therapy, the rats were decapitated, and the hippocampus was collected for the estimated biochemical and neuroinflammatory markers.

RESULTS: The auranofin nanoparticles were characterized, revealing % entrapment efficiency (98%) and % loading dose (76%). The nanoparticles exhibited a morphological surface charge of 27.5 ± 5.10 mV, a polydispersity index of 0.438 ± 0.12, and a mean particle size of 101.5 ± 10.3 nm. In the in vivo study, administering a gold compound (auranofin) and formulation (auranofin nanoparticles) resulted in a significant improvement in cognitive deficits, changes in biochemical parameters, and markers of neuroinflammation triggered with aluminium chloride.

CONCLUSION: The results have suggested that auranofin nanoparticles demonstrate abilities to protect neurons compared to auranofin alone. The noticed therapeutic benefits of the auranofin-encapsulated PLGA nanoparticles can be attributed to modulation in particle size with antioxidative and anti-inflammatory impacts of auranofin. Consequently, the outcome of the research has revealed that gold compound nanoparticles hold the potential to be a promising option for altering the therapeutic course of Alzheimer's disease.},
}

@article {pmid39834810,
year = {2024},
author = {Yang, C and Zhao, E and Zhang, H and Duan, L and Han, X and Ding, H and Cheng, Y and Wang, D and Lei, X and Diwu, Y},
title = {Xixin Decoction's novel mechanism for alleviating Alzheimer's disease cognitive dysfunction by modulating amyloid-β transport across the blood-brain barrier to reduce neuroinflammation.},
journal = {Frontiers in pharmacology},
volume = {15},
number = {},
pages = {1508726},
doi = {10.3389/fphar.2024.1508726},
pmid = {39834810},
issn = {1663-9812},
abstract = {PURPOSE: Xixin Decoction (XXD) is a classical formula that has been used to effectively treat dementia for over 300 years. Modern clinical studies have demonstrated its significant therapeutic effects in treating Alzheimer's disease (AD) without notable adverse reactions. Nevertheless, the specific mechanisms underlying its efficacy remain to be elucidated. This investigation sought to elucidate XXD's impact on various aspects of AD pathology, including blood-brain barrier (BBB) impairment, neuroinflammatory processes, and amyloid-β (Aβ) deposition, as well as the molecular pathways involved in these effects.

METHODS: In vitro experiments were conducted using hCMEC/D3 and HBVP cell coculture to establish an in vitro blood-brain barrier (BBB) model. BBB damage was induced in this model by 24-h exposure to 1 μg/mL lipopolysaccharide (LPS). After 24, 48, and 72 h of treatment with 10% XXD-medicated serum, the effects of XXD were assessed through Western blotting, RT-PCR, and immunofluorescence techniques. In vivo, SAMP8 mice were administered various doses of XXD via gavage for 8 weeks, including high-dose XXD group (H-XXD) at 5.07 g kg[-1]·d[-1], medium-dose XXD group (M-XXD) at 2.535 g kg[-1]·d[-1], and low-dose XXD group (L-XXD) at 1.2675 g kg[-1]·d[-1]. Cognitive function was subsequently evaluated using the Morris water maze test. BBB integrity was evaluated using Evans blue staining, and protein expression levels were analyzed via ELISA, Western blotting, and immunofluorescence.

RESULTS: In vitro experiments revealed that XXD-containing serum, when cultured for 24, 48, and 72 h, could upregulate the expression of P-gp mRNA and protein, downregulate CB1 protein expression, and upregulate CB2 and Mfsd2a protein expression. In vivo studies demonstrated that XXD improved spatial learning and memory abilities in SAMP8 mice, reduced the amount of Evans blue extravasation in brain tissues, modulated the BBB-associated P-gp/ECS axis, RAGE/LRP1 receptor system, as well as MRP2 and Mfsd2a proteins, and decreased the accumulation of Aβ in the brains of SAMP8 mice. Additionally, XXD upregulated the expression of TREM2, downregulated IBA1, TLR1, TLR2, and CMPK2 expression, and reduced the levels of pro-inflammatory factors NLRP3, NF-κB p65, COX-2, TNF-α, and IL-1β in the hippocampal tissues.

CONCLUSION: XXD may exert its effects by regulating the P-gp/ECS axis, the RAGE/LRP1 receptor system, and the expression of MRP2 and Mfsd2a proteins, thereby modulating the transport function of the BBB to expedite the clearance of Aβ, reduce cerebral Aβ accumulation, and consequently inhibit the activation of microglia induced by Aβ aggregation. This process may suppress the activation of the CMPK2/NLRP3 and TLRs/NF-κB pathways, diminish the production of inflammatory cytokines and chemokines, alleviate neuroinflammation associated with microglia in the brain of AD, and ultimately improve AD pathology.},
}

@article {pmid39834440,
year = {2025},
author = {Alkhatabi, HA and Pushparaj, PN},
title = {Untangling the complex mechanisms associated with Alzheimer's disease in elderly patients using high-throughput RNA sequencing data and next-generation knowledge discovery methods: Focus on potential gene signatures and drugs for dementia.},
journal = {Heliyon},
volume = {11},
number = {1},
pages = {e41266},
doi = {10.1016/j.heliyon.2024.e41266},
pmid = {39834440},
issn = {2405-8440},
abstract = {OBJECTIVES: Alzheimer's disease (AD) is a complex neurodegenerative disorder that primarily affects elderly individuals. This study aimed to elucidate the intricate mechanisms underlying AD in elderly patients compared with healthy aged individuals using high-throughput RNA sequencing (RNA-seq) data and next-generation knowledge discovery methods (NGKD), with a focus on identifying potential therapeutic agents.

METHODS: High-throughput RNA-seq data were obtained from the Gene Expression Omnibus (GEO) database (accession number: GSE104704). These data were derived from healthy and diseased human brains (eight young healthy brains [young], 10 aged healthy brains [Old], and 12 aged diseased brains [AD]). We used NGKD tools such as GEO RNA-seq Experiments Interactive Navigator (GREIN) to obtain differentially expressed genes (DEGs) by comparing the AD versus Old RNA-seq data and further filtered and normalized to obtain differentially regulated Kyoto Encyclopedia of Genes and Genomes (KEGG), Reactome and Panther pathways using ExpressAnalyst tool. Besides, WebGestalt was used to identify differentially regulated Gene Ontologies (GO) and the pre-ranked Gene Set Enrichment Analysis (GSEA) was performed using GSEA software. The X2K web tool was used to infer upstream regulator networks and X2K Appyter tool for obtaining transcription factors (TFs) and kinase network information. LFW1000 and L1000CDS[2] tools were used to identify specific drugs that reverse AD-associated gene signatures in elderly patients.

RESULTS: Our study revealed significant downregulation of pathways related to neuroactive receptor-ligand interaction, synaptic vesicle cycle, and neuronal system in elderly individuals with AD. GO analysis showed negative enrichment of functions related to cognition, potassium ion transport, receptor-ligand activity, SNARE binding, and primary lysosomes. The transcription factors SUZ12 and REST, along with increased MAPK signaling, were identified as key regulators of downregulated genes. Several drugs and natural products, including dihydroergocristine, mepacrine, gedunin, amlodipine, and disulfiram have been identified as potential therapeutic agents for reversing AD-associated gene signatures.

CONCLUSIONS: This comprehensive analysis of AD in elderly individuals using RNA-seq data and NGKD tools revealed multiple differentially regulated pathways, gene signatures, and potential drugs for dementia treatment. These findings highlight the complex molecular mechanisms underlying AD and provide insights into potential therapeutic strategies. Further research is needed to validate these findings and to develop personalized treatment approaches for AD in elderly patients.},
}

@article {pmid39834035,
year = {2025},
author = {Asken, BM and Brett, BL and Barr, WB and Banks, S and Wethe, JV and Dams-O'Connor, K and Stern, RA and Alosco, ML},
title = {Chronic traumatic encephalopathy: State-of-the-science update and narrative review.},
journal = {The Clinical neuropsychologist},
volume = {},
number = {},
pages = {1-25},
doi = {10.1080/13854046.2025.2454047},
pmid = {39834035},
issn = {1744-4144},
abstract = {OBJECTIVE: The long-recognized association of brain injury with increased risk of dementia has undergone significant refinement and more detailed study in recent decades. Chronic traumatic encephalopathy (CTE) is a specific neurodegenerative tauopathy related to prior exposure to repetitive head impacts (RHI). We aim to contextualize CTE within a historical perspective and among emerging data which highlights the scientific and conceptual evolution of CTE-related research in parallel with the broader field of neurodegenerative disease and dementia.

METHODS: We provide a narrative state-of-the-science update on CTE neuropathology, clinical manifestations, biomarkers, different types and patterns of head impact exposure relevant for CTE, and the complicated influence of neurodegenerative co-pathology on symptoms.

CONCLUSIONS: Now almost 20 years since the initial case report of CTE in a former American football player, the field of CTE continues evolving with increasing clarity but also several ongoing controversies. Our understanding of CTE neuropathology outpaces that of disease-specific clinical correlates or the development of in-vivo biomarkers. Diagnostic criteria for symptoms attributable to CTE are still being validated, but leveraging increasingly available biomarkers for other conditions like Alzheimer's disease may be helpful for informing the CTE differential diagnosis. As diagnostic refinement efforts advance, clinicians should provide care and/or referrals to providers best suited to treat an individual patient's clinical symptoms, many of which have evidence-based behavioral treatment options that are etiologically agnostic. Several ongoing research initiatives and the gradual accrual of gold standard clinico-pathological data will pay dividends for advancing the many existing gaps in the field of CTE.},
}

@article {pmid39833961,
year = {2025},
author = {Lin, Y and Luo, X and Wang, F and Cai, H and Lin, Y and Kang, D and Fang, W},
title = {Sex differences in cognition, anxiety-phenotype and therapeutic effect of metformin in the aged apoE-TR mice.},
journal = {Biology of sex differences},
volume = {16},
number = {1},
pages = {3},
pmid = {39833961},
issn = {2042-6410},
support = {2023J05136//Natural Science Foundation of Fujian Province/ ; 2022QNA036//Fujian Provincial Health Technology Project/ ; 2023YSJYX-YL-1//Neurosurgery Department, Fujian Neurological Disease Medical Center construction project/ ; },
mesh = {Animals ; *Metformin/pharmacology/therapeutic use ; Female ; Male ; *Anxiety/drug therapy ; *Sex Characteristics ; *Cognition/drug effects ; *Mice, Transgenic ; Hypoglycemic Agents/pharmacology/therapeutic use ; Apolipoprotein E4/genetics ; Aging/drug effects ; Mice ; Phenotype ; Cognitive Dysfunction/drug therapy ; Depression/drug therapy ; Mice, Inbred C57BL ; Blood Glucose ; Apolipoprotein E3/genetics ; },
abstract = {BACKGROUND: Apolipoprotein E4 (ApoE4) is associated with an increased risk of Alzheimer's disease (AD), depression, and anxiety, which were reported to improve after the administration of metformin. However, sex influence on the effect of ApoE4 and metformin on cognition and mental health is poorly understood.

METHODS: ApoE3-TR and apoE4-TR mice of both sexes were randomly assigned to the normal saline and metformin groups from 13 months to 18 months of age. Behavior tests (MWM, EPM, OFT, TST, FST) were conducted to assess cognition, anxiety, and depression-like behaviors. The mice's blood glucose was also recorded.

RESULTS: Male aged apoE4-TR mice are more vulnerable to cognitive decline than females. Metformin improves the spatial memory of female, but not male apoE3-TR mice and female apoE4-TR mice while aggravating the cognitive impairment of male apoE4-TR mice. The anxiety-like phenotypes in male apoE4-TR mice are more severe than in male apoE3-TR mice, while metformin ameliorates the anxiety-like behaviors in the male apoE4-TR mice but not in male apoE3-TR mice. In addition, metformin alleviates depression-like behaviors in male and female apoE4-TR mice. The hypoglycemic effect of metformin is insignificant in both male and female apoE4-TR mice.

CONCLUSIONS: Male sex exacerbates APOE4-related cognitive impairment and anxiety in aged mice and is insensitive to the cognition improvement effect of metformin in the aged apoE3 mice. Male sex with APOE4 may experience more severe cognitive impairment after treatment with metformin while sensitive to the anti-anxiety effects of metformin. These findings identify sex-specific effects on ApoE4-based dementia, anxiety prevention, and therapy, emphasizing the importance of further sex dimension analyses in vivo and clinical studies.},
}

Animals
*Metformin/pharmacology/therapeutic use
Female
Male
*Anxiety/drug therapy
*Sex Characteristics
*Cognition/drug effects
*Mice, Transgenic
Hypoglycemic Agents/pharmacology/therapeutic use
Apolipoprotein E4/genetics
Aging/drug effects
Mice
Phenotype
Cognitive Dysfunction/drug therapy
Depression/drug therapy
Mice, Inbred C57BL
Blood Glucose
Apolipoprotein E3/genetics

@article {pmid39833898,
year = {2025},
author = {Wang, Z and Wang, C and Yuan, B and Liu, L and Zhang, H and Zhu, M and Chai, H and Peng, J and Huang, Y and Zhou, S and Liu, J and Wu, L and Wang, W},
title = {Akkermansia muciniphila and its metabolite propionic acid maintains neuronal mitochondrial division and autophagy homeostasis during Alzheimer's disease pathologic process via GPR41 and GPR43.},
journal = {Microbiome},
volume = {13},
number = {1},
pages = {16},
pmid = {39833898},
issn = {2049-2618},
mesh = {*Propionates/metabolism/pharmacology ; Animals ; *Alzheimer Disease/metabolism/microbiology ; Mice ; *Receptors, G-Protein-Coupled/metabolism ; Humans ; *Gastrointestinal Microbiome ; *Homeostasis ; *Akkermansia ; *Mitochondria/metabolism ; *Autophagy ; *Neurons/metabolism ; Disease Models, Animal ; Male ; Female ; Fatty Acids, Volatile/metabolism ; Aged ; Mitochondrial Dynamics ; Feces/microbiology ; Mitophagy ; Mice, Inbred C57BL ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is a prevalent neurodegenerative disease (ND). In recent years, multiple clinical and animal studies have shown that mitochondrial dysfunction may be involved in the pathogenesis of AD. In addition, short-chain fatty acids (SCFA) produced by intestinal microbiota metabolism have been considered to be important factors affecting central nervous system (CNS) homeostasis. Among the main mediators of host-microbe interactions, volatile fatty acids play a crucial role. Nevertheless, the influence and pathways of microorganisms and their metabolites on Alzheimer's disease (AD) remain uncertain.

RESULTS: In this study, we present distinctions in blood and fecal SCFA levels and microbiota composition between healthy individuals and those diagnosed with AD. We found that AD patients showed a decrease in the abundance of Akkermansia muciniphila and a decrease in propionic acid both in fecal and in blood. In order to further reveal the effects and the mechanisms of propionic acid on AD prevention, we systematically explored the effects of propionic acid administration on AD model mice and cultured hippocampal neuronal cells. Results showed that oral propionate supplementation ameliorated cognitive impairment in AD mice. Propionate downregulated mitochondrial fission protein (DRP1) via G-protein coupled receptor 41 (GPR41) and enhanced PINK1/PARKIN-mediated mitophagy via G-protein coupled receptor 43 (GPR43) in AD pathophysiology which contribute to maintaining mitochondrial homeostasis both in vivo and in vitro. Administered A. muciniphila to AD mice before disease onset showed improved cognition, mitochondrial division and mitophagy in AD mice.

CONCLUSIONS: Taken together, our results demonstrate that A. muciniphila and its metabolite propionate protect against AD-like pathological events in AD mouse models by targeting mitochondrial homeostasis, making them promising therapeutic candidates for the prevention and treatment of AD. Video Abstract.},
}

*Propionates/metabolism/pharmacology
Animals
*Alzheimer Disease/metabolism/microbiology
Mice
*Receptors, G-Protein-Coupled/metabolism
Humans
*Gastrointestinal Microbiome
*Homeostasis
*Akkermansia
*Mitochondria/metabolism
*Autophagy
*Neurons/metabolism
Disease Models, Animal
Male
Female
Fatty Acids, Volatile/metabolism
Aged
Mitochondrial Dynamics
Feces/microbiology
Mitophagy
Mice, Inbred C57BL

@article {pmid39832406,
year = {2025},
author = {Lee, S and Hahn, C and Seong, E and Choi, HS},
title = {Reactive EEG Biomarkers for Diagnosis and Prognosis of Alzheimer's Disease and Mild Cognitive Impairment.},
journal = {Biosensors & bioelectronics},
volume = {273},
number = {},
pages = {117181},
doi = {10.1016/j.bios.2025.117181},
pmid = {39832406},
issn = {1873-4235},
abstract = {Alzheimer's disease (AD) is a devastating neurodegenerative condition characterized by progressive cognitive decline with currently no effective treatment available. One of the most critical areas in AD research is the identification of reliable biomarkers, which are essential for accurate diagnosis, prognostic assessment, and the development of targeted therapies. In this study, we introduce two novel reactive EEG (rEEG) biomarkers aimed at enhancing the diagnosis of AD and mild cognitive impairment (MCI). These biomarkers, previously unexplored in the literature, offer new insights into differentiating between various cognitive states. The first biomarker demonstrates a significant ability to distinguish between AD patients and normal controls (NC), while also effectively distinguishing MCI patients from NC. The second biomarker is designed to identify a subset of AD patients exhibiting hyperconductivity or hyperactivity, characterized by distinctive neural electrical patterns. A cohort of 90 elderly participants (mean age 76.63 ± 6.08 years) was recruited, including 30 AD patients, 30 individuals with MCI, and 30 NC subjects. Psychiatric diagnoses of participants were made by qualified professionals at Daejeon St. Mary's Hospital, The Catholic University of Korea, utilizing comprehensive neuropsychological assessments. Notably, the rEEG biomarkers achieved accuracies of 95%, 95%, and 98% in distinguishing between AD and NC, AD and MCI, and MCI and NC groups, respectively. These results underscore the potential of rEEG as a highly accurate and reliable diagnostic tool for cognitive impairments, including AD and MCI.},
}

