@article {pmid40706761,
year = {2025},
author = {Ohno, M},
title = {BACE1 as an early biomarker and its relevance to risk factors for Alzheimer's disease.},
journal = {Brain research bulletin},
volume = {},
number = {},
pages = {111475},
doi = {10.1016/j.brainresbull.2025.111475},
pmid = {40706761},
issn = {1873-2747},
abstract = {While the β-secretase BACE1 is responsible for the rate-limiting initial step to generate amyloid-β (Aβ) peptides, BACE1 inhibitor clinical trials have been halted due to a lack of efficacy and/or safety concerns at symptomatic/prodromal stages of Alzheimer's disease (AD). These trials were often targeted at high levels of BACE1 inhibition (>70%) and ended up with signs of mild cognitive worsening instead of expected improvement. BACE1 concentration and activity are elevated in the cerebrospinal fluid and plasma/serum as well as brains of patients with mild cognitive impairment and AD dementia. Interestingly, recent evidence suggests that these fluid-based biomarkers reflective of BACE1 elevation may be associated with yet asymptomatic pathological changes in preclinical AD populations who are at high-risk for developing AD. Consistent with these findings, it has been demonstrated that exposures to major environmental and genetic risks such as diabetes, sleep disturbances, seizure, vascular disorders, stress, apolipoprotein E4, etc. converge on BACE1 elevation in humans and animal models, which may contribute to triggering sporadic AD. Moreover, vicious cycles exist between BACE1/Aβ elevations and certain prognostic conditions, further accelerating disease progression. Conversely, protective factors for AD are associated with reduced BACE1 level/activity. This review provides an overview of BACE1 alterations as common responses to a broad battery of AD risk and protective factors. The findings validate BACE1 as a biomarker for preclinical AD status that may be useful for earlier diagnosis and identifying subpopulations of individuals under AD risks who would benefit from preventive low-dose BACE1 inhibitor treatment with a higher probability.},
}

@article {pmid40705095,
year = {2025},
author = {Wang, C and Wang, L and Liu, X and Wang, J and Chen, M and Li, J},
title = {Ponicidin attenuates Aβ1-42-induced hippocampal cell injury through SIRT1 and PI3K/Akt pathways.},
journal = {Molecular biology reports},
volume = {52},
number = {1},
pages = {752},
pmid = {40705095},
issn = {1573-4978},
support = {PW2022B-04//The Scientific Research Program of Shanghai Pudong New Area Health Commission (the Youth Program)/ ; ZQZR202427//the scientific research project of Shanghai Zhongqiao Vocational and Technical University/ ; },
mesh = {*Amyloid beta-Peptides/metabolism/toxicity ; *Sirtuin 1/metabolism ; *Hippocampus/drug effects/metabolism/pathology ; Proto-Oncogene Proteins c-akt/metabolism ; Animals ; Signal Transduction/drug effects ; *Peptide Fragments/metabolism ; Phosphatidylinositol 3-Kinases/metabolism ; Mice ; Oxidative Stress/drug effects ; Apoptosis/drug effects ; Neuroprotective Agents/pharmacology ; Cell Line ; Cell Survival/drug effects ; Neurons/drug effects/metabolism ; Alzheimer Disease/metabolism/drug therapy ; *Diterpenes/pharmacology ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-beta (Aβ) accumulation that leads to synaptic dysfunction and neuronal death. Ponicidin, a natural diterpenoid, possesses anti-inflammatory and neuroprotective properties. However, its potential effects on Aβ-induced neurotoxicity remain unclear. This study investigated whether ponicidin ameliorates Aβ1-42-induced hippocampal neuronal injury by modulating SIRT1 and PI3K/Akt signaling pathways.

METHODS: HT22 cells were exposed to Aβ1-42 to establish an in vitro AD model, followed by treatment with ponicidin. Cell viability, apoptosis, oxidative stress, and inflammatory responses were assessed using MTT assay, flow cytometry, ROS detection, and ELISA. Western blotting and qRT-PCR were performed to evaluate the expression of SIRT1, the components of the PI3K/Akt pathway, and neuroinflammation.

RESULTS: Ponicidin significantly attenuated Aβ1-42-induced cytotoxicity, reduced oxidative stress, and suppressed apoptosis and inflammatory cytokine release. Mechanistically, ponicidin upregulated SIRT1 expression and activated PI3K/Akt pathway. The protective effects of ponicidin were reversed by the PI3K/Akt inhibitor EX-527, confirming the involvement of this pathway.

CONCLUSION: These findings suggest that ponicidin exerts neuroprotective effects against Aβ1-42-induced hippocampal injury by enhancing SIRT1 and activating PI3K/Akt signaling, highlighting its potential as a therapeutic candidate for AD.},
}

*Amyloid beta-Peptides/metabolism/toxicity
*Sirtuin 1/metabolism
*Hippocampus/drug effects/metabolism/pathology
Proto-Oncogene Proteins c-akt/metabolism
Animals
Signal Transduction/drug effects
*Peptide Fragments/metabolism
Phosphatidylinositol 3-Kinases/metabolism
Mice
Oxidative Stress/drug effects
Apoptosis/drug effects
Neuroprotective Agents/pharmacology
Cell Line
Cell Survival/drug effects
Neurons/drug effects/metabolism
Alzheimer Disease/metabolism/drug therapy
*Diterpenes/pharmacology

@article {pmid40703204,
year = {2025},
author = {Ramanan, VK and Heckman, MG and Hofrenning, EI and Przybelski, SA and Graff-Radford, J and Lowe, VJ and Machulda, MM and Murray, ME and Algeciras-Schimnich, A and Figdore, DJ and Bennett, DA and Knopman, DS and Jack, CR and Petersen, RC and Ross, OA and Vemuri, P and , },
title = {Combating Genetic Heterogeneity for Polygenic Prediction of Susceptibility to Brain β-Amyloid Deposition: Beyond APOE.},
journal = {Neurology. Genetics},
volume = {11},
number = {4},
pages = {e200266},
pmid = {40703204},
issn = {2376-7839},
abstract = {BACKGROUND AND OBJECTIVES: The APOE (apolipoprotein E) ε4 allele is the strongest known genetic risk factor for sporadic Alzheimer disease (AD) and for brain amyloidosis, an early marker of disease pathophysiology. However, APOE ε4 is present in only 25% of the general population and is by itself inadequate for explaining susceptibility to amyloid accumulation or AD diagnosis. Existing studies have been limited by potential confounding due to inclusion of individuals carrying APOE ε4 or ε2 (which has a modest protective association). We hypothesized that genome-wide association study (GWAS) and genetic risk score (GRS) analyses in APOE ε3/ε3 individuals would uniquely identify novel predictors of β-amyloid pathology in older adults.

METHODS: We analyzed data from the Mayo Clinic Study of Aging (MCSA), Alzheimer's Disease Neuroimaging Initiative (ADNI), and Rush Religious Orders Study and Memory and Aging Project. Frequency of APOE ε3/ε3 in those samples ranged from 48% to 61%. A GWAS was performed across 1,496 individuals with amyloid PET to identify candidate variants for GRS generation. Postmortem neuropathologic data (N = 710) were used to refine the variant list to capture high-likelihood true associations. An independent sample (N = 641) with plasma p-tau181 data was used for validation.

RESULTS: The GWAS identified previously implicated (e.g., PICALM and RBFOX1) and novel potential associations with amyloid PET burden. A non-APOE GRS of top variants was strongly associated with amyloid PET levels in the MCSA (p = 4.34 × 10[-9], β = 5.88) and ADNI (p = 1.87 × 10[-8], β = 12.1) cohorts. In both cohorts, this non-APOE amyloid GRS outperformed a comparator GRS (based on variants associated with clinically diagnosed AD dementia risk) in explaining phenotypic variation. The non-APOE amyloid GRS was also associated with postmortem neuropathologic β-amyloid and neurofibrillary tangle burden and in an independent sample was associated with plasma p-tau181 concentrations (a robust indicator of cerebral amyloidosis).

DISCUSSION: Our non-APOE amyloid GRS, which appropriately includes variants associated with amyloid deposition in APOE ɛ4/ɛ2 noncarriers, may advance personalized prediction of genetic susceptibility to β-amyloid accumulation within the large segment of the population that is APOE ε3/ε3. This may have future implications for risk modification, trial enrollment, and treatment selection.},
}

@article {pmid40702815,
year = {2025},
author = {Huo, Z and Yip, BH and Lee, AT and Cheng, ST and Chan, WC and Fung, AW and Ma, SL and Cheng, CP and Lai, FH and Wong, SY and Lam, LC},
title = {Healthcare utilization and economic costs of neurocognitive disorders in community-dwelling older Chinese adults: A comparison with 9 Asian economies.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251361057},
doi = {10.1177/13872877251361057},
pmid = {40702815},
issn = {1875-8908},
abstract = {BackgroundIt is increasing recognized that care for people with neurocognitive disorders (NCDs) is costly, and cost of NCDs can be highly context dependent.ObjectiveTo evaluate the healthcare utilization and economic costs of NCDs in Hong Kong, cross referencing with other Asian metropolitan cities.Methods461 older adults aged ≥60 (major NCD: 68, mild NCD: 264, normal cognition: 129) were recruited from a population-based cross-sectional survey, Hong Kong Mental Morbidity Survey for Older People. Healthcare utilization was collected by Resource Utilization of Dementia. Per person cost was estimated from a societal perspective and expressed in 2022 US dollars. Cost-associative factors were explored. Our findings were compared to cost-of-illness evidence in major Asian metropolitan cities by a systematic review.ResultsAnnual costs per community-living adult with mild and major NCD were US$5677 (95%CI: 4985-6465) and US$12,841 (9940-16,590) in Hong Kong. For those with major NCD, costs doubled in severer stages, and diagnosed cases incurred nearly 30% more costs than hidden cases. Dementia cost in Hong Kong was lower than other high-income Asian economies and mainland China, mainly due to methodological heterogeneities and lower utilization of social care services.ConclusionsThe great economic burden of NCDs in Hong Kong reflects a striking social and care needs, particularly in moderate and severe stages. Care planning should prepare for the blowout needs being revealed by hidden cases and the diversified needs by different stages and family caregivers. Region- and population-specific studies with rigor design are warranted to estimate cost-effectiveness of upcoming treatment strategies.},
}

@article {pmid40702549,
year = {2025},
author = {Zhang, P and Song, C and Shi, J and Wei, Z and Wang, J and Huang, W and Zhang, R and Wang, J and Yang, X and Wang, G and Gao, X and Zhang, Y and Chen, H and Wang, H},
title = {Endothelium-specific endoglin triggers astrocyte reactivity via extracellular vesicles in a mouse model of Alzheimer's disease.},
journal = {Molecular neurodegeneration},
volume = {20},
number = {1},
pages = {84},
pmid = {40702549},
issn = {1750-1326},
support = {82204374//National Natural Science Foundation of China/ ; 2022M722140//China Postdoctoral Science Foundation/ ; zyyzdxk-2023070//NATCM's Project of High-level Construction of Key TCM Disciplines/ ; STAR project 20230101//Shanghai Jiao Tong University Trans-med Awards Research/ ; QKHZYD-[2025]030//Central Government Guidance Funds for Local Scientific and Technological Development/ ; KFKT2024-02//Open Funds of Shanghai Jiao Tong University School of Medicine and Affiliated Hospital of Hebei University of Engineering/ ; },
mesh = {Animals ; *Alzheimer Disease/metabolism/pathology ; *Astrocytes/metabolism ; *Extracellular Vesicles/metabolism ; Mice ; Disease Models, Animal ; Humans ; *Endoglin/metabolism ; *Endothelial Cells/metabolism ; Mice, Transgenic ; Brain/metabolism ; Male ; Female ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is a multifaceted neurodegenerative disorder with a complex etiology that extends beyond the well-documented amyloid-β and tau pathologies. Growing evidence implicates cerebrovascular dysfunction, particularly brain microvascular endothelial cells (BMECs) dysfunction, as an early contributor to AD pathogenesis. However, how BMECs influence on neighboring astrocytes needs to be further explored.

METHODS: We employed a multi-omics approach integrating bulk RNA sequencing of human BMECs with proteomic analysis of cerebrospinal fluid (CSF) from AD patients and cerebrovascular endothelial extracellular vesicles (CEEVs). The role of identified candidate proteins was investigated in vitro and in vivo utilizing CEEVs transplantation and BMEC-astrocyte co-cultures. Endothelial cell-specific knockdown or treatment with a monoclonal antibody was used to assess the functional consequences on cognitive impairment and AD pathology via two-photon imaging and behavioral experiments on APP/PS1 mice.

RESULTS: The elevated endothelium-specific protein Endoglin (ENG) was identified in the brain and serum of AD individuals and APP/PS1 mice, and the supernatant of injured BMECs. ENG was released and delivered to adjacent astrocytes via CEEVs, and subsequently upregulated TGFBRI/Smad3 pathway in astrocytes, leading to astrocyte reactivity and the release of pro-inflammatory cytokines. Endothelial cell-specific ENG knockdown or treating with ENG monoclonal antibody Carotuximab significantly suppressed reactive astrocytes, reduced neuroinflammation, and improved cognitive performance of APP/PS1 mice.

CONCLUSIONS: This study reveals a novel mechanism by which BMECs-derived ENG, delivered via CEEVs, drives astrocyte reactivity. These findings redefine the role of cerebrovascular dysfunction in AD pathogenesis and identify ENG as both a potential biomarker and a promising therapeutic target for AD.},
}

Animals
*Alzheimer Disease/metabolism/pathology
*Astrocytes/metabolism
*Extracellular Vesicles/metabolism
Mice
Disease Models, Animal
Humans
*Endoglin/metabolism
*Endothelial Cells/metabolism
Mice, Transgenic
Brain/metabolism
Male
Female

@article {pmid40702219,
year = {2025},
author = {Jamshidiha, S and Rezaee, A and Hajati, F and Golzan, M and Chiong, R},
title = {An explainable transformer model for Alzheimer's disease detection using retinal imaging.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {26773},
pmid = {40702219},
issn = {2045-2322},
support = {A24/2676//University of New England, Australia/ ; A24/2676//University of New England, Australia/ ; },
mesh = {*Alzheimer Disease/diagnostic imaging/diagnosis ; Humans ; *Retina/diagnostic imaging/pathology ; Algorithms ; Aged ; Male ; Female ; Artificial Intelligence ; Image Processing, Computer-Assisted/methods ; },
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder that affects millions worldwide. In the absence of effective treatment options, early diagnosis is crucial for initiating management strategies to delay disease onset and slow down its progression. In this study, we propose Retformer, a novel transformer-based architecture for detecting AD using retinal imaging modalities, leveraging the power of transformers and explainable artificial intelligence. The Retformer model is trained on datasets of different modalities of retinal images from patients with AD and age-matched healthy controls, enabling it to learn complex patterns and relationships between image features and disease diagnosis. To provide insights into the decision-making process of our model, we employ the Gradient-weighted Class Activation Mapping algorithm to visualise the feature importance maps, highlighting the regions of the retinal images that contribute most significantly to the classification outcome. These findings are compared to existing clinical studies on detecting AD using retinal biomarkers, allowing us to identify the most important features for AD detection in each imaging modality. The Retformer model outperforms a variety of benchmark algorithms across different performance metrics by margins of up to 11%.},
}

*Alzheimer Disease/diagnostic imaging/diagnosis
Humans
*Retina/diagnostic imaging/pathology
Algorithms
Aged
Male
Female
Artificial Intelligence
Image Processing, Computer-Assisted/methods

@article {pmid40701934,
year = {2025},
author = {Ataman Sadık, D and Cansız, CS and Turğut, M and Dağ, Ç and Duman, M},
title = {Investigation of Methylsulfonamide's Capability to Prevent Zn[2+]-Induced Aβ Peptide Aggregation Based on Zn[2+] Coordination within the Zinc Binding Region of Aβ for Treatment of Alzheimer's Disease (AD).},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.5c00238},
pmid = {40701934},
issn = {1948-7193},
abstract = {There is no cure for Alzheimer's disease (AD) with the currently suggested therapies. Thus, designing and synthesis of new drugs for the treatment of Alzheimer's disease for safe and effective therapy have become an important task. Metal ions such as Zn[2+], Cu[2+], and Fe[3+] are known to increase the rate of Aβ aggregation and exist in amyloid plaques at high concentrations. Aβ oligomers, whether formed on the way to amyloid fibril formation or formed off-pathway due to the interaction of Aβ monomers with Zn[2+], are considered to be the most neurotoxic aggregates. Using NMR and SPR, this study reports the methylsulfonamide inhibition of Zn[2+]-induced Aβ1-16 dimer formation via methylsulfonamide coordination of Zn[2+] within the Zn[2+] binding region of Aβ, (11EVHH14) and inhibit the H14-Zn[2+] coordination between the 11EVHH14 regions of two Aβ peptides, preventing their interactions and hence the Aβ dimer formation. According to the results of this study, methylsulfonamide has the potential to be used as a drug in Alzheimer's disease for the prevention of the formation of the Zn[2+]-induced toxic Aβ oligomers formed during Aβ aggregation.},
}

@article {pmid40701789,
year = {2025},
author = {Mukherjee, S and Reddy, A and Dutta, N and Vaiphei, KK and Vivek, and Kumar, A and Gulbake, A},
title = {Exploring the potential of repurposed deferoxamine: bridging challenges and novel formulation opportunities.},
journal = {Nanomedicine (London, England)},
volume = {},
number = {},
pages = {1-25},
doi = {10.1080/17435889.2025.2534318},
pmid = {40701789},
issn = {1748-6963},
abstract = {Since the FDA approval of deferoxamine mesylate (Desferal) in 1968, the characteristic low plasma half-life, low plasma protein binding (PB), constrained volume of distribution (Vd), and variety of adverse effects made the dosing, bioavailability, and patient compliance as the main hurdle for clinical application of Deferoxamine (DFO). Nevertheless, these pharmacokinetic and pharmacodynamic constraints have been lessened by recent developments in novel drug carrier systems, which has resulted in an increased acceptance of DFO. The effective use of this drug in the treatment of Alzheimer, Parkinson, cancer, wound healing, and ferroptosis has further increased its clinical importance. According to our literature search on various reputed databases such as ScienceDirect, Nature, Wiley, ACS, etc. accumulating results of last 18 years, there has been a significant increase in the overall number of studies conducted on various novel formulations and strategies regarding DFO e.g. polymeric nanoparticles, micelles, nanofibers, conjugates, photothermal therapy, etc. Clinical trial applications found on clinicaltrials.gov have doubled since 2020, and patent applications found on Google Patent have climbed by 320% since 2011. These results demonstrate DFO's versatility and its potential for usage not just in traditional applications but also as a repurposed therapeutic agent.},
}

@article {pmid40703689,
year = {2024},
author = {Kim, H and Lee, H},
title = {Current status and significance of research on sex differences in neuroscience: a narrative review and bibliometric analysis.},
journal = {Ewha medical journal},
volume = {47},
number = {2},
pages = {e16},
pmid = {40703689},
issn = {2234-2591},
abstract = {This review aims to highlight the importance of research on structural, functional, molecular-biological, and disease-specific sex differences in the brain, and to examine current bibliometric indicators related to research on sex differences. The Web of Science Core Collection was searched for related articles from 2010 to 2023. Structural and functional brain differences according to sex, including variations in communication patterns between hemispheres, may play a role in mental disorders. Sex differences in neurotransmitters such as serotonin, dopamine, and γ-aminobutyric acid contribute to disparities in mental health, addiction, and neurodevelopmental conditions. Neurodevelopmental disorders such as autism spectrum disorder and schizophrenia exhibit sex-based differences in prevalence, symptoms, brain changes, and neurotransmitter disruptions under hormonal influence. There is a growing body of research on depression, adolescence, the hippocampus, the amygdala, and cognition, highlighting the importance of considering sex/gender factors. Recent studies on sex differences in brain diseases have identified variations in brain structure, function, and neurophysiological substances, as well as in hormones and genes between the sexes. The incidence of psychiatric disorders such as autism spectrum disorder, depression, anxiety, and Alzheimer's disease is increasingly being linked to sex differences, and the need for research into the mechanisms underlying these differences is gaining recognition. However, there remains a significant gap in sex-specific neuroscience research related to the diagnosis, treatment, prevention, and management of these conditions. Advancing inclusive research will require comprehensive training, a consensus on methodology, diverse perspectives through collaborative frameworks, governmental/institutional support, and dedicated funding to create suitable research environments and implementation strategies.},
}

@article {pmid40703952,
year = {2023},
author = {Rezakhani, L and Salimi, Z and Zarei, F and Moradpour, F and Khazaei, MR and Khazaei, M and Pourjalili, M},
title = {Protective Effects of Statins against Alzheimer Disease.},
journal = {Ewha medical journal},
volume = {46},
number = {4},
pages = {e17},
pmid = {40703952},
issn = {2234-2591},
abstract = {Alzheimer disease (AD) is a common neurodegenerative disorder, characterized by memory impairment, dementia, and diminished cognitive function. This disease affects more than 20 million people worldwide. Amyloid beta (Aβ) plaques and neurofibrillary tangles (NFTs) are important pathological markers of AD. Multiple studies have indicated a potential association between elevated cholesterol levels and increased risk of AD, suggesting that lowering the cholesterol level could be a viable strategy for AD treatment or prevention. Statins, potent inhibitors of cholesterol synthesis, are widely used in clinical practice to decrease the plasma levels of LDL cholesterol in patients with hyperlipidemia. Statins are known to play a neuroprotective role in limiting Aβ pathology through cholesterol-lowering therapies. In addition to Aβ plaques and neurofibrillary tangles, the brains of AD patients exhibit signs of oxidative stress, neuroinflammatory responses, and synaptic disruption. Consequently, compounds with antioxidant, anti-inflammatory, and/or neuroprotective properties could be beneficial components of AD treatment strategies. In addition to lowering LDL cholesterol, statins have demonstrated therapeutic efficacy in various forms, including antioxidant, anti-inflammatory, and neuroprotective effects. These properties of statins are potential mechanisms underlying their beneficial effects in treating neurodegenerative diseases. Therefore, this review was conducted to provide an overview of the protective effects of statins against AD.},
}

