@article {pmid41314749,
year = {2025},
author = {Priyanka, S and Manjari, T and Hemalatha, S and Ambika, S and Yılmaz, B and Aktürk, B and Arısan, ED and Kumari, A and Manojkumar, Y},
title = {Precision therapeutics for Alzheimer's disease.},
journal = {Progress in brain research},
volume = {297},
number = {},
pages = {247-276},
doi = {10.1016/bs.pbr.2025.08.011},
pmid = {41314749},
issn = {1875-7855},
mesh = {Humans ; *Alzheimer Disease/therapy/genetics/drug therapy ; *Precision Medicine/methods ; Animals ; },
abstract = {Despite extensive research, Alzheimer's disease (AD) a progressive neurodegenerative disorder marked by cognitive decline, neuronal loss, and the build-up of amyloid-beta plaques and tau tangles continues to lack effective treatments. Precision medicine presents a promising shift by customizing interventions to an individual's genetic, molecular, and lifestyle profile. This chapter explores key advancements in precision therapeutics for AD, including biomarker-driven therapies, pharmacogenomics, and targeted disease-modifying agents such as monoclonal antibodies. Recent innovations, including RNA-based therapeutics, stem cell approaches, and CRISPR-mediated gene editing, are also discussed. While precision medicine holds immense promise, challenges in clinical translation, patient stratification, and regulatory pathways must be addressed. By bridging cutting-edge research with clinical applications, this chapter provides insights into the evolving landscape of individualized treatment strategies for AD.},
}

Humans
*Alzheimer Disease/therapy/genetics/drug therapy
*Precision Medicine/methods
Animals

@article {pmid41314745,
year = {2025},
author = {Fatima, S and Tiwari, S and Siddiqi, B and Quadri, SN and Abdin, MZ},
title = {Biomarkers: From early detection to treatment personalization.},
journal = {Progress in brain research},
volume = {297},
number = {},
pages = {131-153},
doi = {10.1016/bs.pbr.2025.08.008},
pmid = {41314745},
issn = {1875-7855},
mesh = {Humans ; *Biomarkers/metabolism ; *Neurodegenerative Diseases/diagnosis/therapy/metabolism ; *Precision Medicine/methods ; Early Diagnosis ; },
abstract = {Neurodegenerative disorders (NDs), such as Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), present increasing issues associated with the unavoidable aging of the world's population. These challenges are further highlighted by the socioeconomic consequences of these diseases. The identification and use of biomarkers for prompt diagnosis, careful observation, and efficient treatment approaches is essential to overcoming these obstacles. The primary methods for diagnosing neurodegenerative illnesses are invasive procedures like lumbar punctures to measure CSF fluid or functional brain imaging methods. Biomarkers for underlying proteinopathy in blood serum and cerebral fluid have been the focus of recent biological research, particularly in vivo. With their ability to provide novel pathways for early detection, illness progression tracking, and individualized treatment plans, biomarkers have become essential instruments in precision medicine. The classification of biomarkers including fluid, digital imaging, and molecular biomarkers is examined in this chapter, with an emphasis on their function in neurodegenerative diseases. In neurodegenerative illnesses and the aging brain, tau, amyloid-β, α-synuclein, and TDP-43 are commonly seen to be deposited together rather than separately. These may be disregarded, and it might be challenging to determine their clinicopathological significance. An overview of illness pathophysiology, diagnostic implications, and the most recent molecular and ultrastructural categories for neurodegenerative disorders are given in this chapter. Addressing these issues through interdisciplinary research and technological advancements will be crucial for the future of biomarker-driven precision medicine. This chapter provides an in-depth overview of the evolving landscape of biomarkers and their transformative impact on the early detection and personalized treatment of neurodegenerative diseases.},
}

Humans
*Biomarkers/metabolism
*Neurodegenerative Diseases/diagnosis/therapy/metabolism
*Precision Medicine/methods
Early Diagnosis

@article {pmid41314744,
year = {2025},
author = {Gunasekaran, B and Arifin, AH and Yu, WH and Hanafi, S and Rao, KDK and Salvamani, S},
title = {Precision medicine in neurodegenerative diseases: From research to clinical practice.},
journal = {Progress in brain research},
volume = {297},
number = {},
pages = {1-52},
doi = {10.1016/bs.pbr.2025.08.006},
pmid = {41314744},
issn = {1875-7855},
mesh = {Humans ; *Precision Medicine/methods ; *Neurodegenerative Diseases/therapy/genetics/diagnosis ; Biomarkers ; },
abstract = {The chapter outlines how precision medicine is reshaping the way neurodegenerative diseases (NDs) which includes Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD) are understood, diagnosed, and treated. It discusses the limitations of current therapies, which mainly address symptoms without altering disease progression. Genetic and molecular factors that influence disease development are described, including distinctions between familial and sporadic forms. The chapter also covers the roles of epigenetic changes, gene expression, protein dysfunction, mitochondrial DNA, and non-coding RNAs in NDs. Biomarkers in blood and cerebrospinal fluid, along with imaging techniques and digital tools, are presented as key elements in early diagnosis and disease monitoring. Patient stratification based on clinical features, molecular profiles, and biomarkers helps guide treatment decisions and improve outcomes. The chapter reviews ongoing developments in genotype-based drug design, gene therapy, pharmacogenomics, and personalized lifestyle strategies. Clinical case studies show how these approaches are being used in practice. The chapter also discusses challenges in applying precision medicine, such as trial design, data integration, unequal access, and regulatory hurdles. Finally, it highlights the future tools like single-cell transcriptomics, digital twins, and global research collaborations that aim to bring precision approaches into everyday care.},
}

Humans
*Precision Medicine/methods
*Neurodegenerative Diseases/therapy/genetics/diagnosis
Biomarkers

@article {pmid41314580,
year = {2025},
author = {Wang, X and Wang, D and Liu, J and Han, F and Liang, P and Yang, J and Xu, W and Ma, J and Wu, Y and An, X and Xue, Y and Chen, H and Zeng, L and Qu, Y and Ai, J},
title = {Systemic delivery of liposome-loaded microRNA-195 ameliorates spatial memory impairment in a rat model of chronic cerebral hypoperfusion.},
journal = {International journal of biological macromolecules},
volume = {},
number = {},
pages = {149290},
doi = {10.1016/j.ijbiomac.2025.149290},
pmid = {41314580},
issn = {1879-0003},
abstract = {Chronic cerebral hypoperfusion (CCH), a subclinical state underlying mild cognitive impairment (MCI), triggers multiple pathological changes associated with Alzheimer's disease (AD) and vascular dementia (VaD), including amyloid-β (Aβ) deposition, tau phosphorylation, microglial activation and neural circuit dysfunction. Developing multitarget therapeutics to effectively prevent the transition from MCI to AD and/or VaD remains an urgent challenge. Herein, we engineered a brain-targeted dual-modified PEGylated nanoliposome (LipTM@miR-195), incorporating mannose (MAN) and the trans-activating protein of HIV type 1 (TAT), which encapsulates polyethyleneimine (PEI) complesed microRNA-195 (miR-195). In a CCH rat model, tail-vein administration of LipTM@miR-195 (0.112 mg/kg) efficiently crossed the blood-brain barrier (BBB) without detectable side effects. Treatment reversed CCH-induced spatial learning and memory deficits, rescued neural circuit dysfunction, and suppressed elevated APP, BACE1, AT8 and CD68 levels. Collectively, these findings provide compelling evidence that LipTM@miR-195 nanoliposome holds therapeutic potential for CCH-induced cognitive impairment, thereby preventing the progression from MCI to AD and/or VaD.},
}

@article {pmid41314098,
year = {2025},
author = {Ye, M and Kim, JS and Shim, I},
title = {CB1 receptor activation and inhibition differentially modulate cognitive deficits and neuropathology in 3xTg-AD mice.},
journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie},
volume = {193},
number = {},
pages = {118818},
doi = {10.1016/j.biopha.2025.118818},
pmid = {41314098},
issn = {1950-6007},
abstract = {Alzheimer's disease (AD) is characterized by amyloid-β (Aβ) deposition, tau hyperphosphorylation, neuroinflammation, oxidative stress, and progressive neuronal loss. The endocannabinoid system regulates synaptic function, inflammation, and redox homeostasis through cannabinoid receptor type 1 (CB1). This study aimed to determine whether pharmacological activation or inhibition of the CB1 receptor differentially modulates Alzheimer's disease-related pathology. 3xTg-AD mice received weekly intraperitoneal injections of the CB1 agonist ACEA (1 mg/kg) or the inverse agonist AM251 (1 mg/kg) from 6 to 12 months of age. Cognitive function was assessed using the Morris Water Maze (MWM) and Y-maze, while hippocampal tissues were analyzed for Aβ, p-Tau, glial markers (GFAP, Iba-1), cytokines (IL-1β, IL-10), oxidative stress markers (SOD, GSH, MDA), and neuronal viability (NeuN). Cerebral glucose metabolism was evaluated using [1] [8]F-FDG positron emission tomography (PET). ACEA administration reduced tau phosphorylation, glial activation, IL-1β expression, and oxidative stress, while increasing IL-10 levels, neuronal preservation, and cerebral glucose metabolism. AM251 treatment aggravated tau pathology, neuroinflammation, oxidative imbalance, and cognitive impairment. Double immunofluorescence demonstrated CB1 receptor colocalization with both Iba-1-positive microglia and GFAP-positive astrocytes, with CB1 predominantly localized to microglia, suggesting a microglia-dependent mechanism underlying CB1-mediated neuroprotection. Aβ levels were not affected by either treatment. Chronic CB1 receptor activation attenuates tau-associated pathology and metabolic dysfunction in 3xTg-AD mice, indicating the therapeutic relevance of CB1 signaling modulation in neurodegenerative disorders.},
}

@article {pmid41313999,
year = {2025},
author = {Pei, Z and Zhu, L and Ren, H and Liu, Y and Shi, X and Lin, Y and Wang, J and Li, P and Wang, P and Ji, Y and Zhou, Y and Tang, X and Jiang, X and Tong, X and Guo, Y},
title = {EEG-based stratification in Alzheimer's disease: Cognitive progression, pathological marker associations, and therapeutic interventions.},
journal = {Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology},
volume = {182},
number = {},
pages = {2111440},
doi = {10.1016/j.clinph.2025.2111440},
pmid = {41313999},
issn = {1872-8952},
abstract = {OBJECTIVE: Clinical cognitive and pathological marker stratification systems have evolved separately, causing mismatches that limit their clinical use. This study retrospectively validated the link between EEG and clinical symptoms, pathological markers, and the therapeutic efficacy of repetitive transcranial magnetic stimulation (rTMS).

METHODS: This multicenter study involved 308 Alzheimer's patients (AD), 176 with Parkinson's (PD), and 181 normal controls. Resting-state EEG were analyzed to identify four oscillation modes. An EEG-based cognitive risk system was created and validated, also evaluating its effect on rTMS therapy effectiveness.

RESULTS: EEG oscillation changes correlated with cognitive decline, revealing distinct brain network disruptions in AD and PD. These oscillation changes were associated with AD biomarkers, particularly tau hyperphosphorylation. Multicenter validation showed an 83% concordance with the Clinical Dementia Rating Scale, and EEG stratification enhanced rTMS therapeutic efficacy.

CONCLUSIONS: This study showed that EEG-based stratification can assess cognitive function, track disease progression, identify key intervention periods, and improve patient selection for better treatment outcomes in clinical settings.

SIGNIFICANCE: This study demonstrates that EEG can connect disease processes to clinical symptoms at a molecular level, offering a unified framework for improved dementia management. This method allows for dynamic monitoring and precise neuromodulation, enhancing personalized care for neurodegenerative diseases.},
}

@article {pmid41313889,
year = {2025},
author = {Jelčić, A and Talić, S and Odak, I and Mlakić, M and Lasić, Z and Roca, S and Šagud, I and Bruketa, T and Bosnar, M and Barić, D and Škorić, I},
title = {Exploring the selective butyrylcholinesterase inhibition potential of phenol carbamates: Experimental and computational study.},
journal = {European journal of medicinal chemistry},
volume = {302},
number = {Pt 3},
pages = {118375},
doi = {10.1016/j.ejmech.2025.118375},
pmid = {41313889},
issn = {1768-3254},
abstract = {A series of fourteen novel phenol carbamates was synthesized and evaluated as potential selective butyrylcholinesterase (BChE) inhibitors targeting cholinergic dysfunction in Alzheimer's disease (AD). The compounds were prepared efficiently from resveratrol analogs via a Wittig reaction followed by carbamoylation, and their structures were confirmed by NMR, MS, and HRMS analyses. All derivatives were screened for inhibitory activity against acetylcholinesterase (AChE) and BChE using a modified Ellman method. None of the compounds inhibited AChE, whereas all selectively inhibited BChE, with IC50 values ranging from 0.045 to 6.840 μM. The most potent inhibitor, compound 13, bearing a pyrrolidine moiety, exhibited an IC50 value of 0.045 μM, outperforming the reference drug galantamine by more than two orders of magnitude. Molecular docking and dynamics simulations confirmed strong π-π and alkyl-π interactions between the ligands and the enzyme's active site, accounting for their high affinity and selectivity. In silico ADME(T) analysis predicted excellent intestinal absorption, blood-brain barrier penetration, and low cytotoxicity, while minor genotoxicity alerts were observed for a few derivatives. In vitro cytotoxicity assays in HepG2 cells confirmed the absence of toxicity at concentrations up to 30 μM. These results highlight methoxy-substituted phenol carbamates, particularly compound 13, as promising lead structures for the design of selective BChE inhibitors and potential therapeutic agents for the treatment of AD.},
}

@article {pmid41313642,
year = {2025},
author = {Mangalmurti, A and Zengeler, KE and Hollis, A and Golden, E and Riddlemoser, G and Lukens, JR},
title = {Microglial CLEC7A restrains amyloid beta plaque pathology in a mouse model of Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {11},
pages = {e70943},
doi = {10.1002/alz.70943},
pmid = {41313642},
issn = {1552-5279},
support = {ADSF-21-816651/ALZ/Alzheimer's Association/United States ; /NH/NIH HHS/United States ; R01AG071996/AG/NIA NIH HHS/United States ; R01AG087406/AG/NIA NIH HHS/United States ; RF1AG078684/AG/NIA NIH HHS/United States ; //Cure Alzheimer's Fund/ ; //The Steven A Newman AD Award/ ; //Rick Sharp Foundation/ ; //Harrison Family Foundation/ ; T32GM007267//Medical Scientist Training Program/ ; T32AI007496//Immunology Training Program/ ; T32AI007496//National Institute of Allergy and Infectious Diseases/ ; T32GM156694/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; *Alzheimer Disease/pathology/metabolism/genetics ; *Plaque, Amyloid/pathology/metabolism ; Disease Models, Animal ; *Microglia/metabolism/pathology ; *Lectins, C-Type/metabolism/genetics ; Mice ; Mice, Transgenic ; Mice, Knockout ; Macrophages/metabolism ; Amyloid beta-Peptides/metabolism ; Humans ; Brain/pathology/metabolism ; },
abstract = {INTRODUCTION: CLEC7A is a surface receptor that is highly upregulated on microglia in many Alzheimer's disease (AD) models. Little is known about the role that microglial CLEC7A signaling plays in AD-related pathogenesis.

METHODS: We utilized an inducible, central nervous system (CNS) macrophage-specific knockout of Clec7a to evaluate the role of CLEC7A in the 5xFAD mouse model of AD at 5 months of age. We used immunofluorescence microscopy, single-nuclei RNA sequencing, along with biochemical assays, to evaluate plaque burden, microglial activity, and neuronal health.

RESULTS: CNS macrophage-targeted deletion of CLEC7A in 5xFAD mice led to a twofold increase in plaque burden, exacerbated neuritic dystrophy, and altered the expression of neuronal health genes, but did not appreciably impact microglial activation, plaque engulfment, or disease-associated microglia acquisition.

DISCUSSION: These findings identify protective roles for CLEC7A in AD-related amyloidosis and suggest that CLEC7A-targeting therapeutics may offer promising strategies for treatment of AD.

HIGHLIGHTS: Conditional loss of CLEC7A in central nervous system (CNS) macrophages of 5xFAD mice results in increased amyloid beta deposition. Loss of CLEC7A does not alter the disease-associated microglia transcriptional program or affect the recruitment of microglia to plaque surfaces. Exacerbation of amyloid deposition with loss of CNS-macrophage CLEC7A is associated with worsened neuronal health highlighted by increased neuritic dystrophy.},
}

Animals
*Alzheimer Disease/pathology/metabolism/genetics
*Plaque, Amyloid/pathology/metabolism
Disease Models, Animal
*Microglia/metabolism/pathology
*Lectins, C-Type/metabolism/genetics
Mice
Mice, Transgenic
Mice, Knockout
Macrophages/metabolism
Amyloid beta-Peptides/metabolism
Humans
Brain/pathology/metabolism

@article {pmid41312814,
year = {2025},
author = {Akpınar, O and Nazıroğlu, M},
title = {Glutathione and TRPM2 Inhibition Reduce Amyloid-Beta and Lipopolysaccharide-Induced Apoptosis, Inflammation, and Oxidative Stress in Microglial Cells.},
journal = {Cell biology international},
volume = {},
number = {},
pages = {},
doi = {10.1002/cbin.70109},
pmid = {41312814},
issn = {1095-8355},
support = {//This study was supported by the Scientific Research Projects Coordination Unit (BAP) of Süleyman Demirel University (project number: TDK-2021-8387). Project owner was Mustafa Nazıroğlu./ ; },
abstract = {Microglia cells impacted by inflammation and Alzheimer's disease produce toxic reactive oxygen species (ROS), emit signaling molecules, and death as a result of microglia being active due to excessive Ca[2+] entering the cells. The TRPM2 channel plays a crucial role in Ca[2+] permeability, inflammation, ROS, and apoptosis changes in the BV2 microglia cells, while glutathione (GSH) treatment reduces the changes through TRPM2 inhibition. However, the effect of TRPM2 inhibitors and GSH treatment on oxidative stress, inflammation, and apoptotic values in BV2 microglia cells activated with LPS and amyloid-beta (Aβ) has not been investigated yet. The study aimed to assess the effects of TRPM2 inhibition and GSH treatment on the values in BV2 cells activated with LPS and Aβ. BV2 cells were divided into five groups: control (CNT), LPS, Aβ, Aβ + LPS, and Aβ + LPS + GSH. Increased levels of inflammation biomarkers (TNF-α, IL-1β, and IL-6), intracellular Ca[2+] level, cytosolic ROS, mitochondrial membrane dysfunction, cell death, apoptosis, caspases (caspase-3, -8, and -9), and TRPM2 current density were observed in the cells stimulated with LPS and Aβ. These values increased more when LPS and Aβ were incubated together. However, these apoptotic, inflammatory, and oxidant levels decreased in cells treated with GSH and TRPM2 blockers. In conclusion, the involvement of TRPM2 stimulation was demonstrated on Aβ and LPS-induced Ca[2+] entry, oxidative stress, inflammation, and apoptosis parameters in microglia cells. TRPM2 inhibition by GSH treatment seems to be a potential source for the prevention of Aβ and LPS-induced oxidative stress, apoptosis, and inflammation.},
}

@article {pmid41312794,
year = {2025},
author = {Healy, M and Thomas, S and Brodtmann, A},
title = {Magnetic resonance imaging eligibility for anti-amyloid monoclonal antibody treatment for Alzheimer disease: a single-centre retrospective review for service planning.},
journal = {Internal medicine journal},
volume = {},
number = {},
pages = {},
doi = {10.1111/imj.70254},
pmid = {41312794},
issn = {1445-5994},
}

@article {pmid41312566,
year = {2025},
author = {Kwinta, R and Morawiec, N and Bączyk, J and Kubicka-Bączyk, K and Adamczyk-Sowa, M},
title = {Aging immunity - the role of T and B cells in neurological disorders among older adults.},
journal = {Neurologia i neurochirurgia polska},
volume = {},
number = {},
pages = {},
doi = {10.5603/pjnns.106498},
pmid = {41312566},
issn = {0028-3843},
abstract = {INTRODUCTION: Immunosenescence is a natural process of immune system aging, which leads to significant changes in the functioning of both innate and adaptive immunity. Alterations in T and B lymphocytes can significantly impact the progression of neurological diseases including multiple sclerosis (MS), Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS).

STATE OF THE ART: Immunosenescence affects T and B cell subsets, reducing their proliferative capacity and altering cytokine profiles. In MS, these changes promote disease progression and diminish responses to immunomodulatory therapies. In AD and PD, dysfunctional T and B cells contribute to sustained neuroinflammation, exacerbating neurodegeneration. ALS is similarly associated with altered adaptive immunity.

CLINICAL IMPLICATIONS: Recognizing how immunosenescent T and B cells contribute to disease in older adults is crucial for refining treatment strategies. These age-related immune changes may explain varied responses to therapies and highlight the need for novel approaches targeting the aged immune system in neurodegenerative diseases.

FUTURE DIRECTIONS: Future research should focus on identifying the mechanisms by which immunosenescent lymphocytes modulate neuroinflammation and neurodegeneration in aging populations. Novel biomarkers and immunomodulatory therapies tailored to older adults could significantly improve outcomes in patients with neurological diseases.},
}

@article {pmid41311387,
year = {2025},
author = {Zhou, Y and Wang, Y and Yang, H and Zhang, C and Meng, J and Zhang, L and Li, K and Huang, LL and Zhang, X and Luo, H and Zhang, Y},
title = {Sorafenib promotes the E3 ubiquitin ligase FBXW7 to increase tau degradation and ameliorate tauopathies.},
journal = {Acta pharmaceutica Sinica. B},
volume = {15},
number = {11},
pages = {5817-5831},
pmid = {41311387},
issn = {2211-3835},
abstract = {Tauopathies, including Alzheimer's disease (AD), are a series of neurodegenerative diseases characterized by pathological accumulation of the microtubule-associated protein tau. Since the abnormal modification and deposition of tau in nerve cells are crucial for tauopathy etiology, methods for reducing tau levels, such as promoting tau degradation, may become effective strategies for disease treatment. Herein, we identified that sorafenib significantly reduced total tau and phosphorylated tau levels through screening FDA-approved drugs. We showed that sorafenib treatment attenuated cognitive deficits and tau pathologies in PS19 tauopathy model mice. Mechanistically, we found that sorafenib inhibited multiple kinases involved in tau phosphorylation and promoted autophagy. Importantly, we further demonstrated that sorafenib also promoted the expression of the E3 ubiquitin ligase FBXW7, which could bind tau and mediate tau degradation through the ubiquitin-proteasome pathway. Finally, we showed that FBXW7 expression decreased in the brains of AD patients and tauopathy model mice, and that overexpression of FBXW7 in the hippocampus attenuated cognitive deficits and tau pathologies in PS19 mice. These results suggest that sorafenib may be a promising treatment option for tauopathies by promoting tau degradation and reducing tau phosphorylation, and that targeting FBXW7 could also serve as an alternative therapeutic strategy for tauopathies.},
}

@article {pmid41311386,
year = {2025},
author = {Zhao, Y and Liu, X and Yang, S and Wang, J and Wu, D and Bu, Y and Xie, X},
title = {Electrochemical biosensors with right-side-out-oriented cell membrane coating for the evaluation of AChE inhibitors as potential anti-Alzheimer's disease agents.},
journal = {Acta pharmaceutica Sinica. B},
volume = {15},
number = {11},
pages = {5988-6000},
pmid = {41311386},
issn = {2211-3835},
abstract = {Biosensors based on acetylcholinesterase (AChE) are crucial for early diagnosis, less invasive treatment, and drug evaluation of Alzheimer's disease (AD). However, existing technologies often suffer from enzyme conformational changes, leading to altered activity and loss and reduced sensor efficacy. To address this challenge, we developed a novel right-side-out-oriented red blood cell membrane-coated electrochemical biosensors (ROCMCBs) to evaluate AChE inhibitors from traditional Chinese medicines (TCMs) as potential anti-AD agents. The developed right-side-out-oriented coating based on immunoaffinity not only fully exposed the binding sites of AChE on the cell membrane but also ensured its conformation and stability as a peripheral membrane-anchoring protein, which was conducive to maintaining its biological activity and producing optimal interaction with drugs. At the same time, the biosensors exhibited a satisfactory sensitivity (limit of detection = 0.41 pmol/L). Ultimately, six potentially active compounds against AD (baicalin, geniposide, gastrodin, berberine, rhynchophylline, and senkyunolide A) were rapidly identified and evaluated from TCMs. This project provides a promising strategy for developing cell membrane-coated electrochemical biosensors. The application of cell membrane-coated electrochemical biosensors with well-defined cell membrane orientation further expands new perspectives and methods for AChE-targeted anti-AD research.},
}

@article {pmid41311299,
year = {2025},
author = {Pini, L and Allali, G and Imbimbo, BP and Germani, M and Corbetta, M},
title = {Brain connectivity as a new target for Alzheimer's disease therapy?.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awaf404},
pmid = {41311299},
issn = {1460-2156},
abstract = {The recent introduction of immunotherapeutic agents targeting amyloid-β (Aβ) has advanced the pharmacological treatment of Alzheimer's disease (AD). Although several anti-Aβ antibodies have dramatically reduced cerebral amyloid plaques, this has not translated into major cognitive or clinical benefits, thus questioning the clinical relevance of these biomarker changes. Indeed, there is an ongoing debate over whether amyloid reduction alone constitutes sufficient evidence of disease modification to justify regulatory approval. Against this backdrop, we propose a third pathway that transcends the binary framework of molecular versus clinical end points by positioning brain connectivity as a system-level intermediate phenotype. This approach is supported by a growing body of evidence. Alterations in brain networks are early, sensitive, and modifiable markers of AD pathology. Connectivity metrics capture the dynamic interplay between genetic and environmental factors, offering a unified model of disease. Advances in precision medicine, such as individualized connectivity 'fingerprints' and the emergence of digital twins, further position brain connectivity as a powerful platform for therapeutic innovation. We argue that adopting brain network analysis as a key outcome measure enables a shift beyond isolated biomarker achievements toward a more integrated, biologically grounded, and clinically meaningful framework for disease modification in AD, bridging the gap between molecular advances and real-world impact.},
}

@article {pmid41311279,
year = {2025},
author = {Garland, H and Jacobson, M and Xu, S and Zissimopoulos, J},
title = {A scoping review of population-based dementia registries: advancing research, care, and policy.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {11},
pages = {e70938},
doi = {10.1002/alz.70938},
pmid = {41311279},
issn = {1552-5279},
mesh = {Humans ; *Registries ; *Dementia/therapy/epidemiology ; *Health Policy ; },
abstract = {Despite their value for public health, research, and care, population-based registries for Alzheimer's disease and related dementias (ADRD) remain limited. We conducted a scoping review of dementia registry studies through December 2023 and identified population-based dementia registries in Organisation for Economic Co-operation and Development countries. We characterized their structure and scope, assessed key themes, and developed recommendations for registry development. We identified 21 population-based dementia registries from a review of 235 publications. These registries help fill gaps in dementia research by providing longitudinal data, improving case identification, and standardizing outcomes for clinical and policy use. However, many registries lack data on healthcare use and caregiving and have limited geographical coverage, thereby reducing their ability to inform research and public health efforts to address dementia burden in an era of rapidly evolving dementia diagnostics and treatments. As dementia cases rise and advancements in prevention, detection, and treatment accelerate, population-based registries are essential for generating real-world evidence to improve dementia care, policy, and outcomes. HIGHLIGHTS: This scoping review identified 21 population-based dementia registries across OECD countries, highlighting the current landscape and structural gaps. Registries provide critical longitudinal data and standardization for research and policy but often lack information on healthcare use, caregiving, and broad geographic representation. With rising dementia rates and evolving treatments, population-based registries are essential for producing real-world evidence to strengthen care, research, and public health planning.},
}

Humans
*Registries
*Dementia/therapy/epidemiology
*Health Policy

@article {pmid41311076,
year = {2025},
author = {Li, X and Zhang, Y and Gu, Y and Chen, N and Qian, X and Zhang, P and Hao, J and Wang, F},
title = {[Association between Tau protein deposition and brain metabolites: N-acetylaspartate and creatine as potential biomarkers for advanced Alzheimer's disease].},
journal = {Nan fang yi ke da xue xue bao = Journal of Southern Medical University},
volume = {45},
number = {11},
pages = {2350-2357},
doi = {10.12122/j.issn.1673-4254.2025.11.07},
pmid = {41311076},
issn = {1673-4254},
mesh = {Humans ; *Alzheimer Disease/metabolism/diagnostic imaging ; *Aspartic Acid/analogs & derivatives/metabolism ; *tau Proteins/metabolism ; *Creatine/metabolism ; *Brain/metabolism ; Biomarkers/metabolism ; Positron-Emission Tomography ; Male ; Female ; Proton Magnetic Resonance Spectroscopy ; Choline/metabolism ; Aged ; Middle Aged ; },
abstract = {OBJECTIVES: To investigate the associations between Tau protein deposition and brain biochemical metabolites detected by proton magnetic resonance spectroscopy ([1]H-MRS) in patients with advanced Alzheimer's disease (AD).