@article {pmid39832109,
year = {2025},
author = {Pelczarski, M and Wolaniuk, S and Zaborska, M and Sadowski, J and Sztangreciak-Lehun, A and Bułdak, RJ},
title = {The role of α-tocopherol in the prevention and treatment of Alzheimer's disease.},
journal = {Molecular and cellular biochemistry},
volume = {},
number = {},
pages = {},
pmid = {39832109},
issn = {1573-4919},
abstract = {Scientific reports from various areas of the world indicate the potential role of tocopherols (vitamin E) in particular α-tocopherol in the prevention and therapy of Alzheimer's disease. The current phenomenon is related to the growing global awareness of eating habits and is also determined by the need to develop the prevention, management and therapy of Alzheimer's disease. This article is a review of current research on the action of the active form of vitamin E-α-tocopherol and its impact on the development and course of Alzheimer's disease. Additionally, to contrast this information, selected primary research on this topic was included. The aim of this article is to analyze and summarize the available scientific information on the effects of the active form of vitamin E, α-tocopherol, on the development and course of Alzheimer's disease. In the structure of the review, particular attention was paid to the analysis of the pathophysiological processes of the disease and the biochemical features of the action of α-tocopherol. To discuss the relationship between the effect of α-tocopherol and the occurrence of Alzheimer's disease, a literature review was conducted using the following databases: PubMed, Google Scholar, and Elsevier. During the search process, the following keywords were used: "tocopherols", "vitamin E", "α-tocopherol", "Alzheimer's disease" in various combinations. The process was conducted in accordance with the adopted search strategy taking into account the inclusion and exclusion criteria. Alzheimer's disease (AD) is the most common, irreversible neurodegenerative disease, so many scientists are actively looking for substances and/or strategies to prevent its development and to slow down its course in patients. Alpha-tocopherols (ATF) are a factor that inhibits the pathophysiological processes associated with the development of AD by reducing the formation of atherogenic amyloid B (AB). Additionally, this type of tocopherols has antioxidant and anti-inflammatory properties and has a positive effect on the metabolic functioning of mitochondria. It has been shown that a higher intake of α-tocopherol (ATF) was associated with a reduced risk of developing dementia and the occurrence of mild types of cognitive impairment (MCI). Various sources indicate an insufficient supply of ATF in the diet. ATF supplementation may potentially help to slow down the course of Alzheimer's disease, which is why this substance may be popularized in the treatment of this disease in the future. However, there is a need for further research on this issue.},
}

@article {pmid39832031,
year = {2025},
author = {Padti, AC and Bhavi, SM and Thokchom, B and Singh, SR and Bhat, SS and Harini, BP and Sillanpää, M and Yarajarla, RB},
title = {Nanoparticle Interactions with the Blood Brain Barrier: Insights from Drosophila and Implications for Human Astrocyte Targeted Therapies.},
journal = {Neurochemical research},
volume = {50},
number = {1},
pages = {80},
pmid = {39832031},
issn = {1573-6903},
mesh = {Animals ; *Blood-Brain Barrier/metabolism/drug effects ; Humans ; *Nanoparticles ; *Astrocytes/metabolism ; *Drosophila ; Drug Delivery Systems/methods ; Neurodegenerative Diseases/drug therapy/metabolism ; },
abstract = {This review explores the intricate connections between Drosophila models and the human blood-brain barrier (BBB) with nanoparticle-based approaches for neurological treatment. Drosophila serves as a powerful model organism due to its evolutionary conservation of key biological processes, particularly in the context of the BBB, which is formed by glial cells that share structural and functional similarities with mammalian endothelial cells. Recent advancements in nanoparticle technology have highlighted their potential for effective drug delivery across the BBB, utilizing mechanisms such as passive diffusion, receptor-mediated transcytosis, and carrier-mediated transport. The ability to engineer nanoparticles with specific physicochemical properties-such as size, surface charge, and functionalization-enhances their targeting capabilities, particularly towards astrocytes, which play a crucial role in maintaining BBB integrity and responding to neuroinflammation. Insights gained from Drosophila studies have informed the design of personalized nanomedicine strategies aimed at treating neurodegenerative diseases, including Alzheimer's, Parkinson's disease etc. As research progresses, the integration of findings from Drosophila models with emerging humanized BBB systems will pave the way for innovative therapeutic approaches that improve drug delivery and patient outcomes in neurological disorders.},
}

Animals
*Blood-Brain Barrier/metabolism/drug effects
Humans
*Nanoparticles
*Astrocytes/metabolism
*Drosophila
Drug Delivery Systems/methods
Neurodegenerative Diseases/drug therapy/metabolism

@article {pmid39831743,
year = {2025},
author = {Maupin, EA and Adams, KL},
title = {Cellular Senescence in Glial Cells: Implications for Multiple Sclerosis.},
journal = {Journal of neurochemistry},
volume = {169},
number = {1},
pages = {e16301},
doi = {10.1111/jnc.16301},
pmid = {39831743},
issn = {1471-4159},
support = {TA-2305-41311//National Multiple Sclerosis Society/ ; },
mesh = {Humans ; *Cellular Senescence/physiology ; *Multiple Sclerosis/pathology/metabolism ; *Neuroglia/pathology/metabolism ; Animals ; },
abstract = {Aging is the most common risk factor for Multiple Sclerosis (MS) disease progression. Cellular senescence, the irreversible state of cell cycle arrest, is the main driver of aging and has been found to accumulate prematurely in neurodegenerative diseases, including Alzheimer's and Parkinson's disease. Cellular senescence in the central nervous system of MS patients has recently gained attention, with several studies providing evidence that demyelination induces cellular senescence, with common hallmarks of p16INK4A and p21 expression, oxidative stress, and senescence-associated secreted factors. Here we discuss the current evidence of cellular senescence in animal models of MS and different glial populations in the central nervous system, highlighting the major gaps in the field that still remain. As premature senescence in MS may exacerbate demyelination and inflammation, resulting in inhibition of myelin repair, it is critical to increase understanding of cellular senescence in vivo, the functional effects of senescence on glial cells, and the impact of removing senescent cells on remyelination and MS. This emerging field holds promise for opening new avenues of treatment for MS patients.},
}

Humans
*Cellular Senescence/physiology
*Multiple Sclerosis/pathology/metabolism
*Neuroglia/pathology/metabolism
Animals

@article {pmid39831085,
year = {2024},
author = {Kollarik, S and Bimbiryte, D and Sethi, A and Dias, I and Moreira, CG and Noain, D},
title = {Pharmacological enhancement of slow-wave activity at an early disease stage improves cognition and reduces amyloid pathology in a mouse model of Alzheimer's disease.},
journal = {Frontiers in aging neuroscience},
volume = {16},
number = {},
pages = {1519225},
doi = {10.3389/fnagi.2024.1519225},
pmid = {39831085},
issn = {1663-4365},
abstract = {INTRODUCTION: Improving sleep in murine Alzheimer's disease (AD) is associated with reduced brain amyloidosis. However, the window of opportunity for successful sleep-targeted interventions, regarding the reduction in pathological hallmarks and related cognitive performance, remains poorly characterized.

METHODS: Here, we enhanced slow-wave activity (SWA) during sleep via sodium oxybate (SO) oral administration for 2 weeks at early (6 months old) or moderately late (11 months old) disease stages in Tg2576 mice and evaluated resulting neuropathology and behavioral performance.

RESULTS: We observed that the cognitive performance of 6-month-old Tg2576 mice significantly improved upon SO treatment, whereas no change was observed in 11-month-old mice. Histochemical assessment of amyloid plaques demonstrated that SO-treated 11-month-old Tg2576 mice had significantly less plaque burden than placebo-treated ones, whereas ELISA of insoluble protein fractions from brains of 6-month-old Tg2576 mice indicated lower Aβ-42/Aβ-40 ratio in SO-treated group vs. placebo-treated controls.

DISCUSSION: Altogether, our results suggest that SWA-dependent reduction in brain amyloidosis leads to alleviated behavioral impairment in Tg2576 mice only if administered early in the disease course, potentially highlighting the key importance of early sleep-based interventions in clinical cohorts.},
}

@article {pmid39831016,
year = {2025},
author = {Liao, H and Liao, S and Gao, YJ and Wang, X and Guo, LH and Zheng, S and Yang, W and Dai, YN},
title = {Near-infrared brain functional characteristics of mild cognitive impairment with sleep disorders.},
journal = {World journal of psychiatry},
volume = {15},
number = {1},
pages = {97945},
doi = {10.5498/wjp.v15.i1.97945},
pmid = {39831016},
issn = {2220-3206},
abstract = {BACKGROUND: Mild cognitive impairment (MCI) has a high risk of progression to Alzheimer's disease. The disease is often accompanied by sleep disorders, and whether sleep disorders have an effect on brain function in patients with MCI is unclear.

AIM: To explore the near-infrared brain function characteristics of MCI with sleep disorders.

METHODS: A total of 120 patients with MCI (MCI group) and 50 healthy subjects (control group) were selected. All subjects underwent the functional near-infrared spectroscopy test. Collect baseline data, Mini-Mental State Examination, Montreal Cognitive Assessment scale, fatigue severity scale (FSS) score, sleep parameter, and oxyhemoglobin (Oxy-Hb) concentration and peak time of functional near-infrared spectroscopy test during the task period. The relationship between Oxy-Hb concentration and related indexes was analyzed by Pearson or Spearmen correlation.

RESULTS: Compared with the control group, the FSS score of the MCI group was higher (t = 11.310), and the scores of Pittsburgh sleep quality index, sleep time, sleep efficiency, nocturnal sleep disturbance, and daytime dysfunction were higher (Z = -10.518, -10.368, -9.035, -10.661, -10.088). Subjective sleep quality and total sleep time scores were lower (Z = -11.592, -9.924). The sleep efficiency of the MCI group was lower, and the awakening frequency, rem sleep latency period, total sleep time, and oxygen desaturation index were higher (t = 5.969, 5.829, 2.887, 3.003, 5.937). The Oxy-Hb concentration at T0, T1, and T2 in the MCI group was lower (t = 14.940, 11.280, 5.721), and the peak time was higher (t = 18.800, 13.350, 9.827). In MCI patients, the concentration of Oxy-Hb during T0 was negatively correlated with the scores of Pittsburgh sleep quality index, sleep time, total sleep time, and sleep efficiency (r = -0.611, -0.388, -0.563, -0.356). It was positively correlated with sleep efficiency and total sleep time (r = 0.754, 0.650), and negatively correlated with oxygen desaturation index (r = -0.561) and FSS score (r = -0.526). All comparisons were P < 0.05.

CONCLUSION: Patients with MCI and sleep disorders have lower near-infrared brain function than normal people, which is related to sleep quality. Clinically, a comprehensive assessment of the near-infrared brain function of patients should be carried out to guide targeted treatment and improve curative effect.},
}

@article {pmid39830657,
year = {2024},
author = {Nikray, N and Abharian, N and Jafari Ashtiani, S and Kobarfard, F and Faizi, M},
title = {Comparative Evaluation of Aminoguanidine, Semicarbazide and Thiosemicarbazide Treatment for Methylglyoxal-Induced Neurological Toxicity in Experimental Models.},
journal = {Iranian journal of pharmaceutical research : IJPR},
volume = {23},
number = {1},
pages = {e153322},
doi = {10.5812/ijpr-153322},
pmid = {39830657},
issn = {1726-6890},
abstract = {BACKGROUND: Advanced glycation end products (AGEs) are complex compounds that play a critical role in neurological disorders, including the pathogenesis of Alzheimer's disease. Methylglyoxal (MG) is recognized as the primary precursor of AGEs. Methylglyoxal is produced endogenously and also introduced through dietary exposures.

OBJECTIVES: This study aimed to investigate and compare the effects of aminoguanidine (AG), semicarbazide (SC), and thiosemicarbazide (TSC) on MG-induced neurological toxicity in rats.

METHODS: Male Wistar rats were exposed orally to MG, MG + AG, MG + SC, and MG + TSC for 70 days. Neurobehavioral, biochemical, and histopathological changes were evaluated.

RESULTS: The findings indicated that oral administration of MG for 70 days resulted in memory impairment and increased anxiety in neurobehavioral tests. Additionally, MG elevated protein carbonylation in brain tissues. Semicarbazide was found to prevent MG-induced memory problems, while both SC and AG reduced carbonyl content in brain tissues. Aminoguanidine and TSC were effective in alleviating anxiety induced by MG exposure. Histopathological analysis revealed that MG caused cell damage and neuronal necrosis in the hippocampus, particularly in the cornu ammonis 1 and 3 (CA1 and CA3) and AG, SC, and TSC improved neuronal survival specifically in the CA1 and DG areas.

CONCLUSIONS: The data suggest that SC, AG, and TSC may offer neuroprotective effects against MG-induced neurobehavioral toxicity. Further studies are required to explore the mechanisms of action of these compounds.},
}

@article {pmid39830554,
year = {2024},
author = {Medel Sánchez, A and Ortiz Hernández, A and Moreno Moreno, RA and Salas López, D and Madrigal Gómez, LE and Dominguez Ibarra, AK and Gutiérrez Rojas, BA and Garcia Navarro, CO and Moreno Becerril, GT and Montelongo Quevedo, M and Flores Valdés, JR},
title = {Aducanumab in Alzheimer's Disease: A Comparative Study of Its Effects on Dementia and Mild Cognitive Impairment.},
journal = {Cureus},
volume = {16},
number = {12},
pages = {e75907},
doi = {10.7759/cureus.75907},
pmid = {39830554},
issn = {2168-8184},
abstract = {Alzheimer's disease (AD) is the leading cause of dementia, characterized by progressive cognitive decline. Cholinesterase inhibitors are commonly used to manage symptoms but have limited efficacy as the disease progresses. Aducanumab, a monoclonal antibody targeting amyloid-β (Aβ) plaques, has emerged as a novel therapeutic approach. Despite its Food and Drug Administration (FDA) approval, its efficacy and safety remain contentious, particularly following the European Medicines Agency's (EMA's) rejection. This systematic review aims to evaluate the efficacy, safety, and clinical outcomes of aducanumab in treating mild AD. Adhering to Preferred Reporting Items for Systematic Reviews (PRISMA) 2020 guidelines, we conducted a comprehensive search of PubMed and Science Direct databases, including randomized controlled trials (RCTs), cohort studies, and case-control studies focusing on aducanumab versus placebo in mild AD. Studies were screened based on predefined inclusion and exclusion criteria, and data were extracted on clinical outcomes, biomarkers, and neuroimaging markers. The risk of bias was assessed using the Cochrane Handbook and Newcastle-Ottawa Scale. Out of 967 identified records, seven studies met the inclusion criteria. Findings indicated a dose-dependent reduction in Aβ plaques with aducanumab, but clinical outcomes varied. High-dose aducanumab (10 mg/kg) demonstrated significant improvements in some studies but not others. Adverse events, notably amyloid-related imaging abnormalities (ARIA), were frequent, especially at higher doses. The studies exhibited heterogeneous treatment effects and underscored the potential of cerebrospinal fluid biomarkers as an alternative to amyloid positron emission tomography (PET) scans. Aducanumab shows promise in reducing Aβ plaques and has potential clinical benefits at high doses; however, its safety profile, particularly concerning ARIA, remains a significant concern. The variability in clinical efficacy highlights the need for further research to optimize dosing regimens and identify patient populations most likely to benefit from treatment. Future studies should focus on refining treatment protocols and exploring alternative biomarkers to improve therapeutic outcomes for AD.},
}

@article {pmid39830039,
year = {2024},
author = {Chen, R and Lu, X and Xiao, A and Ma, J},
title = {Role of insulin-like growth factor-2 in Alzheimer's disease induced memory impairment and underlying mechanisms.},
journal = {Frontiers in cellular neuroscience},
volume = {18},
number = {},
pages = {1520253},
doi = {10.3389/fncel.2024.1520253},
pmid = {39830039},
issn = {1662-5102},
abstract = {Alzheimer's disease (AD) is the most prevalent type of dementia. Treatments for AD do not reverse the loss of brain function; rather, they decrease the rate of cognitive deterioration. Current treatments are ineffective in part because they do not address neurotrophic mechanisms, which are believed to be critical for functional recovery. Given that structural losses are assumed to be the root cause of cognitive impairment in AD, strengthening neurotrophic pathways may be a useful preventative therapeutic approach. Insulin-like growth factor-2 (IGF2), which is widely expressed in the central nervous system (CNS), has emerged as a crucial mechanism of synaptic plasticity and learning and memory, and many studies have indicated that this neurotrophic peptide is a viable candidate for treating and preventing AD-induced cognitive decline. An increase in IGF2 levels improves memory in healthy animals and alleviates several symptoms associated with neurodegenerative disorders. These effects are primarily caused by the IGF2 receptor, which is widely expressed in neurons and controls protein trafficking, synthesis, and degradation. However, the use of IGF2 as a potential target for the development of novel pharmaceuticals to treat AD-induced memory impairment needs further investigation. We compiled recent studies on the role of IGF2 in AD-associated memory issues and summarized the current knowledge regarding IGF2 expression and function in the brain, specifically in AD-induced memory impairment.},
}

@article {pmid39829171,
year = {2025},
author = {Wang, M and Guo, S and Yi, L and Li, Z and Shi, X and Fan, Y and Luo, M and He, Y and Song, W and Du, Y and Dong, Z},
title = {KIF9 Ameliorates Neuropathology and Cognitive Dysfunction by Promoting Macroautophagy in a Mouse Model of Alzheimer's Disease.},
journal = {Aging cell},
volume = {},
number = {},
pages = {e14490},
doi = {10.1111/acel.14490},
pmid = {39829171},
issn = {1474-9726},
support = {CSTB2022NSCQ-LZX0010//Natural Science Foundation of Chongqing Municipality/ ; CSTB2024NSCQ-LZX0008//Natural Science Foundation of Chongqing Municipality/ ; 32371030//National Natural Science Foundation of China/ ; 82071395//National Natural Science Foundation of China/ ; 82371194//National Natural Science Foundation of China/ ; W0044//CQMU Program for Youth Innovation in Future Medicine/ ; },
abstract = {Alzheimer's disease (AD) is a prevalent neurodegenerative disorder affecting the elderly. The imbalance of protein production and degradation processes leads to the accumulation of misfolded and abnormally aggregated amyloid-beta (Aβ) in the extracellular space and forms senile plaques, which constitute one of the most critical pathological hallmarks of AD. KIF9, a member of the kinesin protein superfamily, mediates the anterograde transport of intracellular cargo along microtubules. However, the exact role of KIF9 in AD pathogenesis remains largely elusive. In this study, we reported that the expression of kinesin family member 9 (KIF9) in the hippocampus of APP23/PS45 double-transgenic AD model mice declined in an age-dependent manner, concurrent with macroautophagy dysfunction. Furthermore, we found that KIF9 mediated the transport of lysosomes through kinesin light chain 1 (KLC1), thereby participating in the degradation of amyloidogenic pathway-related proteins of Aβ precursor protein (APP) in AD model cells through promoting the macroautophagy pathway. Importantly, genetic upregulation of KIF9 via adeno-associated virus (AAV) diminished Aβ deposition and alleviated cognitive impairments in AD model mice by enhancing macroautophagy function. Collectively, our findings underscore the ability of KIF9 to promote macroautophagy through KLC1-mediated anterograde transport of lysosomes, effectively ameliorating cognitive dysfunction in AD model mice. These discoveries suggest that KIF9 may represent a novel therapeutic target for the treatment of AD.},
}

@article {pmid39828895,
year = {2025},
author = {Wang, Z and Liang, Q and Lin, Z and Li, H and Chen, X and Zou, Z and Mo, J},
title = {Potential role of formononetin as a novel natural agent in Alzheimer's disease and osteoporosis comorbidity.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877241299104},
doi = {10.1177/13872877241299104},
pmid = {39828895},
issn = {1875-8908},
abstract = {BACKGROUND: The growing aging population has led to an increase in the prevalence of Alzheimer's disease (AD) and osteoporosis (OP), both of which significantly impair quality of life. The comorbid nature of these conditions suggests a shared genetic etiology, the understanding of which is crucial for developing targeted therapies.