@article {pmid40701551,
year = {2025},
author = {Shukla, S and Shukla, S and Sharma, S and Vasudeva, N and Khatri, R and Lather, A and Hooda, T},
title = {Neuroprotective Role of Eupalitin in Streptozotocin-Induced Diabetic Rats: In Silico and In Vivo Studies.},
journal = {Planta medica},
volume = {},
number = {},
pages = {},
doi = {10.1055/a-2654-7657},
pmid = {40701551},
issn = {1439-0221},
abstract = {Alzheimer's disease (AD) is a neurodegenerative condition with marked cognitive loss and impaired thinking abilities as well as spatial memory, working memory, and communication skills. Numerous studies have found that both type 1 and type 2 diabetes lead to neuropathological and neurobehavioral problems, which lead to notable cognitive dysfunction and deterioration in memory. The aims of this study are to find out the neuroprotective potential of eupalitin on memory in streptozotocin-induced diabetic rats and to evaluate its in silico binding affinity on acetylcholinesterase by using molecular docking studies. Eupalitin (dose 1 mg/kg/day) was used to study the behavior model and other biochemical parameters measurement in acute as well as chronic streptozotocin (STZ)-induced diabetic rats. Eupalitin treatment increased the level of acetylcholinesterase (AChE) and lipid peroxidation and decreased glutathione in STZ-infused diabetic rat's brain tissue, suggesting that this substance may modulate cognitive function that is altered by oxidative stress. Results were comparable to standard drugs metformin and donepezil. Docking score and molecular mechanics generalized born surface area (MMGBSA) study results of eupalitin in comparison with donepezil possess superior predicted binding affinity toward AChE. The level of Aβ (1 - 42) was considerably lower in the eupalitin-treated group than in the STZ-treated group during both the acute and chronic phases of treatment, but results were more prominent in the case of chronic-level treatment. In silico studies showed the binding affinity toward AChE. This result concluded that eupalitin antioxidant potential may be utilized as a therapy for diabetes mellitus (DM)-related cognitive impairment.},
}

@article {pmid40701395,
year = {2025},
author = {Yang, FG and Liang, YL and Wang, X and Wang, JT and Gao, W and Ye, QY and Li, XY and Yang, Y and Li, HL},
title = {The Evolution of Alzheimer's Disease: From Mitochondria to Microglia.},
journal = {Ageing research reviews},
volume = {},
number = {},
pages = {102838},
doi = {10.1016/j.arr.2025.102838},
pmid = {40701395},
issn = {1872-9649},
abstract = {Alzheimer's disease (AD) represents the most prevalent neurodegenerative disorder worldwide. Recent studies highlights that mitochondrial dysfunction drives alterations in microglial function, serving as a pivotal mechanism in the pathogenesis and progression of AD. Increasingly, there is evidence that mitochondrial dysfunction encompasses energy metabolism deficits, heightened oxidative stress, impaired mitochondrial dynamics, disrupted autophagy, and calcium homeostasis imbalances. These impairments modulate microglial activation states, precipitating exacerbated neuroinflammation, altered phagocytic capacity, and increased cellular apoptosis, collectively contributing to microglial dysfunction. This paper presents a narrative review on the relationship between mitochondrial dysfunction and AD, elucidating the impact of mitochondrial impairment on microglia. It summarizes therapeutic strategies that target mitochondria to modulate microglial function, aiming to prevent and treat AD. The goal is to provide new perspectives and insights for AD research and treatment, contributing to improving patients' quality of life and prognosis.},
}

@article {pmid40701259,
year = {2025},
author = {Dai, H and Huang, Y and Liu, Y and He, X and Guo, J and Prosperi, M and Bian, J},
title = {Variational temporal deconfounder network for individualized treatment effect estimation with longitudinal observational data.},
journal = {Journal of biomedical informatics},
volume = {},
number = {},
pages = {104880},
doi = {10.1016/j.jbi.2025.104880},
pmid = {40701259},
issn = {1532-0480},
abstract = {OBJECTIVE: By leveraging real-world electronic health record (EHR) data, this study set out to estimate individualized treatment effects (ITE) in longitudinal observational settings to advance personalized medicine, addressing key challenges that are often observed in real-world clinical scenarios and pose statistical challenges, including hidden confounding and dynamic treatment regimens.

METHODS: We propose the Variational Temporal Deconfounder Network (VTDNet), a novel framework designed to account for time-varying hidden confounding using a variational recurrent transformer-based autoencoder. VTDNet comprises two critical components: a Treatment Block that captures interdependencies among multiple treatments and a Potential Outcome Block that predicts both factual and counterfactual outcomes. We assess the effectiveness of the proposed framework using a synthetic dataset and two real-world datasets: MIMIC-III, an EHR dataset focusing on intensive care settings, and NACC, emphasizing neurodegenerative disease, collected using a standardized protocol from participants enrolled in Alzheimer's Disease Research Center (ADRC) clinical cores.

RESULTS: Experimental results on the synthetic dataset demonstrate superior accuracy under varying levels of confounding. On real-world EHR datasets, VTDNet achieves lower root mean squared error, mean absolute error, and influence function precision in the estimation of heterogeneous effects compared to existing state-of-the-art methods.

CONCLUSION: The proposed VTDNet offers a robust framework for estimating individualized treatment effects in longitudinal settings, effectively accommodating irregular time points and high-dimensional data while addressing hidden confounders through a deep generative approach. It holds significant potential to advance personalized medicine and support real-world evidence generation. Future work will aim to extend VTDNet to continuous treatment scenarios, such as dose-response analysis, to further broaden its applicability in clinical practice.},
}

@article {pmid40701134,
year = {2025},
author = {Wu, N and Shao, Y and Wu, Z and Zhu, S and Wang, P and Zhu, Z and Zhang, C and Wu, C and Huo, X and Lin, H and Zhang, G},
title = {Electric field variations across DLPFC targeting methods in TMS therapy for Alzheimer's disease.},
journal = {NeuroImage. Clinical},
volume = {48},
number = {},
pages = {103847},
doi = {10.1016/j.nicl.2025.103847},
pmid = {40701134},
issn = {2213-1582},
abstract = {BACKGROUND: The dorsolateral prefrontal cortex (DLPFC) is crucial for cognitive control and a primary target for transcranial magnetic stimulation (TMS) in Alzheimer's disease (AD). However, understanding the distribution of TMS-induced electric field (E-field) across different targeting methods remains limited, as does its relationship to therapeutic outcomes.

OBJECTIVE: This study assesses differences in TMS-induced E-field using functional versus anatomical targeting methods for DLPFC stimulation.

METHODS: Functional and anatomical targets were identified in 30 (11 M/19F) AD patients and 30 (13 M/17F) age-matched healthy controls (HCs) using T1 and fMRI data. E-field characteristics, including magnitude (EROI) and normal component (E⊥), were calculated via SimNIBS software for comparisons across stimulation targets.

RESULTS: Functional targeting showed greater spatial dispersion compared to anatomical targeting in both groups. Significant E-field differences were observed between the functional target and adjacent anatomical regions when the coil was positioned over the functional target in both groups. Optimal coil orientation exhibited directional specificity: parallel alignment with the LOI E-field produced higher field intensity in the functional target compared to the anatomical target (AD patients: P < 0.001; HCs: P = 0.052), while perpendicular orientation maintained functional stability with reduced anatomical interference (both groups: P < 0.001). And significant variations in E-field ratios were observed across coil orientations.

CONCLUSION: This study reveals key E-field disparities across DLPFC targeting approaches and establishes coil orientation optimization as a critical strategy to improve TMS precision, offering actionable insights for developing personalized protocols in AD therapy that may enhance treatment efficacy while minimizing adverse effects.},
}

@article {pmid40700403,
year = {2025},
author = {Hook, V and Podvin, S and Yoon, MC and Phan, VV and Florio, J and Spencer, B and Mosier, C and Cheng, A and Ahuett, S and Almaliti, J and Gerwick, WH and Rissman, RA and O'Donoghue, AJ},
title = {Neutral pH-Selective Inhibition of Cytosolic Cathepsin B: A Novel Drug Targeting Strategy for Traumatic Brain Injury and Alzheimer's Disease.},
journal = {ACS chemical biology},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschembio.5c00463},
pmid = {40700403},
issn = {1554-8937},
abstract = {Cathepsin B contributes to the behavioral deficits and neuropathology that occur in traumatic brain injury (TBI) and Alzheimer's disease (AD). TBI and AD patients display elevated levels of cathepsin B that correlate with the severity of injury or cognitive deficits, respectively. In animal models of TBI and AD, cathepsin B gene knockout ameliorates behavioral deficits and improves neuropathology. While cathepsin B is normally located in acidic lysosomes, during TBI and AD, lysosomal leakage results in the translocation of cathepsin B to the neutral pH environment of the cytosol, thereby initiating neurodegeneration. Neutral pH-selective inhibitors are hypothesized to specifically target the pathogenic cytosolic cathepsin B without affecting its normal lysosomal form. Therefore, this review focuses on a novel strategy to utilize pH-dependent substrate cleavage properties of cathepsin B for the design of a neutral pH-selective inhibitor. Investigation of the enzymatic properties of cathepsin B at different pH conditions led to the development of Z-Arg-Lys-AOMK, a neutral pH-selective inhibitor that does not affect the enzyme's activity at normal lysosomal acidic pH. Z-Arg-Lys-AOMK potently inhibits cathepsin B at nM concentrations and effectively inhibits cellular cathepsin B in neuronal cell cultures at similar levels. In mice subjected to controlled cortical impact (CCI) brain injury, a model of TBI, cytosolic cathepsin B activity was significantly elevated in the brain. Treatment of the CCI-TBI mice with Z-Arg-Lys-AOMK reduced cytosolic cathepsin B activity and resulted in less motor dysfunction. These findings show that pH-dependent cleavage properties of cathepsin B can be utilized for the development of selective inhibitors to target the neutral cytosolic form of cathepsin B. The new concept of pH-selective inhibitors of cathepsin B reveals novel opportunities for targeting pathogenic, cytosolic cathepsin B involved in brain disorders.},
}

@article {pmid40700397,
year = {2025},
author = {Jamal, QMS and Alharbi, AH and Ahmad, V and Ahmad, K},
title = {Integrated in silico identification of cholinesterase inhibitors from Nyctanthes arbor-tristis.},
journal = {PloS one},
volume = {20},
number = {7},
pages = {e0328457},
doi = {10.1371/journal.pone.0328457},
pmid = {40700397},
issn = {1932-6203},
mesh = {*Cholinesterase Inhibitors/chemistry/pharmacology ; Butyrylcholinesterase/metabolism/chemistry ; Molecular Dynamics Simulation ; Humans ; Acetylcholinesterase/metabolism/chemistry ; Molecular Docking Simulation ; Computer Simulation ; Alzheimer Disease/drug therapy ; *Plant Extracts/chemistry/pharmacology ; },
abstract = {Alzheimer's disease (AD) remains a major neurodegenerative disorder, characterized by cognitive decline alongside functional impairments that affect daily living. Natural therapeutic alternatives have spurred the search for novel inhibitors targeting acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), two well-established targets in AD therapy. This study utilizes an in silico methodology to investigate new cholinesterase inhibitors sourced from Nyctanthes arbor-tristis, a plant known for its abundant bioactive phytochemicals. Through virtual screening, molecular dynamics simulations (MDS), free energy landscape analysis, and ADMET predictions, eight compounds have been identified as potential inhibitors of AChE and/or BChE. These compounds include Apigenin, Arborside-B, Arbortristoside-D, Arbortristoside-E, Nicotiflorin, Arborside-A, Beta-amyrin, and Nyctanthic acid. These compounds exhibited robust binding affinities compared to the control, advantageous ADMET profiles, and sustained stability throughout 200 ns of MDS and energy assessments, highlighting their potential as viable drug candidates for further exploration. Further experimental studies are required to validate their therapeutic efficacies, thereby confirming their potential as neurological therapeutics for the treatment of AD and related disabilities.},
}

*Cholinesterase Inhibitors/chemistry/pharmacology
Butyrylcholinesterase/metabolism/chemistry
Molecular Dynamics Simulation
Humans
Acetylcholinesterase/metabolism/chemistry
Molecular Docking Simulation
Computer Simulation
Alzheimer Disease/drug therapy
*Plant Extracts/chemistry/pharmacology

@article {pmid40699791,
year = {2025},
author = {Klein, BY and Gofrit, ON and Greenblatt, CL},
title = {Testing Protein Stress Signals in Peripheral Immunocytes Under the Same Treatment Capable of Decreasing the Incidence of Alzheimer's Disease in Bladder Cancer Patients.},
journal = {Current issues in molecular biology},
volume = {47},
number = {6},
pages = {},
doi = {10.3390/cimb47060392},
pmid = {40699791},
issn = {1467-3045},
abstract = {Several studies showed that the incidence of Alzheimer's disease (AD) is significantly lower in patients with non-muscle invasive bladder cancer (NMIBC) treated with intravesical bacillus Calmette-Guérin (BCG) instillations compared to treatment by alternative methods. Hypothetically, failure to clear misfolded and aggregated proteins (i.e., beta-amyloid) in AD brains and peripheral blood mononuclear cells (PBMCs) implicates BCG in upgrading the unfolded protein response (UPR). To test this hypothesis, pre- versus post-BCG PBMC proteins of the UPR pathway were compared in six NMIBC patients by capillary immunoelectrophoresis on an Abby instrument. PERK, the endoplasmic reticulum (ER) resident kinase, a stress-activated sensor, and its substrate alpha component of the eIF2 translation factor (eIF2a) complex inactivation were considered as potentially proapoptotic via a downstream proapoptotic transcription factor only if persistently high. GAPDH, a glycolytic marker of innate immunocyte training by BCG, and eight other UPR proteins were considered antiapoptotic. Summation of antiapoptotic %change scores per patient showed that the older the age, the lower the antiapoptotic %change. Higher antiapoptotic scores were observed upon a longer time from BCG treatment (with the exception of the patient in her ninth decade of life). Studies with more individuals could substantiate that BCG enhances the antiapoptotic aggregate-clearance effect of the UPR in PBMCs of NMIBC patients, which hypothetically protects brain cells against AD.},
}

@article {pmid40698680,
year = {2025},
author = {Rohilla, S and Goyal, G},
title = {Computer-aided Drug Design for Alzheimer's Disease: Recent Advancements and Future Perspectives.},
journal = {Current topics in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115680266343814250713100224},
pmid = {40698680},
issn = {1873-4294},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder marked by a decline in cognitive function and memory loss, primarily resulting from cholinergic dysfunction, the accumulation of amyloid plaques, the formation of tau tangles, and the progressive degeneration of neurons. While existing treatments offer limited symptomatic relief, they do not effectively halt or reverse the underlying progression of the disease, presenting a major global challenge in Alzheimer's research. Developing therapeutic strategies for AD remains complex, largely due to the inability of current medications to significantly slow neurodegeneration. Traditional drug discovery processes are often lengthy, costly, and inefficient, further complicating the search for effective treatments. To overcome these obstacles, researchers have turned to a combination of computational approaches alongside conventional drug design techniques. These integrated methodologies help accelerate the discovery process by significantly reducing both time and costs. This review delves into the underlying physiological and pathological mechanisms of Alzheimer's disease, while identifying potential drug targets such as acetylcholinesterase, butyrylcholinesterase, β-Secretase (BACE-1), A2A adenosine receptor, Dickkopf-1 protein, glycogen synthase kinase-3β, indoleamine 2,3-dioxygenase, monoamine oxidase-B, NMDA receptor, Wnt inhibitory factor, cyclindependent kinase-5, glutaminyl cyclase, and cathepsin-B. Furthermore, the review examines various computer-aided drug design (CADD) methodologies, including structure-based and ligandbased approaches, virtual screening, pharmacophore modeling, molecular modelling, and simulation techniques. These computational strategies are playing an increasingly important role in Alzheimer's research, particularly in drug discovery. By investigating promising drug candidates and lead molecules that target key proteins involved in Alzheimer's pathogenesis, the review highlights their binding modes with these targets and assesses the chemical properties essential for the development of effective clinical candidates. The aim is to provide researchers with critical insights and tools to design novel compounds with the necessary chemical and physical characteristics required for the successful treatment of Alzheimer's disease.},
}

@article {pmid40698455,
year = {2025},
author = {Topalis, V and Voros, C and Ziaka, M},
title = {Targeting Inflammation in Alzheimer's Disease: Insights Into Pathophysiology and Therapeutic Avenues-A Comprehensive Review.},
journal = {Journal of geriatric psychiatry and neurology},
volume = {},
number = {},
pages = {8919887251361578},
doi = {10.1177/08919887251361578},
pmid = {40698455},
issn = {0891-9887},
abstract = {Alzheimer's Disease (AD) is the most common dementia, affecting mainly older adults, particularly over 65. Characterized by progressive cognitive decline-including deficits in memory, executive functions, and language, alongside behavioral disturbances-AD arises from complex pathophysiological mechanisms. These include neurotransmitter imbalances, cholinergic deficits, amyloid-beta (Aβ) toxicity, tau protein hyperphosphorylation, oxidative stress, synaptic dysfunction, and neuroinflammatory processes. Growing evidence highlights the protective role of microglia in AD pathology through their immune functions, phagocytic clearance of Aβ proteins, and trophic support to promote tissue repair and maintain cerebral homeostasis, as alterations in their response to Aβ are linked to an increased risk of AD. However, disruptions in homeostasis or tissue alterations may trigger microglial activation, leading to detrimental effects such as increased inflammatory activity, impaired microglial-mediated clearance, synapse loss, and neuronal damage. Astrocytes, a distinct type of glial cell with homeostatic functions, also exhibit neuroprotective effects. However, the presence of Aβ may result in astrocyte reactivity, leading to neurotoxic effects associated with disturbances of calcium levels, activation of proinflammatory pathways, gliotransmission, altered tau metabolism, and impaired clearance of Aβ. Despite substantial research, AD remains challenging to diagnose early and lacks effective treatments. Given its multifactorial nature, therapeutic approaches primarily aim to slow progression and remain limited in achieving a definitive cure. While most current strategies focus on mitigating the toxic effects of Aβ and tau proteins, growing interest has emerged in addressing neuroinflammation as a potential means to delay or prevent neurodegeneration. Targeting neuroinflammation could open new therapeutic avenues for the treatment of AD.},
}

@article {pmid40698100,
year = {2025},
author = {Singh, D and Singhal, S and Kanaujiya, V and Ranjan, A and Mani, VE and Paliwal, VK and Jain, V and Aishwarya, A and Agarwal, R},
title = {Ganglion Cell Layer Thickness as a Biomarker for Amyotrophic Lateral Sclerosis Functional Outcome: An OCT study.},
journal = {Romanian journal of ophthalmology},
volume = {69},
number = {2},
pages = {200-207},
pmid = {40698100},
issn = {2501-2533},
mesh = {Humans ; *Tomography, Optical Coherence/methods ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnosis ; Male ; Middle Aged ; Female ; *Retinal Ganglion Cells/pathology ; *Visual Acuity/physiology ; *Nerve Fibers/pathology ; Adult ; *Optic Disk/pathology ; Aged ; Intraocular Pressure/physiology ; Biomarkers ; },
abstract = {AIM: This study aims to evaluate various optical coherence tomography (OCT) parameters in patients diagnosed with amyotrophic lateral sclerosis (ALS).

METHODS: Assessment of BCVA was done using Snellen charts, and subjective refraction was done to achieve a BCVA for distance and near. Measurement of intraocular pressure (IOP) was done with Goldman applanation tonometry. Stereoscopic fundus examination was performed using a 90D lens to assess the status of the optic nerve and retina, ruling out any ocular pathology. The patients were then subjected to OCT scanning to measure optic nerve head and macular parameters. Optical coherence tomography was performed using CIRRUS™ HD OCT (500-21822) (version 8.0.0.518) (Carl Zeiss Meditec, Dublin, CA, USA). The analyzed area was centered manually, and the absence of segmentation errors was confirmed for each scan.

RESULTS: RE Avg RNFL and LE Avg RNFL showed weak correlations with ALSFRS, indicated by Pearson Correlation coefficients of 0.073 and -0.026, respectively. The p-values (0.637 and 0.86) suggested that these correlations were not statistically significant. RE Avg GCL and LE Avg GCL, on the other hand, exhibited moderate positive correlations with ALSFRS scores, with correlation coefficients of 0.337 (RE) and 0.389 (LE). These correlations were statistically significant, as indicated by p-values of 0.021 and 0.006, respectively, suggesting a substantial association between GCL thickness and ALS functional outcomes.

DISCUSSION: All patients in our study were clinically diagnosed cases of ALS, as per the El Escorial criteria. Age group-wise analysis showed statistically significant thinning overall as well as quadrant-wise RNFL parameters in patients less than 50 years compared to age-matched controls, indicating that the pathological process occurring in larger motor neurons in ALS might also be happening in smaller sensory neurons of the retina, causing thinning, which was not due to age-related process. Although GCIPL thinning was occurring in our cases, though statistically not significant compared to control, the significant positive correlation observed between GCIPL and ALS functional outcome and between RNFL and GCIPL measurements highlighted the fact that though the axonal degeneration in retinal neurons might not be translating to the same extent in ganglion cells in ALS, the subtle thinning of GCIPL correlated strongly with functional disability in patients with ALS, implying better functional scores with higher values of GCIPL parameters.