METHODS: From April, 2022 to December, 2024, 64 Tau-positive AD patients and 29 healthy individuals underwent [18]F-APN-1607 PET/MR and simultaneously acquired multi-voxel [1]H-MRS in the Department of Nuclear Medicine, Nanjing First Hospital. Visual analysis and voxel-based analysis of PET/MR data were performed to investigate the Tau protein deposition patterns in AD patients. Valid voxels within the [1]H-MRS field of view were selected, and their standardized uptake value ratio (SUVr) in PET and metabolite levels of N-acetylaspartate (NAA), choline (Cho), creatine (Cr), NAA/Cr, and Cho/Cr were recorded. The Tau-positive (Tau[+]) voxels and Tau-negative (Tau[-]) voxels of the AD patients were compared for PET and [1]H-MRS parameters, and the correlations between the metabolites and Tau PET SUVr within Tau[+] voxels were analyzed.

RESULTS: Significant Tau protein deposition were observed in the AD patients, involving mainly the bilateral frontal lobes (30.07%), parietal lobes (29.96%), temporal lobes (21.07%), and occipital lobes (15.89%). A total of 1422 valid voxels in AD group (including 994 Tau[+] and 428 Tau[-] voxels) and 814 voxels in the control group were selected. The AD patients showed significantly decreased NAA level and increased SUVr compared with the control group (P<0.05). Subgroup analyses revealed that Tau[+] voxels had higher SUVr and lower Cr and Cho/Cr than Tau[-] voxels (P<0.05). Compared with the control group, Tau[+] voxels exhibited higher SUVr and lower Cr (P<0.05), while Tau[-] voxels showed lower NAA (P=0.004). No significant differences were found in Cho or NAA/Cr among the subgroups (P>0.05). Within Tau[+] voxels, NAA, Cho, and Cr were negatively correlated with SUVr (P<0.001).

CONCLUSIONS: The patients with progressive AD have significant Tau protein deposition in the brain, which is correlated with alterations in metabolite levels. Decreased NAA is more prominent in early or pre-tau deposition stages, while Cr changes is more significant in the regions with Tau protein deposition, suggesting the potential of NAA and Cr as biomarkers for Tau protein deposition in AD for disease monitoring and treatment evaluation.},
}

Humans
*Alzheimer Disease/metabolism/diagnostic imaging
*Aspartic Acid/analogs & derivatives/metabolism
*tau Proteins/metabolism
*Creatine/metabolism
*Brain/metabolism
Biomarkers/metabolism
Positron-Emission Tomography
Male
Female
Proton Magnetic Resonance Spectroscopy
Choline/metabolism
Aged
Middle Aged

@article {pmid41309432,
year = {2025},
author = {Bai, N and Liu, S and Wei, J and Zheng, B and Wang, W and Li, X and Yang, J and Song, X and Wang, L and Yi, F and Cao, L},
title = {Sirtuins in Alzheimer's disease: mechanistic insights and therapeutic opportunities.},
journal = {Trends in pharmacological sciences},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.tips.2025.10.016},
pmid = {41309432},
issn = {1873-3735},
abstract = {Alzheimer's disease (AD) is an irreversible neurodegenerative disorder characterized by progressive cognitive decline and complex neuropathology. Its main features include amyloid-β (Aβ) plaques, tau neurofibrillary tangles (NFTs), and neuroinflammation. Current therapies provide only limited symptomatic relief and cannot stop disease progression, highlighting the urgent need for disease-modifying strategies. Recent research has revealed multiple roles of sirtuins in AD pathology, positioning them as promising therapeutic targets. Studies using small-molecule compounds to target sirtuins, in both cellular and animal models and clinical analyses of AD patients, demonstrate their therapeutic potential. This review discusses the distinct roles of individual sirtuin isoforms in AD pathogenesis and evaluates the therapeutic evidence for small-molecule sirtuin modulators.},
}

@article {pmid41309190,
year = {2025},
author = {Shah, A and Karthikeyan, T and Hashem, S and Kumar, R and Bhat, AA and Macha, MA},
title = {Protein misfolding and neurodegeneration: Mechanisms, implications, and therapeutic strategies.},
journal = {Advances in protein chemistry and structural biology},
volume = {148},
number = {},
pages = {135-177},
doi = {10.1016/bs.apcsb.2025.08.012},
pmid = {41309190},
issn = {1876-1631},
mesh = {Humans ; *Protein Folding ; *Neurodegenerative Diseases/metabolism/pathology/drug therapy/therapy ; *Proteostasis Deficiencies/metabolism/pathology/therapy ; Animals ; Proteostasis ; },
abstract = {Protein misfolding and aggregation play a pivotal role in the development of neurodegenerative diseases such as Alzheimer's, Parkinson's, Huntington's disease, and other related disorders. Proper protein folding is essential for cellular function, but due to the complexity of the folding process and external factors like genetic mutations, oxidative stress, and aging, misfolding is inevitable. These misfolded proteins often aggregate into toxic forms that disrupt cellular processes, leading to neuronal damage and cognitive decline. This chapter provides a comprehensive overview of molecular mechanisms behind protein misfolding, highlighting how these abnormal structures contribute to neurodegeneration. It also explores the role of the proteostasis network and its therapeutic potential in alleviating these processes. Focusing on multitarget therapeutic strategies, the chapter offers insights into promising approaches for addressing the root causes of neurodegenerative diseases while identifying key research gaps that could shape future treatment developments. By blending current knowledge with emerging therapeutic directions, this chapter provides a comprehensive and engaging perspective on combating the challenges of protein misfolding in neurodegeneration.},
}

Humans
*Protein Folding
*Neurodegenerative Diseases/metabolism/pathology/drug therapy/therapy
*Proteostasis Deficiencies/metabolism/pathology/therapy
Animals
Proteostasis

@article {pmid41307609,
year = {2025},
author = {Katayama, S and Tsujimoto, M and Suzuki, K and Ueda, K and Shimoura, K and Suo, S and Hatakeyama, N},
title = {Care Partners' Perceptions of Amyloid-Targeting Therapy and Treat‑to‑Clearance for Alzheimer's Disease in Japan: A Qualitative Study.},
journal = {Neurology and therapy},
volume = {},
number = {},
pages = {},
pmid = {41307609},
issn = {2193-8253},
abstract = {INTRODUCTION: Donanemab has been developed as an amyloid-targeting therapy (ATT) for mild cognitive impairment (MCI) and mild dementia due to Alzheimer's disease (AD). In registration trials involving donanemab, a treat‑to‑clearance approach was used, in which patients discontinued ATT when amyloid plaque levels decreased below a predefined threshold, which differs from previously available symptomatic treatments for AD. Our study explored care partners' perceptions regarding ATT and treat‑to‑clearance.

METHODS: This was a cross-sectional, qualitative interview study. Care partners of individuals with MCI or mild dementia due to AD participated in online semi-structured interviews about their perceptions regarding the impact of MCI or mild dementia diagnoses due to AD, the burden of supporting, and use/cessation of ATT. The qualitative data from the interviews were analyzed using a thematic approach.

RESULTS: The participants were 22 care partners (5 male/17 female), and their median age was 59 (range 35-81) years. The most common relationships between care partners and the individuals with AD were child (50.0%) and spouse/partner (45.5%); 68.2% of the care partners lived with the individuals with AD. Thematic analysis identified three major classifications (Thoughts regarding therapy; Treat‑to‑clearance; and Burdens of support), along with 15 themes and five sub-themes. Care partners expressed experiencing mental burden and time constraints, while treat‑to‑clearance could save care partners' time by reducing hospital waiting time and alleviating financial burden. Confirming the clearance of amyloid β plaques provided care partners with a sense of relief, while they remained concerned about the potential progression of AD symptoms and sought follow-up care after stopping treatment.

CONCLUSIONS: These results suggest that providing clear explanations and facilitating shared decision-making when introducing ATT, as well as introducing follow-up care and long-term evidence after stopping treatment, are needed.},
}

@article {pmid41307478,
year = {2025},
author = {Wang, X and Chen, L and Qiu, J and Wang, K and Xi, P and Cheng, X and He, Z and Jiang, H},
title = {Dipeptidyl Peptidase 4 Mediated Caspase-8 Affects Cognitive Impairment in Mice With Alzheimer's Disease.},
journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology},
volume = {39},
number = {23},
pages = {e71264},
doi = {10.1096/fj.202501322RR},
pmid = {41307478},
issn = {1530-6860},
support = {82204837//MOST | NSFC | National Natural Science Foundation of China-Zhejiang Joint Fund for the Integration of Industrialization and Informatization (NSFC-Zhejiang Joint Fund)/ ; 81760207//MOST | NSFC | National Natural Science Foundation of China-Zhejiang Joint Fund for the Integration of Industrialization and Informatization (NSFC-Zhejiang Joint Fund)/ ; LQ23H290004//Zhejiang Provincial Natural Science Foundation of China/ ; 2024AY10021//Jiaxing Science and Technology Plan Project‌/ ; },
mesh = {Animals ; *Alzheimer Disease/metabolism ; Male ; Mice ; *Dipeptidyl Peptidase 4/metabolism/genetics ; Mice, Inbred C57BL ; *Caspase 8/metabolism/genetics ; *Cognitive Dysfunction/metabolism ; Mice, Knockout ; Amyloid beta-Peptides/toxicity ; Disease Models, Animal ; Pyroptosis ; Dipeptidyl-Peptidase IV Inhibitors/pharmacology ; Maze Learning ; Hippocampus/metabolism ; Neurons/metabolism ; },
abstract = {To investigate the effect of dipeptidyl peptidase 4 (DPP4) on cognitive impairment in Alzheimer's disease (AD), the present study used seven-week-old male C57BL/6J and DPP4 knockout mice. The AD model was induced by microinjection of Aβ25-35 into the lateral ventricle. Morris water maze test showed that DPP4 knockout significantly improved the spatial learning and memory abilities of AD mice. Western blot results showed that DPP4 knockout increased the expression levels of BDNF, CREB and Bcl-2 in the hippocampus of AD mice while the expression levels of Caspase-8, pyroptosis-related proteins NLRP3, Caspase-1, GSDMD, IL-118, IL-1β, and apoptosis-related proteins Caspase-3 and Bax were decreased. Similar results were observed after HT22 neurons were treated with Aβ25-35 and the DPP4 inhibitor sitagliptin (Sit). Moreover, the treatment with a Caspase-8 inhibitor (Z-LETD-FMK) showed that the inhibition of Caspase-8 inhibited the expression of NLRP3 and Caspase-1 in the AD model cells, but had no further inhibitory effect under the treatment of Sit. Our results suggest that DPP4 knockout may ameliorate learning and memory dysfunction in AD model mice by regulating pyroptosis and apoptosis pathways through Caspase-8.},
}

Animals
*Alzheimer Disease/metabolism
Male
Mice
*Dipeptidyl Peptidase 4/metabolism/genetics
Mice, Inbred C57BL
*Caspase 8/metabolism/genetics
*Cognitive Dysfunction/metabolism
Mice, Knockout
Amyloid beta-Peptides/toxicity
Disease Models, Animal
Pyroptosis
Dipeptidyl-Peptidase IV Inhibitors/pharmacology
Maze Learning
Hippocampus/metabolism
Neurons/metabolism

@article {pmid41307069,
year = {2025},
author = {Zhang, Y and Qiu, J and Shang, Y and Zhao, X and Yang, S and Chen, Y and Dai, S and Ai, M and Huang, W and Zhang, J and Liu, X},
title = {Impact of DL-3-n-Butylphthalide on Progression in Alzheimer's Disease: A Retrospective Cohort Analysis.},
journal = {Neuropsychiatric disease and treatment},
volume = {21},
number = {},
pages = {2495-2511},
pmid = {41307069},
issn = {1176-6328},
abstract = {OBJECTIVE: To evaluate the efficacy of DL-3-n-butylphthalide (NBP), a synthetic compound that has shown neuroprotective effects, on cognitive function, psychiatric-behavioral symptoms, and daily activities in patients with Alzheimer's disease (AD).

METHODS: This retrospective cohort study included patients with AD treated with or without NBP. Disease deterioration and decline were defined by changes in Clinical Dementia Rating-Sum of Boxes (CDR-SB) over six months. Multivariate logistic regression, inverse probability of treatment weighting (IPTW) and overlap-weighted propensity score matching (PSM) were used to adjust for confounding.

RESULTS: Totally 100 were included in this study, with 39 classified as the NBP group and 61 as the non-NBP group. NBP was associated with lower odds of deterioration (adjusted odds ratio [OR] = 0.19, 95% confidence interval [CI]: 0.04-0.88, p = 0.034) and decline (adjusted OR = 0.10, 95% CI: 0.03-0.49, p = 0.001). In IPTW and PSM analyses, deterioration occurred in 4.31% vs 22.10% and 4.06% vs 24.27%, and decline in 4.31% vs 39.38% and 4.06% vs 44.28% for the NBP and non-NBP groups, respectively.

CONCLUSION: NBP was associated with reduced risks of clinical worsening and helped preserve cognitive and behavioral functions in patients with AD. These results highlight the potential of NBP as a promising therapeutic option in AD management. Future randomized controlled trials are necessary to validate these findings and assess the long-term efficacy of NBP in clinical settings.

SIGNIFICANCE: This real-world study suggests that NBP may slow disease progression and preserve cognitive and behavioral function in AD.},
}

@article {pmid41306895,
year = {2025},
author = {Duncan, GB and Dickson, SP and Kaplan, JM and Johnson, SB and Duke, TM and Dayley, CW and Hendrix, SB and Altstiel, LD and Mallinckrodt, CH},
title = {Leveraging recent advances in plasma biomarkers to optimize early proof of concept trials in Alzheimer's disease.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {11},
number = {4},
pages = {e70183},
pmid = {41306895},
issn = {2352-8737},
abstract = {INTRODUCTION: The importance of biomarkers as a primary outcome or as supportive evidence of clinical effect is rising as the field shifts toward disease-modifying treatments and earlier intervention, because they have lower variability and can indicate disease progression earlier than clinical outcomes. This study assessed the performance of plasma pTau 181 and 217 as a predictive biomarker and potential primary endpoint in early-phase Alzheimer's disease (AD) trials.

METHODS: Summary data from recent monoclonal antibody (mAb) trials including plasma pTau 181 and 217 were analyzed to evaluate associations between plasma pTau 181/217 and clinical outcomes. The suitability of plasma pTau 181/217 as a surrogate endpoint for internal decision making was assessed using Prentice criteria. Simulations were conducted to explore the statistical power of using plasma pTau 181/217 as a primary outcome in dose-escalation, proof-of-concept (POC) trial designs. Additional criteria for biomarker validation were applied to simulated data.

RESULTS: A strong group-level correlation (r = 0.781) was observed between treatment effects on plasma pTau 181/217 and Clinical Dementia Rating scale - Sum of Boxes (CDR-SB). Mean change in plasma pTau 181/217 significantly predicted mean change in CDR-SB (p = 0.013). The treatment effect on pTau 181/217 was ∼2.6 times greater than on CDR-SB. Prentice Criteria 1, 2, and 4 were met or reasonably met; Criterion 3 is not applicable in the POC setting.

CONCLUSION: Plasma pTau 181/217 at 6 months shows future promise to reasonably likely predict clinical benefit for drugs that reduce pTau 181/217 levels, supporting its use as a primary endpoint in early-phase trials. With effect sizes similar to those seen with donanemab, adequately powered trials may require as few as 100 participants. Such trials should include prespecified analyses to evaluate individual-level Prentice criteria, and pTau 181/217 results can be used to predict potential Phase 3 clinical outcomes.

HIGHLIGHTS: The group-level correlation between a biomarker treatment effect and clinical endpoint treatment effect is a measurement of the biomarker's ability to predict clinical outcome.The correlation of group level plasma pT217 or pT181 effect size at 6 months with clinical outcome Clinical Dementia Rating scale - Sum of Boxes (CDR-SB) effect size at 12 months was approximately 0.781 with p values of 0.013.Cohen's d effect size of plasma pTau as an outcome was 2.6 times greater than the Cohen's d of CDR-SB, leading to higher power or lower sample sizes.As a primary endpoint, plasma pTau meets or reasonably meets Prentice Criteria 1, 2, and 4, while Criterion 3 was deemed not applicable in the proof-of-concept study setting.},
}

@article {pmid41306402,
year = {2025},
author = {Riberas-Sánchez, A and García-Brito, S and Vila-Solés, L and Aldavert-Vera, L and Segura-Torres, P and Huguet, G and Carreras-Badosa, G and Kádár, E},
title = {Intracranial self-stimulation mitigates spatial task deficits, modifies miR-146a and miR-495 serum levels and restores hippocampal NRF2 levels in a rat model of sporadic Alzheimer's disease.},
journal = {Frontiers in aging neuroscience},
volume = {17},
number = {},
pages = {1671196},
pmid = {41306402},
issn = {1663-4365},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is the most prevalent neurodegenerative disease associated with aging. While deep brain stimulation (DBS) shows therapeutic promise, the long-term persistence of its effects remains understudied. Expression patterns of circulating miRNAs, proposed diagnostic biomarkers, and their modulation by DBS are still poorly characterized in longitudinal studies. This study investigates the effect of a 13-week prolonged ICSS treatment on spatial memory and serum miRNA expression in a male rat model of sporadic AD (SAD) by intracerebroventricular injection of streptozotocin (STZ).

METHODS: Morris water maze (MWM) tasks were conducted at 1 and 5 months post-STZ. Serum miRNA levels were quantified by qRT-PCR at 29 (Ser0), 73 (Ser1) and 136 (Ser2) days after STZ administration. Corpus callosum thickness and NRF2 protein levels in the hippocampal CA1 region were assessed using Nissl staining and immunohistochemistry, respectively. Target validation of miR-495 was performed via transfection assays in the human neuroblastoma SH-SY5Y cell line.

RESULTS: MFB-ICSS treatment significantly reduced escape latency in the MWM task in the STZ + ICSS group compared to untreated STZ rats at 5 months post-STZ. At Ser0, levels of miR-16, miR-30c, miR-181, miR-191 and miR-196a were significantly increased in STZ group. In STZ rats, miR-146a and miR-495 levels increased from Ser1 to Ser2, an effect not observed in the Control or STZ + ICSS groups. In SH-SY5Y cells, miR-495 overexpression significantly downregulated both NRF2 mRNA and protein levels. Moreover, STZ exposure increased miR-495 and reduced NRF2 protein levels. MFB-ICSS also reversed the STZ-induced reductions in both CA1 NRF2 levels and corpus callosum thickness.

CONCLUSION: Prolonged MFB-ICSS treatment mitigates cognitive deficits, modulates circulating levels of miRNA-495 and miR-146a, restores hippocampal NRF2 levels, and preserves corpus callosum integrity in the SAD rat model by STZ injection. These findings highlight the therapeutic potential of MFB-ICSS as a non-pharmacological intervention in AD. Furthermore, this study confirms NRF2 as a target of miR-495 in the context of AD.},
}

@article {pmid41306115,
year = {2025},
author = {Li, G and Cobb, B and Nelson, TM and Devanarayan, V and Borentain, S and Mielke, MM and Galvin, JE and Kivipelto, M and Tkatch, R and De Santi, S and Frech, F and Vandercappellen, J and Nakamura, Y and Crislip, R and Meyerhoff, J and Mattke, S and Hampel, H},
title = {Risk prediction of mild cognitive impairment using electronic health record data.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {17},
number = {4},
pages = {e70209},
pmid = {41306115},
issn = {2352-8729},
abstract = {INTRODUCTION: Mild cognitive impairment (MCI) is underdiagnosed by primary care providers (PCPs), with detection rates as low as 6%-15%. Predictive models support the identification of individuals at risk, enabling timely intervention.

METHODS: This retrospective study was conducted on 271,054 cognitively unimpaired and 14,501 confirmed MCI cohorts from electronic health records. A machine learning model was developed with a data-driven variable selection approach based on demographics and comorbidities.

RESULTS: From 101 variables, 26 were chosen for the final model, achieving an overall area under the curve (AUC) of 86%. Age-stratified AUCs were 79.1% (40-49), 77.0% (50-64), 76.9% (65-79), and 74.4% (≥80), showing the highest predictive performance in younger age groups.

DISCUSSION: Demographic factors and comorbidities can serve as effective predictors for the risk of MCI. The model demonstrates strong predictive performance and assists as a triage tool for PCPs, facilitating the identification of individuals with MCI for early treatment.

HIGHLIGHTS: Predictive algorithms using electronic health records (EHRs) are useful for identifying individuals at risk for mild cognitive impairment (MCI) to triage for further clinical evaluation.A machine learning model was developed using EHR data to predict those at risk for MCI.The model identified 26 variables that were able to distinguish the MCI from non-MCI cohorts.The model accurately detected MCI across the cohort (area under the curve [AUC] = 86%) and trended best for younger age groups (AUC was 77%, 77%, and 74% in 50-64, 65-79, and ≥80 age groups, respectively).Implementation of a triage tool could be used to detect MCI across aging patient populations sooner, leading to a timelier diagnosis, intervention, and treatment management.},
}

@article {pmid41304967,
year = {2025},
author = {Akantibila, M and Carabetta, VJ},
title = {Sirtuins as Therapeutic Targets for Treating Cancer, Metabolic Diseases, and Neurodegenerative Diseases.},
journal = {Pharmaceuticals (Basel, Switzerland)},
volume = {18},
number = {11},
pages = {},
doi = {10.3390/ph18111723},
pmid = {41304967},
issn = {1424-8247},
support = {R35GM138303/GM/NIGMS NIH HHS/United States ; },
abstract = {Sirtuins are NAD[+]-dependent enzymes that are conserved in all domains of life, including mammals, metazoans, plasmodia, yeast, bacteria, and archaea. In humans, there are seven isoforms (SIRT1 to 7), and they function in cellular homeostasis, aging, DNA repair, survival, metabolism, and stress responses. Recent advances highlight the diverse functions of sirtuins in the pathogenesis and progression of cancer, metabolic diseases, and neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD). To date, there is evidence that all seven isoforms contribute to cancer development, while SIRT1-3 and 6 contribute to metabolic and neurodegenerative diseases. Modulators of sirtuin activity are being actively explored to understand their biological and molecular mechanisms and potential for the treatment of various diseases. In this review, we begin with a broad discussion of post-translational modifications, protein deacetylation, and the mechanism of action of sirtuins. Next, we discuss the role of sirtuins in cancer, including inhibitors and activators of sirtuin activity as cancer therapies. In addition, we discuss the relationship of sirtuins to metabolic diseases and as possible treatment targets. Finally, we discuss the role of sirtuins in AD, PD, and HD, and sirtuin modulators for treating neurodegenerative diseases.},
}

@article {pmid41304930,
year = {2025},
author = {Almaghrabi, M},
title = {Multitarget-Directed Ligands for Alzheimer's Disease: Recent Novel MTDLs and Mechanistic Insights.},
journal = {Pharmaceuticals (Basel, Switzerland)},
volume = {18},
number = {11},
pages = {},
doi = {10.3390/ph18111685},
pmid = {41304930},
issn = {1424-8247},
support = {447-13-1011//Taibah University/ ; },
abstract = {Alzheimer's disease (AD) is the most prevalent neurodegenerative disease, affecting millions of people and challenging the public health framework globally. While the definitive cause of AD remains unclear, researchers are concentrating their efforts on several prominent theories. Currently, there are very few FDA-approved medications for AD, and these primarily alleviate symptoms rather than alter the disease's progression. In response, research efforts focus on developing new medicines that address the complex nature of AD through multi-targeted approaches. Multitarget-directed ligands (MTDLs) are a promising treatment strategy for AD, despite the significant challenges they pose. This review examines recent advancements in designing prospective targeted MTDLs to combat AD, with a focus on categorizing the lead generation process and investigating the integration methods of key pharmacophores within the 2024-2025 timeframe. The review highlights numerous examples of novel MTDLs that address various AD hallmarks, demonstrating their broad therapeutic potential. These targets and activities include cholinesterase (AChE and/or BuChE) inhibition, monoamine oxidase (MAO-A and/or MAO-B) inhibition, antioxidant activity, amyloid-beta (Aβ) aggregation inhibition, tau protein aggregation inhibition, glycogen synthase kinase 3β (GSK-3β) inhibition, calcium channel blockade, anti-inflammatory activity, and other hallmarks.},
}

@article {pmid41304419,
year = {2025},
author = {Ezzaki, C and Chaari, A and Al-Othman, A},
title = {Recent Advances on Chitosan-Based Nanoparticles for Brain Drug Delivery.},
journal = {Polymers},
volume = {17},
number = {22},
pages = {},
doi = {10.3390/polym17223055},
pmid = {41304419},
issn = {2073-4360},
abstract = {The blood-brain barrier (BBB) represents a major challenge in effective drug delivery systems intended for treating neurological disorders. It restricts the transport of therapeutic agents to the brain. Chitosan-based nanoparticles (CNPs) can be used for brain drug delivery because of their biocompatibility, biodegradability, and ability to enhance drug permeability across the BBB. This review article discusses the design and application of CNPs for brain-targeted drug delivery, exploring their mechanisms of action, including adsorptive-mediated and receptor-mediated endocytosis. Surface modifications with ligands such as chlorotoxin are discussed for improving specificity and therapeutic results. Findings show that CNPs allow controlled drug release, enhance stability, and reduce side effects, which make them effective for treating multiple neurological conditions, including Alzheimer's disease, Parkinson's disease, brain tumors, and ischemic stroke. CNPs can encapsulate multiple therapeutic agents, such as anti-inflammatory drugs, cytotoxic agents, and genetic materials, and maintain stability under different physiological conditions. Intranasal delivery routes are mainly discussed in this paper for their ability to bypass systemic circulation and achieve direct brain targeting. This review also addresses challenges such as cytotoxicity and the need for optimizing nanoparticle size, charge, and surface properties to improve the therapy results. While CNPs are suitable for brain drug delivery, there is a research gap, which is the lack of systematic studies evaluating their long-term effects on brain tissue and health. Most studies focus on acute therapeutic outcomes and in vitro or short-term in vivo analysis, which do not address some questions about the chronic exposure risks, biodistribution, and clearance pathways of CNPs. This review also explores the use of chitosan-based nanoparticles to deliver drugs to the brain for the treatment of multiple neurological disorders.},
}