OBJECTIVE: This study aims to explore the shared genetic etiology underlying AD and OP, using a system biology approach to identify potential therapeutic targets and natural compounds for treatment.

METHODS: We employed Weighted Gene Co-Expression Network Analysis (WGCNA) with molecular docking strategies to uncover the genetic links between AD and OP. MT2A and CACNA1C were identified as key pleiotropic hub genes potentially linking AD and OP. Molecular docking was utilized to screen for compounds with therapeutic potential, leading to the identification of formononetin as a compound with significant binding affinity to these hub genes. Quantitative real-time PCR (qRT-PCR) validation was conducted to confirm the gene expression changes in disease models.

RESULTS: Our study indicate that formononetin exhibits strong binding affinity to the identified hub genes, MT2A and CACNA1C. qRT-PCR validation confirmed the upregulation of these genes in disease models, which was mitigated upon treatment with formononetin, suggesting a reversal of disease markers.

CONCLUSIONS: This study advances our understanding of the genetic intersections between AD and OP and positions formononetin as a promising natural agent for further translational research. Formononetin's multi-target potential makes it a valuable candidate for managing these comorbid conditions, meriting further investigation and development as a therapeutic strategy.},
}

@article {pmid39828502,
year = {2025},
author = {Wang, J and Li, X and Pang, H and Bu, S and Zhao, M and Liu, Y and Yu, H and Jiang, Y and Fan, G},
title = {Differential Connectivity Patterns of Mild Cognitive Impairment in Alzheimer's and Parkinson's Disease: A Large-scale Brain Network Study.},
journal = {Academic radiology},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.acra.2024.09.017},
pmid = {39828502},
issn = {1878-4046},
abstract = {RATIONALE AND OBJECTIVES: Cognitive disorders, such as Alzheimer's disease (AD) and Parkinson's disease (PD), significantly impact the quality of life in older adults. Mild cognitive impairment (MCI) is a critical stage for intervention and can predict the development of dementia. The causes of these two diseases are not fully understood, but there is an overlap in their neuropathology. There is a lack of direct comparison regarding the changes in functional connectivity within and between different brain networks during cognitive impairment in these two diseases.

OBJECTIVE: This study aims to investigate changes in brain network connectivity of AD and PD with mild cognitive impairment, shedding light on the underlying neuropathological mechanisms and potential treatment options.

METHODS: A total of 33 AD-MCI patients, 55 PD-MCI patients, and 34 healthy controls (HCs) underwent resting-state functional MRI and cognitive function assessment using Independent Components Analysis (ICA). We compared intra- and inter-network functional connectivity among the three groups and analyzed the correlation between changes in functional connectivity and cognitive domain performance.

RESULTS: Using ICA, we identified eight functional networks. In the AD-MCI group, reductions in internetwork functional connectivity were mainly around the default mode network (DMN). Intra-network functional connectivity was widely reduced, especially in the DMN, while intra-network functional connectivity in the Salience Network (SN) increased. In contrast, in the PD-MCI group, reductions in internetwork functional connectivity were mainly around the SN. Intra-network functional connectivity in the SN decreased, while intra-network functional connectivity in other networks increased.

CONCLUSION: This study highlights distinct yet overlapping changes in brain network connectivity in AD and PD, providing new insights into the underlying mechanisms of cognitive impairment disorders.},
}

@article {pmid39828086,
year = {2025},
author = {Kara, S and Polat, S and Akillioglu, K and Şaker, D and Evlice, AT and Sencar, L and Bozkaya, FÜ and Polat, S},
title = {Effects of TGF-β1 on Aβ-40 and α- β- γ Secretase Expression in Hippocampus and Prefrontal Cortex in Experimental Alzheimer's Disease.},
journal = {Behavioural brain research},
volume = {},
number = {},
pages = {115432},
doi = {10.1016/j.bbr.2025.115432},
pmid = {39828086},
issn = {1872-7549},
abstract = {Alzheimer's disease is a chronic complex neurodegenerative disease characterized with amyloid plaques and loss of neurons. TGF-β1 is important growth factor, plays critical roles in cell metabolism, tissue homeostasis, neuronal development, and synaptic plasticity. In this study, we aimed to examine the effect of TGF-β1 on the regulation of α, β, and γ-secretase enzymes, Aβ-40 accumulation, apoptosis, and neuronal damage in an experimental Scopolamine-induced AD-like model. The subjects were divided into 5 groups such as control, sham, TGF-β1 control, Scopolamin group, TGF-β1 treatment groups.Then all groups were divided into 2 subgroups according to 28th-56th days. Except for Morris water maze (MWM) test, hippocampus and prefrontal cortex tissues were taken for light-electron microscopic, immunohistochemical, and biochemical examinations. It was observed that learning and memory abilities, which decreased in the MWM test of the Scopolamine group, increased in the treatment groups. In addition, α-secretase expression decreased in the Scopolamin group, while it increased in the TGF-β1 treatment group. It was determined that Aβ-40 and caspase-3 immunoreactivity, β and γ-secretase enzyme levels increased in the Scopolamin group and decreased in TGF-β1 treatment group. Cellular degenerations were relatively decreased in TGF-β1 treatment group. It was thought that TGF-β1 might have a therapeutic effect on Alzheimer's disease by increasing memory performance and preventing Aβ-40 accumulation in the AD-like model induced by Scopolamine and also, may be effective preventing neuronal damage by down-regulating caspase-3 expression. When all the findings evaluated together, it was concluded that TGF-β1 could be evaluated as a therapeutic agent in Alzheimer's disease.},
}

@article {pmid39828018,
year = {2025},
author = {Sharma, D and Singh, V and Kumar, A and Singh, TG},
title = {Genistein: A Promising Ally in Combating Neurodegenerative Disorders.},
journal = {European journal of pharmacology},
volume = {},
number = {},
pages = {177273},
doi = {10.1016/j.ejphar.2025.177273},
pmid = {39828018},
issn = {1879-0712},
abstract = {Neurodegenerative disorders arise when nerve cells in the brain or peripheral nervous system gradually lose functions and eventually die. Although certain therapies may alleviate some of the physical and mental symptoms associated with neurodegenerative disorders, hence slowing their progression, but no sure-shot treatment is currently available. It was shown that the rise in life expectancy and the number of elderly people in the community led to an increasing trend in the incidence and prevalence of neurodegenerative disease. Phytomolecules are demonstrating their effectiveness in combating, regression, and delaying various diseases. Genistein is one of soy isoflavone with antioxidant, anti-inflammatory, and estrogenic effects. Researchers demonstrated that Genistein treatment significantly reduced hyperglycemia, improved cognitive performance by modulating acetylcholinesterase activity and oxidative stress, and alleviated neuroinflammatory conditions in mice. This paper evaluates (in vivo and in vitro) various molecular targets of isoflavones and their ability to effectively counter several neurodegenerative disorders such as Parkinson's, Alzheimer's, and Huntington's diseases and amyotrophic lateral sclerosis. In this review, we aim to provide an overview of the role that genistein plays in delaying the development of neurodegenerative disorders.},
}

@article {pmid39827439,
year = {2025},
author = {Fasth, LM and Kelley, CJ and Colón-Emeric, C and Green, AR and Thorpe, CT and Gilliam, M and Lund, JL and Hanson, LC and Niznik, JD},
title = {How Should Clinicians Discuss Deprescribing with Caregivers of Older Adults Living with Dementia? A Qualitative Study.},
journal = {Drugs & aging},
volume = {},
number = {},
pages = {},
pmid = {39827439},
issn = {1179-1969},
support = {K08AG071794/AG/NIA NIH HHS/United States ; },
abstract = {BACKGROUND: Preventive medications are potential targets for deprescribing in older adults with dementia as goals of care change from preventive to palliative. Yet, prescribers lack communication guidance to address deprescribing.

OBJECTIVE: Using bisphosphonates as a case example, we sought to characterize and compare communication preferences of prescribers and family/informal caregivers regarding deprescribing.

METHODS: We conducted 23 semi-structured interviews with prescribers (12) and caregivers (11) of older adults with Alzheimer's disease or related dementias (ADRD). Prescribers and caregivers were asked to provide their impressions of seven conversation starters for discussing deprescribing, focusing on a case example using bisphosphonates. These phrases focused on topics including life expectancy, treatment burden, adverse effects, and costs. We used a qualitative framework analysis to identify relevant themes as prescribers and caregivers discussed their general perceptions of the potential benefits and harms of bisphosphonates and experiences with deprescribing.

RESULTS: Among prescribers, there were ten physicians and two nurse practitioners; most (nine) female and white. Among caregivers, eight were female, seven were white, and five were Latino/a. For both prescribers and caregivers, preferred conversation starters initiated a risk versus benefit discussion, emphasizing medication adverse effects and patient-specific factors, such as functional status and indication for treatment. While prescribers emphasized discussing common medication adverse effects, caregivers noted the importance of knowing a medication's potential impact on ADRD. The least preferred conversation starter for deprescribing among both groups focused on the extra effort and cost of continuing bisphosphonates. Discordance between caregivers and prescribers were identified in several phrases; notably, caregivers disliked statements that introduced discussions of prognosis and life expectancy.

CONCLUSIONS: Deprescribing conversations may be best perceived by caregivers when introduced with a discussion of a medication's adverse effects and potential impact on cognition. In addition, deprescribing conversations should be tailored to patient-specific factors, including functional status, goals of care, and the role of their caregiver in medical decision-making. Avoiding discussions of medication cost, pill burden, and life expectancy may help reassure the caregiver that deprescribing is a form of medication optimization and not a withdrawal of care.},
}

@article {pmid39826482,
year = {2025},
author = {Zulhafiz, NA and Teoh, TC and Chin, AV and Chang, SW},
title = {Drug repurposing using artificial intelligence, molecular docking, and hybrid approaches: A comprehensive review in general diseases vs Alzheimer's disease.},
journal = {Computer methods and programs in biomedicine},
volume = {261},
number = {},
pages = {108604},
doi = {10.1016/j.cmpb.2025.108604},
pmid = {39826482},
issn = {1872-7565},
abstract = {BACKGROUND: Alzheimer's disease (AD), the most prevalent form of dementia, remains enigmatic in its origins despite the widely accepted "amyloid hypothesis," which implicates amyloid-beta peptide aggregates in its pathogenesis and progression. Despite advancements in technology and healthcare, the incidence of AD continues to rise. The traditional drug development process remains time-consuming, often taking years to bring an AD treatment to market. Drug repurposing has emerged as a promising strategy for developing cost-effective and efficient therapeutic options by identifying new uses for existing approved drugs, thus accelerating drug development.

OBJECTIVES: This study aimed to examine two key drug repurposing methodologies in general diseases and specifically in AD, which are artificial intelligent (AI) approach and molecular docking approach. In addition, the hybrid approach that integrates AI with molecular docking techniques will be explored too.

METHODOLOGY: This study systematically compiled a comprehensive collection of relevant academic articles, scientific papers, and research studies which were published up until November 2024 (as of the writing of this review paper). The final selection of papers was filtered to include studies related to Alzheimer's disease and general diseases, and then categorized into three groups: AI articles, molecular docking articles, and hybrid articles.

RESULTS: As a result, 331 papers were identified that employed AI for drug repurposing in general diseases, and 58 papers focused specifically in AD. For molecular docking in drug repurposing, 588 papers addressed general diseases, while 46 papers were dedicated to AD. The hybrid approach combining AI and molecular docking in drug repurposing has 52 papers for general diseases and 9 for AD. A comparative review was done across the methods, results, strengths, and limitations in those studies. Challenges of drug repurposing in AD are explored and future prospects are proposed.

DISCUSSION AND CONCLUSION: Drug repurposing emerges as a compelling and effective strategy within AD research. Both AI and molecular docking methods exhibit significant potential in this domain. AI algorithms yield more precise predictions, thus facilitating the exploration of new therapeutic avenues for existing drugs. Similarly, molecular docking techniques revolutionize drug-target interaction modelling, employing refined algorithms to screen extensive drug databases against specific target proteins. This review offers valuable insights for guiding the utilization of AI, molecular docking, or their hybrid in AD drug repurposing endeavors. The hope is to speed up the timeline of drug discovery which could improve the therapeutic approach to AD.},
}

@article {pmid39826392,
year = {2025},
author = {Mei, Z and Zhang, Y and Zhao, W and Lam, C and Luo, S and Wang, S and Luo, S},
title = {Music-based interventions for anxiety and depression in older adults with dementia: A systematic review of randomized controlled trials.},
journal = {Complementary therapies in clinical practice},
volume = {59},
number = {},
pages = {101951},
doi = {10.1016/j.ctcp.2025.101951},
pmid = {39826392},
issn = {1873-6947},
abstract = {OBJECTIVE: The objective of this systematic review was to synthesize evidence from randomized controlled trials (RCTs) regarding the efficacy of music-based interventions (MBIs) in improving anxiety and depression in older adults with dementia.

METHODS: Relevant RCTs were identified through searches in electronic databases, including PubMed, Embase, EBSCOhost, Scopus, Web of Science, APA PsycINFO, and Google. The Revised Cochrane risk-of-bias tool for randomized trials (RoB 2) was used to evaluate the risk of bias in the included trials. A narrative synthesis of the included trials was conducted.

RESULTS: Nine RCTs involving 496 patients met the inclusion criteria; five trials evaluated the efficacy of MBIs for anxiety, and six trials evaluated their efficacy for depression in older adults with dementia. Of the nine trials, two reported significant improvements in anxiety in older adults with dementia following MBIs (Cohen's d = -1.71 to -2.48), while one trial reported significant improvements in depression (Cohen's d = -0.66).

CONCLUSIONS: Only a few trials support the efficacy of MBIs in alleviating negative emotions in older adults with dementia, as evidenced by three out of the nine trials. However, due to the small sample sizes and heterogeneity in dementia types, stages, and interventions, quantitative results were not pooled, making it challenging to draw reliable conclusions. Further validation and examination of the findings presented in this study are warranted to strengthen the evidence base for integrating MBIs into dementia care and treatment protocols.},
}

@article {pmid39826816,
year = {2025},
author = {Chen, L and Zhao, X and Sheng, R and Lazarovici, P and Zheng, W},
title = {Artemisinin Alleviates Astrocyte Overactivation and Neuroinflammation by Modulating the IRE1/NF-κB Signaling Pathway in In Vitro and In Vivo Alzheimer's Disease Models.},
journal = {Free radical biology & medicine},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.freeradbiomed.2025.01.027},
pmid = {39826816},
issn = {1873-4596},
abstract = {Recent studies have shown that neuroinflammation and heightened glial activity, particularly astrocyte overactivation, are associated with Alzheimer's disease (AD). Abnormal accumulation of amyloid-beta (Aβ) induces endoplasmic reticulum (ER) stress and activates astrocytes. Artemisinin (ART), a frontline anti-malarial drug, has been found to have neuroprotective properties. However, its impact on astrocytes remains unclear. In this study, we used Aβ1-42 induced astrocyte cultures and 3× Tg-AD mice as in vitro and in vivo models, respectively, to investigate the effects of ART on AD related astrocyte overactivation and its underlying mechanisms. ART attenuated Aβ1-42-induced astrocyte activation, ER stress, and inflammatory responses in astrocyte cultures by inhibiting IRE1 phosphorylation and the NF-κB pathway, as evidenced by the overexpression of IRE1 WT and IRE1-K599A (kinase activity invalidated), along with application of activators and inhibitors related to ER stress. Furthermore, ART alleviated the detrimental effects and restored neurotrophic function of astrocytes on co-cultured neurons, preventing neuronal apoptosis during Aβ1-42 treatment. In 3×Tg-AD mice, ART treatment improved cognitive function and reduced astrocyte overactivation, neuroinflammation, ER stress, and neuronal apoptosis. Moreover, ART attenuated the upregulation of IRE1/NF-κB pathway activity in AD mice. Astrocyte-specific overexpression of IRE1 via adeno-associated virus in AD mice reversed the ameliorating effects of ART. Our findings suggest that ART inhibits astrocyte overactivation and neuroinflammation in both in vitro and in vivo AD models by modulating the IRE1/NF-κB signaling pathway, thereby enhancing neuronal functions. This study underscores the therapeutic potential of ART in AD and highlights the significance of modulating the ER stress-inflammatory cycle and normalizing astrocyte-neuron communication.},
}

@article {pmid39494933,
year = {2024},
author = {Duchesne, S and Collins, DL and Barlow, L and Bartha, R and Black, S and Chertkow, H and Dadar, M and Joshi, M and Rosa-Neto, P and Soucy, JP and Smith, EE},
title = {Recommendations on Imaging in the Context of Alzheimer's Disease-Modifying Therapies from the CCNA Imaging Workgroup.},
journal = {The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques},
volume = {},
number = {},
pages = {1-9},
doi = {10.1017/cjn.2024.338},
pmid = {39494933},
issn = {0317-1671},
abstract = {BACKGROUND: Disease-modifying therapies (DMTs) for Alzheimer's disease (AD) are emerging following successful clinical trials of therapies targeting amyloid beta (Aβ) protofibrils or plaques. Determining patient eligibility and monitoring treatment efficacy and adverse events, such as Aβ-related imaging abnormalities, necessitates imaging with MRI and PET. The Canadian Consortium on Neurodegeneration in Aging (CCNA) Imaging Workgroup aimed to synthesize evidence and provide recommendations on implementing imaging protocols for AD DMTs in Canada.

METHODS: The workgroup employed a Delphi process to develop these recommendations. Experts from radiology, neurology, biomedical engineering, nuclear medicine, MRI and medical physics were recruited. Surveys and meetings were conducted to achieve consensus on key issues, including protocol standardization, scanner strength, monitoring protocols based on risk profiles and optimal protocol lengths. Draft recommendations were refined through multiple iterations and expert discussions.