CONCLUSION: In summary, GCL measurements in both eyes showed a notable relationship with ALSFRS, whereas RNFL did not appear to correlate significantly.},
}

Humans
*Tomography, Optical Coherence/methods
*Amyotrophic Lateral Sclerosis/physiopathology/diagnosis
Male
Middle Aged
Female
*Retinal Ganglion Cells/pathology
*Visual Acuity/physiology
*Nerve Fibers/pathology
Adult
*Optic Disk/pathology
Aged
Intraocular Pressure/physiology
Biomarkers

@article {pmid40697975,
year = {2025},
author = {Gogu, P and Bharti, J and Yadav, JP and Grishina, M and Verma, A and Kumar, V and Singh, AK and Verma, A and Kumar, P and Khalilullah, H and Jaremko, M and Emwas, AH and Dwivedi, AR and Pathak, P},
title = {Exploring GPR120/FFAR4 pharmacology: Unveiling novel therapeutic avenues through molecular signaling pathways for Alzheimer's disease intervention.},
journal = {Brain, behavior, & immunity - health},
volume = {48},
number = {},
pages = {101061},
pmid = {40697975},
issn = {2666-3546},
abstract = {G-protein-coupled receptors (GPCRs) are a major class of membrane proteins involved in numerous physiological and pathological processes. Among them, free fatty acid receptor 4 (FFAR4/GPR120), activated by long-chain free fatty acids, has shown anti-inflammatory effects and is expressed in the brain-implicating its role in neurodegenerative diseases like Alzheimer's disease (AD). AD is characterized by brain atrophy, cognitive decline, and neuroinflammation, involving complex signaling networks. This review explores the pharmacological relevance of GPR120/FFAR4 in AD, focusing on its involvement in neuroinflammatory, amyloidogenic, and intracellular signaling cascades. Targeting GPR120 may help modulate chronic inflammation and amyloid-β accumulation. Additionally, activation of nuclear receptors and regulation of pathways such as MAPK, NLRP3, PPARs, and cAMP have shown promise in mitigating AD pathology. Despite the complexity of brain signaling, GPR120 emerges as a compelling multitarget therapeutic receptor. These insights provide a foundation for developing novel anti-inflammatory strategies in AD treatment.},
}

@article {pmid40697447,
year = {2025},
author = {Senanayake, D and Yapa, P and Dabare, S and Munaweera, I},
title = {Precision targeting of the CNS: recent progress in brain-directed nanodrug delivery.},
journal = {RSC advances},
volume = {15},
number = {32},
pages = {25910-25928},
pmid = {40697447},
issn = {2046-2069},
abstract = {The therapeutic drug penetration into brain tissues meets limitations through the restrictive function of the blood-brain barrier (BBB) within the central nervous system (CNS). The advancement of nanocarrier engineering techniques allows scientists to develop nanoscale delivery vehicles that successfully cross the BBB. This review analyses modern brain-delivery nanodrug delivery platforms by examining the properties and distribution of liposomes and polymeric nanoparticles, dendrimers, solid lipid nanoparticles, and exosomes. Organizations use specific physicochemical approaches designed for each platform to boost brain penetration and enhance therapeutic drug distribution for improving drug effectiveness. An analysis is presented of the various procedures to cross or bypass the BBB where receptor-mediated transcytosis joins focused ultrasound, as well as magnetic targeting and chemical modifications. The article presents therapeutic developments regarding neurological treatment of Alzheimer's disease, alongside Parkinson's disease and glioblastoma. Early laboratory success has produced promising results, yet challenges persist during the translation of these findings for clinical use because of safety issues as well as compatibility problems and difficulties with scaling up manufacturing processes. Finally, it discusses regulatory advancements and describes active market trends in nanomedicine that focus on precise delivery techniques and combination treatment methods, and brain-targeted delivery systems. The innovations combined present an optimistic future for CNS drug development because they create substantial opportunities to reshape neurological disorder treatments.},
}

@article {pmid40697193,
year = {2025},
author = {Zhang, L and Wu, Y and Jin, Q and Wang, C},
title = {Association between genetically proxied PPARG activation and early onset Alzheimer's disease: A drug target Mendelian randomization study.},
journal = {Journal of Alzheimer's disease reports},
volume = {9},
number = {},
pages = {25424823251359579},
pmid = {40697193},
issn = {2542-4823},
abstract = {BACKGROUND: Early-onset Alzheimer's disease (EOAD), which has an onset before the age of 65, is overshadowed by the more prevalent late-onset Alzheimer's disease (LOAD). Nevertheless, rather than being merely a form of LOAD that occurs at a prematurely defined younger age, EOAD differs from LOAD in multiple ways. Given these disparities, understanding the potential treatment options for EOAD becomes crucial.

OBJECTIVE: We aim to assess anti-diabetic drugs' potential utility in treating EOAD and LOAD from a novel perspective via drug-targeted Mendelian randomization (MR) analysis.

METHODS: Through Summary-data-based MR (SMR) and inverse-variance-weighted MR (IVW-MR) analysis, we assessed the associations between anti-diabetic drug targets (including DPP-4 inhibitor, Thiazolidinedione, GLP1R agonist, Sulfonylureas, SLC5A2 inhibitor, and Insulin/Insulin analog) and AD outcomes (EOAD and LOAD). We utilized two types of genetic instruments to represent the exposure to anti-diabetic drugs: eQTLs of genes encoding drug target proteins and genetic variants within or near genes encoding these target proteins associated with HbA1c from genome-wide association studies.

RESULTS: SMR analysis showed that enhanced PPARG gene expression in the blood was a protective factor for EOAD (OR = 0.733, 95%CI = 0.548-0.979, p = 0.035). Additionally, an IVW-MR association was found between HbA1c mediated by PPARG and EOAD (OR = 0.295, 95%CI = 0.092-0.949, p = 0.041).

CONCLUSIONS: This study suggests that Thiazolidinedione therapy could help suppress the development of EOAD, supporting further exploration of PPARG-targeted anti-diabetic drug development.},
}

@article {pmid40696527,
year = {2025},
author = {Jeon, SY and Wang, SM and Roh, HW and Kim, KY and Chang, YY and Kim, E and Bae, JN and Ryu, SH},
title = {Practical Guide of the Korean Association for Geriatric Psychiatry to Anti-Amyloid Monoclonal Antibody Therapy for Alzheimer's Disease: Focused on Lecanemab.},
journal = {Journal of Korean medical science},
volume = {40},
number = {28},
pages = {e215},
doi = {10.3346/jkms.2025.40.e215},
pmid = {40696527},
issn = {1598-6357},
support = {//Korean Association for Geriatric Psychiatry/Korea ; },
mesh = {Humans ; *Alzheimer Disease/drug therapy/pathology ; Republic of Korea ; *Antibodies, Monoclonal, Humanized/therapeutic use ; Amyloid beta-Peptides/antagonists & inhibitors/immunology ; Aged ; Antibodies, Monoclonal/therapeutic use ; },
abstract = {The advent of anti-amyloid monoclonal antibody (mAb) therapies represents a paradigm shift in the treatment of Alzheimer's disease (AD), from symptomatic relief to disease modification. Lecanemab, a humanized mAb targeting soluble Aβ protofibrils and plaque, received regulatory approval in Korea in July 2024, following global randomized controlled trial data demonstrating its efficacy to reduce amyloid burden and slow cognitive decline. However, the introduction of such therapies into routine clinical realm presents several practical and systemic challenges, particularly in the context of Korea's unique healthcare infrastructure and reimbursement environment. In response, the Korean Association for Geriatric Psychiatry has developed the first comprehensive domestic guidance to facilitate the safe, evidence-based, and patient-centered use of anti-amyloid mAb therapies, first focused on lecanemab. This practical guide goes beyond simple eligibility criteria. It provides detailed recommendations on clinical and imaging-based candidate selection, amyloid-related imaging abnormalities (ARIA) risk stratification and monitoring protocols, infusion workflows, adverse event management strategies, and multidisciplinary coordination within hospital systems. It also emphasizes shared decision-making and outlines how to navigate situations where treatment is not appropriate, such as in patients with advanced dementia, high-risk magnetic resonance imaging findings, or poor treatment adherence, reinforcing that non-treatment can also represent a legitimate, evidence-based clinical decision. The guidance further highlights the urgent need to generate real-world data that reflect the treatment experiences of Korean patients. Multicenter collaboration will be essential for collecting data on adherence rates, ARIA incidence, cognitive outcomes, and functional trajectories, which in turn can inform policy decisions, insurance reimbursement models, and future updates to clinical guidelines. This publication represents the first nationwide roadmap in Korea to support clinicians in the appropriate integration of monoclonal antibody therapies for AD. By combining scientific rigor, operational feasibility, and ethical sensitivity, it aims to promote safe and responsible adoption of disease-modifying treatment across various clinical settings.},
}

Humans
*Alzheimer Disease/drug therapy/pathology
Republic of Korea
*Antibodies, Monoclonal, Humanized/therapeutic use
Amyloid beta-Peptides/antagonists & inhibitors/immunology
Aged
Antibodies, Monoclonal/therapeutic use

@article {pmid40696469,
year = {2025},
author = {Oosthoek, M and Vijverberg, EGB and Blujdea, ER and Veld, SGJGI and Avilés, MP and Zsadanyi, SE and Hok-A-Hin, YS and Visser, A and van der Flier, WM and Barkhof, F and Del Campo, M and Schut, MC and Bejanin, A and Alcolea, D and Teunissen, CE and Vermunt, L},
title = {CHIT1 and DDAH1 levels relate to amyloid-related imaging abnormalities risk profile in Alzheimer's disease patients.},
journal = {Alzheimer's research & therapy},
volume = {17},
number = {1},
pages = {169},
pmid = {40696469},
issn = {1758-9193},
support = {WE.03-2018-05//Alzheimer Nederland/ ; WE.03-2018-05//Alzheimer Nederland/ ; NR170065//Selfridges Group Foundation/ ; NR170065//Selfridges Group Foundation/ ; PI21/00791, PI14/01126, PI17/01019, PI20/01473, PI13/01532, PI16/01825, PI18/00335, PI19/00882, PI18/00435, PI22/00611, INT19/00016, INT23/00048, PI17/01896 and AC19/00103//Fondo de Investigaciones Sanitario/ ; PI21/00791, PI14/01126, PI17/01019, PI20/01473, PI13/01532, PI16/01825, PI18/00335, PI19/00882, PI18/00435, PI22/00611, INT19/00016, INT23/00048, PI17/01896 and AC19/00103//Fondo de Investigaciones Sanitario/ ; Program 1, Alzheimer Disease//CIBERNED program/ ; Program 1, Alzheimer Disease//CIBERNED program/ ; NIA grants 1R01AG056850-01A1; R21AG056974; and R01AG061566),//Office of Dietary Supplements/ ; NIA grants 1R01AG056850-01A1; R21AG056974; and R01AG061566),//Office of Dietary Supplements/ ; 2017-SGR-547, SLT006/17/125, SLT006/17/119, SLT002/16/408//Generalitat de Catalunya/ ; 2017-SGR-547, SLT006/17/125, SLT006/17/119, SLT002/16/408//Generalitat de Catalunya/ ; 20141210, 044412 and 20142610//Fundació la Marató de TV3/ ; 20141210, 044412 and 20142610//Fundació la Marató de TV3/ ; },
mesh = {Humans ; *Alzheimer Disease/cerebrospinal fluid/diagnostic imaging/genetics ; Male ; Female ; Aged ; Biomarkers/cerebrospinal fluid ; Amyloid beta-Peptides/cerebrospinal fluid ; Middle Aged ; *Hexosaminidases/cerebrospinal fluid ; Cohort Studies ; Proteomics ; Peptide Fragments/cerebrospinal fluid ; Chitinase-3-Like Protein 1 ; },
abstract = {BACKGROUND: Amyloid-related imaging abnormalities (ARIA) are a common and potentially dangerous side effect in anti-amyloid therapies, creating a need for tools to assess ARIA risk. Several patient factors have been linked to ARIA; namely the presence of microbleeds (MBL[+]), APOE E4 carriership (APOE4[+]), and extremely low CSF Aβ42 concentrations (A[L]). We hypothesize that studying the CSF proteome of Alzheimer's disease (AD) dementia patients from a high-risk group (MBL[+]APOE4[+]A[L]) can inform on the biological underpinnings of ARIA risk and aid the progress of ARIA risk biomarkers.

METHODS: We utilized CSF proteomic data of AD (n = 156) and cognitively unimpaired individuals (CU n = 100) of the Amsterdam Dementia Cohort. The proteome of the defined high-risk (n = 13) was compared to low-risk AD group (n = 23), using age and sex corrected linear regressions followed by gene ontology analysis. For biomarker prioritization, we selected proteins that were abnormal in the high-risk group versus low-risk and CU patients. The biomarkers were validated in an independent cohort (high risk n = 14, low risk n = 9) analyzed using customized multiplex panels. Lastly, we assessed biomarker lead co-expression.

RESULTS: Ninety-four proteins differentiated in the high-risk group compared to low-risk (p < 0.05), none surviving FDR correction. These proteins were enriched for synapse-related proteins and axonogenesis. CHIT1 (vs. low-risk AD: FC = 1.0, p = 0.014, vs. CU: FC = 2.4, p < 0.001) and DDAH1 (vs. low-risk AD: FC=-0.31, p = 0.046, vs. CU: FC = 0.5, p < 0.001) were prioritized as biomarker. DDAH1 protein changes replicated in an independent cohort (FC=-0.37, p = 0.010), and CHIT1 replicated on a trend level (FC = 0.70, p = 0.104). DDAH1 levels had the highest co-expression with synaptic process, energy utilization and RNA-binding cell signaling related proteins (R > 0.8).

CONCLUSIONS: The findings suggest that in the high risk group, there is a lack of upregulation in synapse and axonogenesis related proteins. High CSF CHIT1 and less increased CSF DDAH1 levels within AD relate to ARIA risk. From the literature, the link to ARIA risk for CHIT1 could be its contribution to innate immunity or vascular amyloid deposition, and for DDAH1 to blood-brain barrier integrity. Biomarker assays are available to assess the potential of CHIT1 and DDAH1 in trials and treatment studies in the clinical setting.},
}

Humans
*Alzheimer Disease/cerebrospinal fluid/diagnostic imaging/genetics
Male
Female
Aged
Biomarkers/cerebrospinal fluid
Amyloid beta-Peptides/cerebrospinal fluid
Middle Aged
*Hexosaminidases/cerebrospinal fluid
Cohort Studies
Proteomics
Peptide Fragments/cerebrospinal fluid
Chitinase-3-Like Protein 1

@article {pmid40695613,
year = {2025},
author = {Sun, M and Wang, X and Lu, Z and Yang, Y and Lv, S and Miao, M and Chen, WM and Wu, SY and Zhang, J},
title = {Evaluating GLP-1 receptor agonists versus metformin as first-line therapy for reducing dementia risk in type 2 diabetes.},
journal = {BMJ open diabetes research & care},
volume = {13},
number = {4},
pages = {},
doi = {10.1136/bmjdrc-2025-004902},
pmid = {40695613},
issn = {2052-4897},
mesh = {Humans ; *Metformin/therapeutic use ; *Diabetes Mellitus, Type 2/drug therapy/complications ; Male ; Female ; *Dementia/prevention & control/epidemiology/etiology ; *Glucagon-Like Peptide-1 Receptor Agonists ; *Hypoglycemic Agents/therapeutic use ; Retrospective Studies ; Aged ; Middle Aged ; Risk Factors ; Follow-Up Studies ; Incidence ; Aged, 80 and over ; },
abstract = {INTRODUCTION: No direct comparisons have evaluated glucagon-like peptide-1 receptor agonists (GLP-1 RAs) versus metformin as first-line antidiabetic therapy for preventing dementia in patients with type 2 diabetes mellitus (T2DM). This study aimed to assess the comparative effectiveness of GLP-1 RAs and metformin in reducing dementia risk.

RESEARCH DESIGN AND METHODS: This retrospective cohort study used data from a global health research network between 2004 and 2024. Patients with T2DM initiating GLP-1 RAs or metformin as first-line monotherapy were included. Propensity score matching was employed to balance baseline characteristics. Dementia incidence was analyzed using Cox proportional hazards models, with sensitivity analyses to confirm robustness.

RESULTS: Among 87,229 matched patients per cohort, GLP-1 RA use was associated with a significantly lower risk of overall dementia (adjusted HR (AHR) 0.90; 95% CI 0.85 to 0.95), Alzheimer's disease (AD) (AHR 0.88; 95% CI 0.83 to 0.94), and non-vascular dementias (non-VaDs) (AHR 0.75; 95% CI 0.70 to 0.81) compared with metformin. No significant difference was observed for VaD. Subgroup analyses showed consistent benefit across age and sex, with the strongest effect among older adults and females.

CONCLUSIONS: GLP-1 RAs were more effective than metformin in reducing the risk of dementia-especially AD and non-vascular types-highlighting their potential as a preferred first-line treatment in T2DM. Further randomized trials are warranted to validate these findings.},
}

Humans
*Metformin/therapeutic use
*Diabetes Mellitus, Type 2/drug therapy/complications
Male
Female
*Dementia/prevention & control/epidemiology/etiology
*Glucagon-Like Peptide-1 Receptor Agonists
*Hypoglycemic Agents/therapeutic use
Retrospective Studies
Aged
Middle Aged
Risk Factors
Follow-Up Studies
Incidence
Aged, 80 and over

@article {pmid40695276,
year = {2025},
author = {Li, Y and Pereda Serras, C and Blumenfeld, J and Xie, M and Hao, Y and Deng, E and Chun, YY and Holtzman, J and An, A and Yoon, SY and Tang, X and Rao, A and Woldemariam, S and Tang, A and Zhang, A and Simms, J and Lo, I and Oskotsky, T and Keiser, MJ and Huang, Y and Sirota, M},
title = {Cell-type-directed network-correcting combination therapy for Alzheimer's disease.},
journal = {Cell},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.cell.2025.06.035},
pmid = {40695276},
issn = {1097-4172},
abstract = {Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder characterized by heterogeneous molecular changes across diverse cell types, posing significant challenges for treatment development. To address this, we introduced a cell-type-specific, multi-target drug discovery strategy grounded in human data and real-world evidence. This approach integrates single-cell transcriptomics, drug perturbation databases, and clinical records. Using this framework, letrozole and irinotecan were identified as a potential combination therapy, each targeting AD-related gene expression changes in neurons and glial cells, respectively. In an AD mouse model with both Aβ and tau deposits, this combination therapy significantly improved memory performance and reduced AD-related pathologies compared with vehicle and single-drug treatments. Single-nucleus transcriptomic analysis confirmed that the therapy reversed disease-associated gene networks in a cell-type-specific manner. These results highlight the promise of cell-type-directed combination therapies in addressing multifactorial diseases like AD and lay the groundwork for precision medicine tailored to patient-specific transcriptomic and clinical profiles.},
}

@article {pmid40695043,
year = {2025},
author = {Kritika, and Sanjay, and Lee, HJ},
title = {Eriocitrin and its derivatives against Alzheimer's disease: Cumulative accounts of in vitro and in vivo studies.},
journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie},
volume = {190},
number = {},
pages = {118362},
doi = {10.1016/j.biopha.2025.118362},
pmid = {40695043},
issn = {1950-6007},
abstract = {Alzheimer's disease (AD) is the most prevalent neurodegenerative disease (ND), and its adversities are not limited to the brain. Due to complex and interconnected pathologies with other NDs, an effective treatment for multidimensional AD-related adversities has yet to be reported. Several phytoconstituents have been reported and are currently being studied for their bioactive potential in AD. Eriocitrin, a dihydroflavonoid compound present in citrus fruits, such as lemons, limes, lemon peels, grapefruit, and vegetables, and processed items, such as beverages and wine, along with its derivatives hesperetin, hesperidin, eriodictyol, and homoeriodictyol, has been reported to possess various neuroprotective bioactivities, including anti-inflammatory, anti-oxidative, anti-amyloidogenic, anti-tau phosphorylation, and anti-apoptotic properties, in several in vitro and in vivo models. However, a comprehensive review summarizing and correlating the multidimensional bioactive potentials of eriocitrin and its derivatives against AD has yet to be compiled. This review extensively discusses the in-depth role of eriocitrin and its derivatives in ameliorating different AD-related signaling pathways both in vitro and in vivo, and summarizes the incorporation of eriocitrin like different plant-based flavonoids in long-term dietary practice to combat AD and other similar NDs. Additionally, this review suggests examining various nano-formulations of eriocitrin and its derivatives for their anti-AD effects in comparison to the parent compound. Furthermore, in-depth in vitro and in vivo studies, along with different clinical trials, should be conducted to fully elucidate the true potential of eriocitrin and its derivatives in AD pathology.},
}

@article {pmid40694204,
year = {2025},
author = {Goleij, P and Khazeei Tabari, MA and Poudineh, M and Sanaye, PM and Khan, H and Kumar, AP and Larsen, DS and Daglia, M},
title = {Therapeutic potential of melatonin-induced mitophagy in the pathogenesis of Alzheimer's disease.},
journal = {Inflammopharmacology},
volume = {},
number = {},
pages = {},
pmid = {40694204},
issn = {1568-5608},
abstract = {Neurons rely heavily on functional mitochondria for energy production. Mitochondrial dysfunction is a key player in age-related neurodegenerative diseases like Alzheimer's disease (AD). In AD, damaged mitochondria accumulate early, worsening the disease. This dysfunction disrupts cellular balance in neurons, leading to energy deficiencies, calcium imbalances, and oxidative stress. These issues further aggravate the harmful effects of amyloid beta (Aβ) plaques and tau tangles, ultimately leading to synaptic dysfunction, memory loss, and cognitive decline. While a complex link exists between mitochondrial dysfunction and AD hallmarks like Aβ plaques and tau tangles, the exact cause-and-effect relationship remains unclear. Additionally, recent evidence suggests impaired mechanisms for mitophagy in AD. Mitophagy is crucial for neuronal health, and studies have found changes to proteins involved in this process, mitochondrial dynamics, and mitochondrial production in AD. Impaired mitophagy might also be linked to problems with how cells fuse waste disposal compartments (autophagosomes) with lysosomes, and issues with maintaining proper acidity within lysosomes. Interestingly, melatonin, a hormone known for regulating sleep, has recently emerged as a potential neuroprotective agent. Studies using a mouse model of AD showed that melatonin treatment improved cognitive function by enhancing mitophagy. These findings suggest that melatonin's ability to improve mitophagy may be a promising avenue for future AD therapies. Therefore, in this review, we discuss the therapeutic effect of melatonin on mitochondrial dysfunction, especially mitophagy, in AD.},
}

@article {pmid40694170,
year = {2025},
author = {Shah, Z and Iqbal, A and Badshah, SL and Mir, MA and Sohni, S and Ullah, H and Shah, SA and Bashir, N and Ayaz, M and Daglia, M},
title = {Macroalgae Polysaccharides Enhance Brain Health by Mitigating Scopolamine-induced Oxidative Stress and Inflammation Via Nrf-2/TLR4/NF-kB Pathways.},
journal = {Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology},
volume = {20},
number = {1},
pages = {74},
pmid = {40694170},
issn = {1557-1904},
mesh = {Animals ; *Polysaccharides/pharmacology/isolation & purification ; *Oxidative Stress/drug effects/physiology ; Scopolamine/toxicity ; Mice ; NF-kappa B/metabolism ; Male ; NF-E2-Related Factor 2/metabolism ; Toll-Like Receptor 4/metabolism ; *Seaweed/chemistry ; *Neuroprotective Agents/pharmacology/isolation & purification ; *Brain/drug effects/metabolism ; Signal Transduction/drug effects ; Inflammation/chemically induced/metabolism/drug therapy ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disorder commonly associated with memory loss and difficulties in performing daily activities, particularly in the aging brain.