@article {pmid41303831,
year = {2025},
author = {Uehara, MA and Kalia, S and Garcia Campuzano, M and Moussavi, Z},
title = {ADAS-Cog Trajectories Differ from Expected Decline in Dementia Following Repeated Non-Invasive Interventions over 3 Years.},
journal = {Medicina (Kaunas, Lithuania)},
volume = {61},
number = {11},
pages = {},
doi = {10.3390/medicina61111994},
pmid = {41303831},
issn = {1648-9144},
support = {RGPIN-2023-04308//Natural Sciences and Engineering Research Council of Canada/ ; IT43832//Mitacs/ ; },
mesh = {Humans ; Male ; Female ; Aged ; *Dementia/therapy/psychology ; Aged, 80 and over ; Transcranial Magnetic Stimulation/methods ; *Cognitive Dysfunction/therapy ; Disease Progression ; Alzheimer Disease/therapy/psychology ; Longitudinal Studies ; Neuropsychological Tests ; Middle Aged ; Mental Status and Dementia Tests ; },
abstract = {Background and Objectives: Non-pharmaceutical interventions such as cognitive training, transcranial electrical stimulation (tES), and repetitive transcranial magnetic stimulation (rTMS) have shown promise in improving cognitive outcomes in Alzheimer's disease (AD) and dementia. However, the long-term effects of repeated non-invasive interventions remain unknown. This study investigated whether repeated non-invasive interventions administered over a span of 1 to 3 years were associated with slower cognitive decline compared to typical AD progression, and whether longer no-treatment intervals between treatments predicted greater post-treatment decline. Materials and Methods: Seventy-three participants living with dementia or AD received 2 to 9 blocks of non-invasive treatments (including tES, rTMS, cognitive training). Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog) scores were collected longitudinally up to 3 years (36 months), across multiple intervention and assessment sessions. A mixed-effects model was used to estimate the rate of cognitive decline, adjusting for baseline age, sex, and baseline cognition (MoCA) with participants being the random effect. The observed rate of change was compared to a meta-analysis estimate of AD progression. Additionally, a linear mixed-effects model using robust sandwich estimation of standard errors was employed to assess whether the no-treatment interval was associated with changes in ADAS-Cog scores. Results: Participants showed a significantly slower rate of cognitive decline than expected from the AD reference rate (p < 0.001), with many demonstrating stabilized ADAS-Cog scores during their respective treatment periods, ranging from 1 to 3 years. Medication analyses revealed no significant effect of AD medications, antidepressants, antihypertensives, or cholesterol-lowering agents on cognitive outcomes. Furthermore, longer no-treatment intervals were significantly associated with greater post-treatment decline (p < 0.001). Conclusions: Repeated non-invasive treatments seem to slow the rate of cognitive decline in individuals living with dementia when administered over a prolonged period. This study provides evidence supporting the feasibility and effects of personalized long-term non-invasive treatment strategies for dementia.},
}

Humans
Male
Female
Aged
*Dementia/therapy/psychology
Aged, 80 and over
Transcranial Magnetic Stimulation/methods
*Cognitive Dysfunction/therapy
Disease Progression
Alzheimer Disease/therapy/psychology
Longitudinal Studies
Neuropsychological Tests
Middle Aged
Mental Status and Dementia Tests

@article {pmid41303478,
year = {2025},
author = {Polishchuk, H and Guzik, K and Kantyka, T},
title = {Beyond Hunger: The Structure, Signaling, and Systemic Roles of Ghrelin.},
journal = {International journal of molecular sciences},
volume = {26},
number = {22},
pages = {},
doi = {10.3390/ijms262210996},
pmid = {41303478},
issn = {1422-0067},
support = {UMO-2016/22/E/NZ5/00332//National Science Centre/ ; },
mesh = {*Ghrelin/metabolism/chemistry ; Humans ; *Signal Transduction ; Animals ; *Receptors, Ghrelin/metabolism/chemistry ; *Hunger/physiology ; },
abstract = {Our understanding of Ghrelin, an endogenous ligand of the growth hormone secretagogue receptor 1a (GHSR1a), has expanded from considering it to be a "hunger hormone" to a pleiotropic regulator of whole-body physiology. This review synthesizes the current advances spanning ghrelin biogenesis, signaling, and systems biology. Physiologically, preproghrelin processing and O-acylation by ghrelin O-acyltransferase (GOAT) generate acyl-ghrelin, a high-potency GHSR1a agonist; des-acyl ghrelin predominates in circulation and exerts context-dependent, GHSR1a-independent, or low-potency effects, while truncated "mini-ghrelins" can act as competitive antagonists. The emergence of synthetic ligands, agonists, antagonists, and reverse-agonists has provided the necessary tools to decipher GHSR1a activity. Recent cryo-EM structures of GHSR1a with peptide and small-molecule ligands reveal a bipartite binding pocket and provide a framework for biased signaling, constitutive activity, and receptor partner selectivity. Beyond the regulation of feeding and growth-hormone release, ghrelin modulates glucose homeostasis, gastric secretion and motility, cardiovascular tone, bone remodeling, renal hemodynamics, and innate immunity. Ghrelin broadly dampens pro-inflammatory responses and promotes reparative macrophage phenotypes. In the emerging scholarship on ghrelin's activity in the central nervous system, ghrelin has been found to influence neuroprotection, stress reactivity, and sleep architecture, and has also been implicated in depression, Alzheimer's disease, and substance-abuse disorders. Practical and transitional aspects are also highlighted in the literature: approaches for ghrelin stabilization; recent GHSR1a agonists/antagonists and inverse agonists findings; LEAP-2-based strategies; and emerging GOAT inhibitors. Together, structural insights and pathway selectivity position the ghrelin system as a druggable axis for the management of inflammatory diseases, neuropsychiatric and addiction conditions, and for obesity treatment in the post-GLP-1 receptor agonist era.},
}

*Ghrelin/metabolism/chemistry
Humans
*Signal Transduction
Animals
*Receptors, Ghrelin/metabolism/chemistry
*Hunger/physiology

@article {pmid41303365,
year = {2025},
author = {Faa, G and Meloni, C and Lastretti, M and Pinna, M and Manchia, M and Paribello, P},
title = {Perturbations of Zinc Homeostasis and Onset of Neuropsychiatric Disorders.},
journal = {International journal of molecular sciences},
volume = {26},
number = {22},
pages = {},
doi = {10.3390/ijms262210877},
pmid = {41303365},
issn = {1422-0067},
mesh = {Humans ; *Zinc/metabolism ; *Homeostasis ; *Mental Disorders/metabolism/etiology ; Attention Deficit Disorder with Hyperactivity/metabolism ; Animals ; Schizophrenia/metabolism ; Depressive Disorder, Major/metabolism ; Alzheimer Disease/metabolism ; Autism Spectrum Disorder/metabolism ; Parkinson Disease/metabolism ; Bipolar Disorder/metabolism ; },
abstract = {Zinc (Zn[2+]) is a trace element essential for its catalytic, antioxidant, and immunomodulatory roles extending to synaptic signalling in the central nervous system. In this narrative review, we aim to offer the reader evidence linking perturbations of the Zn[2+] homeostasis, including deficiency, excess, or transportation anomalies, to neuropsychiatric conditions such as Alzheimer's disease (AD), Parkinson's disease (PD), autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), schizophrenia (SCZ), major depressive disorder (MDD), and bipolar disorder (BD). A targeted, unsystematic PubMed search followed by an extensive pearl-growing strategy was applied to further augment study selection based on the extensive expertise of study authors. Overall, most of the evidence currently available suggests a modest benefit for a Zn[2+] supplement of around 25-30 mg/day as an augmentation to MDD treatment, with potential benefits of smaller magnitude in paediatric ADHD. Evidence for perturbations of Zn[2+] as a biomarker of risk for these neuropsychiatric disorders remains unconvincing. The role of Zn[2+] supplements in the treatment of the selected conditions remains largely unknown due to the lack of specific, randomised controlled trials conducted to explore their efficacy. The long-term safety, optimal doses for specific applications, and the exploration of possible biomarkers to stratify patient selection to identify the optimal candidate for Zn[2+] supplements remain unanswered questions.},
}

Humans
*Zinc/metabolism
*Homeostasis
*Mental Disorders/metabolism/etiology
Attention Deficit Disorder with Hyperactivity/metabolism
Animals
Schizophrenia/metabolism
Depressive Disorder, Major/metabolism
Alzheimer Disease/metabolism
Autism Spectrum Disorder/metabolism
Parkinson Disease/metabolism
Bipolar Disorder/metabolism

@article {pmid41303334,
year = {2025},
author = {Pecoraro, M and Serra, A and Lamberti, MJ and Pascale, M and Franceschelli, S},
title = {New Role of Protein Misfolding Corrector in the ER Stress-Inflammation Axis: Possible Therapeutic Indication in Neuronal and Epithelial Tumor Cells.},
journal = {International journal of molecular sciences},
volume = {26},
number = {22},
pages = {},
doi = {10.3390/ijms262210846},
pmid = {41303334},
issn = {1422-0067},
support = {ORSA231580//University of Salerno/ ; },
mesh = {Humans ; *Endoplasmic Reticulum Stress/drug effects ; *Inflammation/metabolism/drug therapy ; *Neurons/metabolism/drug effects/pathology ; Protein Folding/drug effects ; Calcium/metabolism ; Cell Line, Tumor ; Thapsigargin/pharmacology ; A549 Cells ; Epithelial Cells/metabolism/drug effects ; Proteostasis Deficiencies/drug therapy/metabolism ; },
abstract = {Protein misfolding diseases are characterized by structurally abnormal proteins that lose their functionality, resulting in cellular and tissue dysfunction. Neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease and Huntington's disease, share a common etiopathogenesis characterize by the accumulation of misfolded proteins. These proteins autonomously aggregate within neuronal cells, triggering inflammation and cell death. The accumulation of misfolded proteins triggers endoplasmic reticulum (ER) stress, leading to alter Ca[2+] homeostasis. This prolonged stress condition induces the cleavage of procaspase 4 which is resident in ER and activates NF-kB pathway activation, leading to inflammatory responses and cell death. In this study, the efficacy of the drug Vx-445 (Elexacaftor), used in the pharmacological treatment of cystic fibrosis, was assessed in human adenocarcinomic basal alveolar epithelial (A549) and neuronal (SH-SY5Y) cell lines, where ER stress was induced by Thapsigargin. The aim was to assess whether the corrector was able to reduce ER stress by restoring cellular homeostasis and, probably, the proper folding of misfolded proteins and reducing the inflammatory response triggered by these events. Therefore, protein levels of IkBα, p-STAT 3 and COXII were analyzed by flow cytofluorimetry, while Ca[2+] content was measured by spectrofluorimetry. The results obtained suggest a significant effect of Vx-445 in restoring cellular homeostasis, leading to reduced expression of inflammation-related proteins, such as IL-6, tested by ELISA. Although preliminary, these results encourage further studies to explore the potential repurpose of Vx-445 as a therapeutic candidate for conditions involving ER stress and chronic inflammatory diseases associated with protein misfolding, beyond its current use in cystic fibrosis.},
}

Humans
*Endoplasmic Reticulum Stress/drug effects
*Inflammation/metabolism/drug therapy
*Neurons/metabolism/drug effects/pathology
Protein Folding/drug effects
Calcium/metabolism
Cell Line, Tumor
Thapsigargin/pharmacology
A549 Cells
Epithelial Cells/metabolism/drug effects
Proteostasis Deficiencies/drug therapy/metabolism

@article {pmid41301832,
year = {2025},
author = {Christodoulou, RC and Papageorgiou, PS and Sarquis, MD and Rivera, L and Morales Gonzalez, C and Eller, D and Rivera, G and Petrou, V and Vamvouras, G and Vassiliou, E and Papageorgiou, SG and Georgiou, MF},
title = {From Lesion to Decision: AI for ARIA Detection and Predictive Imaging in Alzheimer's Disease.},
journal = {Biomedicines},
volume = {13},
number = {11},
pages = {},
doi = {10.3390/biomedicines13112739},
pmid = {41301832},
issn = {2227-9059},
abstract = {Background: Alzheimer's disease (AD) remains the leading cause of dementia worldwide, with anti-amyloid monoclonal antibodies (MABs) marking a significant advance as the first disease-modifying therapies. Their use, however, is limited by amyloid-related imaging abnormalities (ARIA), which appear as vasogenic edema or effusion (ARIA-E) and hemosiderin-related changes (ARIA-H) on MRI. Variability in imaging protocols, subtle early findings, and the lack of standardized risk models challenge detection and management. Methods: This narrative review summarizes current artificial intelligence (AI) applications for ARIA detection and risk prediction. A comprehensive literature search across PubMed, Embase, and Scopus identified studies focusing on MRI-based AI analysis, lesion quantification, and predictive modeling. Results: The evidence is organized into six thematic domains: ARIA definitions, imaging challenges, foundations of AI in neuroimaging, detection tools, predictive frameworks, and future perspectives. Conclusions: AI offers promising avenues to standardize ARIA evaluation, improve lesion quantification, and enable individualized risk prediction. Progress will depend on multicenter datasets, shared frameworks, and prospective validation. Ultimately, AI-driven neuroimaging may transform how treatment-related complications are monitored in the era of anti-amyloid therapy.},
}

@article {pmid41301782,
year = {2025},
author = {Christodoulou, RC and Vamvouras, G and Papageorgiou, PS and Sarquis, MD and Petrou, V and Rivera, L and Morales, C and Rivera, G and Papageorgiou, SG and Vassiliou, E},
title = {Interpretable Machine Learning for Risk Stratification of Hippocampal Atrophy in Alzheimer's Disease Using CSF Erythrocyte Load and Clinical Data.},
journal = {Biomedicines},
volume = {13},
number = {11},
pages = {},
doi = {10.3390/biomedicines13112689},
pmid = {41301782},
issn = {2227-9059},
abstract = {Background/Objectives: Hippocampal atrophy indicates Alzheimer's disease (AD) progression and guides follow-up and trial enrichment. Identifying high-risk patients is crucial for optimizing care, but accessible, interpretable machine-learning models (ML) are limited. We developed an explainable ML model using clinical data and CSF erythrocyte load (CTRED) to classify adults with AD as high- or low-risk based on hippocampal volume decline. Methods: Included ADNI participants with ≥2 MRIs, baseline lumbar puncture, and vital signs within 6 months of MRI (n = 26). The outcome was the Annual Percentage Change (APC) in hippocampal volume, classified as low or high risk. Predictors were standardized; models included SVM, logistic regression, and Ridge Classifier, tuned and tested on a set (n = 6). Thresholds were based on out-of-fold predictions under a 10-90% positive rate. Explainability used PFI and SHAP for per-patient contributions. Results: All models gave identical classifications, but discrimination varied: Ridge AUC = 1.00, logistic = 0.889, and SVM = 0.667. PFI highlighted MAPres and sex as main signals; CTRED contributed, and age had a minor impact. Conclusions: The explainable ML model with clinical data and CTRED can stratify AD patients by hippocampal atrophy risk, aiding follow-up and vascular assessment planning rather than treatment decisions. Validation in larger cohorts is needed. This is the first ML study to use CSF erythrocyte load to predict hippocampal atrophy risk in AD.},
}

@article {pmid41301520,
year = {2025},
author = {Lope-Piedrafita, S and Serra-Mir, G and Melón, P and Bonaterra, A and Hernández-Guillamon, M and Villegas, S},
title = {ScFv-h3D6 Prevents Bapineuzumab-Induced Hemorrhagic Events in the APP23 Mouse Model of Alzheimer's Disease.},
journal = {Biomolecules},
volume = {15},
number = {11},
pages = {},
doi = {10.3390/biom15111602},
pmid = {41301520},
issn = {2218-273X},
support = {SAF2017-89613R//Ministerio de Economía y Empresa, Spain/ ; PI17-00275//Instituto de Salud Carlos III/ ; },
mesh = {Animals ; *Alzheimer Disease/drug therapy/pathology/metabolism/genetics/diagnostic imaging ; *Single-Chain Antibodies/pharmacology ; Mice ; Disease Models, Animal ; Mice, Transgenic ; *Antibodies, Monoclonal, Humanized/adverse effects ; Humans ; Amyloid beta-Peptides/metabolism ; Cerebral Amyloid Angiopathy/drug therapy ; Magnetic Resonance Imaging ; Amyloid beta-Protein Precursor/genetics ; },
abstract = {The occurrence of amyloid-related imaging abnormalities (ARIAs), found in clinical trials for Aβ-immunotherapy, has been related to the antibody's effector function on glial activation by the Fc portion of the antibody. The use of single-chain variable fragments (scFv) has been proposed as a safer therapeutic strategy. Here, the effects of the mice format of bapineuzumap (mAb-m3D6) and its scFv (scFv-h3D6) on the occurrence of ARIAs in the APP23 mouse model of Alzheimer's disease (AD) and cerebral amyloid angiopathy (CAA) have been addressed by magnetic resonance imaging (MRI). Results are supported by histological and/or biochemical determinations. Aged APP23 mice showed a significantly higher number of microhemorrhages than non-transgenic mice. mAb-m3D6 produced an increase in the number of new hemorrhagic events, mainly in the cortex, whereas scFv-h3D6 did not. Both mAb-m3D6 and scFv-h3D6 reduced Aβ levels by the same extent. Axonal/myelin damage was found in the frontal corpus callosum of APP23 mice, which did not recover after treatment. In conclusion, the scFv-h3D6 format appears safer than the full-length mAb in the APP23 model of AD and CAA. This finding is highly relevant in light of the new FDA- and EMA-approved mAbs, which exclude APOEε4 allele carriers due to the occurrence of hemorrhages.},
}

Animals
*Alzheimer Disease/drug therapy/pathology/metabolism/genetics/diagnostic imaging
*Single-Chain Antibodies/pharmacology
Mice
Disease Models, Animal
Mice, Transgenic
*Antibodies, Monoclonal, Humanized/adverse effects
Humans
Amyloid beta-Peptides/metabolism
Cerebral Amyloid Angiopathy/drug therapy
Magnetic Resonance Imaging
Amyloid beta-Protein Precursor/genetics

@article {pmid41301403,
year = {2025},
author = {Zhang, S and Liu, X and Xu, S and Li, W and Song, J and Tian, Q and Du, Y},
title = {Multi-Omics Integration Reveals Electroacupuncture Ameliorates Cognitive Impairment in Alzheimer's Disease via Gut-Brain Axis.},
journal = {Biomolecules},
volume = {15},
number = {11},
pages = {},
doi = {10.3390/biom15111486},
pmid = {41301403},
issn = {2218-273X},
support = {82374564//National Natural Science Foundation of China/ ; 81873380//National Natural Science Foundation of China/ ; 82074566//National Natural Science Foundation of China/ ; 2025AFD596//Hubei Provincial Joint Fund Project/ ; },
mesh = {Animals ; *Electroacupuncture/methods ; *Alzheimer Disease/therapy/metabolism/microbiology ; Mice ; *Gastrointestinal Microbiome ; *Cognitive Dysfunction/therapy/metabolism ; Male ; *Brain/metabolism ; Disease Models, Animal ; Metabolomics ; RNA, Ribosomal, 16S/genetics ; Metabolome ; *Brain-Gut Axis ; Multiomics ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) lacks effective therapeutic strategies. Electroacupuncture (EA) offers promising neuroprotective effects, but its underlying mechanisms remain unclear.

OBJECTIVE: To explore the mechanisms of EA's neuroprotective effects on AD via microbiome and metabolome integration.

METHODS: Utilizing a well-established model of AD, Senescence-Accelerated Mouse Prone 8 (SAMP8), EA intervention was performed. 16S ribosomal RNA (rRNA) sequencing and serum metabolomics were conducted on SAMP8 mice, SAMP8 mice after EA intervention, and their normal control group Senescence-Accelerated Mouse Resistant 1 (SAMR1) mice.

RESULTS: SAMP8 mice were subjected to electroacupuncture (EA) treatment at the Baihui (GV20) and Shenshu (BL23) acupoints for 15 min daily over a period of four weeks. EA enhanced cognitive function and reduced neuronal damage in AD models. The treatment lowered pro-inflammatory cytokines (TNF-α, IL-1β) and AD-related pathologies (tau, Aβ1-42). EA also rebalanced gut microbiota by increasing beneficial Gastranaerophilales while decreasing harmful Proteobacteria. Additionally, it restored purine and phenylpropanoid metabolism by regulating key metabolites. Importantly, EA reduced levels of specific metabolites linked to pro-inflammatory bacteria (Sphingomonas, Massilia, Escherichia-Shigella), simultaneously decreasing their abundance. These findings highlight EA's multi-target effects on neuroinflammation, gut microbiota, and metabolic pathways in AD. Notably, the interactions between EA-regulated key metabolites and AD-related targets, predicted via PubChem and ChEMBL databases, remain computational and have not been validated by experimental studies.

CONCLUSIONS: EA exerts neuroprotective effects in AD via modulation of gut microbiota and metabolic pathways, representing a novel non-pharmacological therapeutic strategy.},
}

Animals
*Electroacupuncture/methods
*Alzheimer Disease/therapy/metabolism/microbiology
Mice
*Gastrointestinal Microbiome
*Cognitive Dysfunction/therapy/metabolism
Male
*Brain/metabolism
Disease Models, Animal
Metabolomics
RNA, Ribosomal, 16S/genetics
Metabolome
*Brain-Gut Axis
Multiomics

@article {pmid41301354,
year = {2025},
author = {Gao, J and Liu, L and Yang, Z and Fan, J and For The Alzheimer's Disease Neuroimaging Initiative, },
title = {Predictors of Transition from Mild Cognitive Impairment to Normal Cognition and Dementia.},
journal = {Behavioral sciences (Basel, Switzerland)},
volume = {15},
number = {11},
pages = {},
doi = {10.3390/bs15111552},
pmid = {41301354},
issn = {2076-328X},
support = {2024-BS-160//Natural Science Foundation of Liaoning Province/ ; LJ212410165004//Education Department Project of Liaoning Province/ ; 2024BSL004//Ph.D. Start-up Project of Liaoning Normal University/ ; },
abstract = {Mild cognitive impairment (MCI) represents a heterogeneous state between normal aging and dementia, with varied transition pathways. While factors influencing MCI progression are known, their role in cognitive reversal is unclear. This study analyzed 756 Alzheimer's Disease Neuroimaging Initiative (ADNI) participants, classified as progressive MCI (pMCI, N = 272, mean age = 75.10 ± 7.34 years), reversible MCI (rMCI, N = 52, mean age = 69.94 ± 7.98 years) and stable MCI (sMCI, N = 432, mean age = 73.34 ± 7.44 years) based on 36-month follow-up. We compared demographic, lifestyle, clinical, cognitive, neuroimaging, and biomarker data across groups and developed a prediction model. Patients in the rMCI group were significantly younger and had a higher level of education compared with those in the pMCI group. Memory, general cognition, daily functional activities, and hippocampal volume effectively distinguished all three groups. In contrast, Aβ, tau, and other brain regions were able to distinguish only between progressive and non-progressive cases. Informant-reported Everyday Cognition (Ecog) scales outperformed self-reported Ecog scales in differentiating subtypes and predicting progression. Multinomial regression revealed that higher education, larger hippocampal volume, and lower daily functional impairment were associated with reversion, whereas APOE ε4, poorer memory, and greater brain atrophy predicted progression (model accuracy: 78%). The results confirm the significant utility of hippocampal volume, education level, and daily functional activities for assessing baseline disparities and predicting reversion. This study highlights the differential contributions of cognitive abilities and brain regions on MCI reversal, advancing understanding of MCI heterogeneity and providing evidence for precise diagnosis and treatment in early MCI.},
}

@article {pmid41300531,
year = {2025},
author = {Valle, ML and Getaneh, B and William, C and Ghiso, J and Rostagno, A},
title = {Antioxidants Trolox and Methazolamide Protect Microvascular Endothelial Cells from Oxidative Damage Induced by Sporadic and Familial Forms of Oligomeric Amyloid-β.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {14},
number = {11},
pages = {},
doi = {10.3390/antiox14111375},
pmid = {41300531},
issn = {2076-3921},
support = {AG065651//National Institute of Health/ ; },
abstract = {Cerebral amyloid angiopathy (CAA), present in more than 90% of Alzheimer's disease (AD) cases, associates with focal ischemia and neurovascular dysfunction. Genetic variants at positions 21-23 of amyloid beta (Aβ), among them the Dutch mutation (AβE22Q), are primarily linked to CAA and the development of cerebral hemorrhages. An important contributor to CAA pathogenesis is the dysregulation of mitochondria-mediated pathways with concomitant induction of oxidative stress. Using biochemical assays and immunofluorescence microscopy, this work demonstrates the exacerbated formation of reactive oxygen species (ROS) in human brain microvascular endothelial cells after short exposure to soluble oligomers of synthetic homologues of Aβ1-42 and the Dutch variant, inducing lipid peroxidation and protein carbonylation, both markers of oxidative stress. The heterogeneity of the soluble oligomeric assemblies inducing this oxidative response was highlighted by their reactivity with two conformational antibodies recognizing specific and mutually exclusive epitopes associated with either soluble prefibrillar oligomers or soluble fibrillar oligomers. Treatment with the multitarget antioxidants Trolox and methazolamide significantly attenuated the Aβ-mediated ROS production and reduced oxidative stress markers to basal levels. Our data highlight the damaging role of heterogeneous Aβ oligomers and the preventing effect of antioxidants, suggesting ROS modulation as a complementary therapeutic strategy to preserve neurovascular unit integrity.},
}

@article {pmid41300478,
year = {2025},
author = {Fu, Y and Zhang, X and Li, L and Jiang, H and Ren, Q and Yi, T and Zhang, Y and Lu, Y},
title = {PPARα-Mediated Fatty Acid Catabolism in Astrocytes Was Involved in Improvement of Cognitive Dysfunction by Phlorizin in APP/PS1 Mice.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {14},
number = {11},
pages = {},
doi = {10.3390/antiox14111321},
pmid = {41300478},
issn = {2076-3921},
support = {7252230//Yi Lu/ ; },
abstract = {Central lipid metabolism disorders are crucial for the development of Alzheimer's disease (AD). Phlorizin (PHZ) improved lipid metabolism abnormalities in AD nematodes, but its mechanism of action in improving AD-related symptoms and whether it can alleviate AD cognitive impairment remain unclear. To elucidate the effects and mechanisms of PHZ on lipid metabolism disorders in an AD model, gavage administration of PHZ for 8 weeks improved cognitive dysfunction and lipid disorders in APPswe/PSEN1dE9 (APP/PS1) mice. Concurrently, in astrocytes induced by palmitic acid (PA)- mediated lipid metabolic disorder, PHZ treatment improved astrocytic lipid accumulation by upregulating the target peroxisome proliferator-activated receptor α (PPARα) and its downstream pathways, thereby promoting astrocytic fatty acid oxidation. We validated PHZ's strong in vitro binding affinity with PPARα. Co-culture systems of lipid-metabolically disordered astrocytes and neurons further demonstrated that PHZ significantly improved neuronal cell viability and reduced intracellular lipid accumulation, thereby decreasing the expression of enzymes associated with β-amyloid protein (Aβ) production. This study demonstrates that gavage administration of PHZ for 2 months improves cognitive deficits and pathological markers in AD mice. Furthermore, at the cellular level, PHZ may exert its effects by enhancing astrocytic lipid metabolism, thereby preventing neuronal lipotoxicity and mitigating AD progression.},
}

@article {pmid41300346,
year = {2025},
author = {Yeasmin, A and Torrente, MP},
title = {Histone Post-Translational Modifications and DNA Double-Strand Break Repair in Neurodegenerative Diseases: An Epigenetic Perspective.},
journal = {Biology},
volume = {14},
number = {11},
pages = {},
doi = {10.3390/biology14111556},
pmid = {41300346},
issn = {2079-7737},
support = {1R15NS125394-01/NH/NIH HHS/United States ; },
abstract = {DNA damage is a hallmark of the fatal process of neurodegeneration in the central nervous system (CNS). As neurons are terminally differentiated, they accumulate metabolic and oxidative burdens over their whole life span. Unrepaired DNA develops into DNA double-strand breaks (DSBs), which are repaired through homologous recombination (HR) or non-homologous end joining (NHEJ). Being post-mitotic and unable to normally undergo HR, damage and defective repair is especially burdensome to CNS neurons. Current research has not produced treatment to prevent and halt progression of neurodegeneration. Hence, novel targeting strategies are desperately needed. Recent investigations in histone post-translational modifications (PTMs) reveal new mechanistic insight and highlight unexplored targets to ameliorate neurodegeneration. As various histone PTMs dictate and facilitate DSB repair, they represent an underexploited area in investigating DNA damage and incorrect repair aiding neurodegeneration. Here, we review the histone PTM alterations in several neurodegenerative diseases: Amyotrophic Lateral Sclerosis/Frontotemporal Dementia, Parkinson's Disease, Alzheimer's Diseases, Multiple Sclerosis, and Huntington's Disease. These findings emphasize that histone PTM alterations can enable an aberrant DNA damage response (DDR) leading to neurodegeneration. Further research into the connections between histone PTMs and DNA damage in decaying neurons will illuminate novel targets to dampen the aberrant DDR and promote neuronal survival.},
}

@article {pmid41300191,
year = {2025},
author = {Kishimoto, Y and Kubota, T and Nakashima, K and Kirino, Y},
title = {rTg4510 Tauopathy Mice Exhibit Non-Spatial Memory Deficits Prevented by Doxycycline Treatment.},
journal = {Brain sciences},
volume = {15},
number = {11},
pages = {},
doi = {10.3390/brainsci15111183},
pmid = {41300191},
issn = {2076-3425},
support = {20790084//Japan Society for the Promotion of Science/ ; 24590133//Japan Society for the Promotion of Science/ ; 16K08215//Japan Society for the Promotion of Science/ ; },
abstract = {Background: Hyperphosphorylated tau accumulation and neurofibrillary tangles (NFTs) are hallmarks of tauopathies, including Alzheimer's disease (AD), and are strongly associated with cognitive decline. The rTg4510 mouse model, which expresses mutant human tau (P301L), develops progressive tauopathy in the absence of amyloid-β pathology, providing a valuable tool for investigating tau-driven neurodegeneration. Previous studies have demonstrated spatial and object-recognition memory deficits at six months of age, which can be prevented by doxycycline (DOX)-mediated suppression of tau expression. However, it remained unclear whether non-spatial hippocampal learning, particularly temporal associative learning, would be similarly affected. Methods: We evaluated six-month-old rTg4510 mice with or without DOX treatment. To control for potential motor confounds, we first assessed spontaneous home cage activity. We then tested hippocampus-dependent non-spatial learning using two paradigms: trace eyeblink conditioning (500-ms trace interval) and contextual fear conditioning. Results: General motor function remained intact; however, rTg4510 mice without DOX treatment exhibited increased rearing behavior. These mice demonstrated significant deficits in trace eyeblink conditioning acquisition, with particularly clear impairment on the final day of training. Contextual fear conditioning showed milder deficits. Analysis of response peak latency revealed subtle temporal processing abnormalities during early learning. Two months of DOX treatment initiated at four months of age prevented these learning deficits, confirming their association with tau overexpression. Conclusions: Our findings demonstrate that rTg4510 mice exhibit deficits in non-spatial temporal associative learning alongside previously reported spatial and object-recognition impairments. Trace eyeblink conditioning serves as a sensitive behavioral assay for detecting tau-related hippocampal dysfunction, and the prevention of learning deficits by DOX treatment highlights its potential utility as a translational biomarker for evaluating tau-targeted interventions.},
}

@article {pmid41300171,
year = {2025},
author = {Costa, ACS and Brandão, AC and Leiva, V and Taylor, HG and Johnson, MW and Salmona, P and Abreu-Silveira, G and Scheidemantel, T and Roizen, NJ and Ruedrich, S and Boada, R},
title = {Baseline Neuropsychological Characteristics of Adolescents and Young Adults with Down Syndrome Who Participated in Two Clinical Trials of the Drug Memantine.},
journal = {Brain sciences},
volume = {15},
number = {11},
pages = {},
doi = {10.3390/brainsci15111164},
pmid = {41300171},
issn = {2076-3425},
support = {R03AG086928/AG/NIA NIH HHS/United States ; 100.10500.100.0001C//University Hospitals Cleveland's Center for Neurodegenerative Disorders/ ; 3U24AG057437//University Hospitals Cleveland's Center/ ; },
abstract = {BACKGROUND/OBJECTIVES: Down syndrome (DS) is a neurodevelopmental and neurodegenerative disorder typically caused by trisomy 21. We recently concluded a two-site (Ohio, USA and São Paulo, Brazil), phase-2, randomized trial to evaluate the efficacy, tolerability, and safety of the drug memantine in enhancing cognitive abilities of adolescents and young adults with DS. This trial was a follow-up study to a pilot trial performed in Colorado, USA. Results of these two clinical trials have been published elsewhere. Here, we present a comparative analysis of the baseline neuropsychological assessments at the three sites of these two studies, including their psychometric properties, and an account of the considerations involved in the test battery design. We compared test results in the different sites as a way of evaluating the replicability and generalizability of the test results. The distribution of the test results at each site was analyzed and combined when no differences were detected between the mean values of these results. We used post-treatment data from the placebo arms of these studies to quantify test-retest reliability.