RESULTS: The recommendations emphasize standardized acquisition imaging protocols across manufacturers and scanner strengths to ensure consistency and reliability of clinical treatment decisions, tailored monitoring protocols based on DMTs' safety and efficacy profiles, consistent monitoring regardless of perceived treatment efficacy and MRI screening on 1.5T or 3T scanners with adapted protocols. An optimal protocol length of 20-30 minutes was deemed feasible; specific sequences are suggested.

CONCLUSION: The guidelines aim to enhance imaging data quality and consistency, facilitating better clinical decision-making and improving patient outcomes. Further research is needed to refine these protocols and address evolving challenges with new DMTs. It is recognized that administrative, financial and logistical capacity to deliver additional MRI and positron emission tomography scans require careful planning.},
}

@article {pmid39824583,
year = {2025},
author = {Mishra, S and Banerjee, S and Tiwari, BS and Tiwari, AK},
title = {Recent progress in CRISPR-Cas-system for neurological disorders.},
journal = {Progress in molecular biology and translational science},
volume = {210},
number = {},
pages = {231-261},
doi = {10.1016/bs.pmbts.2024.07.017},
pmid = {39824583},
issn = {1878-0814},
mesh = {Humans ; *CRISPR-Cas Systems/genetics ; *Nervous System Diseases/genetics/therapy ; Animals ; Gene Editing ; Genetic Therapy/methods ; },
abstract = {Different neurological diseases including, Parkinson's, Alzheimer's, and Huntington's diseases extant momentous global disease burdens, affecting millions of lives for imposing a heavy disease burden on the healthcare systems. Despite various treatment strategies aimed at alleviating symptoms, treatments remain elusive and ineffective due to the disease's complexity. However, recent advancements in gene therapy via the CRISPR-Cas system offer ground-breaking and targeted treatment options. Based on a bacterial immune mechanism, the CRISPR-Cas system enables precise genome editing, allowing for the alteration of different genetic mutations and the possible cure of genetic diseases. In the context of neurological disorders, the CRISPR-Cas system shows a promising avenue by allowing researchers to conduct genome-editing which is implicated in neurodegenerative disease therapeutics. This book chapter provides an updated overview of the application of the CRISPR-Cas system for addressing target-specific therapeutic approaches for neurodegenerative disorders. Furthermore, we discuss the principles of the CRISPR-Cas mechanism, its role in modeling neurological disorders, identifying molecular targets, and developing gene-based therapies. Additionally, the chapter explores the recent clinical trials and CRISPR-Cas-mediated treatments for neurological conditions. By leveraging the accuracy and versatility of the CRISPR-Cas system, scientists can more effectively handle the genetic underpinnings of neurodegenerative diseases. Furthermore, the chapter extends the critical viewpoints on ethical considerations and technical limitations related to the clinical deployment of this revolutionizing technique.},
}

Humans
*CRISPR-Cas Systems/genetics
*Nervous System Diseases/genetics/therapy
Animals
Gene Editing
Genetic Therapy/methods

@article {pmid39824445,
year = {2025},
author = {Cardaci, V and Di Pietro, L and Zupan, MC and Sibbitts, J and Privitera, A and Lunte, SM and Caraci, F and Hartley, MD and Caruso, G},
title = {Characterizing Oxidative Stress induced by Aβ Oligomers and the Protective Role of Carnosine in Primary Mixed Glia Cultures.},
journal = {Free radical biology & medicine},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.freeradbiomed.2025.01.030},
pmid = {39824445},
issn = {1873-4596},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder characterized by cognitive decline and memory loss. A critical aspect of AD pathology is represented by oxidative stress, which significantly contributes to neuronal damage and death. Microglia and astrocytes, the primary glial cells in the brain, are crucial for managing oxidative stress and supporting neuronal function. Carnosine is an endogenous dipeptide possessing a multimodal mechanism of action that includes antioxidant, anti-inflammatory, and anti-aggregant activities. The present study investigated the effects of Aβ1-42 oligomers (oAβ), small aggregates associated with the neurodegeneration observed in AD, on primary rat mixed glia cultures composed of both microglia and astrocytes, focusing on the ability of these detrimental species to induce oxidative stress. We assessed intracellular reactive oxygen species (ROS) and nitric oxide (NO) levels as markers of oxidative stress. Exposure to oAβ significantly elevated both ROS and NO intracellular levels compared to control cells. However, this effect was completely inhibited by the pre-treatment of mixed cultures with carnosine, resulting in ROS and NO levels similar to those observed in untreated (control) cells. Single-cell analysis of cellular responses to oAβ revealed heterogeneous ROS production, resulting in two distinct clusters of cells, one of which was very responsive to the treatment. The presence of carnosine counteracted the overproduction of ROS, also leading to a single, homogeneous cluster, similar to that observed in the case of control cells. Interestingly, unlike ROS response, single-cell analysis of NO production did not show any distinct clusters. Overall, our findings demonstrated the ability of carnosine to mitigate Aβ-induced oxidative stress in mixed glia cells, by rescuing ROS and NO intracellular levels, as well as to normalize the heterogeneous response to the treatment measured in terms of clusters' formation. The present study suggests a therapeutic potential of carnosine in pathologies characterized by oxidative stress including AD.},
}

@article {pmid39823370,
year = {2025},
author = {Bell, MB and Kane, MS and Ouyang, X and Young, ME and Jegga, AG and Chatham, JC and Darley-Usmar, V and Zhang, J},
title = {Brain Transcriptome Changes Associated With an Acute Increase of Protein O-GlcNAcylation and Implications for Neurodegenerative Disease.},
journal = {Journal of neurochemistry},
volume = {169},
number = {1},
pages = {e16302},
doi = {10.1111/jnc.16302},
pmid = {39823370},
issn = {1471-4159},
support = {NHLBI HL142216/NH/NIH HHS/United States ; P30 AG050886/NH/NIH HHS/United States ; R56AG060959/NH/NIH HHS/United States ; T32 HL007457/NH/NIH HHS/United States ; I01 BX-004251-01//VA merit award/ ; },
mesh = {Animals ; Mice ; *Transcriptome ; *Brain/metabolism/drug effects ; *Neurodegenerative Diseases/metabolism/genetics ; Male ; *Mice, Inbred C57BL ; Thiazoles/pharmacology ; beta-N-Acetylhexosaminidases/metabolism/genetics ; Pyrans/pharmacology ; Acetylglucosamine/metabolism ; },
abstract = {Enhancing protein O-GlcNAcylation by pharmacological inhibition of the enzyme O-GlcNAcase (OGA) has been considered as a strategy to decrease tau and amyloid-beta phosphorylation, aggregation, and pathology in Alzheimer's disease (AD). There is still more to be learned about the impact of enhancing global protein O-GlcNAcylation, which is important for understanding the potential of using OGA inhibition to treat neurodegenerative diseases. In this study, we investigated the acute effect of pharmacologically increasing O-GlcNAc levels, using the OGA inhibitor Thiamet G (TG), in normal mouse brains. We hypothesized that the transcriptome signature in response to a 3 h TG treatment (50 mg/kg) provides a comprehensive view of the effect of OGA inhibition. We then performed mRNA sequencing of the brain using NovaSeq PE 150 (n = 5 each group). We identified 1234 significant differentially expressed genes with TG versus saline treatment. Functional enrichment analysis of the upregulated genes identified several upregulated pathways, including genes normally down in AD. Among the downregulated pathways were the cell adhesion pathway as well as genes normally up in AD and aging. When comparing acute to chronic TG treatment, protein autophosphorylation and kinase activity pathways were upregulated, whereas cell adhesion and astrocyte markers were downregulated in both datasets. AMPK subunit Prkab2 was one gene in the kinase activity pathway, and the increase after acute and chronic treatment was confirmed using qPCR. Interestingly, mitochondrial genes and genes normally down in AD were up in acute treatment and down in chronic treatment. Data from this analysis will enable the evaluation of the mechanisms underlying the impact of OGA inhibition in the treatment of AD. In particular, OGA inhibitors appear to have downstream effects related to bioenergetics which may limit their therapeutic benefits.},
}

Animals
Mice
*Transcriptome
*Brain/metabolism/drug effects
*Neurodegenerative Diseases/metabolism/genetics
Male
*Mice, Inbred C57BL
Thiazoles/pharmacology
beta-N-Acetylhexosaminidases/metabolism/genetics
Pyrans/pharmacology
Acetylglucosamine/metabolism

@article {pmid39822440,
year = {2024},
author = {Barnett, C and Morris, K and Shah, Y},
title = {Clinical Diagnoses and Characterization of Patients With Amyloid-Negative Amyloid-Beta, p-Tau, and Neurofilament Light Chain (ATN) Profiles.},
journal = {Cureus},
volume = {16},
number = {12},
pages = {e75874},
doi = {10.7759/cureus.75874},
pmid = {39822440},
issn = {2168-8184},
abstract = {The novel amyloid-beta, p-Tau, and neurofilament light chain (ATN) classification scheme has become a promising system for clinically detecting and diagnosing Alzheimer's disease (AD). In addition to its utility in Alzheimer's diagnosis and treatment, the ATN framework may also have clinical relevance in identifying non-Alzheimer's pathologies. In this study conducted at Broadlawns Geriatric and Memory Center, 92 amyloid-negative profiles out of 182 patients with an ATN framework were categorized into subjective cognitive impairment (SCI), non-amnestic mild cognitive impairment (non-amnestic MCI), amnestic MCI, Alzheimer's dementia, vascular dementia, mixed dementia, unspecified dementia, or other memory changes based on diagnoses written in the chart. Additionally, other secondary diagnoses were found in the differential, including sleep disorders, anxiety, depressive disorders and grief, and cerebrovascular disease. The results are concordant with our expectations that amyloid-negative ATN profiles are associated with mostly non-Alzheimer's cognitive decline. We were also able to demonstrate that amyloid-negative patients have other secondary neurologic or psychiatric diagnoses related to memory or cognitive changes. However, certain enigmatic patient presentations warrant further scrutiny in the medical chart. It is possible that ATN may pose a risk of misclassification in both Alzheimer and non-Alzheimer pathologies, particularly at early stages. Future work may be required to corroborate findings using other new plasma biomarkers, such as p-Tau217. Overall, we hope that this study will provide options for early detection and future treatment of AD and other neurocognitive disorders. We also anticipate that this work will lead to the recognition of other non-neurocognitive conditions comorbid with such neurocognitive disorders.},
}

@article {pmid39822295,
year = {2025},
author = {Gleerup, HS and Simonsen, AH and Grötschel, L and Gramkow, MH and Høgh, P and Blennow, K and Zetterberg, H and Ashton, N and Hasselbalch, SG},
title = {Plasma biomarkers of amyloid, tau, astrogliosis, and axonal injury in a mixed memory clinic cohort.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {17},
number = {1},
pages = {e70073},
doi = {10.1002/dad2.70073},
pmid = {39822295},
issn = {2352-8729},
abstract = {INTRODUCTION: Studies have shown that blood biomarkers can differentiate dementia disorders. However, the diagnosis of dementia still relies primarily on cerebrospinal fluid and imaging modalities. The new disease-modifying treatments call for more widely applicable biomarkers.

METHODS: Plasma samples (n = 250) from two mixed memory clinic were included. Participants were divided into amyloid beta positives (Aβ+) and Aβ negatives (Aβ-). Plasma phosphorylated tau (p-tau) 181, p-tau231, Aβ1-42 (Aβ42), Aβ40, Aβ42/Aβ40, glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL) were measured by single molecule array.

RESULTS: Significant differences were found among cognitively unimpaired, mild cognitive impairment, Alzheimer's disease (AD), and non-AD, and nearly all of the biomarkers were able to predict amyloid status. When combining p-tau181 and p-tau231 they predicted Aβ positivity with an area under the curve (AUC) of 0.75, and when combining all biomarkers an AUC of 0.86 was found.

DISCUSSION: This study supports previous findings on plasma biomarkers, even when investigated in a typical clinical setting in a consecutive, heterogeneous, mixed memory clinic.

HIGHLIGHTS: This study investigated seven plasma biomarkers in a mixed memory clinic, regardless of amyloid co-pathology or atypical phenotypes.These findings support previous promising results on plasma biomarkers, even when investigated in a heterogeneous population.The combination of phosphorylated tau (p-tau)181 and p-231 performed only slightly worse than a panel of multiple biomarkers, aligning with previous studies.Plasma biomarkers show potential for future applications in primary care, treatment monitoring, and trial selection.},
}

@article {pmid39821693,
year = {2025},
author = {Caruso, A and Tommonaro, G and Vassallo, A and Paris, D and Monné, M and Catalano, A and Sinicropi, MS and Saturnino, C},
title = {Imino and Thioureidic Derivatives as New Tools for Alzheimer's Disease: Preliminary Studies.},
journal = {Chemical biology & drug design},
volume = {105},
number = {1},
pages = {e70049},
doi = {10.1111/cbdd.70049},
pmid = {39821693},
issn = {1747-0285},
mesh = {*Alzheimer Disease/drug therapy/metabolism ; *Acetylcholinesterase/metabolism/chemistry ; *Cholinesterase Inhibitors/chemistry/pharmacology/chemical synthesis/metabolism ; *Molecular Docking Simulation ; Humans ; *Antioxidants/pharmacology/chemistry ; Structure-Activity Relationship ; },
abstract = {Alzheimer's disease is a neurodegenerative chronic disease with a severe social and economic impact in the societies, which still lacks an efficient therapy. Several pathophysiological events (β-amyloid [Aβ] deposits, τ-protein aggregation, loss of cholinergic activity, and oxidative stress) occurs in the progression of the disease. Therefore, the search for efficient multi-targeted agents for the treatment of Alzheimer's disease becomes indispensable. In this paper we evaluated the AChE inhibition by Ellman's method and antioxidant activity by DPPH assay of nine synthetic compounds: two hydroxy-benzene derivatives (1 and 2), three bis-thioureidic derivatives (3-5), two imidazole derivatives (6 and 7), and two phenylacetamide derivatives (8 and 9). The compound 2, (3s,5s,7s)-adamantan-1-yl 4-(((E)-2,5-dihydroxybenzylidene)amino)benzoate, exhibited the best antioxidant activity (30.00 ± 1.05 μM eq Trolox) and compound 4 showed the highest AChE inhibition value (IC50 [μM] 8.40 ± 0.32). In the search for a compound showing combined activities (antioxidant and AChE inhibition), the compound 4, octane-1,8-diyl-bis-S-amidinothiourea dihydrobromide, (19.02 ± 1.52 μM eq Trolox; IC50 [μM] 8.40 ± 0.32) was chosen to carry out a molecular docking study. The results showed that compound 4 has the ability to bind the active site of acetylcholinesterase with considerable affinity (estimated binding energies of -8.5 kcal/mol). All data indicate that compound 4 has the potential to be further investigated as a possible candidate in the Alzheimer's disease treatment.},
}

*Alzheimer Disease/drug therapy/metabolism
*Acetylcholinesterase/metabolism/chemistry
*Cholinesterase Inhibitors/chemistry/pharmacology/chemical synthesis/metabolism
*Molecular Docking Simulation
Humans
*Antioxidants/pharmacology/chemistry
Structure-Activity Relationship

@article {pmid39820731,
year = {2025},
author = {Xiong, R and Liu, H and Zhang, S and Wang, L and Liu, L and Pan, S and Zhang, Y and Zhu, F and Liu, Y and Lai, X},
title = {Integrating network pharmacology and experimental verification to reveal the ferroptosis-associated mechanism of Changpu-Yizhi-Wan in the treatment of Alzheimer's disease.},
journal = {Metabolic brain disease},
volume = {40},
number = {1},
pages = {106},
pmid = {39820731},
issn = {1573-7365},
support = {2022XQN28//Army Military Medical University/ ; },
mesh = {*Ferroptosis/drug effects ; *Alzheimer Disease/drug therapy/metabolism ; Humans ; *Drugs, Chinese Herbal/pharmacology/therapeutic use ; *Network Pharmacology ; Animals ; Mice ; NF-E2-Related Factor 2/metabolism ; Protein Interaction Maps/drug effects ; },
abstract = {To explore the pharmacological mechanism of Changpu-Yizhi-Wan (CYW) in the treatment of Alzheimer's disease (AD) from the perspective of ferroptosis based on network pharmacology and experimental verification. The Encyclopedia of Traditional Chinese Medicine 2.0 (ETCM2.0) database was used to collect the active components of CYW, and the putative targets were predicted in ETCM2.0 and SwissTargetPrediction database. The AD related targets were collected from GeneCards, comparative toxicogenomics database (CTD), Online Mendelian Inheritance in Man (OMIM), DisGeNET and Therapeutic Target Database (TTD), the ferroptosis related targets were collected from FerrDb V2 database, and the common targets of CYW, AD and ferroptosis were calculated by Venny2.1 platform. Protein-protein interaction (PPI) analysis was performed by STRING database, and the active compounds-target network and the PPI network were constructed using Cytoscape software. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) and Reactome pathway enrichment analysis were performed through DAVID database. RSL3 was used to induce HT22 cells to establish a neuronal ferroptosis cell model, and the inhibitory effect of CYW on neuronal ferroptosis was evaluated by cell viability assay, intracellular iron assay and lipid peroxidation staining. The ferroptosis-associated key protein expressions of Nrf2, SLC7A11, GPX4 and FTH1 were detected by Western blot. A total of 100 candidate compounds were identified from CYW, and 1129 putative targets were obtained. 3924 AD-related targets and 564 ferroptosis-related targets were collected, respectively. There were 78 common targets between them and CYW targets, which were potential targets for CYW to regulate ferroptosis in the treatment of AD. PPI network analysis identified 10 key targets, including TP53, IL6, STAT3, HIF1A, NFE2L2, and others. GO, KEGG and Reactome enrichment analysis showed that 78 potential targets were involved in the regulation of ferroptosis and Nrf2-mediated gene transcription. Molecular docking showed that some active components of CYW had good affinity with Nrf2. In RSL3-induced HT22 cells, CYW significantly improved cell viability, reduced intracellular iron levels and inhibited lipid peroxidation, and improved the protein expression of Nrf2, SLC7A11, GPX4 and FTH1. The pharmacological mechanism of CYW in the treatment of AD may be related to the regulation of Nrf2/SLC7A11/GPX4/FTH1 axis to inhibit neuronal ferroptosis.},
}

*Ferroptosis/drug effects
*Alzheimer Disease/drug therapy/metabolism
Humans
*Drugs, Chinese Herbal/pharmacology/therapeutic use
*Network Pharmacology
Animals
Mice
NF-E2-Related Factor 2/metabolism
Protein Interaction Maps/drug effects