PURPOSE OF THE STUDY: This study aimed to evaluate the neuroprotective effects of macroalgae-derived polysaccharides from seaweed against scopolamine-induced amnesia, oxidative stress, and amyloid plaque (Aβ) production in rodents, following standard experimental protocols.

METHODS: Three novel polysaccharides were extracted from Chara vulgaris, Cladophora glomerata, and Spirogyra crassa, namely: methylated pectin-type polysaccharides (PS1), methylated pectin-type polysaccharides (homo galacturonan and rhamno galacturonan, PS2), Ulvan-type polysaccharide, and xyloglucan polysaccharides (PS3). These polysaccharides were characterized using a variety of analytical techniques, including SEM, FTIR, XRD, [1]H-NMR, and [13]C-NMR. The polysaccharides were administered at a dose of 30 mg/kg to male albino mice exposed to scopolamine (1 mg/kg) for three weeks. To assess their neuroprotective effects, Morris Water Maze (MWM) and Y-maze tests, antioxidant enzyme assays (Catalase, GSH, LPO), and western blotting were performed.

RESULTS: The results showed that all three polysaccharides significantly (p ≤ 0.001) mitigated redox imbalance and reduced (p ≤ 0.001) microglial activation, thereby decreasing scopolamine-induced neuroinflammation and amyloid beta (Aβ) accumulation. Additionally, these polysaccharides improved neuronal synapses and cognitive function by modulating the NRf-2/TLR4/NF-kB signaling pathway.

DATA ANALYSIS: The data analysis and graph generation were performed using GraphPad Prism software, version 5.0, with a significance level set at a p-value of < 0.05.

CONCLUSION: The findings highlighted the potential of these three novel natural polysaccharides as promising candidates for the treatment of scopolamine-induced oxidative stress-mediated neurodegenerative disorders, such as Alzheimer's disease.},
}

Animals
*Polysaccharides/pharmacology/isolation & purification
*Oxidative Stress/drug effects/physiology
Scopolamine/toxicity
Mice
NF-kappa B/metabolism
Male
NF-E2-Related Factor 2/metabolism
Toll-Like Receptor 4/metabolism
*Seaweed/chemistry
*Neuroprotective Agents/pharmacology/isolation & purification
*Brain/drug effects/metabolism
Signal Transduction/drug effects
Inflammation/chemically induced/metabolism/drug therapy

@article {pmid40693114,
year = {2025},
author = {Xiao, S and Wei, X and Han, B and Shi, X and Wei, C and Liang, R and Sun, J and Zhang, Z and Han, Z and Shen, L},
title = {Quantitative analysis of targeted lipidomics in the hippocampus of APP/PS1 mice employing the UHPLC-MS/MS method.},
journal = {Frontiers in aging neuroscience},
volume = {17},
number = {},
pages = {1561831},
pmid = {40693114},
issn = {1663-4365},
abstract = {BACKGROUND: Alzheimer's disease (AD) is marked by the pathological features of amyloid-β plaque accumulation, as well as intracellular neurofibrillary tangles formation in the patients' brain. Aberrant lipid metabolism is increasingly recognized as one of the important contributors to AD.

PURPOSE: The main goal of this research was to conduct quantitative detection of targeted lipidomics in hippocampal tissue of APPSwe/PS1dE9 mice in order to identify lipid metabolic biomarkers of early-onset AD mice.

METHODS: Our approach departs from conventional lipid detection methods, employing a highly accurate quantificational Ultra High Performance Liquid Chromatography Tandem Mass Spectrometry (UHPLC-MS/MS) technique to analyze targeted lipid biomarkers. The innovative method was utilized to detect targeted lipids in the hippocampus of AD and wild-type mice. Statistical method was performed by Student's t-test and multivariate analysis. Differential metabolites were identified through fulfilling the standard of Variable Importance in Projection surpassing one and the significance probability lower than 0.05 thresholds.

RESULTS: Both groups utilized identical methodologies and adhered strictly to standardized treatment protocols. Sphingolipids (SPs), Glycerophospholipids (GPs), Glycolipids, Glycerides (GLs), Sterol Lipids (STs), and Free Fatty Acid (FA) were identified as prominent lipids exhibiting alterations in the hippocampus of AD models. Regarding glycolipid and glycerolipid composition, monogalactosyldiacylglycerols (MGDGs) and Triacylglycerols (TGs) constituted a significant proportion (p < 0.05, VIP > 1). Among glycerophospholipids, phosphatidylethanolamines (PEs) and phosphatidylcholines (PCs) emerged as significant constituents (p < 0.05, VIP > 1). Furthermore, hexosylceramides (HexCers) and ceramides (Cers) in the AD model's hippocampus, the prominent sphingolipids in the hippocampus of AD mice, existed as the two primary changed lipid metabolites. The levels of some TGs in GLs and CEs in STs showed a significant elevation (p < 0.05, VIP > 1). In contrast, most kinds of MGDGs, HexCers, Cers, PEs and FA (18:2) demonstrated a notable decrease in the hippocampus of AD group (p < 0.05, VIP > 1).

CONCLUSION: The present research represents the important quantitative identification of distinct lipid biomarker profiles within the hippocampal portion of 7.5-month-aged AD mice. It encompasses glycolipid, GLs, GPs, SPs, STs, and FAs using a targeted HPLC-MS method for quantification. These findings suggest potential diagnostic lipid biomarkers in hippocampus of early-onset AD mice related to cellular membrane integrity, atherosclerosis, oxidative stress damage, and inflammation.},
}

@article {pmid40692324,
year = {2025},
author = {Pereira da Silva, AM and Falcão, L and Virgilio, F and Rodrigues Menezes, I and Leite, M and Farias, E and Nascimento, M and Lee Han, M and Mota Telles, JP and de Souza Franco, E and de Sousa Maia, MB},
title = {Efficacy and APOE ε4-stratified risk of donanemab in Alzheimer's disease: A systematic review and meta-analysis of randomized clinical trials.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251361044},
doi = {10.1177/13872877251361044},
pmid = {40692324},
issn = {1875-8908},
abstract = {BackgroundDonanemab, a monoclonal antibody targeting amyloid-β (Aβ) plaques, has shown the ability to reduce cerebral amyloid burden in early Alzheimer's disease (AD). However, uncertainties remain regarding its clinical relevance, particularly in relation to tau pathology, APOE ε4 genotype, and methodological limitations in existing trials.ObjectiveTo conduct a systematic review and exploratory meta-analysis to evaluate the efficacy, safety, and tolerability of donanemab in patients with mild to moderate AD.MethodsWe conducted a systematic review and exploratory meta-analysis following PRISMA guidelines. Randomized controlled trials comparing donanemab to placebo in individuals aged ≥65 years with biomarker-confirmed mild to moderate AD were included. Outcomes included cognitive measures (ADAS-Cog13, MMSE, CDR-SB, iADRS, ADCS-iADL) and adverse events (ARIA-E, ARIA-H, infusion reactions, discontinuations). Random-effects models were used to estimate pooled mean difference (MD) or risk ratio (RR) with 95% confidence intervals. Subgroup analyses were performed by baseline tau burden and APOE ε4 genotype.ResultsThree trials (n = 2054) were included. Donanemab modestly reduced cognitive decline compared to placebo: ADAS-Cog13 (MD, -1.86), CDR-SB (MD, -0.36), MMSE (MD, 0.64), and iADRS (MD, 3.19), with similar effects across tau subgroups. The risk of ARIA-E was markedly increased (RR, 12.39), especially among APOE ε4 homozygotes. Infusion reactions (RR, 11.90) and discontinuations (RR, 3.22) were also more frequent.ConclusionsDonanemab demonstrated modest cognitive benefits, the clinical significance of which remains uncertain. Independent, longer-term trials with rigorous methodology and active comparators are warranted to more clearly define its therapeutic value in the treatment of AD.},
}

@article {pmid40692317,
year = {2025},
author = {Yin, M and Ding, S and Zhao, M and Liu, J and Su, W and Fu, M and Wu, M and Ma, C and Sun, X and Kong, Y},
title = {The global, regional, and national burden and attributable risk factors of Alzheimer's disease and other dementias, 1990-2021: A systematic analysis for the Global Burden of Disease Study.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251360221},
doi = {10.1177/13872877251360221},
pmid = {40692317},
issn = {1875-8908},
abstract = {BackgroundDementia is a syndrome characterized by a decline in cognitive function, with Alzheimer's disease (AD) being the most common type. Updated global statistics on the burden of AD and other dementias provide critical insights for guiding prevention and treatment strategies.ObjectiveTo estimate the global, regional, and national burden and attributable risk factors of AD and other dementias from 1990 to 2021.MethodsThis cross-sectional study utilized the 2021 Global Burden of Disease (GBD) dataset from 204 countries and territories. The analysis focused on individuals aged 40 years and older with AD and other dementias and included data on incidence, all-cause and cause-specific mortality, disability-adjusted life years (DALYs), and estimated annual percentage changes (EAPCs). These trends were stratified by region, country, age, sex, and Socio-Demographic Index (SDI).ResultsFrom 1990 to 2021, global DALYs attributable to AD and other dementias rose from 3.83 million to 9.84 million. Age-standardized rates (ASRs) of incidence and DALYs increased for both sexes, with a more pronounced rise in males. ASRs for incidence, prevalence, and DALYs were positively correlated with SDI. Smoking was identified as the primary risk factor for dementia burden among males, whereas obesity was the leading risk factor for females.ConclusionsThe global burden of AD and other dementias has significantly increased from 1990 to 2021, especially in high-SDI regions. While females have a higher overall risk, the burden has grown more rapidly in males. These findings highlight the need for targeted interventions to address aging populations and reduce dementia risk factors.},
}

@article {pmid40691719,
year = {2025},
author = {Rafii, MS and Aisen, PS},
title = {Amyloid-lowering immunotherapies for Alzheimer disease: current status and future directions.},
journal = {Nature reviews. Neurology},
volume = {},
number = {},
pages = {},
pmid = {40691719},
issn = {1759-4766},
abstract = {The treatment of Alzheimer disease (AD) has crossed a pivotal threshold, marked by the landmark approvals of the first-ever disease-modifying therapies. These immunotherapies, specifically monoclonal antibodies (mAbs) that target various amyloid-β (Aβ) species including proto-fibrillar and fibrillar forms, substantially lower levels of Aβ in the brain. The therapies have collectively demonstrated the ability to slow cognitive and clinical decline in large placebo-controlled trials, ushering a new era in the management of AD. Here, we review recent progress made in bringing amyloid-lowering mAb therapies to the clinic and explore future directions in this rapidly evolving field. We also delve into the current understanding of AD as a biological continuum, from its asymptomatic preclinical stage to its clinically overt dementia stage. We explore how this conceptualization provides a regulatory framework to evaluate amyloid-lowering mAbs across the entire spectrum of the disease. Additionally, we review key factors that affect the integration of these treatments into clinical practice.},
}

@article {pmid40691577,
year = {2025},
author = {Kim, HB and Yoo, S and Kwak, H and Ma, SX and Kim, R and Lee, M and Ha, N and Pyo, S and Kwon, SG and Cho, EH and Lee, SM and Jang, J and Kim, WK and Park, HC and Baek, M and Park, Y and Park, JY and Park, JW and Hwang, SW and Hwang, JI and Seong, JY},
title = {Inhibition of FAM19A5 reverses synaptic loss and cognitive decline in mouse models of Alzheimer's disease.},
journal = {Alzheimer's research & therapy},
volume = {17},
number = {1},
pages = {168},
pmid = {40691577},
issn = {1758-9193},
mesh = {Animals ; *Alzheimer Disease/metabolism/pathology/drug therapy ; Mice ; *Cognitive Dysfunction/metabolism/drug therapy ; *Synapses/drug effects/pathology/metabolism ; Disease Models, Animal ; Mice, Transgenic ; Hippocampus/metabolism/drug effects/pathology ; Humans ; Male ; Neurons/metabolism/drug effects ; Mice, Inbred C57BL ; Rats ; Excitatory Postsynaptic Potentials/drug effects ; },
abstract = {BACKGROUND: FAM19A5 is a secretory protein primarily expressed in neurons. Although its role in synaptic function has been suggested, the precise molecular mechanisms underlying its effects at the synapse remain unclear. Given that synaptic loss is a critical hallmark of Alzheimer's disease (AD), elucidating the mechanisms involving FAM19A5 could provide valuable insights into reversing synaptic loss in AD.

METHODS: The binding partner of FAM19A5 was identified through co-immunoprecipitation experiments of mouse brain tissue. The effect of FAM19A5 on spine density in hippocampal neurons was evaluated using immunocytochemistry by overexpressing FAM19A5, treating neurons with FAM19A5 protein, and/or an anti-FAM19A5 antibody NS101. Target engagement of NS101 was determined by measuring FAM19A5 levels in mouse, rat, and human plasma at specific time points post NS101 injection using ELISA. Changes in spine density and dynamics in P301S tauopathy mice were assessed via Golgi staining and two-photon microscopy after NS101 administration. The synaptic strengthening of hippocampal neurons in APP/PS1 amyloidopathy mice after NS101 treatment was assessed by measuring miniature excitatory postsynaptic currents (mEPSCs) and field excitatory postsynaptic potentials (fEPSPs). Cognitive performance in AD mice after NS101 treatment was measured using the Y-maze and Morris water maze tests.

RESULTS: FAM19A5 binds to LRRC4B, a postsynaptic adhesion molecule, leading to reductions in spine density in mouse hippocampal neurons. Inhibiting FAM19A5 function with NS101 increased spine density. Intravenous administration of NS101 increased spine density in the prefrontal cortex of P301S mice, which initially showed reduced spine density compared to wild-type (WT) mice. NS101 normalized the spine elimination rate in P301S mice, restoring the net spine count to levels comparable to WT mice. NS101 treatment enhanced the frequency of mEPSCs and fEPSPs in the hippocampal synapses of APP/PS1 mice, leading to improved cognitive function. The increases in plasma FAM19A5 levels upon systemic NS101 administration suggest that the antibody effectively engages its target and facilitates the transport of FAM19A5 from the brain.

CONCLUSIONS: This study demonstrated that inhibiting FAM19A5 function with an anti-FAM19A5 antibody restores synaptic integrity and enhances cognitive function in AD, suggesting a novel therapeutic strategy for AD.

TRIAL REGISTRATION: https://clinicaltrials.gov/study/NCT05143463 , Identifier: NCT05143463, Release date: 3 December 2021.},
}

Animals
*Alzheimer Disease/metabolism/pathology/drug therapy
Mice
*Cognitive Dysfunction/metabolism/drug therapy
*Synapses/drug effects/pathology/metabolism
Disease Models, Animal
Mice, Transgenic
Hippocampus/metabolism/drug effects/pathology
Humans
Male
Neurons/metabolism/drug effects
Mice, Inbred C57BL
Rats
Excitatory Postsynaptic Potentials/drug effects

@article {pmid40690192,
year = {2025},
author = {Jiang, S and Arnold, SE and Betensky, RA},
title = {Design and Analysis of N-Of-1 Trials That Incorporate Sequential Monitoring.},
journal = {Statistics in medicine},
volume = {44},
number = {15-17},
pages = {e70177},
doi = {10.1002/sim.70177},
pmid = {40690192},
issn = {1097-0258},
support = {P01AG036694/NH/NIH HHS/United States ; P30AG066512/NH/NIH HHS/United States ; R01NS094610/NH/NIH HHS/United States ; UL1 TR002345/NH/NIH HHS/United States ; },
mesh = {Humans ; Sample Size ; *Research Design ; *Randomized Controlled Trials as Topic/methods/statistics & numerical data ; Computer Simulation ; Cross-Over Studies ; Alzheimer Disease/drug therapy ; },
abstract = {For many diseases and disorders, such as Alzheimer's disease, patients demonstrate considerable heterogeneity in their responses to treatment interventions. One treatment may be most effective for some patients, while another may be most effective for others, and neither may be effective for another subset of patients. This potentially renders the conventional parallel group design highly inefficient. An attractive alternative is the N-of-1 design, also called the multi-crossover randomized controlled trial. In this design, each participant serves as their own control in a series of randomized blocks of treatment assignments. We propose novel designs for both the single-person and multi-person N-of-1 trials that employ sequential monitoring. In particular, we allow for early stopping for a single participant as soon as there is sufficient evidence of a preferred treatment for them, and early stopping for the group of participants as soon as there is sufficient evidence of a preferred treatment for the population of patients. We provide sample size calculations and decision rules for terminating the trial early and illustrate their properties in simulation studies. We apply our proposed methods to N-of-1 studies of brain tumor excisions and of methylphenidate in mild cognitive impairment.},
}

Humans
Sample Size
*Research Design
*Randomized Controlled Trials as Topic/methods/statistics & numerical data
Computer Simulation
Cross-Over Studies
Alzheimer Disease/drug therapy

@article {pmid40690160,
year = {2025},
author = {Sompol, P and Jicha, GA and Hinman, JD and Brickman, AM and Greenberg, SM and Arfanakis, K and Buckwalter, MS and Llorente, IL and Williamson, JD and Wolf, MS and Smith, EE and Gupta, A and Flanagan, ME and Vazquez, MA and Burns, JM and Carmichael, ST and Barone, FC},
title = {Advancing clinical trial readiness in white matter disease and related dementias: key steps for future research progress.},
journal = {GeroScience},
volume = {},
number = {},
pages = {},
pmid = {40690160},
issn = {2509-2723},
support = {R21AG074146/AG/NIA NIH HHS/United States ; },
abstract = {White matter disease, a broad-spectrum term that covers various types of white matter lesions and degeneration, is strongly related to age-related neurodegenerative disorders including Alzheimer's disease (AD), and vascular contributions to cognitive impairment and dementia (VCID) and Alzheimer's related dementias (ADRD). There is no specific treatment for white matter disease. Therefore, basic research and clinical studies are essential for future outcomes. Since its formation in 2020, the Albert Research Institute for White Matter and Cognition (ARIWMC) mission has been to support white matter research by providing a forum for communication where basic and clinical scientists meet to discuss and debate new knowledge and guidelines for studying white matter in dementia. The 4th annual ARIWMC workshop was held on May 31-June 2, 2023, where researchers met to set strategies for clinical trial readiness. Significant discussion by participants advocated research on multiple levels, including molecular, cellular, metabolic, behavioral, and risk factors that contribute to disease etiology and regeneration processes. Moreover, participants also addressed identifying and validating biomarkers and functional studies in animal models and human trials that are key steps for treatment development. Other areas that were discussed included epidemiological studies and pragmatic clinical trials where health care researchers and everyday medical practice support risk factor management or healthy lifestyle, and prevention trials could mitigate the incident of the disease. In summary, this workshop fostered a better understanding of how white matter lesions contribute to cognitive impairment from bench-to-biomarker-to-bedside-to-translational approaches which will facilitate and support the discovery and development of therapies and prevention strategies that facilitate a healthy brain and reduce white matter-related pathologies associated with and contributing to VCID and ADRD.},
}

@article {pmid40689211,
year = {2025},
author = {Yang, Z and Zhang, FR and Ren, L and Bai, JM and Wang, SC and Li, XY and Yang, HJ and Xiao, HH},
title = {Multi-omics reveal the neuroprotective mechanisms of Xinshubao tablet against scopolamine-induced cognitive dysfunction in mice.},
journal = {Frontiers in pharmacology},
volume = {16},
number = {},
pages = {1596728},
pmid = {40689211},
issn = {1663-9812},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is a progressive neurodegenerative disorder with limited treatments. Xinshubao tablet (XSB), a traditional Chinese medicine, contains several bioactive compounds with notable neuroprotective effects. Our previous studies have demonstrated that XSB can alleviate cognitive deficits in vascular dementia (VaD) models, suggesting its potential as a therapeutic candidate for AD.

METHODS: In this study, scopolamine-induced AD-like mice were orally administered with varying doses of XSB (0.13 g/kg, 0.26 g/kg and 0.52 g/kg) for 28 days. Behavior tests, H&E, Nissl, immunofluorescence staining, and Western blot assays were performed to evaluate the neuroprotection of XSB on AD-like mice. Then, fecal 16S rDNA sequencing, serum metabolomics, and hippocampal mRNA sequencing (mRNA-seq) analysis were performed to investigate the underlying mechanisms.