RESULTS: Most measures had comparable mean values across test sites, and had good-to-excellent feasibility, few floor effects, and good-to-excellent test-retest reliability. A few measures, however, were deemed unsuitable for use in future studies.

CONCLUSIONS: This study demonstrated remarkable consistency of results across studies in two countries with significantly different cultures and levels of socioeconomic development, which provides supporting evidence for the future design and implementation of similar multicenter, international clinical studies involving participants with DS.},
}

@article {pmid41299730,
year = {2025},
author = {Seong, WJ and An, SJ and Gim, J and Gupta, DP and Park, J and Kang, S and Lee, KH and Song, GJ},
title = {Adenylate kinase 5, a novel genetic risk factor for Alzheimer's disease, regulates microglial inflammatory activation.},
journal = {Molecular brain},
volume = {18},
number = {1},
pages = {89},
pmid = {41299730},
issn = {1756-6606},
support = {NRF-2022R1A4A1018963//National Research Foundation of Korea/ ; HU23C0199//Korea Dementia Research Center/ ; },
mesh = {*Alzheimer Disease/genetics/enzymology/pathology ; *Microglia/pathology/enzymology/metabolism/drug effects ; Animals ; Humans ; *Adenylate Kinase/genetics/metabolism ; Polymorphism, Single Nucleotide/genetics ; *Inflammation/pathology/genetics/enzymology ; *Genetic Predisposition to Disease ; Risk Factors ; Mice, Inbred C57BL ; Male ; Lipopolysaccharides ; Mice ; Female ; Genome-Wide Association Study ; Phagocytosis/drug effects ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by memory loss, cognitive decline, and neuroinflammation, primarily mediated by microglia. In this study, we investigate the role of adenylate kinase 5 (AK5) in microglial function and its association with AD-related pathology. Analysis of brain tissues from AD patients and AD model mice revealed a significant reduction in AK5 expression. In vitro knockdown of AK5 in microglial cells attenuated lipopolysaccharide-induced pro-inflammatory responses, including decreased nitric oxide and tumor necrosis factor-alpha production, while enhancing phagocytic activity. Moreover, AK5 silencing induced metabolic reprogramming, evidenced by reduced lipid droplet accumulation and adipose triglyceride lipase mRNA levels, alongside increased farnesoid X receptor mRNA expression. Genome-wide association studies further identified two AK5 single nucleotide polymorphisms (SNPs), rs59556669 and rs75224576, significantly associated with hippocampal and amygdala atrophy as well as increased AD risk. Notably, these SNPs were not in linkage disequilibrium with the apolipoprotein E (APOE) locus, suggesting that AK5 may represent an independent genetic risk factor for AD. Collectively, our findings identify AK5 as a key regulator of microglial immune and metabolic function. The presence of AK5 variants may contribute to AD susceptibility, and AK5 expression or genetic status could serve as a potential biomarker for early risk assessment. Further exploration of AK5-targeted interventions may provide new therapeutic avenues for AD prevention or treatment.},
}

*Alzheimer Disease/genetics/enzymology/pathology
*Microglia/pathology/enzymology/metabolism/drug effects
Animals
Humans
*Adenylate Kinase/genetics/metabolism
Polymorphism, Single Nucleotide/genetics
*Inflammation/pathology/genetics/enzymology
*Genetic Predisposition to Disease
Risk Factors
Mice, Inbred C57BL
Male
Lipopolysaccharides
Mice
Female
Genome-Wide Association Study
Phagocytosis/drug effects

@article {pmid41299186,
year = {2025},
author = {Targett, IL and Pring, K and Valiente, AIM and Qualtrough, D and Conway, ME and Crompton, LA and Craig, TJ},
title = {Chronic Fatty Acid Exposure Disrupts SH-SY5Y and Neuronal Differentiation and Is a Potential Link Between Type-2 Diabetes and Alzheimer's Disease.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {183},
pmid = {41299186},
issn = {1559-1182},
mesh = {Humans ; *Alzheimer Disease/pathology/metabolism/complications ; *Diabetes Mellitus, Type 2/pathology/metabolism ; *Neurons/drug effects/pathology/metabolism ; *Cell Differentiation/drug effects ; Cell Line, Tumor ; *Fatty Acids/toxicity/pharmacology ; Glycogen Synthase Kinase 3 beta/metabolism ; Neurogenesis/drug effects ; Insulin/metabolism ; Signal Transduction/drug effects ; Phosphorylation/drug effects ; },
abstract = {Alzheimer's disease (AD) is the most common cause of dementia, for which there is no curative treatment and few disease-modifying therapies. The vast majority of AD is late onset (LOAD) without a specific genetic cause, although many genetic and non-genetic risk factors have been identified. One of the most significant modifiable risk factors is diet/lifestyle, with type-2 diabetes mellitus (T2DM) increasing LOAD risk by over 50%. Despite the epidemiological data, the reasons for this link are not understood. Here, we investigated whether altered free fatty acid (FFA) levels seen in T2DM can adversely affect neuronal differentiation, a crucial stage in adult hippocampal neurogenesis (AHN), which is defective in LOAD. We show that chronic exposure of the neuroblastoma cell line, SH-SY5Y to T2DM-relevant levels of the FFAs, oleate and palmitate, profoundly affects the differentiation of these cells. This effect is particularly pronounced for the saturated FFA, palmitate, resulting in neuronal cells of altered morphology, lacking expression of key synaptic markers. We further demonstrate that this exposure dysregulates insulin signalling, GSK3β activity, CDK5 levels and CREB phosphorylation. Crucially, these effects were only observed on exposure during differentiation and can be partially replicated in hiPSC-derived forebrain neurones. Although APP expression is increased by palmitate exposure, there was no increase in secreted or intracellular Aβ, and tau phosphorylation was reduced, implying that these defects are separate from the classical hallmarks of AD. We conclude that long-term, chronic exposure of differentiating neurones induces pathological changes that may explain the link between T2DM and LOAD.},
}

Humans
*Alzheimer Disease/pathology/metabolism/complications
*Diabetes Mellitus, Type 2/pathology/metabolism
*Neurons/drug effects/pathology/metabolism
*Cell Differentiation/drug effects
Cell Line, Tumor
*Fatty Acids/toxicity/pharmacology
Glycogen Synthase Kinase 3 beta/metabolism
Neurogenesis/drug effects
Insulin/metabolism
Signal Transduction/drug effects
Phosphorylation/drug effects

@article {pmid41299145,
year = {2025},
author = {Hosseini, E and Sahraian, MA and Negah, SS},
title = {Unlocking the Therapeutic Potential of RGMa: A New Frontier in Neurological Disorder Treatment.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {186},
pmid = {41299145},
issn = {1559-1182},
mesh = {Humans ; Animals ; *Nervous System Diseases/metabolism/drug therapy/therapy ; *Nerve Tissue Proteins/metabolism ; GPI-Linked Proteins/metabolism ; },
abstract = {Finding new biomolecules to target upstream signaling in neurological disorders is a state-of-the-art research strategy. Axon guidance molecules (AGMs) play vital roles in development; however, evidence suggests that these molecules are involved in the pathogenesis of several neurological diseases. Recent studies have shown that repulsive guidance molecule A (RGMa), a member of AGMs, can be targeted as a novel therapeutic option. This molecule has been implicated in several diseases, and inhibiting it improves the outcomes. For example, in various pathological conditions such as multiple sclerosis, neuromyelitis optica, optic nerve crush model, focal cerebral ischemia, traumatic brain injury, and vascular dementia the expression of RGMa is significantly elevated. RGMa has been detected on amyloid plaques and in the glial scar in brains impacted by Alzheimer's disease. Furthermore, RGMa is elevated by activated astrocytes after exposure to TGFβ. Since the role of RGMa in the development of neurological disorders is crucial, inhibiting RGMa can lead to positive outcomes such as axonal regeneration, neuronal repair, and behavioral improvement. Our review explores the impact of RGMa and outlines the positive results achieved by targeting it in preclinical studies. Based on this information, it is clear that RGMa has significant potential as both a predictive biomarker and a therapeutic option.},
}

Humans
Animals
*Nervous System Diseases/metabolism/drug therapy/therapy
*Nerve Tissue Proteins/metabolism
GPI-Linked Proteins/metabolism

@article {pmid41298976,
year = {2025},
author = {Alqahtani, SM and Al-Kuraishy, HM and Al-Gareeb, AI and Albuhadily, AK and Shokr, MM and Alexiou, A and Papadakis, M and Batiha, GE},
title = {Pharmacological modulation of the PI3K/AKT/GSK3β axis: a new frontier in Alzheimer's disease treatment.},
journal = {Inflammopharmacology},
volume = {},
number = {},
pages = {},
pmid = {41298976},
issn = {1568-5608},
abstract = {Amyloid-beta (Aβ) plaques and the intracellular buildup of hyperphosphorylated tau protein are hallmarks of Alzheimer's disease (AD), a progressive neurodegenerative disease that causes synaptic dysfunction and neuronal death. Glycogen synthase kinase 3 beta (GSK3β), protein kinase B (AKT), and phosphatidylinositol 3-kinase all have aberrant signaling pathways that contribute to the pathophysiology of AD. The PI3K/AKT neuroprotective pathway is seriously inhibited in AD, which leads to brain insulin resistance (BIR) and neurodegeneration. However, AD leads to hyperactivation of GSK3β, which in turn produces tau hyperphosphorylation, Aβ accumulation, and cognitive impairment. BIR and PI3K/AKT/GSK3β signaling in AD have a complicated interaction that is covered in this article. The pathway has both neuroprotective and pathogenic functions. The therapeutic use of GSK3β inhibitors and PI3K/AKT activators to decrease AD pathogenesis is also discussed. Changing these pathways can improve cognitive function, reduce tau and Aβ pathology, and restore insulin signaling, according to preclinical and clinical research. Finding highly specialized treatments with minimal side effects remains a challenge. More research is required to thoroughly assess the safety and efficacy of medications that target specific pathways and to clarify the molecular mechanisms underlying PI3K/AKT/GSK3β dysregulation in AD in order to create novel and effective treatment alternatives.},
}

@article {pmid41298245,
year = {2025},
author = {La Joie, R and Cummings, JL and Dage, JL and Galasko, D and Ikonomovic, MD and Karikari, TK and Landau, SM and Llibre-Guerra, JJ and Mummery, CJ and Ossenkoppele, R and Price, JC and Risacher, SL and Smith, R and van Dyck, CH and Carrillo, MC},
title = {Treatment-related amyloid clearance (TRAC): a framework to characterize patients in the era of anti-amyloid therapies.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {11},
pages = {e70997},
doi = {10.1002/alz.70997},
pmid = {41298245},
issn = {1552-5279},
mesh = {Humans ; *Alzheimer Disease/drug therapy/metabolism/diagnostic imaging ; Positron-Emission Tomography ; *Amyloid beta-Peptides/metabolism ; Biomarkers/metabolism ; *Brain/metabolism/diagnostic imaging/drug effects ; },
abstract = {Following regulatory approval of anti-amyloid beta (Aβ) therapies, a better characterization of patients receiving these treatments is needed to guide clinical management and inclusion in future trials. This Alzheimer's Association-convened workgroup proposes a terminology, treatment-related amyloid clearance (TRAC), to reflect alterations in disease pathophysiology based on biomarker evidence for clearance of Aβ deposits. TRAC designates biomarker-defined pharmacodynamic changes, rather than direct neuropathological evidence, and applies to individuals with (1) pretreatment biomarker confirmation of cerebral Aβ deposition, (2) treatment with an Aβ-targeting therapy, and (3) a follow-up biomarker test indicative of partial or full clearance of Aβ deposits. The workgroup currently recommends defining TRAC using amyloid-positron emission tomography (PET) and emphasizes the role of quantitative measurements for defining the degree of clearance. This framework is expected to be adapted over time in response to rapidly evolving biomarker and clinical advances and with the accumulation of real-world data on patients receiving anti-Aβ therapies. Highlights TRAC identifies patients with biomarker evidence for clearance of amyloid deposits. TRAC is currently defined using amyloid-PET. Full TRAC means that PET levels dropped below predetermined positivity threshold. Partial TRAC means that PET levels dropped significantly but remain above threshold. This framework is meant to guide future research on patients receiving treatment.},
}

Humans
*Alzheimer Disease/drug therapy/metabolism/diagnostic imaging
Positron-Emission Tomography
*Amyloid beta-Peptides/metabolism
Biomarkers/metabolism
*Brain/metabolism/diagnostic imaging/drug effects

@article {pmid41297852,
year = {2025},
author = {Adeyemi, O and Christina, W and Arcila-Mesa, M and Dickson, VV and Ferris, R and Tarpey, T and Fletcher, J and Blaum, C and Chodosh, J},
title = {Enhanced quality in primary care for elders with diabetes and dementia: Protocol for a multisite randomized controlled trial.},
journal = {Contemporary clinical trials},
volume = {},
number = {},
pages = {108165},
doi = {10.1016/j.cct.2025.108165},
pmid = {41297852},
issn = {1559-2030},
abstract = {BACKGROUND: The Enhanced Quality in Primary Care for Elders with Diabetes-ADRD (EQUIPED-ADRD) is a quality improvement and pragmatic cluster-randomized controlled trial that uses clinical decision guidelines to streamline the care of older adults with diabetes mellitus and Alzheimer's disease/Alzheimer's disease-related Dementia (DM-AD/ADRD). This study tests whether the EQUIPED-ADRD intervention will increase the proportion of older adults with DM and AD/ADRD with desirable glycemic ranges, and reduce treatment burden, dementia severity, and healthcare utilization among participants and their care partners in the intervention arm compared to those in the control arm.

METHODS: We will recruit older adults (≥65 years) with both DM and AD/ADRD diagnoses, who have care partners, and receive care at the enrolled New York University clinics. The intervention involves the use of panel managers to streamline the integration of clinical decision guidelines among primary care providers and improve the experiences of care partners and patients. Those in the control arm will have no panel management. We will conduct surveys and interviews, and extract data from EMR and Medicare claims to assess the association between the intervention and primary and secondary outcomes. The primary outcome is achieving within-range HbA1c, while the secondary outcomes include measures of healthcare utilization. Patient and care partner treatment burden, dementia symptoms, and care partner diabetes care distress.

CONCLUSIONS: The EQUIPED-ADRD intervention (implemented between 2018 and 2021) will assess the effect of an institutional guideline on the quality of life and health outcomes of older adults with DM-AD/ADRD and their care partners. Clinical Trial NumberNCT03723707.},
}

@article {pmid41297835,
year = {2025},
author = {Zhang, X and Dong, Y and Zou, Z and Chen, L and Li, W and Wang, L and Li, K and He, J and Shi, Q},
title = {Association of human plasma and cerebrospinal fluid metabolomes with vascular dementia and its subtypes: A Mendelian randomization study.},
journal = {Brain research},
volume = {},
number = {},
pages = {150060},
doi = {10.1016/j.brainres.2025.150060},
pmid = {41297835},
issn = {1872-6240},
abstract = {BACKGROUND AND OBJECTIVE: Vascular dementia (VaD) is one of the most common subtypes of dementia after Alzheimer's disease. Investigating body fluid metabolites is critical for understanding VaD pathophysiology and identifying potential therapeutic targets. This study employs Mendelian randomization (MR) analysis to explore the causal relationship between body fluid metabolites and VaD.

METHODS: Data for VaD were retrieved from the FinnGen database. 1,400 plasma metabolites were collected from the GWAS Catalog. 338 cerebrospinal fluid (CSF) metabolites data were obtained from a subset of participants in the WADRC and WRAP studies. The inverse-variance weighted (IVW) method was used to explore causal relationships between plasma/CSF metabolites and VaD, with supplementary analyses using Weighted mode, MR-Egger, and Weighted median methods. Multiple sensitivity analyses were conducted for robustness.

RESULTS: Following strict validation and FDR correction, significant associations (p_fdr < 0.05) were identified exclusively in plasma metabolites. The most significant metabolite was N-acetyl-aspartyl-glutamate (NAAG), with higher NAAG levels linked to reduced risks of VaD of acute onset and SVaD. Metabolonic lactone sulfate also showed significant associations across multiple disease groups, with elevated levels associated with lower disease risk, supported by FDR correction and sensitivity analyses. No significant CSF metabolites were identified after FDR correction. Disparities between CSF and plasma metabolites in disease-risk expression were observed, with only partial overlap in causal relationships (IVW, p < 0.05).

CONCLUSION: This study identified fluid metabolite biomarkers associated with VaD through Mendelian randomization, offering new insights and strategies for the prediction and treatment of VaD.},
}

@article {pmid41296223,
year = {2025},
author = {Bharath, HC and Pradeep, N and Shashidhar, R and Nanjappa, Y},
title = {Synergistic medical genetic evolutionary optimization and deep convolutional generative augmentation with SHAP-driven interpretability for precise Alzheimer's disease severity grading.},
journal = {Brain informatics},
volume = {12},
number = {1},
pages = {31},
pmid = {41296223},
issn = {2198-4018},
abstract = {Alzheimer's disease (AD) diagnosis at an early yet accurate stage is critical to support effective treatment or intervention. Still it is not very feasible due to the presence of image data class imbalance, low interpretability of models, and a high computational cost. This research proposes a novel, end-to-end diagnostic framework that considers a Medical Genetic Algorithm (MedGA)-optimized Convolutional Neural Network (CNN) with a Deep Convolutional Generative Adversarial Network (DCGAN) to generate synthetic MRIs and SHapley Additive Explanations (SHAP) to analyse and interpret the model. The given methodology is trained and tested on the Open Access Series of Imaging Studies (OASIS) dataset. The DCGAN component introduces 700 structurally coherent synthetic images (SSIM = 0.92) into the underrepresented Moderate Dementia class, improving the overall recall by 10% and balancing the dataset. MedGA succeeds in optimizing CNN hyperparameters and resulting in complexity reduction (20%) in networks without loss of testing accuracy (97%) at the four demonstrated stages of AD: Non-Demented, Very Mild Demented, Mild Demented, and Moderate Demented. SHAP analysis emphasises the role of key brain areas, the hippocampus and the amygdala in the results of classification accuracy, leading to 25% greater interpretability and clinician confidence. Comparative evaluation shows that the current framework is exceptionally better in terms of predictive performance and explainability than current state-of-the-art approaches. This combined method provides a powerful and adaptable device to categorize AD at an early age, with promising outcomes in precise diagnosis in health facilities.},
}

@article {pmid41296218,
year = {2025},
author = {Vaz, M and Soares Martins, T and Trigo, D and da Cruz E Silva, OAB and Amado, F and Vitorino, R and Henriques, AG},
title = {Aβ Modulates Extracellular Vesicles Proteomic Profile Impacting Phosphorylation Mediators.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {179},
pmid = {41296218},
issn = {1559-1182},
mesh = {*Extracellular Vesicles/metabolism/drug effects ; *Amyloid beta-Peptides/pharmacology ; Phosphorylation/drug effects ; *Proteomics/methods ; Animals ; Mice ; *Proteome/metabolism ; Glycogen Synthase Kinase 3 beta/metabolism ; Cell Line, Tumor ; Alzheimer Disease/metabolism ; Humans ; Protein Interaction Maps/drug effects ; },
abstract = {Alzheimer's disease (AD) is characterized by the formation of senile plaques and neurofibrillary tangles, mainly composed of amyloid-β (Aβ) peptide aggregates and hyperphosphorylated tau protein, respectively. AD pathophysiology is highly complex, involving multiple abnormal cellular pathways linked to disease progression. Recently, extracellular vesicles (EVs) have emerged as potential contributors to disease development. Thus, this study explored the proteome of neuronal EVs under conditions that mimic Alzheimer's disease by employing mass spectrometry in EVs isolated from N2a cells treated with Aβ. Bioinformatic analysis revealed proteins involved in signal transduction, post-translational protein modification, translation, and proteolysis. Furthermore, Aβ treatment led to either an enrichment or scarcity of proteins related to cytoskeletal and mitochondrial dynamics, calcium-dependent signalling, phosphorylation, as well as proteins involved in Aβ production and aggregation. Overlap between EVs' proteome upon Aβ treatment and key AD-related proteins identified glycogen synthase kinase 3β (GSK3β) as a central node in the resulting protein interaction network. Additionally, the GSK3β interactome, derived from the EVs' proteome, highlighted protein phosphatases as relevant EVs' cargo under Alzheimer's disease mimicking conditions. The activity of GSK3β and protein phosphatases in EVs was monitored, revealing significant differences between control and Aβ-treated conditions. These findings support not only that EVs carry key proteins involved in phosphorylation dynamics but also that Aβ treatment alters EVs' proteomic profile, potentially impacting AD development. Proteomic changes in EVs may provide valuable insights into the mechanisms underlying AD and also contribute to the identification of novel potential therapeutic targets.},
}

*Extracellular Vesicles/metabolism/drug effects
*Amyloid beta-Peptides/pharmacology
Phosphorylation/drug effects
*Proteomics/methods
Animals
Mice
*Proteome/metabolism
Glycogen Synthase Kinase 3 beta/metabolism
Cell Line, Tumor
Alzheimer Disease/metabolism
Humans
Protein Interaction Maps/drug effects

@article {pmid41296090,
year = {2025},
author = {Wang, M and Zeng, Y and Jin, Y and Wu, J and Li, J},
title = {Progress and Perspectives on the Estrogen-Microbiota-Brain Axis in Alzheimer's Disease.},
journal = {Neurochemical research},
volume = {51},
number = {1},
pages = {3},
pmid = {41296090},
issn = {1573-6903},
support = {No. QKHJC-ZK[2022]-260//Guizhou Provincial Science and Technology Projects/ ; NO.gzwjrs2023-005//Guizhou Provincial High level Innovative Talent Fund/ ; },
mesh = {Humans ; *Alzheimer Disease/metabolism/microbiology ; *Estrogens/metabolism ; *Gastrointestinal Microbiome/physiology ; *Brain/metabolism/drug effects ; Animals ; Dysbiosis/metabolism ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder shaped by genetic, metabolic, environmental, and sex-specific factors. Emerging evidence highlights the estrogen-gut microbiota-brain (EGMB) axis as a critical framework linking endocrine regulation, microbial activity, and cognitive outcomes. Estrogen exerts neuroprotective effects by modulating synaptic plasticity, oxidative stress, amyloid and tau pathology, and neuroinflammation, while its decline during menopause increases AD vulnerability. Parallel to this, gut dysbiosis and altered microbial metabolites, particularly short-chain fatty acids (SCFAs) and secondary bile acids (sBAs), contribute to barrier dysfunction, chronic inflammation, and synaptic impairment. Importantly, estrogen remodels microbial composition and metabolite profiles, whereas microbial β-glucuronidase (β-GUS) activity sustains estrogen bioavailability, establishing a reciprocal regulatory loop. Preclinical studies demonstrate that depletion of gut microbiota diminishes estrogen's protective effects, underscoring the central role of microbial metabolites as signaling bridges.Therapeutically, these insights support the integration of hormone replacement therapy with microbiota-targeted interventions such as probiotics, prebiotics, and fecal microbiota transplantation. Such combined strategies may synergistically enhance neuroprotection, though their efficacy depends on timing, dosage, and individual variability. Future precision approaches integrating multi-omics profiling and sex-specific stratification hold promise for identifying predictive biomarkers and optimizing treatment windows. In summary, the EGMB axis offers a mechanistic foundation for understanding sex differences in AD and a translational framework for developing individualized, multidimensional strategies for early diagnosis, prevention, and therapy.},
}

Humans
*Alzheimer Disease/metabolism/microbiology
*Estrogens/metabolism
*Gastrointestinal Microbiome/physiology
*Brain/metabolism/drug effects
Animals
Dysbiosis/metabolism