@article {pmid39820594,
year = {2025},
author = {Guerguer, FZ and Bouribab, A and Karim, EM and Khedraoui, M and Amegrissi, F and Raouf, YS and Samadi, A and Chtita, S},
title = {Moroccan natural products for multitarget-based treatment of Alzheimer's disease: A computational study.},
journal = {PloS one},
volume = {20},
number = {1},
pages = {e0313411},
doi = {10.1371/journal.pone.0313411},
pmid = {39820594},
issn = {1932-6203},
mesh = {*Alzheimer Disease/drug therapy ; Humans ; *Hesperidin/chemistry/pharmacology/therapeutic use ; Biological Products/chemistry/therapeutic use/pharmacology ; Molecular Dynamics Simulation ; Flavanones/chemistry/therapeutic use/pharmacology ; Morocco ; Molecular Docking Simulation ; Acetylcholinesterase/metabolism/chemistry ; Plants, Medicinal/chemistry ; },
abstract = {Alzheimer's disease is a neurodegenerative disorder that impairs neurocognitive functions. Acetylcholinesterase, Butyrylcholinesterase, Monoamine Oxidase B, Beta-Secretase, and Glycogen Synthase Kinase Beta play central roles in its pathogenesis. Current medications primarily inhibit AChE but fail to halt or reverse disease progression due to the multifactorial nature of Alzheimer's. This underscores the necessity of developing multi-target ligands for effective treatment. This study investigates the potential of phytochemical compounds from Moroccan medicinal plants as multi-target agents against Alzheimer's disease, employing computational approaches. A virtual screening of 386 phytochemical compounds, followed by an assessment of pharmacokinetic properties and ADMET profiles, led to the identification of two promising compounds, naringenin (C23) and hesperetin (C24), derived from Anabasis aretioides. These compounds exhibit favourable pharmacokinetic profiles and strong binding affinities for the five key targets associated with the disease. Density functional theory, molecular dynamics simulations, and MM-GBSA calculations further confirmed their structural stability, with a slight preference for C24, exhibiting superior intermolecular interactions and overall stability. These findings provide a strong basis for further experimental research, including in vitro and in vivo studies, to substantiate their potential efficacy in Alzheimer's disease.},
}

*Alzheimer Disease/drug therapy
Humans
*Hesperidin/chemistry/pharmacology/therapeutic use
Biological Products/chemistry/therapeutic use/pharmacology
Molecular Dynamics Simulation
Flavanones/chemistry/therapeutic use/pharmacology
Morocco
Molecular Docking Simulation
Acetylcholinesterase/metabolism/chemistry
Plants, Medicinal/chemistry

@article {pmid39820472,
year = {2025},
author = {Liu, Y and Ding, X and Jia, S and Gu, X},
title = {Current understanding and prospects for targeting neurogenesis in the treatment of cognitive impairment.},
journal = {Neural regeneration research},
volume = {},
number = {},
pages = {},
doi = {10.4103/NRR.NRR-D-24-00802},
pmid = {39820472},
issn = {1673-5374},
abstract = {Adult hippocampal neurogenesis is linked to memory formation In the adult brain, with new neurons in the hippocampus exhibiting greater plasticity during their immature stages compared to mature neurons. Abnormal adult hippocampal neurogenesis is closely associated with cognitive impairment in central nervous system diseases. Targeting and regulating adult hippocampal neurogenesis have been shown to improve cognitive deficits. This review aims to expand the current understanding and prospects of targeting neurogenesis in the treatment of cognitive impairment. Recent research indicates the presence of abnormalities in AHN in several diseases associated with cognitive impairment, including cerebrovascular diseases, Alzheimer's disease, aging-related conditions, and issues related to anesthesia and surgery. The role of these abnormalities in the cognitive deficits caused by these diseases has been widely recognized, and targeting AHN is considered a promising approach for treating cognitive impairment. However, the underlying mechanisms of this role are not yet fully understood, and the effectiveness of targeting abnormal adult hippocampal neurogenesis for treatment remains limited, with a need for further development of treatment methods and detection techniques.By reviewing recent studies, we classify the potential mechanisms of adult hippocampal neurogenesis abnormalities into four categories: immunity, energy metabolism, aging, and pathological states. In immunity-related mechanisms, abnormalities in meningeal, brain, and peripheral immunity can disrupt normal adult hippocampal neurogenesis.Lipid metabolism and mitochondrial function disorders are significant energy metabolism factors that lead to abnormal adult hippocampal neurogenesis. During aging, the inflammatory state of the neurogenic niche and the expression of aging-related microRNAs contribute to reduced adult hippocampal neurogenesis and cognitive impairment in older adult patients. Pathological states of the body and emotional disorders may also result in abnormal adult hippocampal neurogenesis. Among the current strategies used to enhance this form of neurogenesis, physical therapies such as exercise, transcutaneous electrical nerve stimulation, and enriched environments have proven effective. Dietary interventions, including energy intake restriction and nutrient optimization, have shown efficacy in both basic research and clinical trials. However, drug treatments, such as antidepressants and stem cell therapy, are primarily reported in basic research, with limited clinical application. The relationship between abnormal adult hippocampal neurogenesis and cognitive impairment has garnered widespread attention, and targeting the former may be an important strategy for treating the latter. However, the mechanisms underlying abnormal adult hippocampal neurogenesis remain unclear, and treatments are lacking. This highlights the need for greater focus on translating research findings into clinical practice.},
}

@article {pmid39820046,
year = {2025},
author = {Guo, T and Hayat, MA and Hu, J},
title = {Ferritin nanoparticles: new strategies for the diagnosis and treatment of central nervous system diseases.},
journal = {Biomedical materials (Bristol, England)},
volume = {},
number = {},
pages = {},
doi = {10.1088/1748-605X/adab5a},
pmid = {39820046},
issn = {1748-605X},
abstract = {Ferritin nanocarriers, which can penetrate the blood-brain barrier (BBB), have gained significant research interest for the diagnosis and treatment of central nervous system (CNS) diseases, including gliomas, Alzheimer's disease, and brain metastases. In recent years, ferritin has been proved as a candidate to cross the BBB using receptor-mediated transcytosis (RMT) mechanism through transferrin receptor 1 (TfR1) which is overexpressed in the cells of the BBB. Various types of cargo molecules, including therapeutics, imaging agents, nucleic acids, and metal nanoparticles, have been incorporated into ferritin nanocages for the diagnosis and treatment of CNS diseases. In particular, low immunogenicity of ferritin implies safety for its usage in clinical practices, and high biocompatibility add to the perspectives of its applications. Furthermore, contemporary strides in molecular biology have enabled some alteration in the configuration of the ferritin outer layers and surface characters so as to enhance the drug encapsulation capacity and conjugation affinity. Such modifications not only enhance the property of ferritin in crossing the BBB, but also enhance its efficacy when applied to CNS diseases. In summary, ferritin, as a drug delivery system, shows great potential for the treatment and diagnosis of central nervous system diseases.},
}

@article {pmid39819742,
year = {2025},
author = {Xu, B and Lei, X and Yang, Y and Yu, J and Chen, J and Xu, Z and Ye, K and Zhang, J},
title = {Peripheral proteinopathy in neurodegenerative diseases.},
journal = {Translational neurodegeneration},
volume = {14},
number = {1},
pages = {2},
pmid = {39819742},
issn = {2047-9158},
support = {82020108012//National Natural Science Foundation of China/ ; 82371250//National Natural Science Foundation of China/ ; LY24H090006//Natural Science Foundation of Zhejiang Province/ ; LZ23H090002//Natural Science Foundation of Zhejiang Province/ ; 2024C03098//Key Research and Development Program of Zhejiang Province/ ; 2024SSYS0018//Key Research and Development Program of Zhejiang Province/ ; ZR2022QH177//Natural Science Foundation of Shandong Province/ ; },
mesh = {Humans ; *Neurodegenerative Diseases/metabolism/therapy/pathology ; Animals ; Amyloid beta-Peptides/metabolism ; tau Proteins/metabolism ; alpha-Synuclein/metabolism ; },
abstract = {Proteinopathies in neurology typically refer to pathological changes in proteins associated with neurological diseases, such as the aggregation of amyloid β and Tau in Alzheimer's disease, α-synuclein in Parkinson's disease and multiple system atrophy, and TAR DNA-binding protein 43 in amyotrophic lateral sclerosis and frontotemporal dementia. Interestingly, these proteins are also commonly found in peripheral tissues, raising important questions about their roles in neurological disorders. Multiple studies have shown that peripherally derived pathological proteins not only travel to the brain through various routes, aggravating brain pathology, but also contribute significantly to peripheral dysfunction, highlighting their crucial impact on neurological diseases. Investigating how these peripherally derived proteins influence the progression of neurological disorders could open new horizons for achieving early diagnosis and treatment. This review summarizes the distribution, transportation pathways, and pathogenic mechanisms of several neurodegenerative disease-related pathological proteins in the periphery, proposing that targeting these peripheral pathological proteins could be a promising strategy for preventing and managing neurological diseases.},
}

Humans
*Neurodegenerative Diseases/metabolism/therapy/pathology
Animals
Amyloid beta-Peptides/metabolism
tau Proteins/metabolism
alpha-Synuclein/metabolism

@article {pmid39819531,
year = {2025},
author = {Li, C and Chen, Y and Yao, Y and Shang, Y},
title = {Establishment and Validation of the Diagnostic Value of Oligodendrocyte-related Genes in Alzheimer's Disease.},
journal = {CNS & neurological disorders drug targets},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118715273339310241205055554},
pmid = {39819531},
issn = {1996-3181},
abstract = {BACKGROUND: AD is a demyelinating disease. Myelin damage initiates the pathological process of AD, resulting in abnormal synaptic function and cognitive decline. The myelin sheath formed by oligodendrocytes (OL) is a crucial component of white matter. Investigating AD from the perspective of OL may offer novel diagnostic and therapeutic perspectives.

OBJECTIVES: This study aimed to analyze the association between OL-related genes and Alzheimer's disease (AD) using bioinformatics and verify this association via molecular biology experiments.

METHODS: The AD datasets were acquired from the Gene Expression Omnibus (GEO) database of NCBI. Consensus clustering was employed to determine the subtypes of AD, followed by evaluating the clinical characteristics of these subtypes. Subsequently, immune infiltration analysis of relevant genes and Weighted Gene Co-expression Network Analysis (WGCNA) were conducted to identify modules and hub genes associated with AD progression. The intersection of genes obtained was analyzed using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. To narrow down the scope and identify OL-related genes with diagnostic potential, three machine learning algorithms were utilized. In addition, the eXtreme Sum (XSum) algorithm was used to screen small molecule drug candidates based on the connectivity map (CMAP) database. Finally, these identified genes were validated using Real-time fluorescence quantitative PCR (RT-qPCR).

RESULTS: Among the three subtypes of AD, Cluster A and Cluster C exhibited increased levels of Braak and neurofibrillary tangles compared to Cluster B. The proportion of females was greater than that of males among the three subclasses of AD. There were no significant differences in age among the three subclasses, but significant differences in gene expression existed. Through WGCNA analysis, 108 genes were identified. Among these, 16 genes were identified as shared genes by the least absolute shrinkage and selection operator (LASSO), random forest (RF), and support vector machines (SVM) algorithms, and logistic regression further determined 11 genes. The establishment of a nomogram demonstrated the significance of these 11 genes in AD. The "XSum" algorithm revealed five drugs with therapeutic potential for AD. qPCR analysis revealed the upregulation and downregulation of the highlighted genes. According to this study, 11 genes related to OL were also found to be associated with immune cell infiltration in AD patients. These genes demonstrated potential diagnostic value for AD. Additionally, we screened five small molecular drugs that exhibit potential therapeutic effects on AD.

CONCLUSION: This research provides a new perspective for personalized clinical management and treatment of AD.},
}

@article {pmid39819417,
year = {2025},
author = {Khan, SA and Qamar, Z and Rohilla, A and Singh, PP and Parvez, S and Baboota, S and Ali, J},
title = {Prospective Utilization of Nanocarriers Loaded with Drug Combination for Treating Alzheimer's Disease.},
journal = {Current pharmaceutical design},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113816128348877241202053633},
pmid = {39819417},
issn = {1873-4286},
abstract = {Alzheimer's disease (AD) is a debilitating condition that significantly affects the elderly. Early diagnosis is not only critical for improving patient outcomes but also directly influences the success of emerging therapeutic interventions. A therapeutic strategy targeting only one pathogenic mechanism is unlikely to be very effective, as there is increasing evidence that AD does not have a single pathogenic cause. Therefore, combining medications or developing therapies that address multiple pathways may be beneficial. Most clinical trials can be classified under added therapy rather than combination therapy. Effective treatment of AD likely requires targeting multiple mechanisms, such as amyloid-beta (Aβ) and tau pathology. However, many medications face challenges, including poor solubility, low permeability, and the inability to cross the blood- -brain barrier (BBB). This is where nanocarriers come into play, as they can be loaded with these medications to facilitate targeted drug delivery. This approach enhances the pharmacokinetic profile of drugs in both the blood and the brain. Therefore, this paper provides a concise overview of the use of various nanocarriers loaded with drug combinations for treating AD.},
}

@article {pmid39818939,
year = {2025},
author = {Bagán, A and López-Ruiz, A and Abás, S and Ruiz-Cantero, MC and Vasilopoulou, F and Taboada-Jara, T and Griñán-Ferré, C and Pallàs, M and Muguruza, C and Diez-Alarcia, R and Callado, LF and Entrena, JM and Cobos, EJ and Pérez, B and Morales-García, JA and Molins, E and De Jonghe, S and Daelemans, D and Brea, J and Val, C and Loza, MI and Hernández-Hernández, E and García-Sevilla, JA and García-Fuster, MJ and Díaz, C and Fernández-Godino, R and Genilloud, O and Beljkaš, M and Oljačić, S and Nikolic, K and Escolano, C},
title = {Discovery of (3-Phenylcarbamoyl-3,4-dihydro-2H-pyrrol-2-yl)phosphonates as Imidazoline I2 Receptor Ligands with Anti-Alzheimer and Analgesic Properties.},
journal = {Journal of medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.jmedchem.4c01644},
pmid = {39818939},
issn = {1520-4804},
abstract = {Imidazoline I2 receptors (I2-IRs) are altered in Alzheimer's disease (AD) patients and are associated with analgesia. I2-IRs are not structurally described, and their pharmacological characterization relies on their modulation by highly affine ligands. Herein, we describe the synthesis of (3-phenylcarbamoyl-3,4-dihydro-2H-pyrrol-2-yl)phosphonates endowed with relevant affinities for I2-IRs in human brain tissues. The optimal ADME and pharmacokinetic profile of a selected compound, 12d, secured its in vivo exploration in a senescence accelerated prone 8 mice revealing improvement in the cognitive impairment and unveiling the mechanism of action by analyzing specific AD biomarkers. The treatment of a capsaicin-induced mechanical hypersensitivity murine model with 12d revealed analgesic properties devoid of motor coordination issues. The target engagement of 12d was demonstrated by suppression of the analgesic effect by pretreatment with idazoxan. Overall, 12d is a putative candidate for advancing preclinical phases and supports the modulation of I2-IRs as an innovative approach for therapeutics.},
}

@article {pmid39818099,
year = {2025},
author = {Esandi, J and Renault, P and Capilla-López, MD and Blanch, R and Edo, Á and Ramirez-Gómez, D and Bosch, A and Almolda, B and Saura, CA and Giraldo, J and Chillón, M},
title = {HEBE: A novel chimeric chronokine for ameliorating memory deficits in Alzheimer's disease.},
journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie},
volume = {183},
number = {},
pages = {117815},
doi = {10.1016/j.biopha.2025.117815},
pmid = {39818099},
issn = {1950-6007},
abstract = {Alzheimer's disease (AD) is a prevalent neurodegenerative disorder characterized by amyloid-β and Tau protein depositions, with treatments focusing on single proteins have shown limited success due to the complexity of pathways involved. This study explored the potential of chronokines -proteins that modulate aging-related processes- as an alternative therapeutic approach. Specifically, we focused on a novel pleiotropic chimeric protein named HEBE, combining s-KL, sTREM2 and TIMP2, guided by bioinformatic analyses to ensure the preservation of each protein's conformation, crucial for their functions. In vitro studies confirmed HEBE's stability and enzymatic activities, even suggesting it has different activities compared to the individual chronokines. In vivo experiments on APP/Tau mice revealed improved learning and memory functions with HEBE treatment, along with decreased levels of phosphorylated Tau and minor effects on amyloid-β levels. These findings suggest that HEBE is as a promising therapeutic candidate for ameliorating memory deficits and reducing pTau in an AD mouse model.},
}

@article {pmid39818021,
year = {2025},
author = {Dawa, Y and Hua, YC and Hu, FD and Chen, J},
title = {Cellulose filter paper immobilized acetylcholinesterase for rapid screening of enzyme inhibitors in Phyllanthus emblica L.},
journal = {Journal of pharmaceutical and biomedical analysis},
volume = {256},
number = {},
pages = {116669},
doi = {10.1016/j.jpba.2025.116669},
pmid = {39818021},
issn = {1873-264X},
abstract = {Acetylcholinesterase (AChE) is widely recognized as a promising therapeutic target enzyme for Alzheimer's disease (AD). The screening of AChE inhibitors (AChEIs) holds great significance for the treatment of AD. In this study, cellulose filter paper (CFP) -immobilized AChE was prepared and firstly applied to screening AChEIs from 30 % ethanol extract of Phyllanthus emblica L. fruits combined with ultra-high performance liquid chromatography quadrupole time-of-fight mass spectrometry (UHPLC-Q-TOF-MS/MS). Using CFP-immobilized AChE as the bait, AChEIs were harvested and the instantaneous separation characteristics of CFP were utilized to further facilitate the separation of the complex from the inactive components. Ultimately, 27 compounds specifically bound with AChE were screened and identified using UHPLC-Q-TOF-MS/MS. Additionally, molecular docking was employed to explore the binding mechanisms between screened potential inhibitors and AChE. The results show that, most of the screened compounds were found to exhibit higher affinity that of the positive control (huperzine A), and all the compounds expect mucic acid to be well embedded into the active pocket of AChE. To verify the reliability of the screening method and molecular docking, two commercial standards geraniin and ellagic acid were experimented with an AChE inhibition assay in vitro. The results showed that both compounds were found to effectively inhibit AChE with IC50 values of 42.42 ± 7.10 μM, 172.43 ± 9.22 μM. The developed method exhibits the advantages of rapidness and effectiveness in screening of AChEIs from complex herbal extracts.},
}

@article {pmid39817315,
year = {2025},
author = {Goodwin, GJ and Briley, DA and Singsank, K and Tanner, D and Maloy-Robertson, M and John, SE},
title = {Neuropsychiatric symptoms predict rate of change in executive function in Alzheimer's disease and related dementias.},
journal = {Journal of the International Neuropsychological Society : JINS},
volume = {},
number = {},
pages = {1-10},
doi = {10.1017/S1355617724000730},
pmid = {39817315},
issn = {1469-7661},
abstract = {OBJECTIVE: Neuropsychiatric symptoms (NPS) are considered diagnostic and prognostic indicators of dementia and are attributable to neurodegenerative processes. Little is known about the prognostic value of early NPS on executive functioning (EF) decline in Alzheimer's disease and related dementias (ADRD). We examined whether baseline NPS predicted the rate of executive function (EF) decline among older adults with ADRD.