RESULTS AND DISCUSSION: The results revealed that oral administration of XSB improved cognitive function, mitigated neuropathological damage, and alleviated dysfunction in the cholinergic system in AD-like mice. XSB treatment also enhanced gut microbiota diversity, increased the abundance of Enterococcus, Actinobacteriota, Coriobacteriales, and Eggerthellaceae, but reduced the abundance of Helicobacter rodentium and Lachnospiraceae. Integrating mRNA-seq and metabolomics data highlighted key regulatory pathways including the biosynthesis of unsaturated fatty acids, tyrosine metabolism, and glycerophospholipid metabolism. Furthermore, XSB treatment reduced the expression of TNF-α, IL-1β, MPO, enhanced SOD, GSH activities, reduced malondialdehyde (MDA) levels, upregulated the expression of BDNF, SYN, PSD95, and improved synaptic density. Transformation of XSB derived fecal microbiota (XSB-FM) effectively alleviated cognitive dysfunction and intestinal barrier injures. In conclusion, XSB may exert its neuroprotective effects via the microbiota-metabolite-brain axis, thereby improving neuroinflammation, neurotransmission, and synaptic integrity. These findings support the potential of XSB as a multifactorial therapeutic strategy for cognitive deficits in AD.},
}

@article {pmid40689203,
year = {2025},
author = {Mi, X and Ruan, X and Lin, R and Huang, S and Cai, P and Chen, X and Liao, J and Dai, X},
title = {Intranasal administration of Ganoderma lucidum-derived exosome-like nanovesicles ameliorates cognitive impairment by reducing inflammation in a mouse model of Alzheimer's disease.},
journal = {Frontiers in pharmacology},
volume = {16},
number = {},
pages = {1572771},
pmid = {40689203},
issn = {1663-9812},
abstract = {BACKGROUND/OBJECTIVES: Although Alzheimer's disease (AD) is the most prevalent dementia in late life, with amyloid beta (Aβ) deposition and neuroinflammation are recognized among its primary pathological features. Currently, there is currently still a lack of effective therapeutic drugs for AD. Ganoderma lucidum (G. lucidum) is abundant in active ingredients that harbor anti-inflammatory properties in both central nervous system and the periphery. We attempted to determine whether G. lucidum contained exosome-like nanovesicles (GLENVs) and whether these GLENVs can alleviate cognitive impairment.

METHODS: We extracted GLENVs by the differential ultracentrifugation method and identified the components by liquid chromatography-mass spectrometry (LC-MS). The 5×FAD mice underwent a 3-month intranasal administration of GLENVs and their behavioral and pathological changes were evaluated.

RESULTS: GLENVs were successfully extracted and identified to contain multiple ganoderic acids; intranasal administration allowed GLENVs to penetrate the blood-brain barrier to exert their effects directly. The 3-month GLENVs treatment effectively ameliorated the impairment in the memory and learning of the 5×FAD mice. The GLENVs treatment also reduced Aβ deposition in the cortex and hippocampus of 5×FAD mice, overactivated microglia, reactive astrocytes, and pro-inflammatory factors, and inhibited the Janus kinase 2 (JAK2)/Signal transducer and activator of transcription 3 (STAT3) signaling pathway. Moreover, GLENVs exerted no adverse effects on liver and kidney function.

CONCLUSION: GLENVs may be a promising candidate for AD treatment.},
}

@article {pmid40688757,
year = {2025},
author = {Sur, TK and Mondal, T and Noreen, Z and Johnson, J and Nunlee-Bland, G and Loffredo, CA and Korba, BE and Chandra, V and Jana, SS and Kwabi-Addo, B and Sarkar, S and Ghosh, S},
title = {Developing non-invasive molecular markers for early risk assessment of Alzheimer's disease.},
journal = {Biomarkers in neuropsychiatry},
volume = {12},
number = {},
pages = {},
pmid = {40688757},
issn = {2666-1446},
abstract = {Alzheimer's disease (AD) is a heterogeneous neurodegenerative disease, with no standard biomarker(s) to detect or confirm its risk at an early stage. The prevalence of AD increases exponentially worldwide in people of ages over 65 and older. Current improvements have unveiled the disease's pathophysiology and clinical diagnostic tests, targeting the neurological changes (neurodegeneration, amyloid precursor protein metabolism and tangle pathology) with precise PET/MRI imaging and xMAP/SIMOA (Multiplex simultaneous detection/single molecule array) to identify and quantify β-amyloids (Aβ40, Aβ42), total tau (T-tau) and phosphorylated tau (P-tau) proteins in the brain and cerebrospinal fluid (CSF) of patients. However, their utility for diagnosis in routine clinical practice is still challenging because of cost, accessibility, standardization, procedural limitation, and regulatory approval. Further research is needed to establish affordable, patient-friendly, easy, quick, and robust biomarkers for early AD detection, progression, and therapeutic management. Research on blood-based preclinical diagnosis and clinical practice for AD has advanced significantly in the last decade. Emerging literature supports the importance of new molecular biomarkers and signature genes from blood to detect and predict AD in advance. This review examines the potential applications of these blood-based target biomarkers for early disease detection, co-morbid condition risk prediction, and treatment management of AD.},
}

@article {pmid40688669,
year = {2025},
author = {Zhu, RK and Shi, J and Zhou, HJ and Ge, L and Yin, WH and Zeng, H and Wang, XW},
title = {Biological applications of graphene-based nanomaterials in neurodegenerative diseases.},
journal = {Materials today. Bio},
volume = {33},
number = {},
pages = {102064},
pmid = {40688669},
issn = {2590-0064},
abstract = {Neurodegenerative diseases (NDDs) have become a major challenge in global public health due to neurotoxicity caused by progressive neuronal degeneration and abnormal protein aggregation, which has attracted widespread attention. Graphene-based nanomaterials provide innovative solutions for the early diagnosis and precise treatment of NDDs by virtue of their ultra-high conductivity, large specific surface area and multifunctional properties. In this paper, we systematically discuss the key applications of these materials in the diagnosis and treatment of NDDs, and deeply analyze the technological breakthroughs and clinical translation challenges. The core of this paper is to illustrate that graphene-based nanomaterials are expected to reshape the paradigm of NDDs diagnosis and treatment through cross-scale technological innovations, promoting the synergistic development of early diagnosis, personalized treatment and real-time monitoring, and providing a transformative strategy for overcoming NDDs.},
}

@article {pmid40688579,
year = {2025},
author = {Zhang, G and Zhao, W and Lv, S and Wang, Z and Yi, Y and Ma, H and Lu, Y and Yan, W and Teng, J},
title = {Emerging trends in Alzheimer's disease diagnosis and prediction using artificial intelligence: A bibliometric analysis of the top cited 100 articles.},
journal = {Digital health},
volume = {11},
number = {},
pages = {20552076251362098},
pmid = {40688579},
issn = {2055-2076},
abstract = {BACKGROUND: AD is a significant public health challenge, and AI technologies, including deep learning and machine learning, offer the potential to dramatically improve diagnostic and predictive accuracy. These technologies are widely applied in AD research. However, comprehensive literature summaries of this field remain limited. This study uses bibliometric analysis to examine research hotspots, trends, future development potential, and limitations in AI-based AD diagnosis and prediction.

METHODS: We conducted a bibliometric analysis of 100 top cited studies on AI-based diagnosis and prediction of AD, using data from the WoSCC. We performed the analysis using CiteSpace 6.3.R2, VOSviewer 1.6.19, Scimago Graphica 1.0.39, Microsoft Excel 2021, and R package Bibliometrix running in RStudio, visualizing the results through graphical representations.

RESULTS: It was found that the top cited 100 articles came from 51 journals and 31 countries. The journal with both the highest number of published articles and the greatest citation frequency was NEUROIMAGE, while PROTEIN ENGINEERING DESIGN & SELECTION boasted the highest average citation rate. The country with the largest volume of published articles was the United States, followed by China and the United Kingdom. In terms of institutions, the University of North Carolina had produced the most publications. The keywords identified fall into 9 categories. The most frequently occurring keywords are "Alzheimers disease", "mild cognitive impairment", "classification", "MRI", "deep learning", "diagnosis", "dementia", "biomarkers", "brain atrophy", "machine learning", "voxel based morphometry", "prediction", and "patterns".

CONCLUSION: AI-based technologies for AD diagnosis and prediction are becoming indispensable clinical tools. Future research should leverage AI to identify novel AD biomarkers, enabling precision diagnosis and treatment. However, our bibliometric analysis has limitations: language and citation biases may skew interpretation of emerging AI-AD trends.},
}

@article {pmid40688402,
year = {2025},
author = {Espinoza, C and Salinas, M and Morocho, A and Morales, A and Verdezoto, B},
title = {Mortality from Alzheimer's Disease and Other Dementias in Ecuador during the Period 2012-2022.},
journal = {Clinical practice and epidemiology in mental health : CP & EMH},
volume = {21},
number = {},
pages = {e17450179376076},
pmid = {40688402},
issn = {1745-0179},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is a growing concern worldwide in healthcare. In Ecuador, the increasing life expectancy has raised the prevalence of age-related diseases, including dementias. The main objective of this study was to analyze the mortality from AD and other dementias in Ecuador from 2012 to 2022.

METHODOLOGY: A retrospective, descriptive time series analysis was conducted on adult subjects with AD and other dementias across various geographic regions of Ecuador during the 2012-2022 period. A sample of 855,122 individuals registered in the databases of the National Institute of Statistics and Censuses (INEC) was analyzed.

RESULTS: Out of the total evaluated subjects, 4,836 deaths were due to AD (0.56%) and 1,317 deaths from other types of dementia (0.15%). For AD, the distribution of deaths by sex showed a predominant trend in women (n=3,008) within the group aged 65 years or older (n=4,749). For other dementias, women were also the main group (n=766), along with those aged 65 years and older (n=1,294). The national mortality rate showed an upward trend during this decade, increasing from 2.2 per 100,000 inhabitants in 2012 to 4.86 per 100,000 inhabitants in 2022.

DISCUSSION: This study reveals a worrying increase in mortality from Alzheimer's disease (AD) and other dementias in Ecuador between 2012 and 2022, especially among women, adults over 65 years of age, and residents of the Sierra region. Several factors that could negatively influence cognitive function were observed. These findings are consistent with global trends and suggest that biological, environmental, and social variables, such as aging, postmenopausal hormonal changes, chronic exposure to hypoxic altitude conditions, and unequal access to health services, could play a key role in this disease.

CONCLUSION: Mortality from Alzheimer's disease and other dementias in Ecuador showed a sustained increase between 2012 and 2022, reflecting a growing burden of these pathologies in the population and the urgent need to strengthen prevention, early diagnosis, and comprehensive treatment strategies. The disproportionate impact on women, adults over 65 years of age, and residents of the Sierra region suggests the involvement of various biological, environmental, and social determinants of health, which requires more rigorous surveillance and a differentiated approach for these particularly vulnerable populations.},
}

@article {pmid40687177,
year = {2025},
author = {Zhang, Y and Lv, Y and Yang, T and Liu, Q and Guo, Q},
title = {Insulin resistance and Alzheimer's disease: Exploring research hotspots and frontiers from a bibliometric and visual analysis (2005-2024).},
journal = {Journal of Alzheimer's disease reports},
volume = {9},
number = {},
pages = {25424823251361056},
pmid = {40687177},
issn = {2542-4823},
abstract = {BACKGROUND: Alzheimer's disease (AD) and insulin resistance (IR) share intersecting pathological pathways, with IR increasingly implicated in AD pathogenesis. Systematic bibliometric analyses mapping the evolution of this interdisciplinary field remain limited.

OBJECTIVE: To quantify global research trends, collaboration networks, knowledge structures, and emerging frontiers in IR-AD research from 2005-2024.

METHODS: We analyzed 2676 publications from the Web of Science Core Collection. Using VOSviewer, CiteSpace, and bibliometrix R package, we conducted quantitative analyses and visualized multiple dimensions including annual publications/citations, countries/regions, institutions, journals, authors, references, and keywords.

RESULTS: Annual publications grew steadily, peaking at 267 in 2022. The United States dominated productivity (942 papers, 35.2%) and citations (88,170). The University of Kentucky was the top institution (53 papers), while the Journal of Alzheimer's Disease led in output (214 papers) and co-citations (8046). Keyword analysis revealed three clusters: metabolic dysregulation, molecular pathology, and neuroimmune responses. Emerging frontiers highlight neuroimmune mechanisms, with current hotspots focusing on NLRP3 inflammasome activation, gut-brain axis dysregulation, glucose transporter impairment, and therapeutic repurposing of GLP-1 agonists.

CONCLUSIONS: These findings underscore IR-AD as a critical intersection of metabolic and neurodegenerative pathways, advocating for targeted therapies addressing neuroinflammation and cerebral metabolism. By delineating global trends, this study provides a roadmap for future research to bridge translational gaps in AD pathogenesis and treatment.},
}

@article {pmid40686359,
year = {2025},
author = {Ashwin, JV and Shahi, MK and Singh, A and Kumar, ST},
title = {Efficacy and safety of dextromethorphan-bupropion combination (AXS-05) in the treatment of depression: A systematic review and network meta-analysis.},
journal = {Indian journal of pharmacology},
volume = {57},
number = {4},
pages = {262-268},
doi = {10.4103/ijp.ijp_907_24},
pmid = {40686359},
issn = {1998-3751},
mesh = {*Dextromethorphan/adverse effects/therapeutic use/administration & dosage ; Humans ; *Bupropion/adverse effects/therapeutic use/administration & dosage ; Network Meta-Analysis as Topic ; *Depressive Disorder, Major/drug therapy ; Drug Combinations ; Randomized Controlled Trials as Topic ; Treatment Outcome ; Adult ; },
abstract = {This network meta-analysis evaluated the efficacy and safety of the dextromethorphan-bupropion combination (AXS-05) in treating major depressive disorder (MDD). Data were retrieved from multiple databases, including PubMed, Embase, Scopus, Google Scholar, and ClinicalKey, yielding 60 records. After removing duplicates and excluding irrelevant studies, such as reviews, case reports, posters, and studies focusing on unrelated populations (e.g., Alzheimer's dementia), two randomized controlled trials (RCTs) - Tabuteau et al. (2022) and Iosifescu et al. (2022) - were selected for final analysis. The inclusion criteria focused on RCTs published between 2014 and 2024, involving adult participants (18-65 years) diagnosed with MDD, and reporting on the efficacy and safety of the dextromethorphan-bupropion combination. Studies that did not focus on MDD, were not in English, or lacked control groups were excluded. The findings indicate superior efficacy of the dextromethorphan-bupropion combination, with remission rates of 46.5% and 39.5%, compared to 16.2% for Bupropion alone and 17.3% for placebo. Despite a higher incidence of mild to moderate adverse events (72.9% vs. 64.6% for Bupropion), the combination's safety profile remained comparable, with no significant increase in treatment discontinuation. These results suggest that AXS-05 is a promising treatment for MDD, warranting further investigation in larger, diverse populations to confirm its long-term efficacy and safety.},
}

*Dextromethorphan/adverse effects/therapeutic use/administration & dosage
Humans
*Bupropion/adverse effects/therapeutic use/administration & dosage
Network Meta-Analysis as Topic
*Depressive Disorder, Major/drug therapy
Drug Combinations
Randomized Controlled Trials as Topic
Treatment Outcome
Adult

@article {pmid40686118,
year = {2025},
author = {Chen, SL and Wang, ZC and Chen, GZ and Zheng, HB and Huang, SE},
title = {[Causal effects of chronic kidney disease on Alzheimer's disease and its prevention based on "kidney-brain interaction" theory].},
journal = {Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica},
volume = {50},
number = {12},
pages = {3431-3440},
doi = {10.19540/j.cnki.cjcmm.20250306.501},
pmid = {40686118},
issn = {1001-5302},
mesh = {Humans ; *Alzheimer Disease/prevention & control/etiology/genetics ; *Renal Insufficiency, Chronic/complications/genetics ; *Kidney/physiopathology/metabolism ; *Brain/metabolism/physiopathology ; Genome-Wide Association Study ; Medicine, Chinese Traditional ; Mendelian Randomization Analysis ; },
abstract = {Based on the traditional Chinese medicine(TCM) theory of "kidney-brain interaction", a two-sample Mendelian randomization(MR) analysis was conducted to investigate the causal effects of chronic kidney disease(CKD) on Alzheimer's disease(AD) and analyze the potential mechanisms of kidney-tonifying and essence-replenishing TCM to improve AD. From the perspective that CKD is closely related to the core pathogenesis of AD, namely "kidney deficiency, essence loss, and marrow reduction", genome-wide association study(GWAS) data was used, with the inverse variance weighting(IVW) method as the main approach to reveal the causal association between CKD and AD. Sensitivity analysis was conducted to evaluate the robustness of the results. To further investigate the causal effects of CKD on AD, two different AD datasets were used as outcomes, and the urinary albumin-to-creatinine ratio(UACR) data was used as the exposure for a supplementary analysis. On this basis, the modern scientific mechanism of the kidney-tonifying and essence-replenishing method for improving AD was further explored. The IVW analysis show that CKD(ieu-b-2: OR=1.084, 95%CI[1.011, 1.163], P=0.024; ieu-b-5067: OR=1.001, 95%CI[1.000, 1.001], P=0.002) and UACR(ieu-b-2: OR=1.247, 95%CI[1.021, 1.522], P=0.031; ieu-b-5067: OR=1.001, 95%CI[1.000, 1.003], P=0.015) both have significant causal effects on AD in different datasets, with CKD increasing the risk of AD. The sensitivity analysis further confirmed the reliability of the results. Genetic studies have shown that CKD has a significant causal effect on AD, suggesting that controlling CKD is an important intervention measure for preventing and treating AD. Therefore, further research on CKD's role in AD is crucial in clinical practice. The research enriches the theoretical implication of "kidney-brain interaction", deepens the understanding of AD' etiology, and provides further insights and directions for the prevention and treatment of AD with TCM, specifically from a kidney-based perspective.},
}

Humans
*Alzheimer Disease/prevention & control/etiology/genetics
*Renal Insufficiency, Chronic/complications/genetics
*Kidney/physiopathology/metabolism
*Brain/metabolism/physiopathology
Genome-Wide Association Study
Medicine, Chinese Traditional
Mendelian Randomization Analysis

@article {pmid40685770,
year = {2025},
author = {Farooq, U and Islam, M and Batool, Z and Mali, SN and Jawarkar, RD and Gurav, SS and Alharthy, RD and Şenol, H and Sadeghian, N and Taslimi, P and Shafiq, Z and Schenone, S},
title = {Design, Synthesis, In Vitro, and In Silico Studies of 5-(Diethylamino)-2-Formylphenyl Naphthalene-2-Sulfonate Based Thiosemicarbazones as Potent Anti-Alzheimer Agents.},
journal = {Archiv der Pharmazie},
volume = {358},
number = {7},
pages = {e70050},
doi = {10.1002/ardp.70050},
pmid = {40685770},
issn = {1521-4184},
support = {//This Project was funded by the Deanship of Scientific Research (DSR) at King Abdulaziz University, Jeddah, under grant no. GPIP: 46-665-2024./ ; },
mesh = {*Cholinesterase Inhibitors/chemical synthesis/pharmacology/chemistry ; Structure-Activity Relationship ; *Alzheimer Disease/drug therapy/enzymology ; *Thiosemicarbazones/chemical synthesis/pharmacology/chemistry ; *Drug Design ; *Monoamine Oxidase Inhibitors/chemical synthesis/pharmacology/chemistry ; Humans ; Molecular Structure ; Monoamine Oxidase/metabolism ; Molecular Docking Simulation ; Dose-Response Relationship, Drug ; Acetylcholinesterase/metabolism ; Computer Simulation ; Butyrylcholinesterase/metabolism ; },
abstract = {Alzheimer's disease (AD) is known as one of the more devastating neurodegenerative diseases diagnosed in older people. Cholinesterase inhibitors (ChEI) can be used as an effective palliative treatment for AD. An extensive range of new biologically active 4-(diethylamino) salicylaldehyde-based thiosemicarbazone derivatives 5(a-u) was synthesized and evaluated as inhibitors of cholinesterase (ChE) and monoamine oxidase (MAO) enzymes. 2,3-Dichloro-substituted compound 5u was the most potent inhibitor of AChE and MAO-A with IC50 values of 12.89 and 96.25 nM, respectively. In contrast, the 2,3-dichlorophenyl-substituted compound 5a was the most powerful inhibitor of BChE, with an IC50 value of 124.72 nM. Structure-activity analysis revealed that the electron-withdrawing substituents on the phenyl ring play a crucial role in the inhibition potential of synthesized compounds. Compound 5a showed the strongest binding with 4BDS (-11.3 kcal/mol) via hydrogen bonds and π-interactions. Compound 5u exhibited high affinity with 1B41 (-8.2 kcal/mol), 2Z5X (-8.6 kcal/mol), and 2V5Z (-7.8 kcal/mol), forming key hydrogen bonds, salt bridges, and π-interactions, highlighting its multi-target potential. In silico ADME, pharmacokinetics, and drug-likeness studies were conducted and compared with the standard drugs galantamine and clorgyline.},
}

*Cholinesterase Inhibitors/chemical synthesis/pharmacology/chemistry
Structure-Activity Relationship
*Alzheimer Disease/drug therapy/enzymology
*Thiosemicarbazones/chemical synthesis/pharmacology/chemistry
*Drug Design
*Monoamine Oxidase Inhibitors/chemical synthesis/pharmacology/chemistry
Humans
Molecular Structure
Monoamine Oxidase/metabolism
Molecular Docking Simulation
Dose-Response Relationship, Drug
Acetylcholinesterase/metabolism
Computer Simulation
Butyrylcholinesterase/metabolism

@article {pmid40685632,
year = {2025},
author = {Huang, Y and Xu, T and Wang, L and Xiang, R and Zhou, M and Yu, H and Liu, D and Chen, Z},
title = {Application of machine learning reveals diagnostic biomarkers related to pyroptosis in Alzheimer's disease and analysis of immune infiltration.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251360033},
doi = {10.1177/13872877251360033},
pmid = {40685632},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease (AD) is characterized by complex pathological mechanisms, with pyroptosis potentially contributing to neuroinflammation.ObjectiveTo identify pyroptosis-related genes (PRGs) in AD and explore their role in neuroinflammation, aiming to provide potential biomarkers and therapeutic targets for precision medicine in AD treatment.MethodsTranscriptomic data from AD brain tissues (GEO database) were analyzed using multi-omics integration and machine learning. Key PRGs were screened via weighted gene co-expression network analysis (WGCNA), LASSO regression, random forest, and SVM-RFE algorithms. Molecular subtypes and therapeutic potential were assessed through unsupervised clustering and molecular docking.ResultsAnalysis identified 609 differentially expressed genes (DEGs), with upregulated genes enriched in DNA transcription and mitosis-related pathways. Six core PRGs (MIB1, TUG1, GATA1, CA1, CFH, IL17A) demonstrated strong diagnostic accuracy (AUC > 0.85). Unsupervised clustering revealed two AD subtypes: a high-risk subtype with activated pyroptosis-inflammatory pathways and distinct immune microenvironment features (p < 0.05). Molecular docking confirmed stable binding between CFH and the anti-AD drug candidate fludrocortisone (binding energy < -7 kcal/mol).ConclusionsPyroptosis modulates neuroinflammation to drive AD progression. CFH and other PRGs serve as promising biomarkers and therapeutic targets, advancing precision strategies for AD subtyping and intervention.},
}

@article {pmid40685475,
year = {2025},
author = {Shin, S and Kim, M and Hong, SH},
title = {Economic Evaluation of Lecanemab for Early Symptomatic Alzheimer's Disease in South Korea.},
journal = {PharmacoEconomics - open},
volume = {},
number = {},
pages = {},
pmid = {40685475},
issn = {2509-4254},
support = {2023//Health Fellowship Foundation/ ; },
abstract = {BACKGROUND/OBJECTIVES: Alzheimer's disease (AD) exerts a considerable economic burden on South Korea's aging population. Lecanemab, an amyloid-targeting therapy, has demonstrated efficacy in mitigating cognitive decline in early-stage AD but remains non-reimbursed in South Korea due to concerns over its economic feasibility. This study aimed to examine the cost-effectiveness of lecanemab using nationwide claims data for cost estimation within the South Korean healthcare system. Considering the substantial societal burden of AD, we also evaluated the cost-effectiveness of lecanemab from a limited societal perspective.