@article {pmid41295439,
year = {2025},
author = {Zachara, R and Gendosz de Carrillo, D and Wlaszczuk, A and Gorzkowska, A and Mazur, W and Jedrzejowska-Szypulka, H},
title = {The Cognitive Changes Among Patients over 65 Years of Age in a Rural Area-The Preliminary Report of Protective and Predisposing Factors.},
journal = {Neurology international},
volume = {17},
number = {11},
pages = {},
doi = {10.3390/neurolint17110180},
pmid = {41295439},
issn = {2035-8385},
support = {PCN-2-042/N/2/I//Medical University of Silesia/ ; },
abstract = {Background: Aβ1-42 and APOE concentrations, as well as Aβ42/40 ratio, may be considered as a link between hypertension (HTN) or diabetes mellitus (DM), brain amyloidosis, and dementia. HTN and DM are associated with cognitive impairment and may contribute to the development of Alzheimer's disease (AD). This preliminary study aimed to evaluate the impact of vascular risk factors on the concentration of biochemical AD markers and cognitive state. As it is a cross-sectional study in nature, causal relationships cannot be established. Methods: The study was conducted in the south of Poland among a rural population over 65 years of age. A total of 58 patients qualified into the study were divided into groups according to the presence of HTN (n = 18) or HTN coexisting with DM (n = 40). A healthy control group was also formed (n = 20), resulting in 78 study participants. The study population was also divided based on M-ACE results, forming a normal cognition group (NC) and a deteriorated cognition group (DC). Biochemical tests, neurological scales assessments, and ultrasound examinations were conducted. Results: Patients who scored in the normal range on the M-ACE had higher Aβ1-42 (median 38.52 vs. 27.35 pg/mL, p = 0.02) and apoE concentrations (median 125.0 vs. 65.73 μg/mL, p = 0.002), and a higher Aβ42/40 ratio (median 0.39 vs. 0.29 p < 0.000) compared to the DC group. Considering the study groups, the highest Aβ42/40 ratio was found among the HC group (median 0.47). The median score for the M-ACE scale was 3 points lower when HTN and DM coexisted, compared to the sole diagnosis of HTN (25 points and 28 points, respectively). A higher number of years of education correlated with better M-ACE results. Lipid and uric acid concentrations were not related to M-ACE or MMSE scores. An inverse relationship connected Aβ1-40 and Aβ1-42 to BMI, the duration of HTN treatment, and glycated hemoglobin. Conclusions: Aβ1-42, APOE, and Aβ42/40 are not only correlated with cognition but also related to patient's disease profile. The coexistence of DM and HTN was associated with the most significant decline in cognitive functioning. However, a higher number of years of education may protect against the development of dementia in old age. The roles of cholesterol and uric acid in cognitive decline are still inconclusive.},
}

@article {pmid41295407,
year = {2025},
author = {Dimitrova, D and Kehayova, G and Dimitrova, S and Dragomanova, S},
title = {Marine-Derived Natural Substances with Anticholinesterase Activity.},
journal = {Marine drugs},
volume = {23},
number = {11},
pages = {},
doi = {10.3390/md23110439},
pmid = {41295407},
issn = {1660-3397},
mesh = {*Cholinesterase Inhibitors/pharmacology/chemistry/isolation & purification ; *Biological Products/pharmacology/chemistry/isolation & purification/therapeutic use ; Humans ; *Aquatic Organisms/chemistry ; Animals ; Alzheimer Disease/drug therapy ; Butyrylcholinesterase/metabolism ; Neuroprotective Agents/pharmacology/chemistry/isolation & purification ; Acetylcholinesterase/metabolism ; },
abstract = {Alzheimer's disease continues to be one of the most urgent neurodegenerative conditions, with acetylcholinesterase (AChE) inhibitors serving as a fundamental component of contemporary treatment approaches. Growing evidence underscores that marine ecosystems are a rich source of structurally varied and biologically active natural products exhibiting anticholinesterase properties. This review presents a thorough synthesis of marine-derived metabolites-including those sourced from bacteria, fungi, sponges, algae, and other marine life-that demonstrate inhibitory effects against AChE and butyrylcholinesterase (BuChE). Numerous compounds, such as meroterpenoids, alkaloids, peptides, and phlorotannins, not only show nanomolar to micromolar inhibitory activity but also reveal additional neuroprotective characteristics, including antioxidant effects, anti-amyloid properties, and modulation of neuronal survival pathways. Despite these encouraging findings, the transition to clinical applications is hindered by a lack of comprehensive pharmacokinetic, toxicity, and long-term efficacy studies. The structural variety of marine metabolites provides valuable frameworks for the development of next-generation cholinesterase inhibitors. Further interdisciplinary research is essential to enhance their therapeutic potential and facilitate their incorporation into strategies for addressing Alzheimer's disease and related conditions.},
}

*Cholinesterase Inhibitors/pharmacology/chemistry/isolation & purification
*Biological Products/pharmacology/chemistry/isolation & purification/therapeutic use
Humans
*Aquatic Organisms/chemistry
Animals
Alzheimer Disease/drug therapy
Butyrylcholinesterase/metabolism
Neuroprotective Agents/pharmacology/chemistry/isolation & purification
Acetylcholinesterase/metabolism

@article {pmid41294911,
year = {2025},
author = {Abreu, MM and Hosseine-Farid, M and Silverman, DG},
title = {Total Reversal of ALS Confirmed by EMG Normalization, Structural Reconstitution, and Neuromuscular-Molecular Restoration Achieved Through Computerized Brain-Guided Reengineering of the 1927 Nobel Prize Fever Therapy: A Case Report.},
journal = {Diseases (Basel, Switzerland)},
volume = {13},
number = {11},
pages = {},
doi = {10.3390/diseases13110371},
pmid = {41294911},
issn = {2079-9721},
abstract = {BACKGROUND: Neurological disorders are the leading cause of disability, affecting over three billion people worldwide. Amyotrophic lateral sclerosis (ALS) is among the most feared and uniformly fatal neurodegenerative diseases, with no therapy capable of restoring lost function.

METHODS: We report the first application of therapeutic fever to ALS using Computerized Brain-Guided Intelligent Thermofebrile Therapy (CBIT[2]). This fully noninvasive treatment, delivered through an FDA-approved computerized platform, digitally reengineers the 1927 Nobel Prize-recognized malarial fever therapy into a modern treatment guided by the Brain-Eyelid Thermoregulatory Tunnel. CBIT[2] induces therapeutic fever through synchronized hypothalamic feedback, activating heat shock proteins, which are known to restore proteostasis and neuronal function.

CASE PRESENTATION: A 56-year-old woman was diagnosed with progressive ALS at the Mayo Clinic, with electromyography (EMG) demonstrating fibrillation and fasciculation indicative of denervation corroborated by neurological and MRI findings; the patient was informed that she had an expected survival of three to five years. A neurologist from Northwestern University confirmed the diagnosis and thus maintained the patient on FDA-approved ALS drugs (riluzole and edaravone). Her condition rapidly worsened despite pharmacological treatment, and she underwent CBIT[2], resulting in (i) electrophysiological reversal with complete disappearance of denervation; (ii) biomarker correction, including reductions in neurofilament and homocysteine, IL-10 normalization (previously linked to mortality), and robust HSP70 induction; (iii) restoration of gait, swallowing, respiration, speech, and cognition; (iv) reconstitution of tongue structure; and (v) return to complex motor tasks, including golf, pickleball, and swimming.

DISCUSSION: This case provides the first documented evidence that ALS can be reversed through digitally reengineered fever therapy aligned with thermoregulation, which induces heat shock response and upregulates heat shock proteins, resulting in the patient no longer meeting diagnostic criteria for ALS and discontinuation of ALS-specific medications. Beyond ALS, shared protein-misfolding pathology suggests that CBIT[2] may extend to Alzheimer's, Parkinson's, and related disorders. By modernizing this Nobel Prize-recognized therapeutic principle with computerized precision, CBIT[2] establishes a framework for large-scale clinical trials. A century after fever therapy restored lost brain function and so decisively reversed dementia paralytica such that it earned the 1927 Nobel Prize in Medicine, CBIT[2] now safely harnesses the therapeutic power of fever through noninvasive, intelligent, brain-guided thermal modulation. Amid a global brain health crisis, fever-based therapies may offer a path to preserve thought, memory, movement, and independence for the more than one-third of humanity currently affected by neurological disorders.},
}

@article {pmid41294858,
year = {2025},
author = {Thiyagarajan, S and Leclerc, E and Vetter, SW},
title = {The Receptor for Advanced Glycation End-Products (RAGE) Regulates Cell Adhesion Through Upregulation of ITGA8.},
journal = {Cells},
volume = {14},
number = {22},
pages = {},
doi = {10.3390/cells14221805},
pmid = {41294858},
issn = {2073-4409},
support = {1U54GM128729-20/NH/NIH HHS/United States ; },
mesh = {Humans ; *Cell Adhesion ; *Receptor for Advanced Glycation End Products/metabolism/chemistry/genetics ; *Up-Regulation ; },
abstract = {The Receptor for Advanced Glycation End-Products (RAGE) is a cell surface receptor of the immunoglobulin-like receptor superfamily. RAGE is a pattern-recognition, multi-ligand receptor that binds glycated proteins, specific non-glycated proteins, and nucleic acids. RAGE ligands are typically part of the group of damage-associated molecular patterns (DAMPs) or alarmins. As such, RAGE is a receptor for molecular products of cellular stress, abnormal metabolism, and inflammation. Activation of RAGE by its ligands leads to pro-inflammatory signaling, often resulting in persistent RAGE activation in various disease states. Consequently, RAGE has been investigated as a potential drug target in the treatment of diabetic complications, vascular disease, Alzheimer's disease, and multiple types of cancer. An underexplored aspect of RAGE is its role in cell adhesion. Structural comparison of the extracellular domain of RAGE has revealed structural similarity to the activated leukocyte cell adhesion molecule (ALCAM). The present study reveals the role and mechanism of RAGE in regulating cell adhesion. We investigated the role of individual RAGE domains in cell adhesion to extracellular matrix proteins and the changes in protein expression resulting from RAGE upregulation. Key findings include that RAGE displays substrate-specific adhesion to extracellular matrix proteins, that the intracellular domain of RAGE is required for modulating cell spreading, and that regulation of ITGA8 depends on the cytoplasmic domain of RAGE.},
}

Humans
*Cell Adhesion
*Receptor for Advanced Glycation End Products/metabolism/chemistry/genetics
*Up-Regulation

@article {pmid41294748,
year = {2025},
author = {Ki, MR and Kim, DH and Abdelhamid, MAA and Pack, SP},
title = {Cancer and Aging Biomarkers: Classification, Early Detection Technologies and Emerging Research Trends.},
journal = {Biosensors},
volume = {15},
number = {11},
pages = {},
doi = {10.3390/bios15110737},
pmid = {41294748},
issn = {2079-6374},
support = {RS2021NR060107//the National Research Foundation of Korea/ ; the National Research Foundation of Korea//the National Research Foundation of Korea/ ; },
mesh = {Humans ; *Neoplasms/diagnosis ; *Biomarkers, Tumor ; *Aging ; *Early Detection of Cancer ; Biomarkers ; Biosensing Techniques ; Artificial Intelligence ; },
abstract = {Cancer and aging are two distinct biological processes with shared cellular pathways, such as cellular senescence, DNA damage repair, and metabolic reprogramming. However, the outcomes of these processes differ in terms of proliferation. Understanding biomarkers related to aging and cancer opens a pathway for therapeutic interventions and more effective prevention, detection, and treatment strategies. Biomarkers, ranging from molecular to phenotypic indicators, play an important role in early detection, risk assessment, and prognosis in this endeavor. This review comprehensively examines key biomarkers associated with cancer and aging, highlighting their importance in early diagnostic strategies. The review discusses recent advances in biomarker-based diagnostic technologies, such as liquid biopsy, multi-omics integration, and artificial intelligence, and emphasizes their novel potential for early detection, accurate risk assessment, and personalized therapeutic interventions in cancer and aging science. We also explore the current state of biosensor development and clinical application cases. Finally, we discuss the limitations of current early diagnostic methods and propose future research directions to enhance biomarker-based diagnostic technologies.},
}

Humans
*Neoplasms/diagnosis
*Biomarkers, Tumor
*Aging
*Early Detection of Cancer
Biomarkers
Biosensing Techniques
Artificial Intelligence

@article {pmid41294271,
year = {2025},
author = {Gupta, R and Lin, S and DiStefano, MJ and Woo, HYJ and Mao, E and Wilson, R and Amjad, H and Drabo, EF and Segal, JB},
title = {Patient Preferences for Dementia Interventions: A Scoping Review With a Systematic Review of Medications and Choice-Based Methods.},
journal = {Journal of the American Geriatrics Society},
volume = {},
number = {},
pages = {},
doi = {10.1111/jgs.70209},
pmid = {41294271},
issn = {1532-5415},
support = {1R61AG088961-01/AG/NIA NIH HHS/United States ; K23AG064036/AG/NIA NIH HHS/United States ; },
abstract = {BACKGROUND: Despite emerging treatment options for Alzheimer's disease and related dementias (ADRD), patient preferences for treatment and care remain poorly understood.

METHODS: We searched PubMed, PsycINFO, CINAHL, and EMBASE through November 12, 2024 for studies reporting stated preferences for dementia treatment- and care-related interventions. We synthesized key findings from studies using choice-based preference elicitation methods and those addressing medication preferences.

RESULTS: We screened 8300 abstracts and 82 studies published between 1996 and 2024 were included. Most evaluated preferences for non-pharmacological interventions. Studies were experimental (37; 45.1%), observational (36; 43.9%), and qualitative (21; 25.6%). Six studies used choice-based preference elicitation methods and five assessed preferences for medications. Patients valued memory improvement and emotional or social support, despite highly heterogeneous data.

CONCLUSIONS: This review highlights significant gaps in the literature on treatment preferences-particularly for medications-among older adults with cognitive impairment, underscoring the need for further research, development of validated clinical tools, and appropriate methods to elicit preferences to better align interventions with patient values.},
}

@article {pmid41293014,
year = {2025},
author = {Marriott, AE and Schroeder, JP and Korukonda, A and Pate, BS and McCann, KE and Weinshenker, D and Kelberman, MA},
title = {Impact of early locus coeruleus lesions in the TgF344 Alzheimer's disease rat model.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.11.09.687363},
pmid = {41293014},
issn = {2692-8205},
abstract = {INTRODUCTION: In murine models of Alzheimer's disease (AD), lesioning the locus coeruleus-norepinephrine (LC-NE) system with DSP-4 exacerbates AD-like neuropathology and cognitive impairment. However, the impact of LC lesions during prodromal stages is poorly characterized.

METHODS: TgF344-AD and wild-type rats received monthly injections of DSP-4 or saline from 1-5 months of age, a time point preceding forebrain plaque or tangle deposition in TgF344-AD rats, after which behavior and pathology were assessed.

RESULTS: DSP-4 compromised LC cell bodies, fibers, and NE content. LC lesion and the AD transgene each affected several affective behaviors and/or cognition individually, but few interactions were found and DSP-4 failed to exacerbate behavioral phenotypes or neuropathology in TgF344-AD rats.

DISCUSSION: Combined with previous literature, our data suggest that LC lesions exacerbate pre-existing AD-like pathology and behavioral impairments, rather than accelerate their onset. Further characterization of LC lesions in TgF344-AD rats at different ages is warranted.

RESEARCH-IN-CONTEXT: Systemic review: The authors reviewed existing literature using traditional sources, including PubMed. Previous studies investigated the impact of locus coeruleus (LC) lesions on Alzheimer's disease (AD)-like neuropathology and behavior in murine models of AD. However, the impact of LC degeneration in an animal model that expresses both amyloid and endogenous tau pathology at a time point before the emergence of significant forebrain pathology is underexplored.Interpretation: We expanded the behavioral and molecular characterization of TgF344-AD rats in response to N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride (DSP-4)-induced LC lesions during the pre-pathology stages of disease. Unexpectedly, we found that TgF344-AD genotype and DSP-4 rarely interacted to exacerbate AD-related symptoms or pathology.Future Directions: Our results indicate LC lesions do not accelerate onset of AD-like neuropathology or behavioral impairment in this model. Future studies in older TgF344-AD animals and using different DSP-4 treatment regimens would help clarify the relationship between LC integrity and AD progression.

HIGHLIGHTS: Locus coeruleus damage causes apathy-like behavior and changes in arousalTgF344-AD genotype induces social recognition deficits and anxiety-like behaviorLocus coeruleus damage and TgF344-AD genotype rarely interact to worsen deficitsInteractions that exacerbate Alzheimer's disease neuropathology were also scarce.},
}

@article {pmid41292987,
year = {2025},
author = {Gogola, JV and Wee, SWS and Garcia, AJ},
title = {Repeat Opioid Use Modulates Microglia Activity and Amyloid Beta Clearance in a Mouse Model of Alzheimer's Disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.11.14.688256},
pmid = {41292987},
issn = {2692-8205},
abstract = {In addition to driving dependency and overdose, illicit use of opioids, such as fentanyl, is linked to the risk for cognitive decline and dementia. Growing evidence also indicates that opioid use is associated with pathological features, paralleled early in Alzheimer's disease (AD), which raises the possibility of the involvement of mechanistic interactions between opioid use and AD progression. Here, we investigate how chronic fentanyl use (i.e., 20 days) influences the neuroimmune state, microglial activity, and amyloid burden in wildtype and APPPS1-21 mice, a transgenic model of AD. In wild-type mice, fentanyl use promoted a pro-inflammatory state without increasing the incidence of disease-associated microglia. In APPPS1-21 mice, chronic fentanyl use led to a shift favoring an anti-inflammatory state, which was associated with increased microglia clustering and activation at Aβ plaques, increased Aβ internalization in plaque-associated activated microglia, decreased soluble Aβ, and decreased plaque burden. Our findings indicate that chronic fentanyl use fundamentally changes the trajectory of neuroimmune activity and features characteristic of early AD by enabling microglia to enhance Aβ clearance. The interactions demonstrate how substance use can reshape the neuroimmune landscape in neurodegenerative disease, emphasizing the importance of tailored treatment strategies.},
}

@article {pmid41292940,
year = {2025},
author = {Mayeri, Z and Woods, G and Rane, A and Kifle, A and Chamoli, M and Shukla, S and Walton, CC and Andersen, JK},
title = {A Compound Enhancing Lysosomal Function Reduces Tau Pathology, Microglial Reactivity and Rescues Working Memory in 3xTg AD Mice.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.11.09.687389},
pmid = {41292940},
issn = {2692-8205},
abstract = {BACKGROUND: Recent advancements in Alzheimer's disease (AD) therapeutics have validated the use of amyloid beta (Aβ)-clearing antibodies, which reduce Aβ pathology but leave other disease hallmarks largely unaddressed. Since AD involves multiple pathological processes, additional strategies are needed to target complementary mechanisms. One such target is autophagy, a lysosomal mediated degradation pathway essential for cellular homeostasis that removes toxic protein aggregates and damaged organelles. This process is implicated in AD, as impaired lysosomal function promotes Aβ and tau accumulation. Our laboratory recently identified a novel natural mitophagy-inducing compound (MIC) that may serve as a therapeutic intervention for AD.

METHODS: We evaluated the effects of MIC in aged 3xTgAD mice, a transgenic model displaying both Aβ and tau pathology. Mice received either standard diet or diet containing MIC beginning at age 4 months until 20 months on alternating weeks. Age-matched non-transgenic (NonTg) controls were included under standard and MIC-supplemented diets to assess compound effects during normal aging. Neuropathological changes were assessed using immunohistochemistry (IHC) for Aβ, phosphorylated tau (pTau), and microglial reactivity. Cognitive performance was evaluated using the Morris Water Maze (MWM) to assess spatial learning and memory and the Y-maze to measure working memory.

RESULTS: At 20 months of age, our neuropathological assessment showed that 3xTgAD mice fed an MIC-supplemented diet had a significant reduction in pTau accumulation and microglial reactivity, although Aβ burden remained unchanged. At 15 months, MIC diet also improved spatial learning and memory in aged NonTg controls but not in 3xTgAD mice. However, in younger 8-month-old 3xTgAD mice, MIC restored working memory performance to NonTg levels, indicating an age-dependent therapeutic response.

CONCLUSION: MIC emerges as a potential modulator of tau pathology and neuroinflammation. As a naturally derived compound, MIC offers potential for combination therapy with FDA-approved Aβ-clearing antibodies, enabling a multimodal approach to AD treatment that addresses amyloid, tau, and microglia-related pathology.},
}

@article {pmid41292809,
year = {2025},
author = {Steigmeyer, AD and Battison, AS and Liebman, IR and van Dyck, CH and Slusher, BS and Arnsten, AFT and Malaker, SA and Datta, D},
title = {Region-specific proteomic analysis of aging rhesus macaques following chronic glutamate-carboxypeptidase-II (GCPII) inhibition elucidates potential treatment strategies for sporadic Alzheimer's disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.11.07.687004},
pmid = {41292809},
issn = {2692-8205},
abstract = {Sporadic Alzheimer's disease (sAD) lacks effective preventive therapies, underscoring the need to target pathogenic drivers. Aberrant calcium signaling is an established early event in sAD pathogenesis that is closely linked to neuroinflammation. Aged rhesus macaques are predominantly APOE-ε4 homozygotes and naturally exhibit cognitive decline, calcium dysregulation, amyloid deposition, and tau pathology, which allows for a translationally relevant animal model. We previously identified an evolutionarily expanded role for postsynaptic type 3 metabotropic glutamate receptors (mGluR3) in dorsolateral prefrontal and entorhinal cortex, where they regulate cAMP- calcium opening of K[+] channels to sustain neuronal firing and working memory. mGluR3 signaling is driven by N-acetylaspartylglutamate (NAAG) and constrained by glutamate carboxypeptidase II (GCPII), whose expression rises with age and inflammation. In prior work, chronic inhibition of GCPII with the orally bioavailable inhibitor 2-(3-mercaptopropyl) pentanedioic acid (2-MPPA) improved neuronal firing, working memory, and reduced pT217Tau pathology in aged macaques. Here, we employed liquid chromatography-tandem mass spectrometry (LC-MS/MS) to define the proteomic consequences of chronic 2-MPPA treatment in vulnerable (entorhinal cortex, dorsolateral prefrontal cortex) versus resilient (primary visual cortex) regions. We identified >2,400 proteins across experimental conditions, and label-free quantification revealed region-specific differential expression patterns paralleling known vulnerability gradients in sAD. Gene ontology enrichment of vulnerable regions implicated pathways governing protein deneddylation, amyloid and tau-associated processes, synaptic plasticity, mitochondrial homeostasis, and oxidative stress, revealing putative targets for therapeutic intervention in sAD. These findings demonstrate that GCPII inhibition engages distinct, region-selective molecular programs in the aging primate cortex, consistent with the protection of circuits most vulnerable to sAD. By mapping the proteomic shifts that occur with treatment, we reveal molecular signatures that not only serve as candidate biomarkers but also highlight novel mechanistic pathways contributing to calcium-driven degeneration in sAD. As such, more focused investigations into these pathways of therapeutic interest are warranted, in addition to the analysis of key post-translational modifications and their potential roles in sAD.},
}

@article {pmid41292786,
year = {2025},
author = {Dong, Y and Watson, DJ},
title = {Thyrotropin-releasing hormone protects hippocampal neurons against glutamate toxicity via phosphatidylinositol 3-kinase/AKT pathway and new protein synthesis.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.11.11.687668},
pmid = {41292786},
issn = {2692-8205},
abstract = {UNLABELLED: Thyrotropin-releasing hormone is best known as a neuropeptide that stimulates the release of thyroid-stimulating hormone and prolactin in hypothalamic-pituitary-thyroid (HPT) axis. Independent from its activity in the HPT axis, TRH also exerts strong neuroprotective activity against neurodegenerative diseases such as Alzheimer's disease, epilepsy and traumatic brain injury. Although multiple factors have been linked to its neuroprotective action, the cellular mechanism of TRH neuroprotection is still not clear. Here we show that TRH protects hippocampal neurons against glutamate toxicity via phosphatidylinositol 3-kinase (PI3K)/AKT pathway and new protein synthesis. Both adeno-associated virus (AAV) mediated TRH transduction and TRH peptide given exogenously over 24 hours period of time inhibit glutamate-induced lactate dehydrogenase (LDH) release. This effect is not mediated by the decreased intracellular calcium response as TRH treatment (24 hours) has no effect on glutamate-induced increase in intracellular calcium nor the calpain activity. While TRH treatment (10 minutes) significantly inhibits glutamate-induced increase in intracellular calcium, no protective effect is observed when TRH is applied 30 minutes before or after glutamate stimulation. Instead, PI3K inhibitor LY294002 but not mitogen-activated protein kinase (MAPK)/Extracellular signal-regulated kinase (ERK)1/2 inhibitor U0126 completely inhibits the protective effect of TRH. LY294002 also blocks TRH induced AKT activation. In addition, protein synthesis inhibitor cycloheximide inhibits the protective effect of TRH. Taken together, these results suggest PI3K/AKT signaling pathway and new protein synthesis are involved in the protective effect of TRH against glutamate toxicity, thereby providing mechanistic support for its action in neurodegenerative diseases.

HIGHLIGHTS: TRH has strong neuroprotective activity against neurodegenerative diseases such as traumatic brain injury and Alzheimer's disease. Understanding the cellular mechanism for TRH neuroprotection might aid developing novel treatment strategy. In the present study we demonstrate that TRH neuroprotection is mediated via PI3K/AKT signaling pathway and new protein synthesis. This finding provides mechanistic support for the action of TRH in traumatic brain injury and other neurodegenerative diseases.},
}

@article {pmid41292642,
year = {2025},
author = {Jiang, C and Krivinko, J and Yu, Z and Sweet, RA and Zeng, L and Wang, H and Ding, Y and Zeng, Z and Kofler, J and Wang, L},
title = {Comparative Mortality Risk of Aripiprazole, Olanzapine, Quetiapine and Risperidone in Alzheimer's Disease: A Real□World Cohort Study with Treatment Effect Heterogeneity Analysis.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.11.13.25340096},
pmid = {41292642},
abstract = {BACKGROUND: Second-generation antipsychotics (SGAs) are frequently used off-label to manage behavioral symptoms in Alzheimer's disease (AD), despite ongoing concerns about their safety. Comparative evidence on mortality risk across specific SGAs remains limited.

OBJECTIVE: To compare all-cause mortality among AD patients treated with commonly prescribed SGAs and to explore treatment effect heterogeneity using causal machine learning.

METHODS: We conducted a retrospective cohort study using de-identified electronic health records from the Truveta platform (2018-2024). Patients with incident AD initiating treatment with aripiprazole, risperidone, quetiapine, or olanzapine were identified using an active-comparator, new-user design. Drug exposure was modeled as a time-varying covariate in Cox proportional hazards models, with propensity score matching applied to control for confounding. Causal tree and targeted maximum likelihood estimation (TMLE) were used to identify subgroups with heterogeneous treatment effects.

RESULTS: Among 17,004 AD patients, aripiprazole was associated with significantly lower mortality than olanzapine (HR = 0.667, 95% CI: 0.472-0.941) and quetiapine (HR = 0.677, 95% CI: 0.462-0.990). Quetiapine was also associated with lower mortality than olanzapine (HR = 0.833, 95% CI: 0.702-0.990) and risperidone (HR = 0.830, 95% CI: 0.705-0.978). Causal tree analysis revealed treatment effect heterogeneity by clinical characteristics, particularly among patients using type 2 diabetes (T2DM) medications. In subgroup analyses, aripiprazole remained protective in T2DM users (HR = 0.604 vs. quetiapine and risperidone, p = 0.002).