METHOD: Older adults (n = 1625) with cognitive impairment were selected from the National Alzheimer's Coordinating Center database. EF was estimated with a latent factor indicated by scores on Number Span Backward, Letter Fluency, and Trail Making-Part B. A curve of factors (CUFF) latent growth curve model was estimated to examine rate of change over four years. Baseline NPS severity was entered as a predictor in the model to examine its influence on the rate of change in EF over time.

RESULTS: The CUFF models exhibited good fit. EF significantly declined over four waves (slope = -.16, p < .001). Initial visit NPS severity predicted decline in EF (slope = .013, p < .001), such that those with greater baseline NPS severity demonstrated a more rapid decline in EF performance over time. Presence of 2 NPS significantly predicted EF decline, and those with medium total NPS severity (NPS score of 2-4) at baseline exhibited a sharper decline in EF.

CONCLUSIONS: Findings underscore the importance of targeting NPS early across ADRD syndromes to minimize EF decline, offering novel insights into how early NPS treatment may alter cognitive trajectories. We provide an innovative, user-friendly web-based application that may be helpful for personalized treatment planning.},
}

@article {pmid39817194,
year = {2025},
author = {Wu, CY and Kupferschmid, AC and Chen, L and McManus, AJ and Kivisäkk, P and Galler, JA and Schwab, NA and DesRuisseaux, LA and Williams, VJ and Gerber, J and Riley, M and Young, C and Guzmán-Vélez, E and Dodge, HH and Tanzi, RE and Singer, CM and Arnold, SE},
title = {Cognitive and Alzheimer's disease biomarker effects of oral nicotinamide riboside (NR) supplementation in older adults with subjective cognitive decline and mild cognitive impairment.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {11},
number = {1},
pages = {e70023},
pmid = {39817194},
issn = {2352-8737},
abstract = {INTRODUCTION: Age-associated depletion in nicotinamide adenine dinucleotide (NAD+) concentrations has been implicated in metabolic, cardiovascular, and neurodegenerative disorders. Supplementation with NAD+ precursors, such as nicotinamide riboside (NR), offers a potential therapeutic avenue against neurodegenerative pathologies in aging, Alzheimer's disease, and related dementias. A crossover, double-blind, randomized placebo (PBO) controlled trial was conducted to test the safety and efficacy of 8 weeks' active treatment with NR (1 g/day) on cognition and plasma AD biomarkers in older adults with subjective cognitive decline and mild cognitive impairment.

METHODS: The primary efficacy outcome was the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Secondary outcomes included plasma phosphorylated tau 217 (pTau[217]), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL). Exploratory outcomes included Lumosity gameplay (z-scores) for cognition and step counts from wearables. Mixed model for repeated measures was used for between-group comparisons; paired t-tests were used for within-individual comparisons.

RESULTS: Forty-six participants aged over 55 were randomized to NR-PBO or PBO-NR groups; 41 completed baseline visits, and 37 completed the trial. NR supplementation was safe and well tolerated with no differences in adverse events reported between NR and PBO treatment phases. For the between-group comparison, there was a 7% reduction in pTau[217] concentrations after taking NR, while an 18% increase with PBO (p = 0.02). No significant between-group differences were observed for RBANS, other plasma biomarkers(GFAP and NfL), Lumosity gameplay scores or step counts. For the within-individual comparison, pTau[217] concentrations significantly decreased during the NR phase compared to the PBO (p = 0.02), while step counts significantly increased during the NR phase than PBO (p = 0.04).

DISCUSSION: Eight weeks NR supplementation is safe and lowered pTau[217] concentrations but did not alter cognition as measured by conventional or novel digital assessments. Further research is warranted to validate NR's efficacy in altering pathological brain aging processes.

HIGHLIGHTS: The integrated study design combines a two-arm parallel trial with a crossover phase, offering the opportunity to enhance sample size for within-individual analysis and assess carryover effects.NR is safe but did not alter cognition as measured by multi-modal assessments in SCD/MCI.For between-group comparison, pTau[217] levels decreased with NR and increased with PBO at 8-week follow-up.For within-individual comparison, step counts increased after NR and decreased after PBO.A larger, longer study with pharmacodynamic and pathophysiological biomarkers is needed to assess NR's disease-modifying effects.},
}

@article {pmid39816194,
year = {2025},
author = {Yulug, B and Altay, O and Li, X and Hanoglu, L and Cankaya, S and Velioglu, HA and Lam, S and Yang, H and Coskun, E and Idil, E and Bayraktaroglu, Z and Nogaylar, R and Ozsimsek, A and Yildirim, S and Bolat, I and Kiliclioglu, M and Bayram, C and Yuksel, N and Tozlu, OO and Arif, M and Shoaie, S and Hacimuftuoglu, A and Zhang, C and Nielsen, J and Turkez, H and Borén, J and Uhlén, M and Mardinoglu, A},
title = {Multi-omics characterization of improved cognitive functions in Parkinson's disease patients after the combined metabolic activator treatment: a randomized, double-blinded, placebo-controlled phase II trial.},
journal = {Brain communications},
volume = {7},
number = {1},
pages = {fcae478},
pmid = {39816194},
issn = {2632-1297},
abstract = {Parkinson's disease is primarily marked by mitochondrial dysfunction and metabolic abnormalities. We recently reported that the combined metabolic activators improved the immunohistochemical parameters and behavioural functions in Parkinson's disease and Alzheimer's disease animal models and the cognitive functions in Alzheimer's disease patients. These metabolic activators serve as the precursors of nicotinamide adenine dinucleotide and glutathione, and they can be used to activate mitochondrial metabolism and eventually treat mitochondrial dysfunction. Here, we designed a randomized, double-blinded, placebo-controlled phase II study in Parkinson's disease patients with 84 days combined metabolic activator administration. A single dose of combined metabolic activator contains L-serine (12.35 g), N-acetyl-L-cysteine (2.55 g), nicotinamide riboside (1 g) and L-carnitine tartrate (3.73 g). Patients were administered either one dose of combined metabolic activator or a placebo daily for the initial 28 days, followed by twice-daily dosing for the next 56 days. The main goal of the study was to evaluate the clinical impact on motor functions using the Unified Parkinson's Disease Rating Scale and to determine the safety and tolerability of combined metabolic activator. A secondary objective was to assess cognitive functions utilizing the Montreal Cognitive Assessment and to analyse brain activity through functional MRI. We also performed comprehensive plasma metabolomics and proteomics analysis for detailed characterization of Parkinson's disease patients who participated in the study. Although no improvement in motor functions was observed, cognitive function was shown to be significantly improved (P < 0.0000) in Parkinson's disease patients treated with the combined metabolic activator group over 84 days, whereas no such improvement was noted in the placebo group (P > 0.05). Moreover, a significant reduction (P = 0.001) in Montreal Cognitive Assessment scores was observed in the combined metabolic activator group, with no decline (P > 0.05) in the placebo group among severe Parkinson's disease patients with lower baseline Montreal Cognitive Assessment scores. We showed that improvement in cognition was associated with critical brain network alterations based on functional MRI analysis, especially relevant to areas with cognitive functions in the brain. Finally, through a comprehensive multi-omics analysis, we elucidated the molecular mechanisms underlying cognitive improvements observed in Parkinson's disease patients. Our results show that combined metabolic activator administration leads to enhanced cognitive function and improved metabolic health in Parkinson's disease patients as recently shown in Alzheimer's disease patients. The trial was registered in ClinicalTrials.gov NCT04044131 (17 July 2019, https://clinicaltrials.gov/ct2/show/NCT04044131).},
}

@article {pmid39816083,
year = {2024},
author = {Widaja, E and Pawitan, JA},
title = {Integrating epigenetic modification and stem cell therapy strategies: A novel approach for advancing Alzheimer's disease treatment - A literature review.},
journal = {Narra J},
volume = {4},
number = {3},
pages = {e935},
pmid = {39816083},
issn = {2807-2618},
mesh = {*Alzheimer Disease/therapy/genetics/metabolism ; Humans ; *Epigenesis, Genetic ; *Stem Cell Transplantation/methods ; DNA Methylation ; MicroRNAs/genetics/metabolism ; },
abstract = {Alzheimer's disease (AD) is the most frequent form of dementia and represents an increasing global burden, particularly in countries like Indonesia, where the population has begun to age significantly. Current medications, including cholinesterase inhibitors and NMDA receptor antagonists, have modest effects on clinical symptoms in the early to middle stages, but there is no curative treatment available so far despite progress. Activating or repressing epigenetic modifications, including DNA methylation, histone modification and microRNA regulation, appears to play an important role in AD development. These alterations further enact transcriptional changes relevant to the signature AD pathologies of amyloid-β deposition, tau protein malfunctioning, neuroinflammation, and neuronal death. Here, we discuss the feasibility of targeting these epigenetic alterations as a new treatment strategy due to the reversibility of epigenetics and their ability to correct faulty gene expression. We also review the combined promise of stem cell therapies and epigenetic modulation in neurodegeneration, inflammation and cognitive decline. This combined approach may provide a multifaceted strategy to slow disease progression, replace lost neurons, and restore neural function. Despite challenges, including ethical, financial, and methodological barriers, ongoing research in epigenetic modulation and stem cell therapy holds promise for pioneering therapies in AD.},
}

*Alzheimer Disease/therapy/genetics/metabolism
Humans
*Epigenesis, Genetic
*Stem Cell Transplantation/methods
DNA Methylation
MicroRNAs/genetics/metabolism

@article {pmid39815655,
year = {2025},
author = {Bhattacharya, RS and Singh, R and Panghal, A and Thakur, A and Singh, L and Verma, RK and Singh, C and Goyal, M and Kumar, J},
title = {Multi-Targeting Phytochemicals for Alzheimer's Disease.},
journal = {Phytotherapy research : PTR},
volume = {},
number = {},
pages = {},
doi = {10.1002/ptr.8435},
pmid = {39815655},
issn = {1099-1573},
abstract = {Alzheimer's disease (AD) is a type of neurodegenerative illness in which β-amyloid (Aβ) and tau protein accumulate in neurons in the form of tangles. The pathophysiological pathway of AD consists of Aβ-amyloid peptides, tau proteins, and oxidative stress in neurons and increased neuro-inflammatory response. Food and Drug Administration in the United States has authorized various drugs for the effective treatment of AD, which include galantamine, rivastigmine, donepezil, memantine, sodium oligomannate, lecanemab, and aducanumab. The major disadvantage of these drugs is that they only provide "symptomatic" relief. They are most effective in the early stages or for mild to moderate cases of the disease, but are not suitable for long-term use. Besides conventional therapies, phytochemicals have the potential to stop the progression of AD. According to research, the use of potential phytochemicals against AD has gained attention due to their potent anti-inflammatory, antioxidant, anti-hyperphosphorylation of the tau protein, metal chelation, and anti-amyloid properties. This study seeks to provide an up-to-date compilation of the most current and promising breakthroughs in AD therapy using phytochemicals. It could be concluded that phytochemicals light serve as an effective therapy for AD. However, more mechanistic investigations are needed to determine the clinical implications of phytochemicals in AD treatment.},
}

@article {pmid39815147,
year = {2025},
author = {Gao, M and Kong, W and Liu, K and Wen, G and Yu, Y and Zhu, Y and Jiang, Z and Wei, K},
title = {Exploring Brain Imaging and Genetic Risk Factors in Different Progression States of Alzheimer's Disease Through OSnetNMF-Based Methods.},
journal = {Journal of molecular neuroscience : MN},
volume = {75},
number = {1},
pages = {7},
pmid = {39815147},
issn = {1559-1166},
mesh = {*Alzheimer Disease/genetics/diagnostic imaging ; Humans ; *Magnetic Resonance Imaging/methods ; *Brain/diagnostic imaging/metabolism ; Cognitive Dysfunction/diagnostic imaging/genetics ; Algorithms ; Female ; Aged ; Male ; Disease Progression ; Hypoxia-Inducible Factor 1, alpha Subunit/genetics/metabolism ; },
abstract = {Alzheimer's disease (AD) is a neurodegenerative disease with no effective treatment, often preceded by mild cognitive impairment (MCI). Multimodal imaging genetics integrates imaging and genetic data to gain a deeper understanding of disease progression and individual variations. This study focuses on exploring the mechanisms that drive the transition from normal cognition to MCI and ultimately to AD. As an effective joint feature extraction and dimensionality reduction method, non-negative matrix factorization (NMF) and its improved variants, particularly the network-based non-negative matrix factorization (netNMF), have been widely used in multimodal analysis to mine brain imaging and genetic data by considering the interactions between different features. However, many of these methods overlook the importance of the coefficient matrix and do not address issues related to data accuracy and feature redundancy. To address these limitations, we propose an orthogonal sparse network non-negative matrix factorization (OSnetNMF) algorithm, which introduces orthogonal and sparse constraints based on netNMF. By establishing linear relationships between structural magnetic resonance imaging (sMRI) and corresponding gene expression data, OSnetNMF reduces feature redundancy and decreases correlation between data, resulting in more accurate and reliable biomarker extraction. Experiments demonstrate that the OSnetNMF algorithm can accurately identify risk regions of interest (ROIs) and key genes that characterize AD progression, revealing significant trends in ROI pairs such as l4thVen-HIF1A, rBst-MPO, and rBst-PTK2B. Comparative experiments show that the improved algorithm outperforms traditional methods, identifying more disease-related biomarkers and achieving better reconstruction performance.},
}

*Alzheimer Disease/genetics/diagnostic imaging
Humans
*Magnetic Resonance Imaging/methods
*Brain/diagnostic imaging/metabolism
Cognitive Dysfunction/diagnostic imaging/genetics
Algorithms
Female
Aged
Male
Disease Progression
Hypoxia-Inducible Factor 1, alpha Subunit/genetics/metabolism

@article {pmid39814774,
year = {2025},
author = {Rajkumar, M and Davis Presley, SI and Thiyagarajulu, N and Girigoswami, K and Janani, G and Kamaraj, C and Madheswaran, B and Prajapati, B and Ali, N and Khan, MR},
title = {Gelatin/PLA-loaded gold nanocomposites synthesis using Syzygium cumini fruit extract and their antioxidant, antibacterial, anti-inflammatory, antidiabetic and anti-Alzheimer's activities.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {2110},
pmid = {39814774},
issn = {2045-2322},
support = {SSN/CE/SRF/2024//SSN College of Engineering/ ; RSPD2024R940//King Saud University/ ; RSPD2024R940//King Saud University/ ; },
mesh = {*Syzygium/chemistry ; *Anti-Bacterial Agents/pharmacology/chemistry ; *Antioxidants/pharmacology/chemistry ; *Plant Extracts/chemistry/pharmacology ; Animals ; *Gold/chemistry ; *Nanocomposites/chemistry ; *Hypoglycemic Agents/chemistry/pharmacology ; *Anti-Inflammatory Agents/pharmacology/chemistry ; *Alzheimer Disease/drug therapy ; *Gelatin/chemistry ; Zebrafish ; Fruit/chemistry ; Humans ; Staphylococcus aureus/drug effects ; Metal Nanoparticles/chemistry ; },
abstract = {Nanotechnology has experienced significant advancements, attracting considerable attention in various biomedical applications. This innovative study synthesizes and characterizes Ge/PLA/AuNCs (gelatin/PLA/gold nanocomposites) using Syzygium cumini extract to evaluate their various biomedical applications. The UV-Visible spectroscopy results in an absorption peak at 534 nm were primarily confirmed by Ge/PLA/AuNCs synthesis. The FTIR spectrum showed various functional groups and the XRD patterns confirmed the crystalline shape and structure of nanocomposites. The FESEM and HRTEM results showed a oval shape of Ge/PLA/AuNCs with an average particle size of 21 nm. The Ge/PLA/AuNC's remarkable antioxidant activity, as evidenced by DPPH (70.84 ± 1.64%), ABTS activity (86.17 ± 1.96%), and reducing power activity (78.42 ± 1.48%) at a concentration of 100 μg/mL was observed. The zone of inhibition against Staphylococcus aureus (19.45 ± 0.89 mm) and Echericia coli (20.83 ± 0.97 mm) revealed the excellent antibacterial activity of Ge/PLA/AuNCs. The anti-diabetic activity of Ge/PLA/AuNCs was supported by inhibition of α-amylase (82.56 ± 1.49%) and α-glucosidase (80.27 ± 1.57%). The anti-Alzheimer activity was confirmed by inhibition of the AChE (76.37 ± 1.18%) and BChE (85.94 ± 1.38%) enzymes. In vivo studies of zebrafish embryos showed that Ge/PLA/AuNCs have excellent biocompatibility and nontoxicity. The SH-SY5Y cell line study demonstrated improved cell viability (95.27 ± 1.62%) and enhanced neuronal cell growth following Ge/PLA/AuNCs treatment. In conclusion, the present study highlights the cost-effective and non-toxic properties of Ge/PLA/AuNCs. Furthermore, it presents an attractive and promising approach for various future biomedical applications.},
}

*Syzygium/chemistry
*Anti-Bacterial Agents/pharmacology/chemistry
*Antioxidants/pharmacology/chemistry
*Plant Extracts/chemistry/pharmacology
Animals
*Gold/chemistry
*Nanocomposites/chemistry
*Hypoglycemic Agents/chemistry/pharmacology
*Anti-Inflammatory Agents/pharmacology/chemistry
*Alzheimer Disease/drug therapy
*Gelatin/chemistry
Zebrafish
Fruit/chemistry
Humans
Staphylococcus aureus/drug effects
Metal Nanoparticles/chemistry

@article {pmid39814656,
year = {2025},
author = {Schöll, M and Vrillon, A and Ikeuchi, T and Quevenco, FC and Iaccarino, L and Vasileva-Metodiev, SZ and Burnham, SC and Hendrix, J and Epelbaum, S and Zetterberg, H and Palmqvist, S},
title = {Cutting through the noise: A narrative review of Alzheimer's disease plasma biomarkers for routine clinical use.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {},
number = {},
pages = {100056},
doi = {10.1016/j.tjpad.2024.100056},
pmid = {39814656},
issn = {2426-0266},
abstract = {As novel, anti-amyloid therapies have become more widely available, access to timely and accurate diagnosis has become integral to ensuring optimal treatment of patients with early-stage Alzheimer's disease (AD). Plasma biomarkers are a promising tool for identifying AD pathology; however, several technical and clinical factors need to be considered prior to their implementation in routine clinical use. Given the rapid pace of advancements in the field and the wide array of available biomarkers and tests, this review aims to summarize these considerations, evaluate available platforms, and discuss the steps needed to bring plasma biomarker testing to the clinic. We focus on plasma phosphorylated(p)-tau, specifically plasma p-tau217, as a robust candidate across both primary and secondary care settings. Despite the high performance and robustness demonstrated in research, plasma p-tau217, like all plasma biomarkers, can be affected by analytical and pre-analytical variability as well as patient comorbidities, sex, ethnicity, and race. This review also discusses the advantages of the two-point cut-off approach to mitigating these factors, and the challenges raised by the resulting intermediate range measurements, where clinical guidance is still unclear. Further validation of plasma p-tau217 in heterogeneous, real-world cohorts will help to increase confidence in testing and support establishing a standardized approach. Plasma biomarkers are poised to become a more affordable and less invasive alternative to PET and CSF testing. However, understanding the factors that impact plasma biomarker measurement and interpretation is critical prior to their implementation in routine clinical use.},
}

@article {pmid39814340,
year = {2025},
author = {Yang, W and Yu, W and Lv, Y},
title = {Neuroprotective effects of chitinase-1 and calcitonin gene-related peptide on Alzheimer's disease by promoting lysosomal function.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877241307257},
doi = {10.1177/13872877241307257},
pmid = {39814340},
issn = {1875-8908},
abstract = {BACKGROUND: The amyloid cascade hypothesis still dominates in Alzheimer's disease (AD), and the acceleration of the clearance efficiency of amyloid-β (Aβ) has been always considered as an effective treatment option to slow the occurrence and progression of AD.