METHODS: A Markov state transition cohort model was developed to compare costs and outcomes of lecanemab combined with standard of care (SoC) versus SoC alone. The model simulated five stages of AD progression: mild cognitive impairment, mild AD, moderate AD, severe AD, and death. Transition probabilities between health states were derived from data provided by the National Alzheimer's Coordinating Center. Formal medical costs and long-term care costs were obtained from the national claims database, while drug cost and other medical expenses were derived from previous studies. Additional cost components such as opportunity cost of caregiver time, out-of-pocket expenses, and time and travel costs for hospital visits were included in the limited societal perspective. Korean-specific utilities for patients and caregivers differentiated by states of AD progression and care settings were obtained from the published literature. Effectiveness was measured in quality-adjusted life years (QALYs) over a lifetime horizon. Scenario analyses were conducted by varying compositions of the cohort, age of onset, and drug pricing.

RESULTS: The incremental cost-effectiveness ratio (ICER) of lecanemab combined with SoC was 198,171,820 Korean Won (KRW)/QALY from the healthcare payer perspective and 181,185,820 KRW/QALY from the limited societal perspective, which significantly exceeded South Korea's willingness-to-pay (WTP) threshold of 30 million KRW/QALY. Sensitivity analyses revealed that the ICER was highly influenced by variations in treatment effect and discount rates. The result of scenario analyses suggested that targeting lecanemab to patients with mild AD or implementing price reductions could substantially improve its cost-effectiveness.

CONCLUSIONS: Lecanemab's high cost poses a challenge to its inclusion in the National Health Insurance formulary under South Korea's current WTP thresholds. Strategic price adjustments and patient targeting are essential to enhance its economic viability. These findings provide valuable insights for policymakers and stakeholders in balancing treatment outcomes and resource allocation for AD management.},
}

@article {pmid40685330,
year = {2025},
author = {Far, BF and Akbari, M and Habibi, MA and Katavand, M and Nasseri, S},
title = {CRISPR Technology in Disease Management: An Updated Review of Clinical Translation and Therapeutic Potential.},
journal = {Cell proliferation},
volume = {},
number = {},
pages = {e70099},
doi = {10.1111/cpr.70099},
pmid = {40685330},
issn = {1365-2184},
abstract = {CRISPR-Cas9 technology has rapidly advanced as a transformative genome-editing platform, facilitating precise genetic modifications and expanding therapeutic opportunities across various diseases. This review explores recent developments and clinical translations of CRISPR applications in oncology, genetic and neurological disorders, infectious diseases, immunotherapy, diagnostics, and epigenome editing. CRISPR has notably progressed in oncology, where it enables the identification of novel cancer drivers, elucidation of resistance mechanisms, and improvement of immunotherapies through engineered T cells, including PD-1 knockout CAR-T cells. Clinical trials employing CRISPR-edited cells are demonstrating promising results in hematologic malignancies and solid tumours. In genetic disorders, such as hemoglobinopathies and muscular dystrophies, CRISPR-Cas9 alongside advanced editors like base and prime editors show significant potential for correcting pathogenic mutations. This potential was affirmed with the FDA's first approval of a CRISPR-based therapy, Casgevy, for sickle cell disease in 2023. Neurological disorders, including Alzheimer's, ALS, and Huntington's disease, are increasingly targeted by CRISPR approaches for disease modelling and potential therapeutic intervention. In infectious diseases, CRISPR-based diagnostics such as SHERLOCK and DETECTR provide rapid, sensitive nucleic acid detection, particularly valuable in pathogen outbreaks like SARS-CoV-2. Therapeutically, CRISPR systems target viral and bacterial genomes, offering novel treatment modalities. Additionally, CRISPR-mediated epigenome editing enables precise regulation of gene expression, expanding therapeutic possibilities. Despite these advances, significant challenges remain, including off-target effects, delivery methodologies, immune responses, and long-term genomic safety concerns. Future improvements in editor precision, innovative delivery platforms, and enhanced safety assessments will be essential to fully integrate CRISPR-based interventions into standard clinical practice, significantly advancing personalised medicine.},
}

@article {pmid40685037,
year = {2025},
author = {Wang, T and Gao, C and Dong, X and Li, L},
title = {Therapeutic potential of traditional chinese medicine polysaccharides in alzheimer's disease via modulation of gut microbiota: A review.},
journal = {International journal of biological macromolecules},
volume = {},
number = {},
pages = {146160},
doi = {10.1016/j.ijbiomac.2025.146160},
pmid = {40685037},
issn = {1879-0003},
abstract = {Alzheimer's disease (AD) is a chronic and progressively deteriorating neurodegenerative condition characterized by a strong association with gut microbiome imbalances. It is estimated that by 2025, there will be 35 million patients worldwide, imposing a substantial burden on society. Currently, AD treatments predominantly rely on single-target approaches aimed at alleviating symptoms, which exhibit limited efficacy and fail to influence disease progression. Consequently, there is an urgent need to investigate novel therapeutic strategies to enhance treatment outcomes. Polysaccharides derived from traditional Chinese medicine (TCMPs) are renowned for their capacity to target multiple pathways and function as potent natural immune regulators, delivering comprehensive treatment effects. TCMPs possess prebiotic properties and can be fermented by the intestinal flora, promoting the proliferation of beneficial bacteria, inhibiting pathogens, and exerting anti-inflammatory, antioxidant, and Aβ-deposition inhibitory effects within the intestine. This article provides a systematic review of the interplay between gut microbiota, AD, and TCMPs, showcasing specific TCMP examples that demonstrate significant anti-AD effects mediated through gut flora modulation. The aim is to deepen understanding of TCMPs' role in AD therapy involving gut microbiota and to propose innovative strategies for optimizing AD treatment.},
}

@article {pmid40684900,
year = {2025},
author = {Liu, Q and Siadat, SD},
title = {MicroRNA-155 in neurodegeneration.},
journal = {Clinica chimica acta; international journal of clinical chemistry},
volume = {},
number = {},
pages = {120506},
doi = {10.1016/j.cca.2025.120506},
pmid = {40684900},
issn = {1873-3492},
abstract = {MicroRNA-155 (miR-155) is recognized for its multifaceted roles in neuroinflammation and neurodegeneration. This abstract explores the emerging significance of miR-155, both as an intracellular regulator and encapsulated within exosomes, as a biomarker and therapeutic target in neurodegenerative disorders. Dysregulation of miR-155 is implicated in various conditions, including Alzheimer's disease, Parkinson's disease, and multiple sclerosis, where it modulates key pathways involved in neuronal survival, synaptic plasticity, and immune cell activation. Specifically, miR-155 has been shown to influence microglial activation, cytokine production, and the clearance of protein aggregates, all critical processes in neurodegenerative pathogenesis. Exosomal miR-155, released by various cell types including immune cells and neurons, offers a particularly exciting avenue. These nanovesicles facilitate intercellular communication, delivering their cargo, including miR-155, to recipient cells and influencing their function. As such, exosomal miR-155 levels in biofluids like cerebrospinal fluid and blood are being investigated as potential non-invasive diagnostic and prognostic biomarkers for neurodegenerative diseases. Furthermore, the ability of exosomes to cross the blood-brain barrier makes them attractive vehicles for targeted delivery of therapeutic agents. This review highlights the dual promise of miR-155 and exosomal miR-155: first, as readily measurable indicators of disease progression and response to treatment, and second, as actionable targets for novel therapeutic strategies aimed at modulating neuroinflammation and protecting neuronal integrity.},
}

@article {pmid40684705,
year = {2025},
author = {Yu, J and Ma, D and Li, S and Yang, S and Li, T and Kong, L and Liu, Y and Zang, J and Yu, Y and Li, X},
title = {Construction of ROS-responsive cascade-targeted liposomes and investigation of their anti-AD effects.},
journal = {International immunopharmacology},
volume = {163},
number = {},
pages = {115234},
doi = {10.1016/j.intimp.2025.115234},
pmid = {40684705},
issn = {1878-1705},
abstract = {Oxidative stress is considered a critical factor in the pathogenesis of Alzheimer's disease (AD). The interaction between oxidative stress and neuroinflammation is closely associated with the production of beta-amyloid (Aβ). Although many drugs exhibit potent anti-inflammatory and antioxidant properties, their poor water solubility and limited ability to penetrate the blood-brain barrier (BBB) often result in reduced efficacy, making accurate AD treatment challenging. Previous studies have shown that borneol (Bor) can enhance BBB permeability, while the MG1 peptide can specifically target M1-type microglial cells. In this study, we constructed reactive oxygen species (ROS)-responsive cascade-targeting liposomes (ROS@Res-Lip) using DSPE-PEG2000-MG1 and DSPE-TK-PEG2000-Bor co-modification. This design aimed to reduce ROS accumulation and enhance BBB penetration by incorporating ROS-responsive thioketal (TK) bonds and Bor, while leveraging the MG1 peptide to improve the targeting of resveratrol (Res) to M1-type microglia. As a result, the drug concentration in the brain was significantly increased, thereby improving therapeutic efficacy. Our findings demonstrate that ROS@Res-Lip can achieve anti-inflammatory, antioxidant, and neuroprotective effects by targeting M1-type microglia and promoting the conversion of M1-type microglia to M2-type microglia.},
}

@article {pmid40684632,
year = {2025},
author = {Li, M and Li, C and He, M and Chen, L and Wang, Q},
title = {Neurotoxic effects of Cis-bifenthrin on microbe-gut-brain axis: Disruption of neurolipid balance in Xenopus laevis.},
journal = {Ecotoxicology and environmental safety},
volume = {302},
number = {},
pages = {118675},
doi = {10.1016/j.ecoenv.2025.118675},
pmid = {40684632},
issn = {1090-2414},
abstract = {The neurotoxic effects of cis-bifenthrin (cis-BF) on amphibians and its molecular mechanisms are unclear despite its common presence in aquatic environments. In present study, female Xenopus laevis were subjected to a three-month treatment with environmentally relevant concentrations of 60 and 300 ng/L cis-BF. Metabolomic analysis of brain tissue revealed differential metabolites enriching bile acid (BA) synthesis, impacting β-amyloid protein deposition. Reduced polyunsaturated fatty acids (PUFAs), essential for membrane integrity, were observed. Elevated amyloid β-protein and lipopolysaccharide (LPS) levels suggested potential Alzheimer's-like symptoms induced by cis-BF. Given PUFAs and BAs are processed via enterohepatic circulation, a notable decrease in the abundance of genera linked to PUFAs and BAs metabolism was observed. Gut metabolomics revealed decreased concentrations of PUFAs and secondary BAs across cis-BF treatment groups, attributed to changes in associated microbial communities. Cis-BF exposure raised intestinal LPS levels and plasma proinflammatory cytokines, resulting in intestinal damage. This facilitated the entry of LPS into the bloodstream and brain tissue, indicating a cytokine-LPS interaction that promotes LPS transit to the brain through the bloodstream. Our study suggests that cis-BF-induced alterations in gut microbiota and metabolism may trigger Alzheimer's-related neurological disorders in Xenopus laevis via the gut-brain axis by inducing neurolipid disorder and inflammation.},
}

@article {pmid40684252,
year = {2025},
author = {Idris, M and Saini, F and Ivain, P and Baksh, RA and Bianchi, LA and Pape, SE and Zetterberg, H and Wijeratne, PA and Strydom, A},
title = {Staging of Alzheimer's disease progression in Down syndrome using mixed clinical and plasma biomarker measures with machine learning.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {7},
pages = {e70446},
doi = {10.1002/alz.70446},
pmid = {40684252},
issn = {1552-5279},
support = {MR/S011277/1/MRC_/Medical Research Council/United Kingdom ; MR/S005145/1/MRC_/Medical Research Council/United Kingdom ; MR/R024901/1/MRC_/Medical Research Council/United Kingdom ; 098330/Z/12/Z//Wellcome Trust Strategic Award/ ; //Baily Thomas Charitable Fund/ ; //Fondation Jérôme Lejeune/ ; AS-CP-18-0020//Alzheimer's Society/ ; 2023-00356//Swedish Research Council/ ; 101053962//Swedish Research Council/ ; 2022-01018//Swedish Research Council/ ; 2019-02397//Swedish Research Council/ ; ALFGBG-71320//Swedish State Support for Clinical Research/ ; 201809-2016862//Alzheimer's Drug Discovery Foundation/ ; //AD Strategic Fund/ ; ADSF-21-831376-C/ALZ/Alzheimer's Association/United States ; ADSF-21-831381-C/ALZ/Alzheimer's Association/United States ; ADSF-21-831377-C/ALZ/Alzheimer's Association/United States ; ADSF-24-1284328-C/ALZ/Alzheimer's Association/United States ; //European Partnership on Metrology/ ; 22HLT07//European Union's Horizon Europe Research and Innovation Programme/ ; //The Bluefield Project/ ; //Cure Alzheimer's Fund/ ; //Erling-Persson Family Foundation, Familjen Rönströms Stiftelse/ ; //Stiftelsen för Gamla Tjänarinnor/ ; FO2022-0270//Hjärnfonden/ ; 860197//Marie Skłodowska-Curie/ ; UKDRI-1003//UK Dementia Research Institute/ ; //Olav Thon Stiftelsen/ ; //UCLH Biomedical Research Centre/ ; JPND2021-00694//EU Joint Programme - Neurodegenerative Disease Research/ ; //H2020 Marie Skłodowska-Curie/ ; 101053962//HORIZON EUROPE European Research Council/ ; 2023-00356//Vetenskapsrådet/ ; 101053962//Vetenskapsrådet/ ; 2023-00356//Vetenskapsrådet/ ; 2022-01018//Vetenskapsrådet/ ; 2019-02397//Vetenskapsrådet/ ; //The Alzheimer's Society/ ; //National Institute for Health and Care Research University College London Hospitals Biomedical Research Centre/ ; UKDRI-1003//UK Dementia Research Institute at UCL/ ; },
mesh = {Humans ; *Down Syndrome/blood/complications ; *Biomarkers/blood ; *Alzheimer Disease/blood/diagnosis ; Female ; *Disease Progression ; Male ; Middle Aged ; *Machine Learning ; Amyloid beta-Peptides/blood ; Adult ; tau Proteins/blood ; Neurofilament Proteins/blood ; Peptide Fragments/blood ; Neuropsychological Tests ; Aged ; Cross-Sectional Studies ; },
abstract = {INTRODUCTION: Adults with Down syndrome (DS) have a high risk for Alzheimer's disease (AD). Although the sequence of plasma biomarker and cognitive changes in AD in DS is well studied, their related trajectories are not fully characterized. Data-driven methods can estimate disease progression from cross-sectional data.

METHODS: In 57 adults with DS and no AD, we used the event-based model to sequence plasma biomarker and cognitive changes in preclinical AD. Generalized additive models assessed the relationship between age and plasma biomarkers.

RESULTS: The earliest changes occurred in the amyloid beta 42/40 ratio, followed by memory changes. Later alterations in neurofilament light and tau concentrations preceded executive and visuomotor function changes, with glial fibrillary acidic protein levels changing last. The highest rate of plasma biomarker changes occurred between ages 39 and 52.

CONCLUSION: Changes in DS follow a pattern similar to that of sporadic and familial AD. Event-based modeling offers individual-level staging, potentially optimizing diagnosis and clinical trial patient selection.

HIGHLIGHTS: The pre-clinical stages of Alzheimer's disease (AD) development in Down syndrome (DS) are not well defined, despite the extremely high prevalence of AD. Better understanding of early AD progression would aid in diagnostics and treatment. Data-driven methods, such as the event-based model, can aid in clarifying the sequence of cognitive and plasma biomarker changes in the early stages of AD while accounting for baseline variability. We find that plasma amyloid beta 42/40 ratio and memory changes precede changes in plasma biomarker levels of neurodegeneration, with changes in executive and visuomotor functions occurring later, before neuroinflammatory marker changes. Combining plasma biomarkers could be a useful measure of preclinical AD for trials, particularly in individuals between 39 and52 years of age.},
}

Humans
*Down Syndrome/blood/complications
*Biomarkers/blood
*Alzheimer Disease/blood/diagnosis
Female
*Disease Progression
Male
Middle Aged
*Machine Learning
Amyloid beta-Peptides/blood
Adult
tau Proteins/blood
Neurofilament Proteins/blood
Peptide Fragments/blood
Neuropsychological Tests
Aged
Cross-Sectional Studies

@article {pmid40684196,
year = {2025},
author = {Choi, Y and Kim, PW and Jung, IC and Kim, AR and Park, HJ and Kwon, O and Lee, JH and Kim, JH},
title = {Acupuncture for patients with mild cognitive impairment: a randomized, patient-assessor-blinded, sham-controlled pilot study.},
journal = {BMC complementary medicine and therapies},
volume = {25},
number = {1},
pages = {277},
pmid = {40684196},
issn = {2662-7671},
support = {K16122 and KSN2122211//Korea Institute of Oriental Medicine/ ; K16122 and KSN2122211//Korea Institute of Oriental Medicine/ ; },
mesh = {Humans ; *Cognitive Dysfunction/therapy ; *Acupuncture Therapy/methods ; Pilot Projects ; Male ; Female ; Aged ; Middle Aged ; Aged, 80 and over ; Neuropsychological Tests ; Treatment Outcome ; },
abstract = {BACKGROUND: Mild cognitive impairment (MCI) is the transitional stage between normal aging and early dementia. Although acupuncture is a promising non-pharmacological treatment, higher-quality evidence is needed to confirm its effectiveness.

METHODS: A randomized, patient- and assessor-blinded, sham-controlled, pilot clinical trial was conducted to evaluate the feasibility of acupuncture for treating MCI. In total, 30 participants were randomized into acupuncture and sham acupuncture groups. The participants underwent 24 treatment sessions over 12 weeks. The primary outcome was a change in the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-cog) score over 12 weeks, whereas the secondary outcomes included the Seoul Neuropsychological Screening Battery (SNSB-II) score. Adverse events and the success of blinding were also assessed.

RESULTS: Of the 30 participants, 28 completed the study. Participants in the acupuncture and sham acupuncture groups exhibited a decrease in ADAS-cog scores from 10.27 ± 4.03 and 11.47 ± 3.85 at baseline to 5.78 ± 3.04 and 6.27 ± 2.83 at week 12, respectively. Both groups exhibited clinically meaningful improvements, with no significant difference between groups (P = 0.6590). The SNSB-II memory domain exhibited a moderate effect size favoring acupuncture (Cohen's d = 0.57, P = 0.1317). No intervention-related adverse events were reported, and participant blinding was adequate throughout the trial.

CONCLUSIONS: The 12-week acupuncture treatment is feasible for patients with MCI and may improve memory. Although the primary outcomes did not reach statistical significance, the secondary outcomes suggested potential benefits. Larger confirmatory trials are warranted to investigate the effectiveness of acupuncture in patients with MCI.