CONCLUSIONS: Mortality risks vary substantially across SGAs in AD patients. Aripiprazole and quetiapine were associated with lower mortality compared to olanzapine and risperidone. Treatment effect heterogeneity suggests the need for individualized prescribing based on patient characteristics such as comorbid T2DM.},
}

@article {pmid41292493,
year = {2025},
author = {Li, Y and Liu, W and Wang, X and Qin, W and Liu, Z and Lyu, D and Li, Y and Li, B and Xu, L and Cao, S and , and Chong, JRF and Lai, MKP and Chen, CLH and Jia, J},
title = {Effect of SSRIs on clinical progression in amnestic mild cognitive impairment stratified by Alzheimer's disease pathology.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {11},
pages = {e70946},
doi = {10.1002/alz.70946},
pmid = {41292493},
issn = {1552-5279},
support = {2021ZD0201802//STI2030-Major Projects/ ; Z201100005520016//Beijing Municipal Science & Technology Commission/ ; Z201100005520017//Beijing Municipal Science & Technology Commission/ ; CX23YZ15//Chinese Institutes for Medical Research/ ; 31627803//National Key Scientific Instrument and Equipment Development Project/ ; U20A20354//Key Project of the National Natural Science Foundation of China/ ; 81530036//Key Project of the National Natural Science Foundation of China/ ; NMRC/CG/NUHS/2010//National Medical Research Council/ ; NMRC/CG/013/2013//National Medical Research Council/ ; NMRC/CIRG/1485/2018//National Medical Research Council/ ; CG21APR2010//National Medical Research Council/ ; MOH-000707//National Medical Research Council/ ; 2024KCJY0104//Key Project of the Science and Technology Innovation Elite Program/ ; GZC20240164//Postdoctoral Fellowship Program (Grade C) of China Postdoctoral Science Foundation/ ; 2024M750266//China Postdoctoral Science Foundation/ ; },
mesh = {Humans ; *Cognitive Dysfunction/pathology/drug therapy/diagnostic imaging ; *Selective Serotonin Reuptake Inhibitors/therapeutic use ; *Alzheimer Disease/pathology/drug therapy ; Male ; Female ; Disease Progression ; Aged ; Positron-Emission Tomography ; Amyloid beta-Peptides/metabolism ; *Amnesia/pathology ; Aged, 80 and over ; tau Proteins/metabolism ; Longitudinal Studies ; },
abstract = {INTRODUCTION: This study examined whether selective serotonin reuptake inhibitors (SSRIs) treatment influenced cognitive trajectory and progression to Alzheimer's disease (AD) dementia in amnestic mild cognitive impairment (MCI) patients, stratified by AD pathology.

METHODS: Four hundred fifty-seven amnestic MCI participants in the ADNI database were analyzed. AD pathology was determined by baseline amyloid beta (Aβ) and tau positron emission tomography. Kaplan-Meier survival analysis and Cox proportional hazards models evaluated MCI-to-AD progression. Linear mixed models analyzed longitudinal cognitive trajectories, amyloid accumulation, and cortical thickness.

RESULTS: SSRI treatment showed no significant effect on AD dementia progression (hazard ratio = 1.64, 95% confidence interval: 0.61 to 4.38) or cognitive trajectories, regardless of AD pathology. No significant differences in Aβ accumulation or cortical thickness were observed between SSRI users and non-users. External validation confirmed no significant SSRI effect on AD progression or cognitive decline.

DISCUSSION: SSRI treatment was not associated with long-term cognitive effects in amnestic MCI, irrespective of underlying AD pathology.

HIGHLIGHTS: SSRI treatment was not associated with long-term AD dementia risk in MCI. SSRI treatment had no impact on long-term cognitive performance changes in MCI. SSRI treatment did not affect Aβ accumulation or cortical thickness in MCI. SSRIs had no effect on MCI progression, regardless of underlying AD pathology.},
}

Humans
*Cognitive Dysfunction/pathology/drug therapy/diagnostic imaging
*Selective Serotonin Reuptake Inhibitors/therapeutic use
*Alzheimer Disease/pathology/drug therapy
Male
Female
Disease Progression
Aged
Positron-Emission Tomography
Amyloid beta-Peptides/metabolism
*Amnesia/pathology
Aged, 80 and over
tau Proteins/metabolism
Longitudinal Studies

@article {pmid41291954,
year = {2025},
author = {Xiao, L and Sharma, P and Yang, X and Abebe, D and Loh, YP},
title = {Neurotrophic factor-α1/carboxypeptidase E regulates critical protein networks to rescue neurodegeneration, defective synaptogenesis and impaired autophagy in Alzheimer's disease mice.},
journal = {Translational neurodegeneration},
volume = {14},
number = {1},
pages = {59},
pmid = {41291954},
issn = {2047-9158},
support = {Intramural research grant//National Institute of Child Health and Human Development/ ; },
mesh = {Animals ; *Alzheimer Disease/metabolism/pathology/genetics/therapy ; Mice ; *Autophagy/physiology ; *Synapses/metabolism/pathology ; Male ; Mice, Transgenic ; *Carboxypeptidase H/genetics/metabolism ; Hippocampus/metabolism/pathology ; Humans ; Disease Models, Animal ; Genetic Therapy/methods ; Proteomics ; Mice, Inbred C57BL ; },
abstract = {BACKGROUND: The global aging population is increasingly inflicted with Alzheimer's disease (AD), but a cure is still unavailable. Neurotrophic factor-α1/carboxypeptidase E (NF-α1/CPE) gene therapy has been shown to prevent and reverse memory loss and pathology in AD mouse models. However, the mechanisms of action of NF-α1/CPE are not fully understood. We investigated if a non-enzymatic form of NF-α1/CPE-E342Q is efficient in reversing AD pathology and carried out a proteomic study to uncover the mechanisms of action of NF-α1/CPE in AD mice.

METHODS: AAV-human NF-α1/CPE or a non-enzymatic form, NF-α1/CPE-E342Q, was delivered into the hippocampus of 3 × Tg-AD male mice. The effects on cognitive function, neurodegeneration, synaptogenesis and autophagy were investigated. A quantitative proteomic analysis of the hippocampus was carried out.

RESULTS: Hippocampal delivery of AAV-NF-α1/CPE-E342Q prevented memory loss, neurodegeneration and microglial activation in 3 × Tg-AD mice, indicating that the action is independent of its enzymatic activity. Quantitative proteomic analysis of the hippocampus of 3 × Tg-AD mice revealed differential expression of > 2000 proteins involving many metabolic pathways after NF-α1/CPE gene therapy. Of these, two new proteins, Snx4 and Trim28, which increase Aβ production and tau levels, respectively, were down-regulated by NF-α1/CPE. Western blot analysis verified their reduction in AAV-NF-α1/CPE-treated 3 × Tg-AD mice compared to untreated mice. Our proteomic analysis indicated synaptic organization as the top signaling pathway altered in response to CPE expression. Synaptic markers PSD95 and Synapsin1 were decreased in 3 × Tg-AD mice and were restored with AAV-NF-α1/CPE treatment. Proteomic analysis hypothesized involvement of autophagic signaling pathway. Indeed, multiple protein markers of autophagy were down-regulated in 3 × Tg-AD mice, accounting for impaired autophagy. NF-α1/CPE gene therapy upregulated the levels of these proteins in 3 × Tg-AD mice, thereby reversing autophagic impairment.

CONCLUSIONS: This study uncovered vast actions of NF-α1/CPE in restoring expression of networks of critical proteins including those necessary for maintaining neuronal survival, synaptogenesis and autophagy, while down-regulating many proteins that promote tau and Aβ accumulation to reverse memory loss and AD pathology in 3 × Tg-AD mice. AAV-NF-α1/CPE gene therapy uniquely targets many metabolic levels, offering a promising holistic approach for AD treatment (Graphical Abstract).},
}

Animals
*Alzheimer Disease/metabolism/pathology/genetics/therapy
Mice
*Autophagy/physiology
*Synapses/metabolism/pathology
Male
Mice, Transgenic
*Carboxypeptidase H/genetics/metabolism
Hippocampus/metabolism/pathology
Humans
Disease Models, Animal
Genetic Therapy/methods
Proteomics
Mice, Inbred C57BL

@article {pmid41291841,
year = {2025},
author = {Li, L and Xu, F and Duan, H and Qi, J and Zhang, J and Ma, K},
title = {Identification and validation of PANoptosis-related biomarkers in Alzheimer's disease via single-cell RNA sequencing and machine learning.},
journal = {European journal of medical research},
volume = {30},
number = {1},
pages = {1170},
pmid = {41291841},
issn = {2047-783X},
support = {QNYJ2023001//Henan Academy of Medical Sciences/ ; },
mesh = {Humans ; *Alzheimer Disease/genetics/pathology ; *Machine Learning ; Biomarkers/metabolism ; *Single-Cell Analysis/methods ; Sequence Analysis, RNA/methods ; Gene Regulatory Networks ; Gene Expression Profiling ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder with complex underlying mechanisms. PANoptosis, a newly defined form of programmed cell death that integrates pyroptosis, apoptosis, and necroptosis, may play a crucial role in AD pathogenesis. However, the involvement of PANoptosis-related genes in AD remains unclear.

METHODS: We analyzed single-cell RNA-seq data (GSE181279) to identify differentially expressed genes (scDEGs) between AD patients and normal controls. PANoptosis-associated genes (PAGs), curated from published studies, were intersected with differentially expressed genes (DEGs) from GSE85426 to identify differentially expressed PAGs (DE-PAGs). Weighted gene co-expression network analysis was performed to identify key gene modules. Candidate genes were identified by overlapping scDEGs, DEGs, and module genes. Hub genes were screened via three machine learning algorithms: least absolute shrinkage and selection operator (LASSO), support vector machine (SVM), and random forest (RF). Genes with consistent expression across GSE85426 and GSE48350 were considered potential biomarkers. These were evaluated by receiver operating characteristic analysis and incorporated into a nomogram. Gene set enrichment analysis was used to explore associated pathways. Immune infiltration analysis was used to assess the biomarkers' roles in the immune microenvironment and identify potential therapeutic targets. Finally, qRT-PCR was performed to validate biomarker expression in clinical samples.

RESULTS: Overlapping 987 scDEGs, 991 DEGs, and 5327 module genes yielded 27 candidate genes. LASSO, SVM, and RF analyses identified eight hub genes, among which five (BACH2, CKAP4, DDIT4, GGNBP2, and ZFP36L2) were ultimately validated as biomarkers. A nomogram based on these genes showed good predictive performance (area under the curve (AUC) = 0.779). Seven immune cell types differed significantly between the AD and control groups, with T follicular helper cells strongly correlated with most biomarkers except CKAP4 (cor > 0.36, p < 0.001). Several Aβ- and tau-related genes and immune factors also showed significant associations (|cor|> 0.3, p < 0.05). These biomarkers were further linked to AD and other functional pathways. qRT-PCR was used to validate the transcriptomic findings, with the exception of BACH2.

CONCLUSIONS: This study identified five novel PANoptosis-related biomarkers with diagnostic and therapeutic potential in AD. These findings provide a theoretical basis for future clinical research and may contribute to improved AD diagnosis and treatment strategies.},
}

Humans
*Alzheimer Disease/genetics/pathology
*Machine Learning
Biomarkers/metabolism
*Single-Cell Analysis/methods
Sequence Analysis, RNA/methods
Gene Regulatory Networks
Gene Expression Profiling

@article {pmid41291238,
year = {2025},
author = {Li, H and Yu, C and Markovic, T and Nestler, EJ and Dong, Y},
title = {Chemical strategies for brain delivery of genomic therapy.},
journal = {Nature reviews. Chemistry},
volume = {},
number = {},
pages = {},
pmid = {41291238},
issn = {2397-3358},
abstract = {Genomic therapy has emerged as a transformative strategy for the prevention, diagnosis and treatment of a wide array of diseases, including Alzheimer's disease, amyotrophic lateral sclerosis and other CNS-related diseases. Recent developments in chemical strategies and delivery platforms have enhanced the potential of genomic therapies for brain disorders. In this Review, we summarize such strategies, focusing on advances in delivery platforms such as lipid nanoparticles, polymers and oligonucleotide conjugates to facilitate the brain delivery of DNA-based or RNA-based therapeutics into the CNS. We present an overview of the chemical structures and functional moieties of lipids, polymers and oligonucleotides used in these platforms. Lastly, we provide an outlook on future chemical directions to further improve the delivery of genomic medicines to the brain.},
}

@article {pmid41290974,
year = {2025},
author = {Salmani, M and Anoush, M and Kalantari-Hesari, A and Jahani-Maleki, A and Nouri, F and Hosseini, MJ and Mohammadi, M},
title = {Protective role of fucoidan against cognitive deficits and redox imbalance in a scopolamine-induced Alzheimer's disease model in rats.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {41813},
pmid = {41290974},
issn = {2045-2322},
mesh = {Animals ; *Polysaccharides/pharmacology ; *Scopolamine/toxicity/adverse effects ; *Alzheimer Disease/chemically induced/drug therapy/metabolism ; Male ; Rats ; Disease Models, Animal ; Oxidative Stress/drug effects ; Rats, Wistar ; *Cognitive Dysfunction/drug therapy/chemically induced/metabolism ; *Neuroprotective Agents/pharmacology ; Hippocampus/drug effects/metabolism ; Oxidation-Reduction/drug effects ; Donepezil/pharmacology ; Prefrontal Cortex/drug effects/metabolism ; Maze Learning/drug effects ; Antioxidants ; },
abstract = {This study examined the neuroprotective impacts of fucoidan on behavioral performance and oxidative damage in an animal model with scopolamine-induced cognitive deficits. Male Wistar rats, aged 8 weeks, were administered scopolamine (2 mg/kg) for 10 days. Fucoidan (15-60 mg/kg) or donepezil (1 mg/kg) was administered prior to behavioral tests over three consecutive weeks. To assess memory and learning, all rats underwent the Morris water maze (MWM) task and the Novel Object Recognition (NOR) test. Following the tests, the hippocampi and prefrontal cortex (PFC) of the rats were collected to evaluate oxidative stress parameters across all treatment groups. A significant decrease in the mean Q2 time was observed during the probe trial in the water maze task after scopolamine injection on the test day. Administration of fucoidan (15-60 mg/kg) or donepezil (1 mg/kg) notably improved cognitive dysfunction (p < 0.001). Biochemical analysis demonstrated a decline in protein carbonyl and malondialdehyde levels, along with an elevation in reduced glutathione and total antioxidant capacity in the fucoidan-treated rats (15-60 mg/kg). It is supposed that cholinergic dysfunction and oxidative stress are key contributors to cognitive deficits, and fucoidan may protect the hippocampus and prefrontal cortex by mitigating oxidative damage biomarkers.},
}

Animals
*Polysaccharides/pharmacology
*Scopolamine/toxicity/adverse effects
*Alzheimer Disease/chemically induced/drug therapy/metabolism
Male
Rats
Disease Models, Animal
Oxidative Stress/drug effects
Rats, Wistar
*Cognitive Dysfunction/drug therapy/chemically induced/metabolism
*Neuroprotective Agents/pharmacology
Hippocampus/drug effects/metabolism
Oxidation-Reduction/drug effects
Donepezil/pharmacology
Prefrontal Cortex/drug effects/metabolism
Maze Learning/drug effects
Antioxidants

@article {pmid41290806,
year = {2025},
author = {Nasiri, H and Khosravi, F and Saberian, P and Kavian, M and Mozafar, M and Torabi, P and Malekzadeh, T and Hadavi, SM and Rezaee, A and Ghorbanalinejad, M and Heidari, Z and Zangene, D and Abdi, M and Houshyar, M and Habibzadeh, A and Bemanalizadeh, M},
title = {White matter hyperintensity burden predicts domain-specific cognitive decline across the Alzheimer's disease continuum.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {41780},
pmid = {41290806},
issn = {2045-2322},
mesh = {Humans ; *Alzheimer Disease/pathology/diagnostic imaging ; *White Matter/pathology/diagnostic imaging ; Male ; Female ; *Cognitive Dysfunction/pathology/diagnostic imaging ; Aged ; Magnetic Resonance Imaging ; Cross-Sectional Studies ; Aged, 80 and over ; Executive Function ; Neuropsychological Tests ; Neuroimaging ; Cognition ; },
abstract = {White matter hyperintensity (WMH), indicative of cerebral small vessel disease, has emerged as a potential biomarker for cognitive decline in Alzheimer's disease (AD). However, their predictive role across specific cognitive domains within the AD spectrum remains unclear. This study investigates the relationship between WMH volume and cognitive performance in memory, executive function, and language across the AD continuum. A cross-sectional analysis was conducted using data from the Alzheimer's Disease Neuroimaging Initiative (ADNI), comprising 557 participants categorized into cognitively normal (CN; n = 158), mild cognitive impairment (MCI; n = 334), and Alzheimer's dementia (AD; n = 65) groups. Cognitive function was assessed using composite scores for memory (ADNI-MEM), executive function (ADNI-EF), and language (ADNI-LAN). WMH volume was quantified through validated Bayesian segmentation of MRI data. Associations between cognitive scores and WMH volume, adjusted for age, gender, APOE ε4 status, and vascular risk factors, were evaluated via multiple linear regression analyses. WMH volume showed numerically progressive increases from CN to MCI and AD groups; however, between-group differences did not reach statistical significance. Within the MCI group, significant negative associations emerged between WMH volume and memory (β=-0.13, adjusted p = 0.045) and language scores (β=-0.12, adjusted p = 0.045). Conversely, these relationships were absent in both the CN and AD groups. WMH volume relates specifically to declines in memory and language abilities, particularly in individuals with MCI. These results support using WMH measurements as early markers to identify cognitive decline in AD, potentially helping to guide earlier diagnosis and treatment decisions.},
}

Humans
*Alzheimer Disease/pathology/diagnostic imaging
*White Matter/pathology/diagnostic imaging
Male
Female
*Cognitive Dysfunction/pathology/diagnostic imaging
Aged
Magnetic Resonance Imaging
Cross-Sectional Studies
Aged, 80 and over
Executive Function
Neuropsychological Tests
Neuroimaging
Cognition

@article {pmid41290768,
year = {2025},
author = {Shafiee, L and Pishva, MS and Hosseinzadegsn, R and Bahadori, Z and Baziyar, P and Mehboodi, M and Khademee, S and Akbari, M and Motamed, M and Nadimi, E},
title = {Hesperetin reduces neuronal death in an SHSY5Y Alzheimer's model by inhibiting inflammation and apoptosis and pyroptosis cell death pathways.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {41901},
pmid = {41290768},
issn = {2045-2322},
mesh = {Humans ; *Hesperidin/pharmacology ; *Pyroptosis/drug effects ; *Alzheimer Disease/metabolism/drug therapy/pathology ; *Apoptosis/drug effects ; Amyloid beta-Peptides/metabolism ; Cell Line, Tumor ; *Inflammation/drug therapy/metabolism/pathology ; *Neurons/drug effects/metabolism/pathology ; Peptide Fragments/metabolism ; Lipopolysaccharides ; Cytokines/metabolism ; },
abstract = {Alzheimer's disease (AD) features amyloid-β (Aβ)1-42 plaques, neuroinflammation, and neuronal loss. Apoptosis and pyroptosis contribute to AD, with inflammatory cytokines involved. Flavonoids like Hesperetin may reduce Aβ1-42 deposition through anti-inflammatory effects. This study introduces a novel method combining LPS and Aβ1-42 to investigate Hesperetin's mechanism for potential AD treatments. Using computational and experimental methods, we evaluated the physicochemical properties and their correlation with protein aggregation at the molecular level. Human neuroblastoma SH-SY5Y cells were induced to differentiate and then exposed to Hesperetin (1 µM and 10 µM), LPS (1 µg/mL), and Aβ1-42 (20 µM) for 24 h. The expression levels of pro- (Bak, Bax, and Caspase-3) and anti-apoptotic genes (Bcl-2), pyroptosis-related genes (Caspase-1, Caspase-4, Caspase-5, NLRP3, and GSDMD), and pro-inflammatory cytokines genes (interleukins 6 and 1β, and TNF-α) were analyzed via qRT-PCR. The obtained simulation of our result clearly showed that Hesperetin led to the disintegration of the cross-linked structure of organized Aβ1-42 fibrils. Increased RMSD, Rg, and SASA values might lead to destabilization of Aβ1-42 fibrils in the presence of Hesperetin. Our experimental study also demonstrated that Hesperetin increased cell viability in SH-SY5Y cells induced by LPS and Aβ1-42. Hesperetin effectively reverses the enhanced apoptosis caused by LPS and Aβ1-42. Our findings indicated that Hesperetin significantly reduced the elevated expression levels of pro-inflammatory cytokines in the SH-SY5Y cells induced by LPS and Aβ1-42. Treatment with Hesperetin led to a notable downregulation of the enhanced expression of pyroptotic-related genes in LPS and Aβ1-42 induced cells. The details of the molecular level along with the investigation of the physicochemical properties of Hesperetin regarding the mechanism of destabilization of Aβ1-42 fibrils introduce it as a promising therapeutic agent for AD management. Our experimental findings also indicate that Hesperetin is a compound that prevents neuronal death by reducing inflammation and inhibiting apoptosis and pyroptosis.},
}

Humans
*Hesperidin/pharmacology
*Pyroptosis/drug effects
*Alzheimer Disease/metabolism/drug therapy/pathology
*Apoptosis/drug effects
Amyloid beta-Peptides/metabolism
Cell Line, Tumor
*Inflammation/drug therapy/metabolism/pathology
*Neurons/drug effects/metabolism/pathology
Peptide Fragments/metabolism
Lipopolysaccharides
Cytokines/metabolism

@article {pmid41290365,
year = {2025},
author = {Chiotis, K and Wang, Y and La Joie, R and Rabinovici, GD},
title = {The Role of Amyloid-β and Tau PET in the New Era of Alzheimer Disease Therapies.},
journal = {Journal of nuclear medicine : official publication, Society of Nuclear Medicine},
volume = {},
number = {},
pages = {},
doi = {10.2967/jnumed.124.268339},
pmid = {41290365},
issn = {1535-5667},
abstract = {The advent of amyloid-β (Aβ) and tau PET imaging has revolutionized Alzheimer disease (AD) research, enabling in vivo detection of hallmark pathologies and transforming both diagnosis and therapeutic development. These imaging modalities have played a central role in the clinical trials that led to the recent approval of Aβ-targeting therapies, with Aβ PET used for participant selection and treatment monitoring and tau PET increasingly integrated to assess disease staging and prognosis. This continuing-education article reviews the current clinical validation of Aβ and tau PET imaging in AD, outlines the available evidence for the recently approved anti-Aβ therapies, and examines how PET imaging was operationalized in the trials for these novel therapeutic agents. We explore the potential for translating trial-based imaging protocols into clinical practice-particularly how PET quantification beyond binary visual reads can support nuanced decisions regarding patient eligibility, risk stratification, therapeutic monitoring, and duration of treatment. In addition, we discuss the emerging landscape of tau-targeting therapies and the anticipated central role of tau PET in their clinical evaluation. Finally, we identify key knowledge gaps and unmet needs that must be addressed to facilitate broader clinical adoption of PET imaging, including standardization efforts, accessibility and reimbursement, and evidence-based guidelines for interpretation and use.},
}

@article {pmid41289912,
year = {2025},
author = {Verma, A and Waiker, DK and Gupta, PS and Shrivastava, SK},
title = {Recent advances in bioisosteric modifications for targeting Alzheimer's disease pathways.},
journal = {Bioorganic chemistry},
volume = {167},
number = {},
pages = {109248},
doi = {10.1016/j.bioorg.2025.109248},
pmid = {41289912},
issn = {1090-2120},
abstract = {The drug development process is highly challenging due to high cost, ethical consideration and takes a long time to reach in to the market for the ultimate benefit of the patients. Considering the global health issues, brain disorders such as Parkinsons disease (PD) and Alzheimer's disease (AD) are major concerns and are difficult to treat because of the complex nature of the disease. The complexity of these diseases, poor efficacy of the current drugs, and their low ability to cross blood brain barrier (BBB) limits the overall biological effectiveness of the treatment. These challenges must be addressed urgently to reduce the burden of these diseases and to improve the quality and expectancy of life. In a drug molecule its molecular properties are the key attributes in determining selectivity, stability, pharmacokinetics and BBB permeability. Any unfavorable changes in these molecular properties may compromise, whereas favorable modification can enhance the overall biological effectiveness of the drug molecule. Bioisosterism is a powerful chemical tool that offers replacement of undesired functional group on the drug molecule with more suitable group resulting in improved pharmacokinetics, minimizing side effects and toxicity, and could tailored it to complex environments such as brain. In this review we present recent bioisosteric replacement approaches which have been employed to optimize the existing molecular properties of the compound to improve their biological effectiveness particularly focusing on AD.},
}

@article {pmid41289288,
year = {2025},
author = {Angelvy, P and Badin, M and Pelletier-Visa, M and Givron, P and Pereira, B and Coudeyre, E},
title = {Musical intervention to reduce stress during botulinum toxin injection for spasticity: Protocol for a randomized controlled trial (MUSIBOT).},
journal = {PloS one},
volume = {20},
number = {11},
pages = {e0327259},
doi = {10.1371/journal.pone.0327259},
pmid = {41289288},
issn = {1932-6203},
mesh = {Humans ; *Music Therapy/methods ; *Muscle Spasticity/drug therapy/psychology ; *Stress, Psychological/therapy/prevention & control/etiology ; *Botulinum Toxins/administration & dosage/adverse effects/therapeutic use ; Adult ; Male ; Female ; Randomized Controlled Trials as Topic ; Prospective Studies ; Heart Rate ; Middle Aged ; Injections, Intramuscular ; },
abstract = {INTRODUCTION: Botulinum toxin injections are a common treatment for managing spasticity resulting from central nervous system damage, including stroke, multiple sclerosis, and traumatic brain injury. However, the injections are associated with perceived pain, and many patients experience significant anticipatory stress regarding future sessions. The intensity of this stress varies among individuals. Music therapy, particularly receptive musical interventions structured around a U-shaped sequence, promotes progressive relaxation through distinct musical phases. This method has demonstrated efficacy in reducing pain and anxiety across various clinical contexts, including chronic and acute pain, Alzheimer's disease, fibromyalgia, and neurologically mediated pain. Given the painful nature of botulinum toxin injections, this study proposes the use of receptive music therapy to improve patient tolerance of the procedure. We hypothesize that receptive musical intervention can reduce injection-induced stress in adults undergoing botulinum toxin treatment. To our knowledge, no studies have specifically investigated the effect of music therapy on stress related to botulinum toxin injections. We aim to conduct a prospective randomized (1:1) controlled trial to evaluate the impact of receptive music intervention on stress levels, measured via heart rate variability (HRV), during botulinum toxin injection sessions. The primary objective is to assess the effect of receptive musical intervention during botulinum toxin injections on injection-induced stress, measured by HRV. Secondary objectives include evaluating the intervention's effects on pain intensity and anxiety levels.

METHODS AND ANALYSIS: Patient satisfaction following the music-assisted injection session will also be assessed. Additionally, the physician's evaluation of the procedure and the patient's perception of time during the session will be recorded.

ETHICS AND DISSEMINATION: All participants will provide written informed consent prior to enrollment. The study has received approval from the relevant institutional ethics committee (Comité de Protection des Personnes - ID: 25.00156.000468, Sud-Méditerranée IV, approved on 3 April 2025). Findings will be disseminated through peer-reviewed publications and presentations at scientific conferences.

TRIAL REGISTRATION: ClinicalTrials.gov NCT06920524.},
}

Humans
*Music Therapy/methods
*Muscle Spasticity/drug therapy/psychology
*Stress, Psychological/therapy/prevention & control/etiology
*Botulinum Toxins/administration & dosage/adverse effects/therapeutic use
Adult
Male
Female
Randomized Controlled Trials as Topic
Prospective Studies
Heart Rate
Middle Aged
Injections, Intramuscular

@article {pmid41287966,
year = {2025},
author = {Cui, A and Patel, R and Bosco, P and Akcan, U and Richters, E and Barrilero Delgado, P and Agalliu, D and Sproul, AA},
title = {Generation of hiPSC-Derived Brain Microvascular Endothelial Cells Using Directed Differentiation and Transcriptional Reprogramming.},
journal = {Arteriosclerosis, thrombosis, and vascular biology},
volume = {},
number = {},
pages = {},
doi = {10.1161/ATVBAHA.125.323397},
pmid = {41287966},
issn = {1524-4636},
abstract = {BACKGROUND: Modeling the human blood-brain barrier (BBB) is limited by the lack of robust protocols to generate induced pluripotent stem cell (iPSC)-derived brain microvascular endothelial cells (BMECs). Current methods generate cells that do not fully recapitulate key BMEC functions or the brain endothelial transcriptome identity.