OBJECTIVE: This study aims to explore the role of zkscan3 and its related pathways in AD of the microglia-mediated pathogenesis, and whether the combined effect of drugs can exert neuroprotective function.

METHODS: N9 mouse microglia and HT-22 mouse hippocampal neurons were randomly divided into 6 groups, qRT-PCR technique was used to detect the gene expression level of zkscan3 and the genes related to lysosome generation and function. Fourteen C57 mice were randomly divided into two groups, and drug intervention model mice were randomly selected to establish from the AD group. Transmission electron microscope was used to detect the cell status and lysosome function in the hippocampus together with the other two groups.

RESULTS: Compared with the AD model group, the gene expression of zkscan3 in the drug intervention group was downregulated, and the degree of neuronal injury in the hippocampus was reduced, the structure and number of synapses were improved, and the function of intracellular lysosome was enhanced.

CONCLUSIONS: Zkscan3 and its related genes play a vital role in the development of AD. CGRP and CHIT-1, as a combined intervention, imparts effects through zkscan3-related pathways to improve lysosomal function and exert certain neuroprotective effects.},
}

@article {pmid39814203,
year = {2025},
author = {Chen, B and Yang, H and Bai, R and Du, X and Gao, Y and Liangyu, Z},
title = {Engineering silica nanocoated whole-cell asymmetric biocatalyst for efficient preparation of a key chiral intermediate of (S)-Rivastigmine.},
journal = {Journal of biotechnology},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jbiotec.2025.01.005},
pmid = {39814203},
issn = {1873-4863},
abstract = {In our previous study, the whole cells containing an aldo-keto reductase (yhdN) and glucose dehydrogenase (GDH) were constructed and applied in a stereoselective carbonyl reduction reaction to prepare (S)-NEMCA-HEPE, being a key chiral intermediate of (S)-Rivastigmine which is widely prescribed for the treatment of Alzheimer's disease. Although the conversion and enantiomeric excess (e.e.) could reach to 78.2% and 99%, respectively, ionic liquid as an additive was required to improve the permeability of cell membrane. To further simplify the reaction, the molecular docking and saturation mutagenesis technology were used here to obtain an activity-improved yhdN variant such as G19A. And then, both excellent conversion and e.e. of 99% for (S)-NEMCA-HEPE could be achieved within 40min by using only G19A-GDH whole cell as a catalyst without any additive. However, the use of the whole cells still faces the issues of poor operation stability and adverse application prospect. Subsequently, a hydrophobic "cell-in-shell" complex of G19A-GDH@O-Silica was constructed by using a silica nanocoated technology. The obtained G19A-GDH@O-Silica exhibited an excellent conversion towards the asymmetric carbonyl reduction, and a good tolerance in changing thermal, pH, and storage environmental. Giving 76.3% of reaction conversion even after the 11th cycle of reuse, indicated that G19A-GDH@O-Silica also possessed ideal recyclability. The aim of this study is to provide a rapid, and cost-effective nanocoated whole-cell biocatalyst for efficient preparation of (S)-NEMCA-HEPE. The simplicity and robustness of the immobilization approach may become a powerful tool to utilize whole-cell catalysts towards organic catalysis.},
}

@article {pmid39814858,
year = {2025},
author = {Li, G and Hsu, LM and Wu, Y and Bozoki, AC and Shih, YI and Yap, PT},
title = {Revealing excitation-inhibition imbalance in Alzheimer's disease using multiscale neural model inversion of resting-state functional MRI.},
journal = {Communications medicine},
volume = {5},
number = {1},
pages = {17},
pmid = {39814858},
issn = {2730-664X},
support = {R01MH125479//U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH)/ ; R01EB006733//U.S. Department of Health & Human Services | NIH | National Institute of Biomedical Imaging and Bioengineering (NIBIB)/ ; R01EB008374//U.S. Department of Health & Human Services | NIH | National Institute of Biomedical Imaging and Bioengineering (NIBIB)/ ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is a serious neurodegenerative disorder without a clear understanding of pathophysiology. Recent experimental data have suggested neuronal excitation-inhibition (E-I) imbalance as an essential element of AD pathology, but E-I imbalance has not been systematically mapped out for either local or large-scale neuronal circuits in AD, precluding precise targeting of E-I imbalance in AD treatment.

METHOD: In this work, we apply a Multiscale Neural Model Inversion (MNMI) framework to the resting-state functional MRI data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) to identify brain regions with disrupted E-I balance in a large network during AD progression.

RESULTS: We observe that both intra-regional and inter-regional E-I balance is progressively disrupted from cognitively normal individuals, to mild cognitive impairment (MCI) and to AD. Also, we find that local inhibitory connections are more significantly impaired than excitatory ones and the strengths of most connections are reduced in MCI and AD, leading to gradual decoupling of neural populations. Moreover, we reveal a core AD network comprised mainly of limbic and cingulate regions. These brain regions exhibit consistent E-I alterations across MCI and AD, and thus may represent important AD biomarkers and therapeutic targets. Lastly, the E-I balance of multiple brain regions in the core AD network is found to be significantly correlated with the cognitive test score.

CONCLUSIONS: Our study constitutes an important attempt to delineate E-I imbalance in large-scale neuronal circuits during AD progression, which may facilitate the development of new treatment paradigms to restore physiological E-I balance in AD.},
}

@article {pmid39814324,
year = {2025},
author = {Fu, Q and Yu, Q and Luo, H and Liu, Z and Ma, X and Wang, H and Cheng, Z},
title = {Protective effects of wogonin in the treatment of central nervous system and degenerative diseases.},
journal = {Brain research bulletin},
volume = {},
number = {},
pages = {111202},
doi = {10.1016/j.brainresbull.2025.111202},
pmid = {39814324},
issn = {1873-2747},
abstract = {Wogonin, an O-methylated flavonoid extracted from Scutellaria baicalensis, has demonstrated profound neuroprotective effects in a range of central nervous system (CNS) diseases. This review elucidates the pharmacological mechanisms underlying the protective effects of wogonin in CNS diseases, including ischemic stroke, hemorrhagic stroke, traumatic brain injury, epilepsy, anxiety, neurodegenerative diseases, and CNS infections. Wogonin modulates key signaling pathways, such as the MAPK, NF-κB, and ROS pathways, contributing to its anti-inflammatory, antioxidant, and antiapoptotic properties. In ischemic stroke models, wogonin reduces infarct size and enhances neurological outcomes by mitigating inflammation and oxidative stress. For patients with hemorrhagic stroke and traumatic brain injury, it accelerates hematoma regression, mitigates secondary brain damage, and promotes neurogenesis, making it an entirely new treatment option for patients with limited access to this type of therapy. Its anticonvulsant and anxiolytic effects are mediated through GABA-A receptor modulation. Moreover, wogonin shows promise in treating neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease by promoting autophagy and reducing neuroinflammation. Additionally, it exhibits antiviral properties, offering potential benefits against CNS infections. Despite extensive preclinical evidence, further clinical studies are warranted to confirm its efficacy and safety in humans. This review highlights the great therapeutic potential of wogonin in terms of CNS protection. However, despite the substantial preclinical evidence, further large-scale clinical studies are necessary. Future researchers need to further explore the long-term efficacy and safety of wogonin in clinical trials and translate it for early application in the clinical treatment of true CNS disorders.},
}

@article {pmid39814004,
year = {2025},
author = {Xu, M and Wang, L and Meng, Y and Kang, G and Jiang, Q and Yan, T and Che, F},
title = {The role of lipid metabolism in cognitive impairment.},
journal = {Arquivos de neuro-psiquiatria},
volume = {83},
number = {1},
pages = {1-13},
doi = {10.1055/s-0044-1792097},
pmid = {39814004},
issn = {1678-4227},
support = {2023M732121//China Postdoctoral Science Foundation/ ; ZR2023QH090//Natural Science Foundation of Shandong Province/ ; ZR2022MH119//Natural Science Foundation of Shandong Province/ ; XYFY202343//Development fund of the Affiliated Hospital of Xuzhou Medical University/ ; },
mesh = {Humans ; *Lipid Metabolism/physiology ; *Cognitive Dysfunction/metabolism/physiopathology/etiology ; *Insulin Resistance/physiology ; *Alzheimer Disease/metabolism/physiopathology ; Amyloid beta-Peptides/metabolism ; Apolipoproteins E/metabolism ; Dementia, Vascular/metabolism/physiopathology ; Disease Progression ; tau Proteins/metabolism ; Brain/metabolism ; },
abstract = {Alzheimer's disease (AD), diabetic cognitive impairment (DCI), and vascular dementia (VD) are considered the most common causes of severe cognitive impairment in clinical practice. Numerous factors can influence their progression, and many studies have recently revealed that metabolic disorders play crucial roles in the progression of cognitive impairment. Mounting evidence indicate that the regulation of lipid metabolism is a major factor in maintaining brain homeostasis. Generally, abnormalities in lipid metabolism can affect amyloid-beta (Aβ) deposition, tau hyperphosphorylation, and insulin resistance through lipid metabolic signaling cascades; affect the neuronal membrane structure, neurotransmitter synthesis and release; and promote synapse growth, which can impact neural signal transmission and exacerbate disease progression in individuals with cognitive impairment, including AD, DCI, and VD. Moreover, apolipoprotein E (APOE), a key protein in lipid transport, is involved in the occurrence and development of the aforementioned diseases by regulating lipid metabolism. The present article mainly discusses how lipid metabolic disorders in the brain microenvironment are involved in regulating the progression of cognitive impairment, and it explores the regulatory effects of targeting the key lipid transport protein APOE in the context of the role of lipid metabolism in the common pathogenesis of three diseases-Aβ deposition, tau hyperphosphorylation, and insulin resistance-which will help elucidate the potential of targeting lipid metabolism for the treatment of cognitive impairment.},
}

Humans
*Lipid Metabolism/physiology
*Cognitive Dysfunction/metabolism/physiopathology/etiology
*Insulin Resistance/physiology
*Alzheimer Disease/metabolism/physiopathology
Amyloid beta-Peptides/metabolism
Apolipoproteins E/metabolism
Dementia, Vascular/metabolism/physiopathology
Disease Progression
tau Proteins/metabolism
Brain/metabolism

@article {pmid39813887,
year = {2025},
author = {Maji, M and Khajanchi, S},
title = {Mathematical models on Alzheimer's disease and its treatment: A review.},
journal = {Physics of life reviews},
volume = {52},
number = {},
pages = {207-244},
doi = {10.1016/j.plrev.2025.01.004},
pmid = {39813887},
issn = {1873-1457},
abstract = {Alzheimer's disease is a gradually advancing neurodegenerative disease. According to the report by "World Health Organization (WHO)", there are over 55 million individuals currently living with Alzheimer's disease and other dementia globally, and the number of sufferers is increasing every day. In absence of effective cures and preventive measures, this number is predicted to triple by 2050. The disease's origin is still unclear, and also no such treatment is available for eradicating the disease. Based on the crucial factors that are connected to the disease's progression, the authors developed several types of mathematical models. We review such mathematical models that are utilized to better understand the pathophysiology of Alzheimer's disease. Section-wise, we categorize the mathematical models in terms of different components that might be responsible for Alzheimer's disease. We explain the mathematical models with their descriptions and respective conclusions. In addition to mathematical models, we concentrate on biological aspects of the disease and possible therapeutic targets. We explore the disease's biological basis primarily to understand how proteins, glial cells, cytokines, genes, calcium signaling and oxidative stress contribute to the disease. We go through several treatment targets that might stop the progression of the disease or at least slow it down. We present a table that summarizes the mathematical models in terms of their formalisms, highlighting key components and important remarks.},
}

@article {pmid39813317,
year = {2025},
author = {Brandao, W and Jain, N and Yin, Z and Kleemann, KL and Carpenter, M and Bao, X and Serrano, JR and Tycksen, E and Durao, A and Barry, JL and Baufeld, C and Guneykaya, D and Zhang, X and Litvinchuk, A and Jiang, H and Rosenzweig, N and Pitts, KM and Aronchik, M and Yahya, T and Cao, T and Takahashi, MK and Krishnan, R and Davtyan, H and Ulrich, JD and Blurton-Jones, M and Ilin, I and Weiner, HL and Holtzman, DM and Butovsky, O},
title = {Inhaled xenon modulates microglia and ameliorates disease in mouse models of amyloidosis and tauopathy.},
journal = {Science translational medicine},
volume = {17},
number = {781},
pages = {eadk3690},
doi = {10.1126/scitranslmed.adk3690},
pmid = {39813317},
issn = {1946-6242},
mesh = {Animals ; *Microglia/drug effects/metabolism/pathology ; *Xenon/pharmacology/administration & dosage ; *Disease Models, Animal ; Administration, Inhalation ; *Tauopathies/drug therapy/pathology ; Mice ; Amyloidosis/drug therapy/pathology ; Mice, Transgenic ; Alzheimer Disease/drug therapy/pathology ; Humans ; Brain/pathology/drug effects/metabolism ; Plaque, Amyloid/pathology ; Mice, Inbred C57BL ; },
abstract = {Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder. Antiamyloid antibody treatments modestly slow disease progression in mild dementia due to AD. Emerging evidence shows that homeostatic dysregulation of the brain immune system, especially that orchestrated by microglia, plays an important role in disease onset and progression. Thus, a major question is how to modulate the phenotype and function of microglia to treat AD. Xenon (Xe) gas is a noble gas used in human patients as an anesthetic and a neuroprotectant used for treating brain injuries. Xe penetrates the blood-brain barrier, which could make it an effective therapeutic. To assess the effect of Xe on microglia and AD pathology, we designed a custom Xe inhalation chamber and treated several mouse models of AD with Xe gas. Xe treatment induced mouse microglia to adopt an intermediate activation state that we have termed pre-neurodegenerative microglia (pre-MGnD). This microglial phenotypic transition was observed in mouse models of acute neurodegeneration and amyloidosis (APP/PS1 and 5xFAD mice) and tauopathy (P301S mice). This microglial state enhanced amyloid plaque compaction and reduced dystrophic neurites in the APP/PS1 and 5xFAD mouse models. Moreover, Xe inhalation reduced brain atrophy and neuroinflammation and improved nest-building behavior in P301S mice. Mechanistically, Xe inhalation induced homeostatic brain microglia toward a pre-MGnD state through IFN-γ signaling that maintained the microglial phagocytic response in APP/PS1 and 5xFAD mice while suppressing the microglial proinflammatory phenotype in P301S mice. These results support the translation of Xe inhalation as an approach for treating AD.},
}

Animals
*Microglia/drug effects/metabolism/pathology
*Xenon/pharmacology/administration & dosage
*Disease Models, Animal
Administration, Inhalation
*Tauopathies/drug therapy/pathology
Mice
Amyloidosis/drug therapy/pathology
Mice, Transgenic
Alzheimer Disease/drug therapy/pathology
Humans
Brain/pathology/drug effects/metabolism
Plaque, Amyloid/pathology
Mice, Inbred C57BL

@article {pmid39812690,
year = {2025},
author = {Zhao, C and Li, T and Hao, S and Zhao, L and Han, Y and Cai, Y},
title = {Dysregulation of the molecular clock by blood-borne factors in Alzheimer's disease patients.},
journal = {Journal of neurology},
volume = {272},
number = {2},
pages = {121},
pmid = {39812690},
issn = {1432-1459},
support = {2021YFC2501205//Key Technologies Research and Development Program of Anhui Province/ ; 2021ZD0201101//the STI2030-Major Project/ ; 2022ZD0211800//the STI2030-Major Project/ ; YC202301QX0148//Beijing Translational Medicine Promotion Project/ ; 82020108013//the National Nature Science Foundation of China/ ; },
mesh = {Humans ; *Alzheimer Disease/blood ; Male ; Female ; Aged ; *Cognitive Dysfunction/etiology/blood/physiopathology ; Longitudinal Studies ; Aged, 80 and over ; Circadian Rhythm/physiology ; Middle Aged ; Amyloid beta-Peptides/blood/metabolism ; ARNTL Transcription Factors/genetics ; Nuclear Receptor Subfamily 1, Group D, Member 1/genetics ; Biomarkers/blood ; },
abstract = {BACKGROUND: Circadian disruptions are increasingly recognized in Alzheimer's disease (AD) patients and may influence disease onset and progression. This study examines how AD pathology affects blood-borne factors that regulate circadian rhythms.

METHODS: Eighty-five participants from the Sino Longitudinal Study on Cognitive Decline were enrolled: 35 amyloid-beta negative normal controls (Aβ- NCs), 23 amyloid-beta positive normal controls (Aβ+ NCs), 15 patients with amnestic mild cognitive impairment (aMCI), and 12 with Alzheimer's disease dementia (ADD). Patients with aMCI and ADD were grouped as cognitively impaired (CI). Cellular circadian period length was assessed using a serum-based assay. Expression levels of clock genes in serum-treated cells and in leukocytes of participants were measured via real-time PCR. Plasma biomarkers were quantified using a single-molecule array immunoassay. Pineal parenchymal and hippocampal volumes were determined by magnetic resonance imaging.