TRIAL REGISTRATION: Clinical Research Information Service (cris.nih.go.kr) KCT0001938 (Registered on June 3, 2016).},
}

Humans
*Cognitive Dysfunction/therapy
*Acupuncture Therapy/methods
Pilot Projects
Male
Female
Aged
Middle Aged
Aged, 80 and over
Neuropsychological Tests
Treatment Outcome

@article {pmid40682852,
year = {2025},
author = {Guan, X and Zha, L and Zhu, X and Rao, X and Huang, X and Xiong, Y and Guo, Y and Zhang, M and Zhou, D and Tu, Q and Wu, J and Wang, X and Hua, F and Xu, J},
title = {Mechanism of action and therapeutic potential of S100A8/A9 in neuroinflammation and cognitive impairment: From molecular target to clinical application (Review).},
journal = {International journal of molecular medicine},
volume = {56},
number = {4},
pages = {},
doi = {10.3892/ijmm.2025.5588},
pmid = {40682852},
issn = {1791-244X},
mesh = {Humans ; *Calgranulin B/metabolism ; *Calgranulin A/metabolism ; *Cognitive Dysfunction/metabolism/drug therapy ; *Neuroinflammatory Diseases/metabolism/drug therapy ; Animals ; Biomarkers/metabolism ; Molecular Targeted Therapy ; },
abstract = {The complex of proteins S100A8/A9 has been recognized as a major initiator of cognitive disorder onset, including, but not restricted to, neuroinflammation. Cognitive impairment or decline in memory, attention and executive function has been on the rise and is a major public health priority. Several neurological conditions that affect the brain and cognitive processes, including central nervous system diseases such as Alzheimer's disease and stroke, and systemic diseases, such as sepsis and systemic lupus erythematosus, are associated with S100A8/A9. Experiments have progressively demonstrated that S100A8/A9 plays a role in cognitive decline, as it regulates cognitive domains, including sleep, learning, memory, and emotion control, via several mechanisms. In this review, a critical overview of the role of S100A8/A9 in the treatment of neurocognitive diseases is provided, including the regulation of brain function and the pathogenesis of diseases, and potential novel therapies are suggested. It is necessary to study S100A8/A9 alone as an alternative marker for the diagnosis and treatment of neurocognitive diseases, and in line with the requirements of therapy for cognitive impairment. As S100A8/A9 research continues, the understanding and treatment of neurocognitive diseases may improve.},
}

Humans
*Calgranulin B/metabolism
*Calgranulin A/metabolism
*Cognitive Dysfunction/metabolism/drug therapy
*Neuroinflammatory Diseases/metabolism/drug therapy
Animals
Biomarkers/metabolism
Molecular Targeted Therapy

@article {pmid40682719,
year = {2025},
author = {Ryu, HS and Sanjay, and Choi, SK and Lee, KH and Jang, SS and Yang, SY and Kwon, YS and Ku, SK and Lee, HJ},
title = {Golden Oyster Mushroom Extract Ameliorates Oxidative Stress-Induced Cell Death in Neurons and Scopolamine-Induced Cholinergic System Impairment in Mice.},
journal = {Molecular neurobiology},
volume = {},
number = {},
pages = {},
pmid = {40682719},
issn = {1559-1182},
support = {(RS-2023-00236592)//This research was supported by Korea Institute of Marine Science & Technology Promotion (KIMST) funded by the Ministry of Oceans and Fisheries/ ; (RS-2023-00236592)//This research was supported by Korea Institute of Marine Science & Technology Promotion (KIMST) funded by the Ministry of Oceans and Fisheries/ ; },
abstract = {Impaired cholinergic system is an important therapeutic target to develop drugs against Alzheimer's disease (AD), as cholinergic signal transduction is associated with the memory, learning, and behavior of an individual. Acetylcholine (ACh) is an important neurotransmitter and is degraded by an enzyme, acetylcholinesterase (AChE), blocking neuronal signal transmission, which leads to amnesia or memory loss. Oxidative stress (OS) also worsens AD pathology by damaging lipids, proteins and DNA of the neuronal cells, leading to neuronal cell death. Golden oyster mushroom (GOM), an edible mushroom native to the regions of Japan, Korea, Russia, and China, has been reported to possess several bioactivities. However, there is no study reported till date, studying the anti-amnesic properties of GOM. The objectives of this study were to assimilate the in vitro neuroprotective and in vivo anti-amnesic properties of GOM. The GOM at 0.1, 0.5, 1, 5, and 10 mg/ml was nontoxic and was able to prevent H2O2 (500 µM) and glutamate (5 mM)-induced OS-mediated cell death in HT-22 cells. In addition, all the selected concentrations of GOM extract (50, 100, and 200 mg/kg, 28 days) were able to prevent scopolamine (ACh receptor antagonist, 1 mg/kg, 1 h post-treatment after the 7[th], 14[th], and 28[th] administrations)-induced cholinergic system impairment, memory loss, histopathological alteration, antioxidant defense system disruption, and reduced memory susceptibility markers in C57BL mice compared to the positive control tacrine (10 mg/kg, 28 days). In conclusion, GOM extract emerged as a natural AChE inhibitor and could be seen as a potential therapeutic AD agent.},
}

@article {pmid40682580,
year = {2025},
author = {Degan, S and Feng, Y and Colton, C and Schmidt, S and Peterchev, AV and Turner, DA},
title = {Cerebral Blood Flow Responses to Extracranial Alternating Current Brain Stimulation in CVN Mouse Model of Alzheimer's Disease: A Pilot Study Determining Optimal Dose.},
journal = {Neuromodulation : journal of the International Neuromodulation Society},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neurom.2025.06.002},
pmid = {40682580},
issn = {1525-1403},
abstract = {INTRODUCTION: Insufficient metabolic supply in response to neural demand is a key mechanism of degeneration in Alzheimer's disease [AD]. However, extracranial alternating current [AC] stimulation can increase cerebral blood flow [CBF] and metabolic substrate supply to the brain. In this work, we investigate in an initial, pilot study the optimal dosage of extracranial AC brain stimulation appropriate for long-term treatment to retard degeneration in a mouse AD model [CVN].

MATERIALS AND METHODS: We applied extracranial AC (0.5-2.0 mA; 10 Hz; 20-second bursts) to CVN and control C57Bl/6 mice while measuring CBF and intracerebral electric field in vivo in anesthetized animals, and behavioral responses in awake animals.

RESULTS: We found a significant, diffuse increase in cortical CBF (2.6% increase at 0.75 mA) and intracerebral electric field (6.36mV/mm gradient at 0.75 mA) in response to extracranial AC brain stimulation in both CVN and control mice. In awake, behaving mice, the optimal dose of stimulation was 0.75 mA (in 30-second bursts), causing no adverse behavioral effects.

CONCLUSION: Scheduled (at fixed times) or demand-triggered (during dynamic metabolic need) bursts of extracranial brain stimulation could enhance CBF to improve brain metabolic supply. The goal of this potential AD treatment is to alleviate mismatches between neural metabolic demand and brain substrate supply, to prevent AD phenotypic disease progression. Based on these pilot data, 0.75 mA is an optimal stimulation treatment dose leading to an appreciable net change in CBF, at a moderate intracranial electrical field, while also indicating behavioral tolerability, now being implemented in a long-term treatment trial.},
}

@article {pmid40681915,
year = {2025},
author = {Shah, A and Estilo, A and Sheridan, PL and Kalu, U and Chen, D and Chang, D and Slomkowski, M and Lee, D and Hefting, N and Hobart, M and Behl, S and Such, P and Brubaker, M and Grossberg, GT},
title = {Safety and Tolerability of Brexpiprazole in Participants with Agitation Associated with Dementia due to Alzheimer's Disease: Pooled Analysis of Three Randomized Trials and an Extension Trial.},
journal = {CNS drugs},
volume = {},
number = {},
pages = {},
pmid = {40681915},
issn = {1179-1934},
abstract = {BACKGROUND AND OBJECTIVE: Older adults with dementia are particularly vulnerable to antipsychotic side effects. Brexpiprazole, an atypical antipsychotic, is approved in a number of countries for the treatment of agitation associated with dementia due to Alzheimer's disease. This pooled analysis aimed to evaluate the safety and tolerability of brexpiprazole in this patient population.

METHODS: Data were included from three Phase 3, 12-week, randomized, double-blind, placebo-controlled trials and a Phase 3, 12-week, active-treatment extension trial in participants with agitation associated with dementia due to Alzheimer's disease. Safety outcomes included treatment-emergent adverse events (TEAEs), weight change, suicidality, extrapyramidal symptoms, and cognitive dysfunction. Two datasets were considered: a 12-week dataset that pooled data from the three randomized trials for brexpiprazole 0.5-3 mg/day and placebo, and a 24-week dataset that combined data from the parent randomized trial and the extension trial for brexpiprazole 2-3 mg/day.

RESULTS: Over 12 weeks, 335/655 (51.1%) participants on brexpiprazole and 178/388 (45.9%) participants on placebo reported ≥ 1 TEAE, which led to discontinuation in 41 (6.3%) and 13 (3.4%) participants, respectively. Headache was the only TEAE with incidence ≥ 5% (brexpiprazole, 50 [7.6%] participants; placebo, 36 [9.3%] participants). The incidences of cerebrovascular TEAEs (brexpiprazole, 0.5%; placebo, 0.3%), cardiovascular TEAEs (3.7%; 2.3%), extrapyramidal symptom-related TEAEs (5.3%; 3.1%), and somnolence/sedation TEAEs (3.7%; 1.8%) were generally similar between treatment groups. Six (0.9%) participants on brexpiprazole and 1 (0.3%) participant on placebo died; causes of death were not considered related to brexpiprazole and were generally in line with those expected in Alzheimer's disease. Over 24 weeks, 110/226 (48.7%) participants on brexpiprazole reported ≥ 1 TEAE, which led to discontinuation in 19 (8.4%) participants. Headache was the only TEAE with incidence ≥ 5% (18 [8.0%] participants). No participants died during the extension trial. Over 12 and 24 weeks, mean changes in weight, suicidality, and extrapyramidal symptoms were minimal, with no worsening of cognition.

CONCLUSIONS: Considering pooled data from > 1000 participants on brexpiprazole or placebo, brexpiprazole appears to be generally well tolerated for up to 24 weeks in participants with agitation associated with dementia due to Alzheimer's disease.

STUDY REGISTRATION: ClinicalTrials.gov identifiers: NCT01862640, NCT01922258, NCT03548584, NCT03594123.},
}

@article {pmid40680978,
year = {2025},
author = {Zhang, Y and Liu, M and Wang, Y and Hu, D and Wu, S and Zhao, B and Zhou, B and Yang, L},
title = {Nasal Nanotherapeutics for Central Nervous System Disorders: Bridging the Translational Gap in Central Nervous System Drug Delivery.},
journal = {European journal of pharmacology},
volume = {},
number = {},
pages = {177958},
doi = {10.1016/j.ejphar.2025.177958},
pmid = {40680978},
issn = {1879-0712},
abstract = {Neurological disorders such as neurodegenerative diseases (Alzheimer's disease, Parkinson's disease), cerebrovascular accidents, brain tumors, and functional impairments are becoming an increasingly urgent global health concern, particularly as aging populations expand worldwide. The blood-brain barrier significantly limits current treatment strategies, such as pharmacological therapies (oral or systemic), neurosurgical procedures, and neuromodulation. This highly selective barrier prevents most small-molecule drugs and virtually all biologics from reaching effective concentrations within the central nervous system (CNS), thereby restricting their therapeutic potential. Therefore, traditional drug delivery methods face challenges in effectively delivering therapeutic agents to the CNS. Intranasal delivery circumvents this limitation through direct nose-to-brain transport via olfactory/trigeminal pathways, achieving higher cerebrospinal fluid drug bioavailability compared to intravenous routes. In this review, we present a comprehensive elucidation of the pathophysiology of CNS disorders and the intricate mechanisms governing drug transport from the nasal cavity. Significantly advancing the field, we provide an exhaustive overview of cutting-edge nanocarriers and inhalation devices specifically designed for inhalable formulations, highlighting their unique advantages and limitations. This review combines clinical and engineering insights to evaluate innovative treatment methods through intranasal delivery, while identifying critical research pathways for improving central nervous system therapies.},
}

@article {pmid40680673,
year = {2025},
author = {Meng, D and Luo, G and Liu, P},
title = {Copper metabolism and cuproptosis in Alzheimer's disease: mechanisms and therapeutic potential.},
journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie},
volume = {190},
number = {},
pages = {118354},
doi = {10.1016/j.biopha.2025.118354},
pmid = {40680673},
issn = {1950-6007},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder with an increasing incidence rate year by year. The pathogenesis of AD is complex and closely related to protein misfolding and aggregation, neuroinflammation, oxidative stress, mitochondrial dysfunction, and other factors. Cuproptosis is a newly discovered form of programmed cell death caused by excessive intracellular copper. Unlike other known forms of cell death, it shows significant potential in the treatment of neurodegenerative diseases. Copper binds to the acylated components of the tricarboxylic acid cycle, causing protein toxicity stress, which ultimately leads to cell cuproptosis. AD is characterized by pathological features such as β-amyloid plaque formation and excessive phosphorylation of tau protein, which are closely linked to the cuproptosis mechanism. However, the specific relationship between the pathogenesis of AD and copper metabolism remains unclear. This article summarizes the metabolism of copper in the brain, the mechanisms of cuproptosis, and the pathogenesis of cuproptosis in AD, and also discusses the regulation of cuproptosis in the treatment of AD. This article provides a basis for targeted research on cuproptosis in AD.},
}

@article {pmid40680380,
year = {2025},
author = {Wang, B and Li, W and Hong, C and Jin, F and Xu, B and Guo, Z and Chen, S and Zhang, Q},
title = {Amyloid β (Aβ) inhibits retinal angiogenesis in Alzheimer's disease via LncRNA-XIST/miRNA-126-5p/VEGF axis.},
journal = {Immunobiology},
volume = {230},
number = {4},
pages = {153097},
doi = {10.1016/j.imbio.2025.153097},
pmid = {40680380},
issn = {1878-3279},
abstract = {Alzheimer's disease (AD) is often accompanied by retinal lesions, in which Amyloid β (Aβ) is a key mediator. Vascular dysfunction is always associated with the malignant progression of AD, but the precise mechanisms remain poorly understood. The aim of this study is to investigate how Aβ regulates retinal angiogenesis in AD models through the LncRNA-XIST/miR-126-5p/VEGF axis. The research results showed that in the retina of AD model mice, the expression of Aβ and miR-126-5p increased, while the expression of LncRNA-XIST and VEGF decreased. In vitro experiments demonstrated that Aβ treatment downregulated LncRNA-XIST and VEGF expression in RF/6 A cells, while upregulating miR-126-5p and significantly suppressing angiogenesis. Overexpression of LncRNA-XIST can reverse the inhibitory effect of Aβ on angiogenesis, while further overexpression of miR-126-5p can counteract the pro-angiogenic effect of LncRNA-XIST. The dual-luciferase reporter assay results showed that Aβ repressed the transcriptional activity of the LncRNA-XIST promoter by targeting the -800 to -600 fragment. Mechanism studies have revealed that LncRNA-XIST competitively binds to miR-126-5p, preventing its binding to VEGF mRNA and upregulating VEGF expression. In vivo experiments demonstrated that miR-126-5p inhibitor resulted in elevated expression of LncRNA-XIST and VEGF in the mouse retina. This study reveals the molecular mechanism by which Aβ regulates retinal angiogenesis in AD models through the LncRNA-XIST/miR-126-5p/VEGF axis, providing a potential new strategy for targeted therapy of AD-related retinal lesions.},
}

@article {pmid40680313,
year = {2025},
author = {Hamuľaková, S and Gucký, A and Mezencev, R and Kožurková, M and Bednáriková, Z and Marek, J and Soukup, O and Janoušek, J and Gažová, Z},
title = {Inhibition of amyloid fibrillization of amyloid β peptide by 4,7-disubstituted coumarin derivatives.},
journal = {Bioorganic & medicinal chemistry},
volume = {129},
number = {},
pages = {118302},
doi = {10.1016/j.bmc.2025.118302},
pmid = {40680313},
issn = {1464-3391},
abstract = {Coumarins are well-known for their unique chemical structure and a wide range of biological effects. Various substituted coumarin-based compounds have emerged as promising candidates for the development of novel therapeutic agents against numerous diseases. This study was focused on the synthesis of new 4,7-disubstituted coumarin derivatives and investigation of their ability to inhibit the aggregation of Aβ40 peptide, their cytotoxic effect on SH-SY5Y cells, their antioxidant properties, and their ability to penetrate the blood-brain barrier (BBB). The results revealed that the trihydroxy derivatives 5a-c had been the most effective inhibitors of Aβ aggregation, promoting the formation of non-toxic, amorphous aggregates instead. Importantly, no significant decrease in the viability of SH-SY5Y neuroblastoma cells was observed after treatment with the studied coumarins. Among them, coumarin 5a demonstrated the strongest antioxidant activity, while compound 5b also exhibited good antioxidant properties, along with the best inhibition of Aβ aggregation (IC50 = 13.5 μM), and adequate permeability across the blood-brain barrier. These findings suggest that compound 5b is a promising candidate for further investigation in Alzheimer's disease pharmacotherapy.},
}

@article {pmid40679987,
year = {2025},
author = {Li, B and Golovynska, I and Stepanov, YV and Golovynskyi, S and Golovynskyi, A and Kolesnik, D and Stepanova, LI and Lai, P and Lin, F and Qu, J},
title = {Transcranial photobiomodulation therapy with 808 nm light changes expression of genes and proteins associated with neuroprotection, neuroinflammation, oxidative stress, and Alzheimer's disease: Whole RNA sequencing of mouse cortex and hippocampus.},
journal = {PloS one},
volume = {20},
number = {7},
pages = {e0326881},
pmid = {40679987},
issn = {1932-6203},
mesh = {Animals ; *Alzheimer Disease/genetics/metabolism/therapy ; *Hippocampus/metabolism/radiation effects ; *Oxidative Stress/radiation effects/genetics ; Mice ; *Low-Level Light Therapy/methods ; *Neuroprotection/genetics/radiation effects ; *Neuroinflammatory Diseases/genetics ; *Cerebral Cortex/metabolism/radiation effects ; Mice, Inbred BALB C ; Sequence Analysis, RNA ; Male ; Gene Expression Regulation/radiation effects ; Gene Regulatory Networks ; },
abstract = {Light therapy, using red and near-infrared (NIR) irradiation, is currently applied for the treatment of various neurodegenerative diseases, such as Alzheimer's disease (AD). Transcranial photobiomodulation therapy (tPBMT) can alleviate neurodegeneration, neuronal loss, and β-amyloid peptide plaque burden. Alternatively, potential early inhibition of oxidative stress, neuroinflammation, apoptosis, and amyloidogenic cellular pathways may constrain pathological changes with aging. In this research, we conduct an 808-nm tPBMT with a 30-day course of daily 1-hour sessions for mice and assess its influence on molecular mechanisms related to the potential onset of neurodegeneration. To comprehensively identify molecular mechanisms of tPBMT on the brain cells, the next-generation whole RNA sequencing of over 30,000 mRNA of the cortex and hippocampus of BALB/c mice is performed. After tPBMT, transcriptional alterations are found in 1,005 genes in the hippocampus and 1,482 genes in the cortex. Pathway-gene enrichment network analysis identifies genes associated with about 20 pathways of neurodegeneration, and a disease-gene network is constructed. Particularly, tPBMT alters the transcription and expression of the essential genes associated with oxidative stress (NF-κBIα, JUN, JUND, and PKC genes), inflammation (DOCK4/6, IL-1RAPL1, and TNFαIP6), and apoptosis (CASP3, TNFαIP6, AKT3, CDKN1A, CYP51, RASA2, and RESTAT). Additionally, 808-nm light modulates the main risk genes for AD (BACE1, BACE2, PSEN2, APH1B, GATA2, YY2, RELA, STAT3, JUN, JUND, ARNTL, CREB3L1, CELF2, E2F4, ELK3, and CEBPD), involved in APP processing supporting AD development. Moreover, the APP concentration is reduced after tPBMT. Hence, PBMT may help inhibit the development of different neurodegeneration types and maintain normal brain conditions.},
}

Animals
*Alzheimer Disease/genetics/metabolism/therapy
*Hippocampus/metabolism/radiation effects
*Oxidative Stress/radiation effects/genetics
Mice
*Low-Level Light Therapy/methods
*Neuroprotection/genetics/radiation effects
*Neuroinflammatory Diseases/genetics
*Cerebral Cortex/metabolism/radiation effects
Mice, Inbred BALB C
Sequence Analysis, RNA
Male
Gene Expression Regulation/radiation effects
Gene Regulatory Networks

@article {pmid40679583,
year = {2025},
author = {Sun, X and Zhong, G and Zeng, Y and Xu, T and Liu, Y},
title = {Fully Integrated Wearable Biosensor for Multiple In Situ Phosphorylated Tau Protein Detection.},
journal = {Analytical chemistry},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.analchem.5c02541},
pmid = {40679583},
issn = {1520-6882},
abstract = {Early diagnosis is critical for the prevention and treatment of Alzheimer's disease (AD), as it allows for timely detection and intervention. Here, we developed a fully integrated wearable electrochemical sensing patch for early screening of AD, which combines sample collection and detection within a device. This wearable patch integrates a custom-developed microneedle sampling system with a wearable multimodal electrochemical biosensor. Such a microneedle sampling system can deliver interstitial fluid (ISF) to the detection area through a microneedle array, where the electrochemical sensing system can directly detect AD-related biomarkers P-tau181 and P-tau217 in situ with detection limits of 0.058 and 0.079 pg/mL. Additionally, the sensing patch includes a Bluetooth module, enabling the transmission of detection results to a mobile phone APP for display and further detection control. This fully integrated wearable electrochemical sensing patch provides a promising strategy for early multiple in situ diagnosis of AD.},
}

@article {pmid40678834,
year = {2025},
author = {Islam, MR and Rauf, A and Akter, S and Akter, H and Al-Imran, MIK and Fakir, MNH and Thufa, GK and Islam, MT and Hemeg, HA and Abdulmonem, WA and Aljohani, ASM and Iriti, M},
title = {Neuroprotective Potential of Curcumin in Neurodegenerative Diseases: Clinical Insights Into Cellular and Molecular Signaling Pathways.},
journal = {Journal of biochemical and molecular toxicology},
volume = {39},
number = {8},
pages = {e70369},
doi = {10.1002/jbt.70369},
pmid = {40678834},
issn = {1099-0461},
mesh = {*Curcumin/therapeutic use/pharmacology ; Humans ; *Neurodegenerative Diseases/drug therapy/metabolism/pathology ; *Neuroprotective Agents/therapeutic use/pharmacology ; *Signal Transduction/drug effects ; Animals ; Oxidative Stress/drug effects ; },
abstract = {Progressive neuronal loss and dysfunction characterize neurodegenerative diseases (NDs) such as Alzheimer's, Parkinson's, and Huntington's diseases, spinal cord injury, and stroke, making them difficult to treat. Curcumin, a bioactive substance derived from the turmeric plant (Curcuma longa), is interesting due to its potential neuroprotective properties. This review thoroughly shows the cellular and molecular signaling mechanisms that curcumin utilizes to provide neuroprotective effects in NDs. Curcumin regulates several signaling pathways linked to neuroprotection, such as those that reduce oxidative stress, prevent Aβ formation, and decrease neuroinflammation. NF-κB suppression reduces inflammatory responses, while Nrf2 activation boosts antioxidant response element expression. Furthermore, curcumin enhances autophagy and neurotrophic factor expression, facilitating the removal of harmful protein aggregates. The function of curcumin as a metal chelator is emphasized particularly to iron and other metal dysregulations linked to neurodegenerative processes. Curcumin's capacity to regulate metal ion homeostasis is essential since the pathophysiology of NDs is significantly influenced by metal-induced oxidative stress and toxic buildup. It shows potential therapeutic effects by reducing oxidative damage and chelating excess metals. Clinical research indicates that curcumin can penetrate the blood-brain barrier, making it an effective treatment option. The regulation of these pathways reduces neuronal damage and improves neurons' survival and functionality. In addition, curcumin's anti-inflammatory properties and low toxicity make it a promising long-term treatment option for NDs. Therefore, this review emphasizes the potential of curcumin as a targeted neuroprotective compound, presenting recent clinical insights and experimental data. Future studies should optimize curcumin formulations and delivery systems to enhance its bioavailability and therapeutic efficacy.},
}

*Curcumin/therapeutic use/pharmacology
Humans
*Neurodegenerative Diseases/drug therapy/metabolism/pathology
*Neuroprotective Agents/therapeutic use/pharmacology
*Signal Transduction/drug effects
Animals
Oxidative Stress/drug effects

@article {pmid40678772,
year = {2025},
author = {Choi, SH and Shim, Y and Kim, S and Yang, DW and Park, KH and Kim, J and Youn, YC},
title = {The Care Pathway for Patients with Mild Cognitive Impairment in Korea: A Survey of Dementia Specialists.},
journal = {Dementia and geriatric cognitive disorders extra},
volume = {15},
number = {1},
pages = {99-107},
pmid = {40678772},
issn = {1664-5464},
abstract = {INTRODUCTION: Mild cognitive impairment (MCI) represents a loss of memory or other cognitive function while maintaining the ability to independently perform most activities of daily living. This study assessed how Korean specialists in dementia care diagnosed and treated patients with MCI symptoms.