METHODS: To address this gap, we combined directed differentiation of human iPSCs into BBB-primed endothelial cells with overexpression of FOXF2 and ZIC3, transcription factors critical for BMEC identity, to generate reprogrammed BMECs (rBMECs) from 3 iPSC lines. We performed immunofluorescence, functional analyses, and bulk RNA sequencing to characterize these cells. We cocultured rBMECs with iPSC-derived astrocytes and pericytes in the MIMETAS microfluidics platform to assess how 3-dimensional culture influences their BBB properties. Finally, we generated rBMECs expressing familial Alzheimer disease mutation APP V717I to elucidate how this genetic variant affects barrier properties compared with exposure to oAβ42 (oligomeric amyloid-β [1-42] peptide).

RESULTS: Transcriptomic and functional analyses show that rBMECs express a subset of the BBB transcriptome and exhibit stronger paracellular barrier properties, lower caveolar-mediated transport, and comparable PGP (P-glycoprotein) activity compared with primary human BMECs. rBMECs interact with human iPSC-derived pericytes and astrocytes to form a 3D neurovascular system in the MIMETAS microfluidics platform with robust BBB properties. Finally, APP V717I rBMECs show decreased barrier integrity and upregulation of inflammatory markers. In contrast, treatment of control rBMECs with oAβ42 increases inflammatory markers but does not alter barrier integrity.

CONCLUSIONS: This protocol generates rBMECs with strong BBB properties and a brain-specific transcriptome signature. In addition, the iPSC-derived 3D neurovascular unit system shows some similar properties to the in vivo human BBB. Finally, familial Alzheimer disease mutation APP V717I alters several BBB-related properties of rBMECs and their inflammatory state, independent of Aβ42 (amyloid-β [1-42] peptide).},
}

@article {pmid41287525,
year = {2025},
author = {Um, YH and Wynveen, P and Holland, M and Bhatt, K and Vucetic, Z and Engel, B and Carlson, C and Becker, A and Meier, IB and Narayan, VA and Wang, SM and Kang, DW and Kim, S and Kim, S and Kim, D and Choe, YS and Kim, REY and Ha, S and Lim, HK},
title = {Neuroimaging correlates and biomarker performance of a fully automated plasma p-tau217/Aβ42 ratio assay in a clinical cohort with Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {11},
pages = {e70942},
doi = {10.1002/alz.70942},
pmid = {41287525},
issn = {1552-5279},
support = {//Korea Creative Content Agency/ ; R2022020030//Korea Ministry of Culture, Sports, and Tourism in 2023/ ; //Basic Medical Science Facilitation Program/ ; //Catholic University of Korea/ ; //Catholic Education Foundation/ ; },
mesh = {Humans ; *Alzheimer Disease/blood/diagnostic imaging/pathology ; *tau Proteins/blood ; *Amyloid beta-Peptides/blood ; Male ; Female ; Biomarkers/blood ; Cross-Sectional Studies ; Aged ; Positron-Emission Tomography ; *Neuroimaging ; *Peptide Fragments/blood ; Phosphorylation ; Cohort Studies ; Aged, 80 and over ; Brain/diagnostic imaging/pathology ; Middle Aged ; },
abstract = {INTRODUCTION: Blood-based biomarkers offer scalable, non-invasive tools for Alzheimer's disease (AD) detection. We investigated the performance of plasma biomarkers associated with AD on the automated Beckman Coulter Access DxI 9000 analyzer.

METHODS: This cross-sectional study included 262 individuals from across the AD continuum. Plasma phosphorylated tau at threonine 217 (p-tau217), amyloid beta (Aβ)42, and their ratio were measured. Diagnostic accuracy for amyloid positron emission tomography (PET) positivity (Centiloid > 20), using a dual cutoff approach, was assessed via receiver operative characteristic curve. Associations with tau PET (n = 76) were also assessed.

RESULTS: The p-tau217/Aβ42 ratio showed the highest diagnostic accuracy for amyloid PET positivity (area under curve = 0.943) and the smallest indeterminate zone (8.0%). It correlated strongly and consistently with tau PET across Braak stages and with AD-related cortical atrophy.

DISCUSSION: The p-tau217/Aβ42 ratio was the most reliable plasma biomarker, closely tracking tau PET. It has potentials for clinical use in diagnosis and treatment monitoring.

HIGHLIGHTS: This is the first validation of the Beckman Coulter plasma immunoassay. The plasma phosphorylated tau at threonine 217 amyloid beta 42 ratio showed the highest accuracy across the full Alzheimer's disease (AD) spectrum. Plasma biomarkers correlated with tau positron emission tomography and AD-related brain atrophy. Glial fibrillary acidic protein offered complementary value reflecting astrocytic activation.},
}

Humans
*Alzheimer Disease/blood/diagnostic imaging/pathology
*tau Proteins/blood
*Amyloid beta-Peptides/blood
Male
Female
Biomarkers/blood
Cross-Sectional Studies
Aged
Positron-Emission Tomography
*Neuroimaging
*Peptide Fragments/blood
Phosphorylation
Cohort Studies
Aged, 80 and over
Brain/diagnostic imaging/pathology
Middle Aged

@article {pmid41286555,
year = {2025},
author = {Zhang, J and Zheng, Z and Liu, Y and Feng, S and Feng, G},
title = {Blood-Brain Barrier-Permeable Dual-Responsive Fluorescent Probe Reveals an Increased Risk of Alzheimer's Disease in Diabetic Patients.},
journal = {Analytical chemistry},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.analchem.5c06216},
pmid = {41286555},
issn = {1520-6882},
abstract = {Alzheimer's disease (AD) is a global concern, and revealing its early diagnostic signals is crucial for timely intervention and treatment. Fluorescent probes hold great promise in disease diagnosis due to their high sensitivity and specificity. However, most existing probes struggle to effectively penetrate the blood-brain barrier (BBB), which significantly limits their application in brain disease imaging, including AD. Herein, a novel BBB-permeable fluorescent probe CL was reported. CL contains a quinolinium group and a C12 alkyl chain, enabling it to effectively target mitochondria without being affected by mitochondrial membrane potential. CL exhibits a dual response to viscosity and ONOO[-], displaying sensitive fluorescence responses at 812 and 495 nm, respectively. These characteristics enable CL to simultaneously monitor fluctuations in mitochondrial viscosity and ONOO[-], thereby achieving dual-channel detection and providing more comprehensive pathological information. More importantly, compared with the control probe DL containing a short C1 chain, CL exhibits superior BBB penetration ability and efficient brain imaging performance. Utilizing CL, alterations in viscosity and ONOO[-] in the brains of AD and diabetes mice were successfully monitored. The results not only show that both viscosity and ONOO[-] are important biomarkers of brain diseases but also reveal that diabetes patients have a higher risk of AD, laying a foundation for AD diagnosis and prevention.},
}

@article {pmid41286448,
year = {2025},
author = {Albertini, G and Zielonka, M and Cuypers, ML and Snellinx, A and Xu, C and Poovathingal, S and Wojno, M and Davie, K and van Lieshout, V and Craessaerts, K and Wolfs, L and Pasciuto, E and Jaspers, T and Horré, K and Serneels, L and Fiers, M and Dewilde, M and De Strooper, B},
title = {The Alzheimer's therapeutic Lecanemab attenuates Aβ pathology by inducing an amyloid-clearing program in microglia.},
journal = {Nature neuroscience},
volume = {},
number = {},
pages = {},
pmid = {41286448},
issn = {1546-1726},
support = {ERC-834682 CELLPHASE_AD//EC | EU Framework Programme for Research and Innovation H2020 | H2020 Priority Excellent Science | H2020 European Research Council (H2020 Excellent Science - European Research Council)/ ; METH/21/05//KU Leuven (Katholieke Universiteit Leuven)/ ; G087523N//Fonds Wetenschappelijk Onderzoek (Research Foundation Flanders)/ ; G087523N//Fonds Wetenschappelijk Onderzoek (Research Foundation Flanders)/ ; AARF-22-968623/ALZ/Alzheimer's Association/United States ; },
abstract = {Controversies over anti-amyloid immunotherapies underscore the need to elucidate their mechanisms of action. Here we demonstrate that Lecanemab, a leading anti-β-amyloid (Aβ) antibody, mediates amyloid clearance by activating microglial effector functions. Using a human microglia xenograft mouse model, we show that Lecanemab significantly reduces Aβ pathology and associated neuritic damage, while neither fragment crystallizable (Fc)-silenced Lecanemab nor microglia deficiency elicits this effect despite intact plaque binding. Single-cell RNA sequencing and spatial transcriptomic analyses reveal that Lecanemab induces a focused transcriptional program that enhances phagocytosis, lysosomal degradation, metabolic reprogramming, interferon γ genes and antigen presentation. Finally, we identify SPP1/osteopontin as a major factor induced by Lecanemab treatment and demonstrate its role in promoting Aβ clearance. These findings highlight that effective amyloid removal depends on the engagement of microglia through the Fc fragment, providing critical insights for optimizing anti-amyloid therapies in Alzheimer's disease.},
}

@article {pmid41285347,
year = {2025},
author = {Li, X and Liu, R and He, Y and Yang, X and Li, T and Feng, Y},
title = {TEMPOL alleviated tau pathology and cognitive deficits induced by P301S-tau.},
journal = {Neuroscience letters},
volume = {},
number = {},
pages = {138465},
doi = {10.1016/j.neulet.2025.138465},
pmid = {41285347},
issn = {1872-7972},
abstract = {Alzheimer's disease (AD) is the most frequent of neurodegenerative disease affecting elderly people. However, there is still no curative therapeutic strategies in clinical practice. Here, we studied whether TEMPOL as a free radical scavenger can prevent memory deficits in P301S-tau mice. We found that TEMPOL administration markedly restored learning and memory impairments inducing by P301S-tau. We showed that TEMPOL had a potent capacity of inhibiting the expression of tau protein and its phosphorylation levels. The inflammatory response and synaptic defects induced by P301S-tau was also obviously improved TEMPOL treatment. Furthermore, proteomics showed 121 reversed proteins by TEMPOL treatment were primarily involved in immune system processes, innate immune responses, inflammatory responses, autophagosome assembly, lysosome organization, and autophagy. Taken together, TEMPOL played a critical role in P301S-tau-related cognitive impairments. These findings demonstrate that TEMPOL shows promise as a multi-target therapeutic agent for AD by modulating critical pathways implicated in its pathogenesis.},
}

@article {pmid41285280,
year = {2025},
author = {Hu, Q and Xu, K and Ran, Q and Zhang, W and Gan, C and Fang, Q and Hui, A},
title = {Hybrid molecules with dual inhibition of acetylcholinesterase and Tau hyperphosphorylation: design, inhibitory activity evaluation, apoptosis assessment, and mechanistic exploration.},
journal = {Chemico-biological interactions},
volume = {},
number = {},
pages = {111848},
doi = {10.1016/j.cbi.2025.111848},
pmid = {41285280},
issn = {1872-7786},
abstract = {A comprehensive therapeutic strategy for Alzheimer's disease (AD) requires simultaneous inhibition of acetylcholinesterase (AChE) and targeting of hyperphosphorylated Tau (P-Tau)-mediated pathogenesis. To address this need, the present study designed a series of hybrid molecules by integrating three pharmacophoric scaffolds with established P-Tau-modulating activity (phenothiazine, dibenzazepine and benzothiazepinones) into AChE-inhibiting frameworks: indanone (derived from the clinical AChE inhibitor Donepezil) or 9-chloro-1,2,3,4-tetrahydroacridine (derived from Tacrine, another clinically approved AChE inhibitor). Following preliminary in silico evaluations including druggability predictions and absorption, distribution, metabolism, excretion, toxicity (ADMET) profiling, twelve compounds (C1-C12) with potential AChE/Tau dual-target binding affinity were identified and subsequently synthesized. Among these, four compounds (C5, C6, C7, and C11) exhibited significant AChE inhibitory activity, with IC50 values ranging from 205.3 to 257.1 nM, comparable to that of tacrine (226.0 nM). Notably, the indanone-phenothiazine hybrid compound C11 stood out as the most promising candidate, it achieved the lowest P-Tau/total Tau (T-Tau) ratio (5.30 × 10[-6]) in okadaic acid (OA)-induced SH-SY5Y cells, outperforming hydromethylthionine mesylate (5.40 × 10[-6]), a leading clinical candidate for Tau aggregation inhibition. Beyond its dual inhibitory activities, C11 ameliorated OA-induced cell apoptosis, further supporting its potential as anti-AD agent. Subsequent mechanistic explorations confirmed that C11 alleviated oxidative stress and downregulated Tau phosphorylation at specific pathogenic sites (Ser396, Ser262, Thr181). Concurrently, C11 modulated the expression of glycogen synthase kinase-3β (GSK-3β), a critical kinase driving P-Tau formation. In conclusion, this study identifies novel dual-target inhibitors against AChE and P-Tau, and provides new therapeutic insights into AD treatment.},
}

@article {pmid41284585,
year = {2025},
author = {Ismail, Z and Guan, DX and Babulal, GM and Bateman, JR and Cantillon, M and Creese, B and D'Antonio, F and Fischer, CE and Gatchel, JR and Ghahremani, M and Guerrero-Cantera, J and Lanctôt, KL and Mielke, MM and Mortby, ME and Feldman, O and Pereira, AC and Pereiro, AX and Perry, G and Potter, WZ and Rabl, M and Ravona-Springer, R and Rosen, AC and Rouse, HJ and Sankhe, K and Schindler, SE and Udeh-Momoh, CT and Tarawneh, R and Oliveira, FF and , },
title = {Plasma biomarkers in neuropsychiatric syndromes: A narrative review.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251392185},
doi = {10.1177/13872877251392185},
pmid = {41284585},
issn = {1875-8908},
abstract = {Neuropsychiatric symptoms (NPS) are common features of neurodegenerative disease (NDD) but are relatively understudied compared to cognition, especially regarding biomarkers. Further, emerging evidence describes the utility of systematic assessment of NPS across the cognitive continuum, even in advance of dementia. In this narrative review, we discuss the role of plasma biomarkers in relation to NPS across the cognitive continuum of unimpaired, subjective cognitive decline, mild cognitive impairment, and dementia. While Alzheimer's disease is the primary focus, vascular, Lewy body, and frontotemporal dementia etiologies are also discussed. Literature searches included NPS and dementia-related search terms with additional literature identified based on the author group's subject area expertise. We found that plasma biomarkers are a burgeoning field, and scalability and accessibility make them well-suited for the study of NPS across the disease continuum. In early-stage NDD, diagnostic biomarkers are best suited for discriminating NDD-related NPS from non-NDD psychiatric syndromes and/or NPS due to other causes. In those with dementia, monitoring and prognostic biomarkers may enable the assessment of treatment response or help predict the risk of worsening symptoms. We conclude that plasma amyloid-β and tau show great promise in assessing NPS, especially during early-stage disease, but inflammatory and genetic biomarkers may also play a role across the disease course. Systematic research is required, keeping in mind the ethical considerations of knowing biomarker status in early-stage disease.},
}

@article {pmid41284069,
year = {2025},
author = {Rodrigues, KDC and Oliveira, MDC and de Souza, IC and Igansi, AW and Lopes, AVB and de Oliveira Pacheco, C and Hass, SE and Schumacher, RF and Luchese, C},
title = {Sex-dependent therapeutic effects of nano-curcumin on alzheimer's disease: enhanced cognitive and physiological restoration in female mice.},
journal = {Psychopharmacology},
volume = {},
number = {},
pages = {},
pmid = {41284069},
issn = {1432-2072},
support = {PqG 24/2551-0001249-4//Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul/ ; 160674/2020-4//Conselho Nacional de Desenvolvimento Científico e Tecnológico/ ; 001//Coordenação de Aperfeiçoamento de Pessoal de Nível Superior/ ; },
abstract = {Curcumin (Cur) is a bioactive compound with neuroprotective and anti-inflammatory effects, though its clinical application is limited by poor bioavailability. This study assessed the impact of nanocapsulated curcumin (NcCur), formulated Eudragit (EUD) polymer, in a sporadic Alzheimer's disease (AD) mouse model induced by intracerebroventricular streptozotocin (STZ), with attention to sex-specific differences. Mice received STZ (3 nmol/3 µL) or 0.9% saline on days 1 and 3, followed by intragastric treatment with Cur or NcCur (10 mg/kg, on alternate days) from day 22 until euthanasia - a dose previously shown to be effective in behavioral and biochemical modulation in rodent models of neurodegeneration. Behavioral assessments included open field, elevated plus maze (EPM), tail suspension (TST), object recognition, Y-maze, and step-down avoidance tasks (SDAT), performed before and after treatment. After euthanasia, thymus, spleen and adrenal glands were weighed; biochemical assays evaluated oxidative stress, monoaminergic and cholinergic enzymes, and Na[+]K[+]-ATPase activity. NcCur improved short- and long-term memory in both sexes, with greater effects in females (42% and 35%) than males (28% and 25%). In the EPM, NcCur increased open arm time more prominently in females (40%) than males (25%), while TST immobility time was reduced similarly in both. Spatial and aversive memory improved in both sexes, but females showed greater performance in the SDAT. Biochemical analyses showed reductions in reactive species in males (45%) and females (55%) with NcCur; Na[+]K[+]-ATPase activity increased in females (60%) and males (50%). AChE activity was restored in both sexes. NcCur reduced MAO-A/B activities more in females (65%/55%) than in males (45%/35%). Thymus and spleen weights were normalized in both sexes, with stronger effects in females. NcCur also mitigated alterations in thymus and spleen relative weights, suggesting immunomodulatory effects. Some biochemical and behavioral responses were more prominent in females, both sexes benefited from treatments. These findings suggest that NcCur enhances Cur therapeutic potential through multimodal actions linked involving modulation of oxidative stress, cholinergic and monoaminergic systems, and immune-related parameters. NcCur emerges as a promising candidate for AD-like intervention in both sexes.},
}

@article {pmid41282905,
year = {2025},
author = {Andrews, D and Golchi, S and Collins, DL and , },
title = {A digital twin methodology using real patient data for sample size reduction in Alzheimer's disease randomized controlled clinical trials.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.10.28.25338899},
pmid = {41282905},
abstract = {INTRODUCTION: Recruitment for Alzheimer's disease randomized controlled trials (RCTs) is difficult and expensive. To reduce RCT sample sizes, our Digital Twin Trial (DTT) methodology combines an interpretable cognitive decline prediction model with prediction-powered inference.

METHODS: For DTT participants, our model identifies similar individuals ("Digital Twins") from a retrospective database and uses their cognitive scores to predict decline. Predictions adjust observed scores, reducing variance within treatment groups. We simulated 18-month DTTs and standard RCTs using mixed effects models of decline in Alzheimer's Disease Neuroimaging Initiative subjects meeting lecanemab's Phase 3 inclusion criteria.

RESULTS: Predicted and observed change in Clinical Dementia Rating Sum-of-Boxes correlated at r = 0.4. DTTs required 1,855 subjects versus 2,170 for standard RCTs to detect a simulated 25% decline-slowing drug effect at 0.9 power. DTT Type 1 error was consistent with 0.05.

DISCUSSION: DTTs could reduce recruitment and cost burdens. Model interpretability could help clinicians trust individualized prognoses.},
}

@article {pmid41282780,
year = {2025},
author = {Yang, B and Earnest, T and Bilgel, M and Albert, MS and Johnson, SC and Davatzikos, C and Erus, G and Masters, CL and Resnick, SM and Miller, MI and Bakker, A and Morris, JC and Benzinger, TLS and Gordon, BA and Sotiras, A and , and , },
title = {Predicting future cognitive impairment in preclinical Alzheimer's disease using multimodal imaging: a multisite machine learning study.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.10.15.25337507},
pmid = {41282780},
abstract = {UNLABELLED: Predicting the likelihood of developing Alzheimer's disease (AD) dementia in at-risk individuals is important for the design of and optimal recruitment for clinical trials of disease-modifying therapies. Machine learning (ML) has been shown to excel in this task; however, there remains a lack of models developed specifically for the preclinical AD population, who display early signs of abnormal brain amyloidosis but remain cognitively unimpaired. Here, we trained and evaluated ML classifiers to predict whether individuals with preclinical AD will progress to mild cognitive impairment or dementia within multiple fixed time windows, ranging from one to five years. Models were trained on regional imaging features extracted from amyloid positron emission tomography and magnetic resonance imaging pooled across seven independent sites and from two amyloid radiotracers ([ [18] F]-florbetapir and [ [11] C]-Pittsburgh-compound-B). Out-of-sample generalizability was evaluated via a leave-one-site-out and leave-one-tracer-out cross-validation. Classifiers achieved an out-of-sample receiver operating characteristic area-under-the-curve of 0.66 or greater when applied to all except one hold-out sites and 0.72 or greater when applied to each hold-out radiotracer. Additionally, when applying our models in a retroactive cohort enrichment analysis on A4 clinical trial data, we observed increased statistical power of detecting differences in amyloid accumulation between placebo and treatment arms after enrichment by ML stratifications. As emerging investigations of new disease-modifying therapies for AD increasingly focus on asymptomatic, preclinical populations, our findings underscore the potential applicability of ML-based patient stratification for recruiting more homogeneous cohorts and improving statistical power for detecting treatment effects for future clinical trials.

HIGHLIGHTS: Machine learning can predict future cognitive impairment in preclinical Alzheimer'sModels achieved high out-of-sample ROC-AUC on external sites and PET tracersModels were able to distinguish cognitively stable from decliners in the A4 cohortML cohort enrichment enhanced secondary treatment effect detection in the A4 cohort.},
}

@article {pmid41282773,
year = {2025},
author = {Ackley, SF and La Joie, R and Caunca, M and Mukherjee, S and Choi, SE and Trittschuh, EH and Crane, PK and Hayes-Larson, E and , },
title = {Substituting Blood-Based Biomarkers for Imaging Measures in Alzheimer's Disease Studies: Implications for Sample Size and Bias.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.11.06.25339696},
pmid = {41282773},
abstract = {BACKGROUND: Blood-based biomarkers for Alzheimer's disease (AD) pathology are appealing options in large population-based studies due to their low cost, minimal invasiveness, and feasibility of collection in non-clinical settings. Despite these benefits, blood-based biomarkers have lower test-retest reliability than neuroimaging measures like amyloid positron emission tomography (amyloid-PET) Centiloids; trade-offs in power and bias remain unexplored.

METHODS: We use data from Alzheimer's Disease Neuroimaging Initiative (ADNI) and the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) studies, which include both amyloid-PET and blood-based measures, to assess differences in statistical power, required sample size, and bias when replacing a neuroimaging measure with a blood-based measure. We use simulations parameterized based on these studies to show potential implications of using plasma p-tau181 or p-tau217, blood-based AD biomarkers, in place of Centiloids from amyloid-PET, when the biomarker is either the exposure or the outcome in an analysis of interest.

RESULTS: We demonstrated that substituting amyloid-PET Centiloids with a blood-based measure of p-tau can substantially reduce power, requiring 3 to 6 times the sample size to achieve 80% power compared to amyloid-PET. In addition, using a blood-based biomarker as the exposure can introduce significant regression dilution bias, attenuating estimated associations.

CONCLUSIONS: Due to their lower cost and ease of collection compared with neuroimaging, blood-based biomarkers facilitate AD pathology measures on larger, more diverse samples with longitudinal follow-up. Consideration of the sample sizes they necessitate and their potential for bias is critical for the design and interpretation of studies employing these biomarkers.},
}

@article {pmid41282720,
year = {2025},
author = {Khorsand, B and Teichrow, D and Ghanbarian, E and Zheng, L and Sajjadi, SA and Glover, CM and Grill, JD and Rabin, LA and Ezzati, A},
title = {Scalable Markers for Early Cognitive Decline: Plasma p-tau217, Subjective Cognitive Concerns, and Digital Testing: Results from the A4/LEARN studies.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.10.14.25338009},
pmid = {41282720},
abstract = {BACKGROUND AND OBJECTIVES: Although amyloid positron emission tomography (PET) and Cerebrospinal fluid (CSF) biomarkers remain the standard for confirming Alzheimer's disease (AD) pathology, their use is impractical for screening or routine prognostic assessment. Plasma phosphorylated tau 217 (p-tau217), subjective cognitive concerns, and computerized cognitive testing are non-invasive, scalable, and feasible to implement in large populations. We tested whether these measures independently predict the onset of cognitive impairment and whether combining them improves prognostic accuracy.

METHODS: We analyzed 1,071 cognitively unimpaired adults aged 65-85 years from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) trial (amyloid-positive; solanezumab or placebo arms) and the parallel Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) cohort (amyloid-negative). At baseline, participants completed plasma p-tau217 measurement, the Cognitive Function Index (CFI), and the Cogstate Computerized Battery (CCB). Over 240 weeks of follow-up, incident impairment was defined as conversion from a Global Clinical Dementia Rating Score (CDR-GS) of 0 to 0.5 or higher. The predictive value of each measure for subsequent decline was examined after adjustment for demographic and genetic covariates.

RESULTS: During the follow-up, 365 of 1,071 participants (34.1%) developed cognitive impairment. Higher plasma p-tau217 (per-standard-deviation increase) was associated with higher odds of converting to CDR-GS>0 across all cohorts: A4-Placebo (HR=1.56; 95% CI, 1.37-1.78), A4-Solanezumab (HR=1.46; 95% CI, 1.29-1.65), LEARN (HR=1.25; 95% CI, 1.05-1.48). Similarly, higher CFI predicted incident impairment: A4-Placebo (HR=1.59; 95% CI, 1.42-1.79), A4-Solanezumab (HR=1.67; 95% CI, 1.47-1.91), LEARN (HR=1.37; 95% CI, 1.12-1.68). Lower CCB also conferred higher risk: A4-Placebo (HR=0.76; 95% CI, 0.65-0.91), A4-Solanezumab (HR=0.73; 95% CI, 0.62-0.87), LEARN (HR=0.68; 95% CI, 0.53-0.87). In models including all three predictors, each remained independently associated with progression.