RESULTS: The cellular circadian period length was significantly extended by serum from CI patients than by that from Aβ- NCs (p < 0.01). Treatment of cells with serum from the CI patients resulted in suppressed expression of the clock genes Bmal1 and Nr1d1. Strong relationships between the expression levels of clock genes observed in leukocytes of the Aβ- NC group did not appear in those of the Aβ+ NC or CI groups. The significant correlation of cellular circadian period length and the pineal volume was only observed in the Aβ- NC group, but not in the Aβ+ NC or CI groups.

CONCLUSIONS: This study indicates the presence of significant changes in blood-borne factors that could affect the circadian rhythms in AD, starting even at preclinical stages. These alterations could precede cognitive decline and contribute to AD pathogenesis.

TRIAL REGISTRATION: The cohort is registered at ClinicalTrials.gov (SILCODE: NCT03370744; Registered on Mar 15[th], 2017).},
}

Humans
*Alzheimer Disease/blood
Male
Female
Aged
*Cognitive Dysfunction/etiology/blood/physiopathology
Longitudinal Studies
Aged, 80 and over
Circadian Rhythm/physiology
Middle Aged
Amyloid beta-Peptides/blood/metabolism
ARNTL Transcription Factors/genetics
Nuclear Receptor Subfamily 1, Group D, Member 1/genetics
Biomarkers/blood

@article {pmid39812543,
year = {2025},
author = {Zong, NC and Zhang, Y and Huang, Y and Cai, H},
title = {Addressing Healthy Aging: Time to Stop a Tsunami of Rising Alzheimer's Disease.},
journal = {Aging and disease},
volume = {},
number = {},
pages = {},
doi = {10.14336/AD.2024.1476},
pmid = {39812543},
issn = {2152-5250},
abstract = {Alzheimer's disease [AD] disproportionately affects our seniors, diminishing their health and life expectancy. As the world population grows older, the collective burden of AD has become unsustainable. Globally, there were 43.8 million patients in 2016, with a projection of affecting 152 million by 2050. Recent discoveries have shown that molecular changes characteristic to AD manifested 20 years before discernable neurological phenotypes emerge. It is feasible to halt or reverse this pathological process before reaching an irremediable stage. To take advantage of this treatment window, we need to make rapid progress in early detection and monitoring, targeted implementation of preventative measures, invention of novel therapeutics, and pragmatic ramping-up of relevant supporting policies. PET is a powerful tool for prognosis. The utilization of AI technology, on the other hand, has favorable features of low cost per capita, easy dissemination and broad scale data collection to uncover previously unknown hotspots or risk factors. FDA approved drugs, lecanemab and donanemab, have started to show efficacy to put a pause on AD progression. Additional clinical data will enable comprehensive evaluation of the impacts of these drugs. Gene therapy holds the potential of eliciting long term protection, while several candidate loci have been identified. The urgency of a tsunami of rising AD epidemiology demands rapid actions on all fronts of advanced diagnostics, monitoring, preventative and interventive strategies.},
}

@article {pmid39812538,
year = {2025},
author = {Iqbal, Z and El Hamamy, A and Le, NM and Ranjan, A and Zhang, Y and Qi, L and Manwani, B and Tan, C and McCullough, LD and Li, J},
title = {Targeting Astrogliosis in the Retrotrapezoid Nucleus: A Novel Approach to Ameliorate Respiratory Dysfunction and Alzheimer's Pathology in Mice.},
journal = {Aging and disease},
volume = {},
number = {},
pages = {},
doi = {10.14336/AD.2024.0523},
pmid = {39812538},
issn = {2152-5250},
abstract = {Alzheimer's disease (AD), a leading cause of dementia, is associated with significant respiratory dysfunctions. Our study explores the role of astrogliosis in the brainstem retrotrapezoid nucleus (RTN), a key breathing regulatory center, and its impact on breathing control and AD pathology in mice. Using Tg-2576 AD and wild-type mice, we investigated the effect of silencing the transforming growth factor-beta receptor II (TGFβR II) in the RTN. We performed behavioral tests, including the Barnes maze and novel object recognition test, along with whole-body plethysmography to assess breathing disorders. Our results showed that AD mice exhibited increased apneas and cognitive impairment, which were significantly mitigated following TGFβR II gene silencing. Immunohistochemistry revealed elevated levels of GFAP and TGFβR II in the RTN of AD mice, which were reduced post-gene silencing, alongside a decrease in amyloid-beta expression in the cortex and hippocampus. These findings suggest that targeting astrogliosis and improving respiratory control may offer a novel therapeutic avenue for managing Alzheimer's disease. Our study provides the first mechanistic insights into how TGFβ signaling influences both respiratory control and AD pathogenesis, highlighting the potential benefits of stabilizing breathing patterns in AD treatment.},
}

@article {pmid39812537,
year = {2025},
author = {Wu, Y and Zhou, YM and Wu, W and Jiang, WR and Zhang, XY and Song, SY and Yao, ZH},
title = {TBC1D15 Inhibits Autophagy of Microglia through Maintaining the Damaged Swelling Lysosome in Alzheimer's Disease.},
journal = {Aging and disease},
volume = {},
number = {},
pages = {},
doi = {10.14336/AD.2024.1373},
pmid = {39812537},
issn = {2152-5250},
abstract = {Autophagy in microglia is essential for the clearance of amyloid-beta (Aβ) and amyloid plaques in Alzheimer's disease. However, reports regarding the levels of autophagy in microglia have been inconsistent; some studies indicate an early enhancement followed by a subsequent reduction, while others describe a persistently weakened state. Notably, there is a lack of systematic studies documenting the temporal changes in microglial autophagy. TBC1D15, a Rab GTPase, plays a crucial role in lysosomal membrane repair, yet its function in regulating microglial autophagy in Alzheimer's disease remains unexplored. Current research suggests that microglial autophagy is activated in 3-month-old AD mice but gradually decreases by 12 months of age. Furthermore, TBC1D15 levels are significantly elevated in the lysosomes of microglia in Alzheimer's disease. Silencing TBC1D15 markedly inhibits swelling and Aβ phagocytosis in BV2 cells following Aβ treatment while simultaneously promoting autophagy and lysophagy. LIMP II/ATG8-TBC1D15-Dynamin2/RAB7 might participate in lysosome swelling of microglia in AD. These findings indicate that TBC1D15 in microglia is critical for the decline of autophagy in Alzheimer's disease. It is suggested that targeting microglial TBC1D15 may be an important strategy for enhancing autophagy, which facilitates the clearance of amyloid plaques as a therapeutic approach for Alzheimer's disease.},
}

@article {pmid39812331,
year = {2025},
author = {Huang, X and Jannu, AJ and Song, Z and Jury-Garfe, N and Lasagna-Reeves, CA and , and Johnson, TS and Huang, K and Zhang, J},
title = {Predicting Alzheimer's disease subtypes and understanding their molecular characteristics in living patients with transcriptomic trajectory profiling.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {},
number = {},
pages = {e14241},
doi = {10.1002/alz.14241},
pmid = {39812331},
issn = {1552-5279},
support = {//Alzheimer's Disease Neuroimaging Initiative/ ; U01 AG024904/NH/NIH HHS/United States ; W81XWH-12-2-0012//Department of Defense/ ; /AG/NIA NIH HHS/United States ; /EB/NIBIB NIH HHS/United States ; //AbbVie/ ; /ALZ/Alzheimer's Association/United States ; //Alzheimer's Drug Discovery Foundation/ ; //Araclon Biotech/ ; //BioClinica, Inc./ ; //Biogen/ ; //Bristol-Myers Squibb Company/ ; //CereSpir, Inc./ ; //Cogstate; Eisai Inc./ ; //Elan Pharmaceuticals, Inc./ ; //Eli Lilly and Company/ ; //EuroImmun/ ; //F. Hoffmann-La Roche Ltd/ ; 5U54AG065181//Indiana University Precision Health Initiative NIH TREAT-AD U54/ ; 5R01NS119280//Indiana University Precision Health Initiative NIH TREAT-AD U54/ ; },
abstract = {INTRODUCTION: Deciphering the diverse molecular mechanisms in living Alzheimer's disease (AD) patients is a big challenge but is pivotal for disease prognosis and precision medicine development.

METHODS: Utilizing an optimal transport approach, we conducted graph-based mapping of transcriptomic profiles to transfer AD subtype labels from ROSMAP monocyte samples to ADNI and ANMerge peripheral blood mononuclear cells. Subsequently, differential expression followed by comparative pathway and diffusion pseudotime analysis were applied to each cohort to infer the progression trajectories. Survival analysis with real follow-up time was used to obtain potential biomarkers for AD prognosis.

RESULTS: AD subtype labels were accurately transferred onto the blood samples of ADNI and ANMerge living patients. Pathways and associated genes in neutrophil degranulation-like immune process, immune acute phase response, and IL-6 signaling were significantly associated with AD progression.

DISCUSSION: The work enhanced our understanding of AD progression in different subtypes, offering insights into potential biomarkers and personalized interventions for improved patient care.

HIGHLIGHTS: We applied an innovative optimal transport-based approach to map transcriptomic data from different Alzheimer's disease (AD) cohort studies and transfer known AD subtype labels from ROSMAP monocyte samples to peripheral blood mononuclear cell (PBMC) samples within ADNI and ANMerge cohorts. Through comprehensive trajectory and comparative analysis, we investigated the molecular mechanisms underlying different disease progression trajectories in AD. We validated the accuracy of our AD subtype label transfer and identified prognostic genetic markers associated with disease progression, facilitating personalized treatment strategies. By identifying and predicting distinctive AD subtypes and their associated pathways, our study contributes to a deeper understanding of AD heterogeneity.},
}

@article {pmid39811702,
year = {2025},
author = {Terao, CM and Alexander, MW and Chalmers, RP and Boshmaf, SZ and Paterson, J and Black, SE and Papp, KV and Sperling, RA and Rabin, JS},
title = {Identifying cognitive test scores associated with early tau burden in Alzheimer's disease.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {17},
number = {1},
pages = {e70052},
pmid = {39811702},
issn = {2352-8729},
abstract = {INTRODUCTION: This study aimed to identify cognitive tests that optimally relate to tau positron emission tomography (PET) signal in the inferior temporal cortex (ITC), a neocortical region associated with early tau accumulation in Alzheimer's disease (AD).

METHODS: We analyzed cross-sectional data from the harvard aging brain study (HABS) (n = 128) and the Anti-Amyloid Treatment in Asymptomatic Alzheimer's (A4) study (n = 393). We used elastic net regression to identify the most robust cognitive correlates of tau PET signal in the ITC. Secondary analyses examined whether the cognitive correlates remained significantly associated with tau after adjusting for structural brain measures.

RESULTS: Episodic memory measures, including both total and "process" scores, were the most robust correlates of ITC tau across both cohorts. These cognitive test scores remained significant after accounting for structural brain measures.

DISCUSSION: These findings highlight the potential of specific episodic memory test scores to detect and monitor neuropathological changes associated with early AD.

HIGHLIGHTS: Machine learning identified cognitive correlates of early Alzheimer's disease tau burden.Both traditional and process scores predicted early tau burden.Episodic memory scores were among the strongest correlates.Cognitive scores remained significant after accounting for structural brain measures.},
}

@article {pmid39811699,
year = {2025},
author = {Blotenberg, I and Wittström, F and Michalowsky, B and Platen, M and Wucherer, D and Teipel, S and Hoffmann, W and Thyrian, JR},
title = {Modifiable risk factors and symptom progression in dementia over up to 8 years-Results of the DelpHi-MV trial.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {17},
number = {1},
pages = {e70050},
pmid = {39811699},
issn = {2352-8729},
abstract = {INTRODUCTION: This study investigated the association between modifiable factors and symptom progression in dementia over up to 8 years.

METHODS: Multilevel growth curve models assessed the role of modifiable risk factors (low education, hearing impairment and its treatment, depression, physical inactivity, diabetes and its treatment, smoking, hypertension and its treatment, obesity, alcohol consumption, social isolation, and visual impairment) on cognitive and functional trajectories in 353 people with dementia.

RESULTS: Higher education was associated with higher initial cognitive status but faster decline. Antidiabetic medication was associated with slower cognitive decline, whereas depression and visual impairment were linked to low baseline functioning and faster cognitive decline.

DISCUSSION: Several modifiable risk factors influenced symptom progression. Education initially had a protective effect, whereas depressive symptoms were linked to worse symptom progression. Treatment of comorbidities (diabetes, visual impairment) could have a positive impact on dementia symptoms. Modifiable risk factors are promising targets for tertiary prevention.

HIGHLIGHTS: Modifiable risk factors were associated with symptom progression in dementia over up to 8 years.More education was associated with higher initial cognitive status but faster decline.Depressive symptoms were linked to less favorable symptom progression.Treatment of comorbidities (diabetes, visual impairment) may positively impact the course of symptoms.Modifiable risk factors are promising targets for tertiary prevention.},
}

@article {pmid39810446,
year = {2024},
author = {Biswal, B and Satapathy, BS and Mishra, A and Maharana, L and Pattnaik, S},
title = {Potential of Nanoparticle Based Antimicrobial Drug Repurposing to Efficiently Target Alzheimer's: A Concise Update on Evidence-based Research and Challenges Ahead.},
journal = {Current drug discovery technologies},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115701638329824241220055621},
pmid = {39810446},
issn = {1875-6220},
abstract = {Repurposing of drugs through nanocarriers (NCs) based platforms has been a recent trend in drug delivery research. Various routine drugs are now being repurposed to treat challenging neurodegenerative disorders including Alzheimer disease (AD). AD, at present is one of the challenging neurodegenerative disorders characterized by extracellular accumulation of amyloid-β and intracellular accumulations of neurofibrillary tangles. In spite of catchy progress in drug development, effective treatment outcome in AD patients is far-fetched dream. Out of several proposed hypothesis in the development and progression of AD, potential role of microorganisms causing dementia and AD cannot be ruled out. Several recent researches have been documented a clear correlation in between microbial infection and neuronal damage leading to progression of AD. Thus, antimicrobial drugs repurposing has been emerged as alternate, potential, cost-effective strategy to check progression of AD. Further, for efficient delivery of antimicrobial drugs to brain tissue, novel NCs based platforms are the preferred option to bypass blood-brain barrier. Several polymeric and lipid NCs have been extensively studied over the past years to improve antimicrobial drug delivery to brain. The present review encompasses various repurposing strategy of antimicrobial drugs delivered through various NCs to target AD. Evidence-based research outcome compiled from authentic database like Scopus, PubMed, Web of science have been pooled to provide an updated review. Side by side some light has been thrown on the practical problems faced by nanodrug carriers during technology transfer.},
}

@article {pmid39810384,
year = {2025},
author = {Mandal, PK and Maroon, JC and Guha Roy, R and Patira, R and Gogniat, MA and Sindhu, B},
title = {The Missing Link in Antiamyloid Therapy.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.4c00825},
pmid = {39810384},
issn = {1948-7193},
abstract = {Alzheimer's disease (AD) impacts millions of elderly adults worldwide causing cognitive decline and severe deterioration of activities of daily life. The popular causal hypotheses for several decades include beta-amyloid (Aβ) deposition and tau hyperphosphorylation. AD research and more than 34% of clinical trials in AD are based on these two hypotheses. A phase-III clinical trial of lecanemab in early AD and mild cognitive impaired (MCI) patients reported a delay in cognitive decline of 27% over an 18-month treatment schedule. This multicenter trial found high specificity of lecanemab toward toxic protofibrils and subsequent clearance of beta-amyloid. There were, however, adverse events, which included cerebral edema and intracerebral hemorrhages in 23.1% of patients compared to 9.3% for those who received a placebo. Suboptimal clinical outcomes, brain volume loss, and adverse events in lecanemab treatment prompted a search for an alternative etiopathogenic explanation. Our research and others have focused on the oxidative stress (OS) hypothesis in AD. Autopsy studies have found significant depletion of the master antioxidant glutathione (GSH) in the hippocampal region, and is believed to be an early event in AD progression. Hippocampal GSH depletion is positively correlated with memory impairment. We have confirmed non-invasively with magnetic resonance spectroscopy (MRS) the depletion of GSH in patients with MCI and AD. We therefore propose a combinational therapy involving oral supplementation of gamma-glutamylcysteine (GGC), an early precursor of glutathione, to replenish brain GSH in addition to lecanemab, potentially to maximize desirable outcomes from combined therapeutic approach.},
}

@article {pmid39809960,
year = {2025},
author = {Saunders, MR and Qi, M and Huang, ES and Konetzka, RT},
title = {Trends in Co-morbid Dementia and Chronic Kidney Disease.},
journal = {Journal of general internal medicine},
volume = {},
number = {},
pages = {},
pmid = {39809960},
issn = {1525-1497},
support = {K24AG069080/AG/NIA NIH HHS/United States ; RFIAG069857/AG/NIA NIH HHS/United States ; P50MD17349/MD/NIMHD NIH HHS/United States ; R01DK124597/DK/NIDDK NIH HHS/United States ; },
abstract = {BACKGROUND: Little is known about the population of Medicare beneficiaries with both chronic kidney disease (CKD) and Alzheimer's disease and related dementias (ADRD).

METHODS: Using data from Medicare fee-for-service (FFS) beneficiaries aged 65 and over identified through 2011-2019 Master Beneficiary Summary File (MBSF), we estimated the size, growth, and racial-ethnic characteristics of the ADRD and CKD populations. Individuals were classified as having ADRD and CKD based on CMS Chronic Conditions Data Warehouse (CCW) indicators in the MBSF Chronic Conditions file.

RESULTS: Among FFS beneficiaries, the prevalence of CKD has increased from 17.5% in 2011 to 27.9% in 2019, and the prevalence of ADRD has decreased over that time from 13.3 to 12.5%. The prevalence of individuals with co-morbid ADRD and CKD has risen from 4.4 to 6.3% which represents 1.72 million older adults. Black and Hispanic individuals have the highest prevalence of co-morbid CKD and ADRD, averaging 10.0% and 9.0% in 2019, respectively, compared to other racial-ethnic groups (≤ 7.2% all others). In addition, among those previously diagnosed with ADRD, the proportion with co-morbid CKD has been steadily increasing from 25.5% in 2011 to 44.4% in 2019. While the proportion of individuals with ADRD who have co-morbid CKD has increased across all race-ethnicities, it is highest in Black and Hispanic individuals (56.7 and 51%, respectively in 2019).

CONCLUSION/RELEVANCE: The prevalence of Medicare FFS enrollees with both ADRD and CKD is increasing. Although the ADRD prevalence has declined, there is a rising number of individuals with CKD who are diagnosed with ADRD and a rising proportion of those with ADRD who also have CKD. Due to shared clinical and demographic risk factors, interventions to reduce CKD progression could also delay ADRD onset. In patients with both advanced ADRD and advanced CKD, clinicians and policymakers should focus on treatment options that consider both co-morbidities.},
}