CONCLUSION: Plasma p-tau217, subjective cognitive concerns, and computerized cognitive testing each independently predicted progression to cognitive impairment in cognitively unimpaired older adults. Together, these non-invasive and scalable measures provide practical tools for risk stratification years before clinical diagnosis. Combining biological, subjective, and digital markers may support earlier detection in clinical care and enhance efficiency in prevention trial enrollment.},
}

@article {pmid41282187,
year = {2025},
author = {O'Brien, EK and Cox, T and Fernandez, S and Bourgeat, P and Porter, T and Goudey, B and Doecke, JD and Masters, CL and Fripp, J and Nho, K and Villemagne, VL and Cruchaga, C and Rowe, CC and Saykin, AJ and Dore, V and Laws, SM},
title = {Predicting accumulation and age at onset of amyloid-β from genetic risk and resilience for Alzheimer's disease.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-7911284/v1},
pmid = {41282187},
issn = {2693-5015},
abstract = {Accumulation of brain amyloid beta (Aβ) is a key pathological hallmark of Alzheimer's disease (AD) and begins many years before cognitive symptoms. Being able to predict the risk of Aβ accumulation, or the age at which this accumulation exceeds a critical threshold, may enable early intervention and treatment to slow or prevent the onset of AD. We utilised published genome-wide association studies (GWAS) to develop polygenic scores (PGS) based on AD risk (PGS risk) and resilience (PGS resilience). We tested whether these could predict (i) whether an individual was an accumulator of Aβ ('Accumulator Status'), and (ii) in accumulators, the age at which brain Aβ is estimated to exceed a threshold of 20 centiloids (CL)('Estimated Age at onset of Aβ'; AAO-Aβ) among 2175 participants (1158 with AAO Aβ) from the Alzheimer's Dementia Onset and Progression in International Cohorts (ADOPIC) study. Additionally, we conducted genome-wide association studies (GWAS) of these traits and developed phenotype-specific PGSs using cross-validation (CV). Higher PGS risk was associated with a greater risk of being an accumulator and a younger AAO-Aβ. When stratified by number of APOE ε4 alleles, PGS risk predicted Accumulator Status in APOE ε4 heterozygotes, and AAO-Aβ in ε4 non-carriers and heterozygotes, with the same directions of effect as were seen in the whole cohort. PGS resilience was not significantly associated with Accumulator Status, but higher PGS resilience was associated with later AAO-Aβ overall and in ε4 heterozygotes. Trait-specific PGSs, developed using CV, were not significantly associated with either trait overall and the direction of association varied across CV folds. Polygenic scores, alongside other risk factors, may be useful for identifying individuals at risk of accumulating Aβ, and predicting the age at which this exceeds a critical threshold. This could provide a window for administering disease-modifying treatment or lifestyle interventions to prevent or delay the onset of AD.},
}

@article {pmid41282120,
year = {2025},
author = {Li, M and Niu, S and Xu, Y and Li, J and Hu, X and Liu, D and Atik, M and Xu, X and Wang, L and Taner, NE and Tao, C},
title = {Bridging the Computational-Experimental Gap: Leveraging Large Language Model to Prioritize Alzheimer's Therapeutics Based on Comparison of Learning Models.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-7811754/v1},
pmid = {41282120},
issn = {2693-5015},
abstract = {Alzheimer's Disease (AD) [1] is a progressive neurodegenerative disorder with limited therapeutic options, driving interest in drug repurposing to accelerate treatment discovery. Drug repurposing has emerged as a promising strategy to accelerate therapeutic discovery by repositioning existing drugs for new clinical indications. Recent computational repurposing approaches, including knowledge graph reasoning, transcriptomic signature analysis, and integrative literature mining, have demonstrated strong predictive capabilities [2] . However, these methods often yield divergent drug rankings, which makes it difficult to decide which candidates to advance for experimental follow-up and results in substantial gaps between computational predictions and feasible in vivo validation [2] .To bridge this computational-experimental gap, we proposed an advanced prioritization framework leveraging large language models (LLMs). Our method systematically evaluated three state-of-the-art (SOTA) and representative computational methods (TxGNN [3] , Composition-based Graph Convolutional Network (CompGCN) [4] , and a regularized logistic regression (RLR) [5] , to analyze both their predictive performance and pharmaceutical class distributions. By integrating the strengths and divergences of these models, we generated a unified, streamlined list of 90 candidate drugs for further prioritization. We then utilized an LLM-based agent to perform evidence synthesis from biomedical literature abstracts for each candidate. This process mimics expert manual curation but significantly reduces human effort and time by efficiently distilling vast textual data into actionable insights. Applying consistent and transparent selection criteria, we obtained a refined and prioritized list of drug candidates suitable for subsequent in vivo experimental validation. The robustness and clinical relevance of our framework were validated using real-world data from Alzheimer's patient cohorts, clinical trial registries, and expert pharmacological reviews. This comprehensive validation confirmed that our LLM-driven approach enhances efficiency, consistency, scalability, and generalizability. By integrating computational predictions with scalable evidence synthesis and multifaceted validation, our framework facilitated rapid and informed prioritization of repurposed drugs. Our framework can potentially accelerate the translational pathway toward viable AD therapeutics. Moreover, the versatility of our framework can also be applied to drug repurposing efforts for other diseases beyond AD.},
}

@article {pmid41281734,
year = {2025},
author = {Wang, D and Florian, H and Lynch, SY and Robieson, W and Zhuang, R and Kusiak, C and Ross, JL and Walsh, JR and Graff, O},
title = {Using AI-generated digital twins to boost clinical trial efficiency in Alzheimer's disease.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {11},
number = {4},
pages = {e70181},
pmid = {41281734},
issn = {2352-8737},
abstract = {INTRODUCTION: Machine learning models leverage baseline data to create artificial intelligence (AI)-generated digital twins (DTs)-individualized predictions of each participant's clinical outcomes if they had received placebo. Incorporating DTs may increase statistical power or reduce required sample sizes in Phase 2 or 3 trials, and therefore improve efficiency in Alzheimer's disease (AD) trials. Here we demonstrate these properties using data from an AD Phase 2 clinical trial (AWARE, NCT02880956).

METHODS: A conditional restricted Boltzmann machine (CRBM) model was trained on historical clinical trials and observational data from 6736 unique subjects after data harmonization to generate DTs of participants from the AWARE trial. The AWARE trial enrolled 453 subjects with mild cognitive impairment (MCI) or mild AD. DTs were assessed as prognostic covariates to evaluate gains in variance and sample size reduction.

RESULTS: Positive partial correlation coefficients were found between DTs and change score from baseline in key cognitive assessments ranging from 0.30 to 0.39 at Week 96 in the AWARE trial. These correlations were consistent with validation results from three independent trials, which ranged from 0.30 to 0.46. Total residual variance was reduced by ~9% to 15% with DTs. While maintaining statistical power, DTs could reduce total sample size by ~9% to 15%, and control arm sample size by 17% to 26% in future AD trials.

DISCUSSION: Efficiency was improved in AD clinical trials using machine learning models to generate prognostic DTs by including them in statistical analysis modeling. This methodology aligns with regulatory guidance and represents an application of machine learning models suitable for the analysis of pivotal trial data. Validated DTs have the potential to improve clinical development efficiency in AD and in other neurological indications.

HIGHLIGHTS: Digital twins (DTs) were generated by artificial intelligence (AI) models trained on historical datasets.Use of digital twin (DT) as a covariate in the analysis model can reduce treatment effect variability.By coupling DT with the analysis model, trial sample size can be reduced.DT technology was accepted by the U.S. Food and Drug Administration and European Medicines Agency for applications in clinical trials.},
}

@article {pmid41281561,
year = {2025},
author = {Melamed, I and Buckley, C and Bayko, ME and Williams, JL and Or-Geva, N},
title = {Does C1 esterase inhibitor play a role in post COVID-19 neurological symptoms? A randomized, double-blind, placebo-controlled, crossover, proof-of-concept study.},
journal = {Frontiers in neurology},
volume = {16},
number = {},
pages = {1523814},
pmid = {41281561},
issn = {1664-2295},
abstract = {BACKGROUND: Many patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection experience neurologic changes post-infection, which has been hypothesized to be due to dysregulation in the infectious-immune axis that leads to a neuro-immune response. This immune dysfunction has been termed "Alzheimer's of the Immune System" or AIS and there are several immune factors that may play a key role. These include, among others, complement activation due to low levels of C1-esterase inhibitor (C1-INH) and function, and a decrease in signaling of Toll-like receptor (TLR)-3. We propose that C1-INH replacement may upregulate the immune dysfunction, thereby improving neurological symptoms.

METHODS: In this randomized, double-blind, placebo-controlled, crossover, proof-of-concept study, adults experiencing SARS-CoV-2 post-viral fatigue syndrome for >4 weeks post-recovery from coronavirus disease 2019 (COVID-19) infection were randomized 1:1 to two arms: Arm 1 (C1-INH for 8 weeks, then placebo for 8 weeks) or to Arm 2 (placebo for 8 weeks, then C1-INH for 8 weeks). Patients were assessed for adult executive function, abnormal cognitive decline, depression [Beck Depression Inventory-II (BDI-II)], migraine, fatigue [Fatigue Severity Scale (FSS)] and pain (Short-form McGill Pain Questionnaire). Percent change in TLR signaling in response to zymosan was compared with controls at baseline, Week 8 and Week 16. Safety was assessed throughout.

RESULTS: At this interim analysis, 36 patients with SARS-CoV-2 post-viral fatigue syndrome had completed the two 8-week treatment periods. In Arm 1, trends toward improvements from baseline at Week 8 of C1-INH therapy were observed in BDI-II score (-8.7 points), mean FSS score (0.6 points), and mean McGill Pain Questionnaire score (-0.4 points). These improvements were either sustained or worsened at Week 16, following crossover to placebo. The outcomes in Arm 2 were compatible with those in Arm 1. Patients with SARS-CoV-2 post-viral fatigue syndrome had low levels of TLR-related signaling biomarkers compared with healthy controls.

CONCLUSION: This proof-of-concept study demonstrates sustained dysregulation of the immune system after COVID-19 infection. Improvements in depression, fatigue, and pain were observed with C1-INH treatment in patients with SARS-CoV-2 post-viral fatigue syndrome, indicating C1-INH may be a potential therapeutic target.

CLINICAL TRIAL REGISTRATION: The study was registered on September 21, 2024, with the identifier number NCT04705831.},
}

@article {pmid41281560,
year = {2025},
author = {Sun, Q and Wang, F},
title = {Using artificial intelligence and radiomics to analyze imaging features of neurodegenerative diseases.},
journal = {Frontiers in neurology},
volume = {16},
number = {},
pages = {1624867},
pmid = {41281560},
issn = {1664-2295},
abstract = {INTRODUCTION: Neurodegenerative diseases such as Alzheimer's and Parkinson's are characterized by complex, multifactorial progression patterns that challenge early diagnosis and personalized treatment planning.

METHODS: To address this, we propose an integrated AI-radiomics framework that combines symbolic reasoning, deep learning, and multi-modal feature alignment to model disease progression from structural imaging and behavioral data. The core of our method is a biologically informed architecture called NeuroSage, which incorporates radiomic features, clinical priors, and graph-based neural dynamics. We further introduce a symbolic alignment strategy (CAIS) to ensure clinical interpretability and cognitive coherence of the learned representations.

RESULTS AND DISCUSSION: Experiments on multiple datasets-including ADNI, PPMI, and ABIDE for imaging, and YouTubePD and PDVD for behavioral signals-demonstrate that our approach consistently outperforms existing baselines, achieving an F1 score of 88.90 on ADNI and 85.43 on PPMI. These results highlight the framework's effectiveness in capturing disease patterns across imaging and non-imaging modalities, supporting its potential for real-world neurodegenerative disease monitoring and diagnosis.},
}

@article {pmid41281523,
year = {2025},
author = {Li, YP and Niu, Y and Ding, H and Chen, Z and Zhang, Q},
title = {Potential role of meningeal lymphatic drainage in repetitive transcranial magnetic stimulation-induced cognitive improvement: A call for further research.},
journal = {World journal of psychiatry},
volume = {15},
number = {11},
pages = {111985},
pmid = {41281523},
issn = {2220-3206},
abstract = {Mild cognitive impairment (MCI), which is a high-risk transitional phase leading to Alzheimer's disease, is characterized by mild memory deficits and specific cognitive dysfunctions. Without effective intervention, a significant proportion of patients with MCI progress to dementia. However, current pharmacological treatments are characterized by side effects and poor patient compliance. Therefore, it is necessary to develop effective, noninvasive alternative treatments. Repetitive transcranial magnetic stimulation (rTMS) is becoming a widely studied noninvasive treatment for central nervous system disease. The therapeutic effects of rTMS on patients with MCI and its underlying mechanism are noteworthy issues. Recently, a growing number of studies have shown that meningeal lymphatic vessel damage may be related to cognitive dysfunction. Whether the improvement of the meningeal lymphatic system is an important mechanism through which rTMS improves the clinical manifestations of MCI is worthy of further study.},
}

@article {pmid41281504,
year = {2025},
author = {Teixeira, AL and Kim, Y and Cordeiro, TM and de Erausquin, GA and Rocha, NP},
title = {Agitation in Alzheimer's disease: From assessment to therapeutics.},
journal = {World journal of psychiatry},
volume = {15},
number = {11},
pages = {109581},
pmid = {41281504},
issn = {2220-3206},
abstract = {Agitation is a neuropsychiatric syndrome characterized by excessive motor and/or verbal behaviors, with or without aggressive behaviors. The prevalence of agitation in Alzheimer's disease varies from 5% to over 50%. Multiple factors have been implicated in its pathophysiology, including disease stage, comorbidity with other symptoms (e.g., psychosis, anxiety/depression), and psychosocial factors. Ruling out delirium and identifying environmental triggers are fundamental steps in the management of agitation in Alzheimer's disease. For establishing an effective therapeutic plan, it is important to define duration, severity, and potential for harm. While non-pharmacological approaches are considered the first line of intervention, pharmacological agents are frequently used in the treatment of agitation. Antipsychotics are commonly used in acute agitation. For chronic agitation, serotonin-selective reuptake inhibitors, especially citalopram and escitalopram, are often preferred due to safety concerns associated with the long-term use of antipsychotics. Promising novel strategies, such as new compounds and neuromodulation, are likely to be incorporated into agitation therapeutics in the next few years.},
}

@article {pmid41281281,
year = {2025},
author = {Jing, S and Wang, Y and Liu, Y and Luo, Y and Wen, X and Ma, Y and Zhu, H and Chen, G and Ouyang, X},
title = {Folic acid as a potential therapeutic agent for Alzheimer's disease: Effects on inflammatory cytokines, amyloid deposition, and neurotransmitter metabolism.},
journal = {Journal of medical biochemistry},
volume = {44},
number = {7},
pages = {1551-1557},
pmid = {41281281},
issn = {1452-8258},
abstract = {BACKGROUND: Alzheimer's disease (AD) is a degenerative disease of the central nervous system characterized by neuroinflammation and amyloid deposition. Folic acid (FA), a B vitamin, may improve the course of AD by modulating inflammation and neuroprotection. This study aimed to investigate the effects of FA supplementation on serum inflammatory cytokines (IL-1b, IL-6, TNF-a), amyloid (Ab1-42), Tau proteins, and neurotransmitters (GABA, 5-HT, Ach) in AD patients.

METHODS: We conducted a follow-up-controlled trial; 114 AD patients were included and randomly divided into a control group (donepezil treatment) and an experimental group (donepezil + FA treatment) for 3 months. Inflammatory factors, Ab1-42, Tau, neurotransmitter levels and nutritional status were assessed before and after treatment.

RESULTS: The total effective rate of the experimental group (89.47%) was significantly higher than that of the control group (75.44%), and the levels of inflammatory factors (IL-1b, IL-6, and TNF-a), Ab1-42, and Tau were significantly lower (P<0.05), and neurotransmitters (GABA, 5-HT, and Ach) and nutritional indexes (albumin and hemoglobin) were substantially higher.

CONCLUSIONS: FA supplementation can effectively delay AD progression by inhibiting neuroinflammation, reducing amyloid deposition, regulating neurotransmitter metabolism and improving nutritional status.},
}

@article {pmid41280486,
year = {2025},
author = {Taube, PS and Fernandes, D and Vasconcelos, AA and Costa, JAS and de Araujo, MP and Lima, AKO and Wahab, N and Dos Santos, EKL and de Oliveira, MI and da Silva, JP and Andriani, KF and da Silva Oliveira, TP and Sampaio, MC and de Campos Braga, H and de Araújo, ACS and Gul, K},
title = {Perspectives and state-of-the-art use of metal-derived, porous nanomaterials and metallo-drugs for biomedical applications.},
journal = {3 Biotech},
volume = {15},
number = {12},
pages = {416},
pmid = {41280486},
issn = {2190-572X},
abstract = {Due to a combination of genetic, environmental, and behavioral factors, the number of infectious and non-infectious diseases affecting humans has been rising. Many illnesses are in the forefront of research and development such as neoplasms of different forms, chronic conditions related to inflammation and lifestyle (e.g., cancer, diabetes mellitus, Alzheimer's and Parkinson's diseases) and infectious diseases that are difficult to treat (e.g., due to drug resistance). Due to current challenges in diagnosis and treatment of diseases and health conditions, the field of nanotechnology has witnessed numerous advancements. In particular, metal-based, porous nanomaterials and metallo-drugs have gained attention due to their ability to be used for various diagnostic and therapeutic applications. These systems exhibit excellent physicochemical properties, with amenable functionalization and varying optical, scattering and electronic properties, enabling for both imaging and therapy of diseases (i.e., theranostics), involving techniques such as photoacoustic imaging, magnetic resonance imaging (MRI), computed tomography (CT), photothermal therapy (PTT), photodynamic therapy (PDT) and radiotherapy. This review discusses the important aspects of metal nanoparticles, porous-based materials and metallo-drugs for biomedical applications, exploring their physical and chemical characteristics, cellular/molecular processes and biopotencies that make them effective in treating a variety of illnesses or diseases.},
}

@article {pmid41280332,
year = {2025},
author = {Wu, Z and Yu, S and Tian, D and Cheng, L and Jing, J},
title = {Microglial TREM2 and cognitive impairment: insights from Alzheimer's disease with implications for spinal cord injury and AI-assisted therapeutics.},
journal = {Frontiers in cellular neuroscience},
volume = {19},
number = {},
pages = {1705069},
pmid = {41280332},
issn = {1662-5102},
abstract = {Cognitive impairment is a frequent but underrecognized complication of neurodegenerative and traumatic central nervous system disorders. Although research on Alzheimer's disease (AD) revealed that microglial triggering receptor expressed on myeloid cells 2 (TREM2) plays a critical role in inhibiting neuroinflammation and improving cognition, its contribution to cognitive impairment following spinal cord injury (SCI) is unclear. Evidence from AD shows that TREM2 drives microglial activation, promotes pathological protein clearance, and disease-associated microglia (DAM) formation. SCI patients also experience declines in attention, memory, and other functions, yet the specific mechanism of these processes remains unclear. In SCI, microglia and TREM2 are involved in inflammation and repair, but their relationship with higher cognitive functions has not been systematically examined. We infer that TREM2 might connect injury-induced neuroinflammation in the SCI with cognitive deficits, providing a new treatment target. Artificial intelligence (AI) offers an opportunity to accelerate this endeavor by incorporating single-cell transcriptomics, neuroimaging, and clinical data for the identification of TREM2-related disorders, prediction of cognitive trajectories, and applications to precision medicine. Novel approaches or modalities of AI-driven drug discovery and personalized rehabilitation (e.g., VR, brain-computer interface) can more precisely steer these interventions. The interface between lessons learned from AD and SCI for generating new hypotheses and opportunities for translation.},
}

@article {pmid41280310,
year = {2025},
author = {Inamdar, A and Bugadannavar, P and Palled, M and Umarani, S and Salve, P and Gurupadayya, B and Patil, P and Sharma, H},
title = {Biological determinants of blood-based biomarker levels in Alzheimer's disease: role of nutrition, inflammation, and metabolic factors.},
journal = {Frontiers in aging neuroscience},
volume = {17},
number = {},
pages = {1614962},
pmid = {41280310},
issn = {1663-4365},
abstract = {OBJECTIVES: The review discusses the effect of biological determinants such as nutritional deficiency, systemic inflammation, and metabolic disorders affect blood-based biomarker (BBBM) levels, influencing their use in diagnosing, prognosticating, and treatment in Alzheimer's disease (AD). While the individual contributions of neuroinflammation, brain insulin resistance, and micronutrient deficiencies to AD pathology are well-established, a significant knowledge gap exists in understanding their intricate, synergistic interactions. This review proposes a novel integrated framework of bidirectional crosstalk where these three factors create a self-perpetuating cycle of neurodegeneration.

METHODS: A comprehensive literature review was conducted, including all aspects of epidemiological and biological context associated with vitamins, micronutrients, and dietary patterns; inflammatory cytokines; insulin resistance; metabolic syndrome; and hormonal changes. Emerging integrative approaches such as multi-omics, AI modeling, and systems biology were also reviewed for their possible refinement in biomarker interpretation.

RESULTS: The results prove that the deprivation of vitamins E, D, B12, and antioxidants contributes to oxidative stress and subsequent neuroinflammation that changes levels of blood-based biomarkers. A chronic state of inflammation caused by cytokines like IL-6, IL-18, and TNF-α represents a major link to the formation of increased amyloid plaques and tau tangles. Metabolically deregulated states, such as insulin resistance, dyslipidemia, and thyroid imbalance, further alter variability in biomarkers. All these factors would act together to affect the expression of key biomarkers-Aβ, p-tau, and neurofilament light chain (NFL). Individualized interpretation, stratified clinical trials, and digital monitoring tools are potentially effective for achieving better diagnostic precision and boosting treatment efficacy.

CONCLUSION: To a large extent, factors must all be understood thoroughly from multiple biological angles to improve early diagnosis, risk prevention, and treatment personalization in AD. Future studies should develop integrative models that consider nutrition, metabolism, and inflammation to address and fully exploit biomarker utility as well as support precision medicine approaches.},
}

@article {pmid41280213,
year = {2025},
author = {Ali, SH and Osmaniye, D and Kaplancıklı, ZA},
title = {Synthesis and biological evaluation of novel hydrazone derivatives for the treatment of Alzheimer's disease.},
journal = {RSC advances},
volume = {15},
number = {53},
pages = {45729-45743},
pmid = {41280213},
issn = {2046-2069},
abstract = {In recent years, Alzheimer's disease has emerged as a silent epidemic neurodegenerative disorder. Due to its complex pathophysiology, there has been significant scientific interest in developing effective treatments that go beyond symptomatic relief. The main aim is to improve patients' quality of life and lower the death rate associated with Alzheimer's disease. Since this has not yet been achieved, continued research on Alzheimer's disease remains a global priority. In this study, a total of 27 hybrid molecules (D1a-D1i, D2a-D2i, and D3a-D3i) were designed based on the molecular scaffold of donepezil, a well-known acetylcholinesterase inhibitor (AChEI). These hybrids incorporate dihydrothiazolyl hydrazone and phenyl piperidine moieties. All compounds were synthesized and characterized using IR, NMR, and HRMS spectroscopy, and subsequently evaluated for acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibition using the in vitro Ellman method. Evaluation of biological activity revealed that compound D1f exhibited the highest inhibitory activity against the AChE enzyme, with an IC50 of (0.039 ± 0.001 Mm). In contrast, none of the compounds showed significant inhibitory activity against the BChE enzyme. Cytotoxicity testing of compound D1f on NIH3T3 fibroblast cells demonstrated non-cytotoxic effects (IC50 = 3.324 ± 0.155 µM) and the highest selectivity index (SI = 85.231), respectively. Molecular docking and molecular dynamics simulations verified the stable binding affinity and favorable interactions of compound D1f within the active site of acetylcholinesterase (AChE). The results further demonstrated that the AChE enzyme preserved its structural integrity and compactness throughout its interaction with D1f. Collectively, these observations highlight D1f as a promising lead molecule for subsequent optimization and development of novel anti-Alzheimer's therapeutic agents.},
}

@article {pmid41280038,
year = {2025},
author = {Terzioglu, G and Karp, ES and Heuer, SE and Haage, VC and De Jager, PL and Young-Pearse, TL},
title = {INPP5D/SHIP1 is a dual regulator of endo-lysosome function and selective phagocytosis in human microglia.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.10.27.684632},
pmid = {41280038},
issn = {2692-8205},
abstract = {INPP5D, the gene encoding SHIP1, is genetically associated with Alzheimer's disease (AD) risk and plays a central role in regulating immune function. Here, we aimed to elucidate the mechanism by which SHIP1 mediates its role in suppressing inflammatory pathways, with a focus on human microglia. Our findings illuminate an essential role for SHIP1 in endosome maturation and lysosomal function. We show that SHIP1 localizes to both the plasma membrane and to endo-lysosomal compartments and binds to the CapZ family of proteins, which are important for endosome maturation. Reduction of SHIP1 levels via genome editing impairs endosome maturation and lysosomal function, leading to lipid droplet accumulation and leakage of lysosomal cathepsin B into the cytosol, which in turn activates the NLRP3 inflammasome. CITE-seq profiling of SHIP1-deficient microglia revealed a shift from an immune-responsive state toward a DAM-like, phagocytic state, accompanied by impaired response to LPS and enhanced phagocytosis of synaptic material and apoptotic neurons via TREM2. While amyloid-β uptake was not affected, amyloid-β accumulated intracellularly due to defective lysosomal degradation, further driving lipid droplet formation. Together, these results identify SHIP1 as a regulator of endo-lysosomal function and selective phagocytosis of lipid-rich substrates in microglia. These findings have important implications for therapeutic hypotheses that target SHIP1 for treatment of AD, autoimmune diseases, and cancer.},
}

@article {pmid41279689,
year = {2025},
author = {Schurman, CA and Kaur, G and Kaya, S and Bons, J and Aguirre, CG and Liu, Q and King, CD and Wilson, KA and Baker, HL and Hady, M and Luna, NM and Bieri, G and Villeda, SA and Ellerby, LM and Schilling, B and Alliston, T},
title = {Alzheimer's disease risk factor APOE4 exerts dimorphic effects on female bone.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.10.16.682922},
pmid = {41279689},
issn = {2692-8205},
abstract = {Individuals diagnosed with Alzheimer's disease (AD) are at an increased risk of bone fractures. Conversely, a diagnosis of osteoporosis in women is the earliest known predictor for AD. However, mechanisms responsible for the coupled decline in cognitive and skeletal health remain unclear. Proteomic analysis of cortical bone from aged mice revealed neurological disease-associated proteins that are highly enriched in aged mouse bones, including apolipoprotein E (Apoe) and amyloid precursor protein. Further, Apoe localized specifically to bone-embedded osteocytes with expression twice as high in aged female bone as in young or male counterparts. In humans, APOE allele variants carry differing AD risk with age. To investigate APOE allelic roles in bone, we utilized a humanized APOE knock-in mouse model that expresses either the protective APOE2, the neutral APOE3, or the AD risk factor APOE4, and analyzed bone and hippocampus from the same mice. APOE4 exerted strong sex-specific effects on the bone transcriptome and proteome, relative to APOE2 or APOE3. Interestingly, the APOE4-associated perturbation in the female bone proteome was more pronounced than the corresponding alterations observed in the hippocampus. APOE4 protein causes bone fragility in females, but not males, even without changes in cortical bone structure. These bone quality deficits arose from suppression of osteocyte perilacunocanalicular remodeling. We find that APOE4 is a new molecular culprit capable of disrupting osteocyte maintenance of bone quality as early as midlife in a manner that disproportionately affects females. These findings highlight osteocytes as potential targets for early diagnosis of age-related cognitive impairment, and treatment for bone fragility, in females.},
}

@article {pmid41279475,
year = {2025},
author = {Veerareddy, V and Wang, Z and Kashyap, PC and Kandimalla, KK},
title = {Butyrate regulates the blood-brain barrier transport and intra-endothelial accumulation of Alzheimer's disease Amyloid-beta peptides.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.10.24.684335},
pmid = {41279475},
issn = {2692-8205},
abstract = {Alzheimer's disease (AD) is characterized by the pathological deposition of amyloid beta (Aꞵ) proteins as amyloid plaques, tau aggregates, and cerebrovascular dysfunction that drive disease progression. Butyrate, a gut microbial metabolite, has been found to be reduced in AD patients; butyrate supplementation improved cognition and decreased amyloid burden in animal models. However, the precise underlying mechanisms are unclear. Our previous studies have demonstrated that insulin signaling impacts Aꞵ transport kinetics at the blood-brain barrier (BBB). In this study, we investigated the effect of butyrate treatment on intra-endothelial Aꞵ accumulation and BBB integrity by modulating the insulin signaling pathway. The effect of butyrate on Aꞵ accumulation was assessed by flow cytometry in BBB cell culture models. Insulin signaling activation and the expression of various receptors and transporters at the BBB were evaluated by Western blots and confocal microscopy. The roles of various molecular mediators were confirmed using specific inhibitors (MK2206, Trametinib, Rapamycin, VX-745). The effect of butyrate on the expression of BBB receptors and transporters that play a critical role in Aꞵ trafficking was examined in mouse brains colonized with butyrate-producing bacteria via immunohistochemistry. Butyrate significantly decreased Aβ42 accumulation in endothelial cells. This effect was associated with insulin signaling pathway activation, particularly AKT and ERK phosphorylation. Inhibitor studies established the critical role of these specific arms, as co-incubation with MK2206 (AKT inhibitor) or Trametinib (ERK inhibitor) reversed the protective effect of butyrate and increased Aβ42 accumulation. However, mTOR and p38 inhibitors did not show a similar effect. In addition, butyrate restored P-glycoprotein efflux transporter expression and claudin-5 tight junction protein levels that were reduced with Aβ treatment. These effects were supported by in vivo work, which demonstrated the upregulation of Tissue Inhibitor of Metalloproteinases-2 (TIMP-2). This protein is associated with AKT activation and extracellular matrix stabilization in mice colonized with butyrate-producing bacteria. In conclusion, we have demonstrated that butyrate decreases Aβ42 uptake at the BBB endothelium by activating the AKT and ERK arms of the insulin signaling pathway. These changes may also improve the integrity of BBB tight junctions by increasing claudin-5 expression and extracellular matrix, and by upregulating TIMP-2 expression. This study highlights butyrate's potential as a therapeutic modulator of AD-related BBB dysfunction.},
}