METHODS: A questionnaire on the current management of MCI was developed by 6 experts in MCI care. Specialists in MCI care (n = 24: 14 neurologists/10 psychiatrists) verbally answered questions relating to their experience/views in caring for MCI patients.

RESULTS: Respondents diagnosed MCI using the Seoul Neuropsychological Screening Battery (79%) and the Consortium to Establish a Registry for Alzheimer's Disease - Korea (21%) neuropsychological battery tests. All or nearly all respondents also assessed patients with Mini-Mental State Examination, Geriatric Depression Scale, Clinical Dementia Rating, Activities of Daily Living (ADL), and Instrumental ADL tests. All respondents used MRI or CT for differential diagnosis of diseases causing MCI, about one-third used amyloid PET. Most respondents (96%) treated patients with MCI due to Alzheimer's disease (AD) with medication, commonly choline alfoscerate (71%) and donepezil (53%), mainly as combination therapy. Unmet needs included patient/caregiver education (63%) and time constraints for consulting patients (54%). Most respondents considered that increased amyloid-β testing for patients with MCI due to AD or subjective cognitive decline is likely to increase.

CONCLUSIONS: This survey described the current management of MCI due to AD, identified unmet needs and considered possible future developments in the changing landscape of early AD treatment. Early detection and diagnosis and continued development of emerging preventative or therapeutic interventions are critical for MCI outcomes.},
}

@article {pmid40678242,
year = {2025},
author = {Batista, AF and Presumey, J and Singh, B and Schroeder, MK and Khan, K and , and Li, S and Carroll, MC and Lemere, CA},
title = {Global C3 lowering in adulthood protects against hippocampal dysfunction and cognitive impairment in aged mice.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-6924607/v1},
pmid = {40678242},
issn = {2693-5015},
abstract = {Background: Complement component 3 (C3) is increasingly recognized for its role in neurodegenerative processes; however, its specific impact on age-related hippocampal dysfunction remains poorly understood. This study investigates the effects of inducible C3 knockdown in adulthood on hippocampal function using a novel mouse model. Methods: We developed a chimeric floxed C3 mouse line (C3 [fl/fl]) and crossed it with Rosa-26-Cre-ERT2+/- mice, resulting in C3 [fl/fl] ; Rosa-26-Cre-ERT2 [+/-] (C3 iKO) mice that allow for global C3 knockdown via Tamoxifen (TAM) administration at any age. Young adult female and male C3iKO mice were treated with TAM or corn oil (CO) as a control, to induce global C3 lowering in 4 cohorts of mice. Serum C3 levels were monitored throughout the lifespan for all cohorts. Other outcome measures varied by cohort and included behavior, C3 mRNA and protein levels in brain, C1q levels, immune gene expression in brain, gliosis, synaptic changes in hippocampus. Results: TAM treatment led to a sustained reduction in C3 levels in serum, liver, and brain tissues of C3 iKO mice. Global C3 lowering was associated with reduced expression of C1q, C4b, IFNa, IFNb,and APOE , and increase expression of homeostatic genes Tgfb1 and Tgfbr1 in mouse brain one-year following TAM treatment. Notably, C3 lowering in adulthood conferred significant neuroprotection against age-related cognitive decline, which corresponded to increased hippocampal synaptic density and dendritic spine formation and increased pre-synaptic proteins in hippocampal synaptosomes. Moreover, long-term potentiation (LTP) impairments induced by Aβ-oligomers were rescued following C3 knockdown, highlighting potential therapeutic implications. Conclusion: Our C3iKO mouse model was consistently effective in lowering C3 levels in the brain and periphery in mice. The findings reported here demonstrate that global C3 lowering in adulthood, after brain development, protected the brain against age-associated hippocampal dysfunction and cognitive decline, suggesting that complement modulation may provide a neuroprotective strategy against brain aging. The C3iKO model provides a valuable platform for understanding the role of complement C3 in age-related neurodegenerative conditions, including Alzheimer's disease. Further studies are needed to better understand these neuroprotective effects in models of neurodegeneration and to assess the therapeutic potential of complement modulation in the brain.},
}

@article {pmid40677108,
year = {2025},
author = {Hakim, MA and Sanni, A and Osman, ST and Hamdy, NA and Purba, WT and Bhuiyan, MMAA and Onigbinde, S and El-Khordagui, LK and El-Yazbi, A and Mechref, Y},
title = {Serum Proteome Profiling of Diabetic Patients Treated With DPP4 and SGLT2 Inhibitors Shows Improved Cognitive and Cardiovascular Functions.},
journal = {Proteomics},
volume = {},
number = {},
pages = {e70000},
doi = {10.1002/pmic.70000},
pmid = {40677108},
issn = {1615-9861},
support = {D-0005//Robert A. Welch Foundation/ ; //The CH Foundation/ ; },
abstract = {Type 2 diabetes (T2D) is a complex metabolic disorder with rising global prevalence, leading to major complications such as cognitive decline, cardiovascular disease, and systemic inflammation. Although advances in T2D pharmacotherapy have shown promise in addressing these complications, the underlying protective mechanisms remain unclear, especially as they appear to be independent of glycemic control. In this study, we performed a comprehensive proteomic analysis using LC-MS/MS to explore the molecular effects of newer antidiabetic drugs, specifically dipeptidyl peptidase 4 (DPP4) and sodium-glucose cotransporter 2 (SGLT2) inhibitors (SGLT2is), when combined with metformin, the first-line treatment for T2D. Serum samples from 76 individuals were analyzed, including 16 healthy subjects, 32 T2D patients on metformin monotherapy, and 28 T2D patients receiving combination therapy. We identified and quantified 505 low-abundance proteins, followed by statistical analysis and ingenuity pathway analysis. Our findings revealed significant changes in key biological pathways related to synaptogenesis, insulin-like growth factor transport, and neurovascular coupling signaling. These results were further validated using parallel reaction monitoring. Notably, pathways associated with cognitive function and cardiovascular health were adversely affected in T2D patients on metformin monotherapy but showed improvement with combination therapy. These results suggest that the combination of DPP4 and SGLT2is offers a therapeutic advantage, underscoring the importance of personalized treatment strategies in managing T2D complications. Summary: Type 2 diabetes (T2D) is a chronic metabolic disorder that contributes to the progression of cognitive impairment, cardiovascular diseases, and renal dysfunction. Cognitive decline in T2D patients can also increase the risk of developing neurological conditions like Alzheimer's disease. Recently developed antidiabetic drugs have shown promising cardiovascular and renal health effects, such as dipeptidyl peptidase 4 (DPP4) inhibitors and sodium-glucose cotransporter 2 (SGLT2) inhibitors (SGLT2is). However, the precise mechanisms by which these drugs influence biological pathways related to cognitive function and central nervous system (CNS) development remain unclear. In this study, we explored the impact of these newer antidiabetic drugs in combination with metformin, compared to metformin monotherapy and healthy controls, by investigating differentially expressed proteins and their role in cognitive processes. Our findings reveal that DPP4 and SGLT2is activate key biological pathways-such as synaptogenesis, insulin-like growth factor regulation, and neurovascular coupling-that are either suppressed or not enriched in the metformin-only group. These pathways are critical for maintaining and regulating CNS function and cognitive health.},
}

@article {pmid40676911,
year = {2025},
author = {Chhipa, RR and Kurien, BT and Scofield, RH and Wolf, RF and Huang, H and Sundaram, P},
title = {Amytrapper Catheter: A Prototype Extracorporeal Device That Traps Blood Amyloid-β in a Rat Model of Alzheimer's Disease.},
journal = {American journal of Alzheimer's disease and other dementias},
volume = {40},
number = {},
pages = {15333175251361265},
doi = {10.1177/15333175251361265},
pmid = {40676911},
issn = {1938-2731},
mesh = {Animals ; *Alzheimer Disease/blood/therapy ; *Amyloid beta-Peptides/blood ; Disease Models, Animal ; Rats ; Male ; *Catheters ; },
abstract = {Alzheimer's disease (AD) presents a pressing global health challenge, with amyloid-β (Aβ) accumulation in the brain being a hallmark feature. While monoclonal antibodies targeting Aβ have shown cognitive benefits, safety concerns remain. Here, we introduce the Amytrapper catheter, a novel extracorporeal device developed by Recombinant Technologies to trap circulating Aβ using a retro-inverso peptide conjugated to polyethylene glycol. Through in vivo experiments using a rat model of AD, we demonstrate significant reductions in blood Aβ levels and behavioral improvements following Amytrapper catheter treatment. This innovative approach holds promise as a disease-modifying therapy for AD, offering a complementary strategy to existing treatments and advocating for further clinical development.},
}

Animals
*Alzheimer Disease/blood/therapy
*Amyloid beta-Peptides/blood
Disease Models, Animal
Rats
Male
*Catheters

@article {pmid40676897,
year = {2025},
author = {Sánchez-Soblechero, A and Gil, M and Rojo, JM and Muñiz, R and Hoyos-Alonso, MC and Olazarán, J},
title = {Trends of antipsychotic prescribing for people with dementia in Spain.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251359682},
doi = {10.1177/13872877251359682},
pmid = {40676897},
issn = {1875-8908},
abstract = {BackgroundAntipsychotic medications are frequently prescribed in people with dementia (PwD), despite concern regarding risk-benefit balance.ObjectiveTo describe the evolution of antipsychotic prescribing for PwD in Spain, with special interest in the effect of administration regulatory warnings (2004 and 2008).MethodsLongitudinal retrospective study using the national Spanish Database for Pharmacoepidemiological Research in Primary Care (BIFAP). We included patients with incident dementia during the study period (January 1, 2002 to December 31, 2018) and excluded those with major psychiatric conditions, mental retardation, or previous use of antipsychotics. Paper-based and electronic prescriptions of antipsychotics were collected. Annual prevalence of prescribing was obtained for single medications and antipsychotic group. All calculations were conducted for the total sample and stratified by sex. The results were compared with those of other countries.ResultsAntipsychotic prescribing doubled during the study period, raising from 12.6% (2002) to 23.8% (2018). A mild decrease of prescribing was observed from 2004 to 2007, followed by steady increase from 2007 on. This increase was due to atypical antipsychotic use, specifically quetiapine, which grew from 0.2% (2002) to 16.4% (2018) and was more frequently utilized in men. Spain prevalence of antipsychotics doubled the UK's.ConclusionsBetter designed warnings appear as a key means to rationalize use of antipsychotics in Spain and other countries, ideally as part of national dementia strategies. Dearly needed non-pharmacological approaches for comprehensive treatment of neuropsychiatric symptoms could be generalized as a first step through nursing home and day care networks. Quetiapine requires the agencies' urgent attention.},
}

@article {pmid40676867,
year = {2025},
author = {Chen, G and McKay, NS and Gordon, BA and Joseph-Mathurin, N and Liu, J and Schindler, SE and Hassenstab, J and Doering, S and Aschenbrenner, AJ and Wang, Q and LaMontagne, PJ and Keefe, SJ and Massoumzadeh, P and Cruchaga, C and Xiong, C and Morris, JC and Benzinger, TL},
title = {Baseline and longitudinal changes in cortical thickness and hippocampal volume predict cognitive decline.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251352202},
doi = {10.1177/13872877251352202},
pmid = {40676867},
issn = {1875-8908},
abstract = {BackgroundAs we transition to disease-modifying treatment for Alzheimer's disease (AD), identifying individuals most at risk for future cognitive decline is crucial. Amyloid PET, cerebrospinal fluid and more recently blood-based biomarkers can identify the first stage of AD. However, changes detectable by PiB-PET may precede the onset of the dementia by 20-30 years. MRI is a widely available tool for detecting longitudinal changes in brain structure, such as cortical thickness and hippocampal volume and may provide additional insight into which patients are at greatest risk to develop cognitive decline.ObjectiveTo determine how well the hippocampal volume and cortical thickness, without specific AD biomarkers, can predict cognitive decline.MethodsMRI data from 344 participants (cognitively unimpaired or mild cognitive impairment, age 50-86) were used to evaluate if changes in cortical thickness and hippocampal volume predict cognitive decline, measured by a global cognitive composite score. A random coefficient model was employed to calculate longitudinal changes in cortical thickness and hippocampal volume and assess their ability to predict cognitive decline.ResultsBaseline cortical thickness as well as hippocampal volume predicted cognitive decline, regardless of baseline cognitive status. In individuals unimpaired at baseline, decreases in cortical thickness and hippocampal volume independently predicted cognitive decline. For participants with baseline mild impairment, decreases in hippocampal volume predicted further cognitive decline.ConclusionsThese findings indicate that MRI could serve as an effective tool for identifying individuals at elevated risk of cognitive decline, a growing public health concern as global populations continue to age.},
}

@article {pmid40676669,
year = {2025},
author = {Li, B and Wang, L and Xiao, Y and Tang, Z and Wang, Y and Sun, T and Qi, X},
title = {Modulation of neuronal α1-adrenergic receptor reduces tauopathy and neuroinflammation by inhibiting the STING/NF-κB/NLRP3 signaling pathway in Alzheimer's disease mice.},
journal = {Journal of neuroinflammation},
volume = {22},
number = {1},
pages = {187},
pmid = {40676669},
issn = {1742-2094},
support = {Qiankehe Basic-[2024] Youth 228//the Guizhou Provincial Science and Technology Program Project/ ; Qiankehe Platform Talents-GCC[2023]035//the Guizhou Provincial Science and Technology Program Project/ ; QianJiaoji [2024]92//the Guizhou Provincial Department of Education Youth Science and Technology Talent Project/ ; 82260263//This research was funded by the Chinese National Natural Science Foundation/ ; },
mesh = {Animals ; *NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; Mice ; *Alzheimer Disease/metabolism/pathology/genetics ; *Signal Transduction/physiology/drug effects ; NF-kappa B/metabolism ; Mice, Transgenic ; *Neuroinflammatory Diseases/metabolism/pathology ; *Tauopathies/metabolism/pathology/genetics ; *Receptors, Adrenergic, alpha-1/metabolism/genetics/biosynthesis ; *Neurons/metabolism/pathology ; Humans ; Mice, Inbred C57BL ; Membrane Proteins/metabolism ; Male ; Disease Models, Animal ; },
abstract = {BACKGROUND: Neuroinflammation is closely associated with the pathological progression of Alzheimer's disease (AD). The α1-adrenergic receptor (ADRA1), a G protein-coupled receptor, has been identified as a critical therapeutic target in inflammatory disorders. However, its precise mechanistic role in AD pathogenesis remains unclear.

METHODS: To investigate ADRA1's role in AD, we employed 3xTg-AD and wild-type (WT) mice, modulating neuronal ADRA1 expression via intracerebroventricular delivery of adeno-associated viruses. Cognitive function, tau pathology, neuronal morphology, and activation of the STING/NF-κB/NLRP3 signaling pathway were evaluated using behavioral tests, Western blot, Golgi-Cox staining, immunohistochemistry, and immunofluorescence. In vitro AD models were established using Aβ42 oligomer-stimulated SH-SY5Y cells and primary murine neurons, along with SH-SY5Y cells transfected with full-length human tau (SH-SY5Y/htau). Pharmacological antagonists, inhibitors, lentiviral transduction, co-immunoprecipitation, and calcium flux assays were utilized to dissect ADRA1-mediated molecular mechanisms in tauopathy and neuroinflammation.

RESULTS: Hippocampal ADRA1 expression was significantly elevated in 10-month-old 3xTg-AD mice. Neuronal ADRA1 knockdown suppressed STING/NF-κB/NLRP3 pathway activation, ameliorated tauopathy and neuroinflammation, restored neuronal structure/function, and improved cognitive deficits in 3xTg-AD mice. Conversely, ADRA1 overexpression in C57/BL6 mice induced tauopathy, neuroinflammation, and cognitive impairment. Mechanistically, ADRA1 interacts with CXCR4 to form heterodimers, triggering cytoplasmic Ca[2]⁺ overload and subsequent STING/NF-κB/NLRP3 pathway activation.

CONCLUSIONS: ADRA1 critically mediates tauopathy and neuroinflammation through STING/NF-κB/NLRP3 signaling. These results identify ADRA1 as a promising therapeutic target for AD prevention and treatment.},
}

Animals
*NLR Family, Pyrin Domain-Containing 3 Protein/metabolism
Mice
*Alzheimer Disease/metabolism/pathology/genetics
*Signal Transduction/physiology/drug effects
NF-kappa B/metabolism
Mice, Transgenic
*Neuroinflammatory Diseases/metabolism/pathology
*Tauopathies/metabolism/pathology/genetics
*Receptors, Adrenergic, alpha-1/metabolism/genetics/biosynthesis
*Neurons/metabolism/pathology
Humans
Mice, Inbred C57BL
Membrane Proteins/metabolism
Male
Disease Models, Animal

@article {pmid40676541,
year = {2025},
author = {Zhang, Y and Xu, K and Wang, Y and Shen, Y and Liu, Z and Zhang, C and Zhou, Y and Lv, P and Bai, Y and Wang, S},
title = {Efficacy of repetitive transcranial magnetic stimulation in cognitive impairment of neurodegenerative diseases: a systematic review and meta-analysis.},
journal = {BMC neurology},
volume = {25},
number = {1},
pages = {295},
pmid = {40676541},
issn = {1471-2377},
mesh = {Humans ; *Transcranial Magnetic Stimulation/methods ; *Cognitive Dysfunction/therapy/etiology ; *Neurodegenerative Diseases/therapy/complications/psychology ; Randomized Controlled Trials as Topic/methods ; Treatment Outcome ; *Alzheimer Disease/therapy/psychology ; *Parkinson Disease/therapy/complications/psychology ; },
abstract = {OBJECTIVE: Currently, there is a lack of reliable evidence to prove the effectiveness of repetitive transcranial magnetic stimulation (rTMS) in the cognitive and emotional domains of neurodegenerative diseases (ND), leading to the absence of a unified and effective rTMS treatment protocol or stimulation targets. This systematic review and meta-analysis summarizes existing evidence to evaluate the efficacy of rTMS targeting the dorsolateral prefrontal cortex (DLPFC) and non-DLPFC in the cognitive and emotional aspects of ND.

METHODS: For two common types of ND Alzheimer's disease (AD) and Parkinson's disease (PD), we included 17 relevant randomized controlled trials (RCTs) from five databases. Search terms included rTMS, Parkinson's disease, Alzheimer's disease, cognitive impairment, and randomized controlled studies. Two independent reviewers assessed the risk of bias in the included literature, performed data extraction, and evaluated the evidence. Treatment effects were assessed using the Montreal Cognitive Assessment (MoCA), the Mini-Mental State Examination (MMSE), the Hamilton Depression Rating Scale (HAMD), the Hamilton Anxiety Rating Scale (HAMA), and Activities of Daily Living (ADL). Data were analyzed using R software to evaluate effect sizes and 95% confidence interval (CI). Heterogeneity tests were conducted to assess differences in treatment effects between DLPFC and non-DLPFC.

RESULTS: We screened 3,467 articles and identified 17 studies that met the inclusion criteria. The pooled results showed significant effects: MoCA (MD: 2.13, 95% CI [0.75, 3.52], p < 0.001); MMSE (MD: 1.16, 95% CI [0.91, 1.41], p = 0.0075); HAMD (MD: -2.63, 95% CI [-6.45, -1.20], p = 0.14); HAMA (SMD: -0.62, 95% CI [-0.91, -0.33], p < 0.001); ADL (MD: -0.56, 95% CI [-1.10, 2.22], p = 0.48).

CONCLUSION: rTMS has a positive effect on cognitive impairment and emotional abnormalities associated with ND. There is a significant difference in MoCA scores between rTMS applied to DLPFC and non-DLPFC. DLPFC may serve as a reliable stimulation target for treating non-motor symptoms related to ND (such as cognitive and emotional issues), which is beneficial for developing an rTMS treatment protocol with broad applicability for ND. However, due to the small number of included studies and the indirect nature of the comparison methods, we should interpret these results with caution.},
}

Humans
*Transcranial Magnetic Stimulation/methods
*Cognitive Dysfunction/therapy/etiology
*Neurodegenerative Diseases/therapy/complications/psychology
Randomized Controlled Trials as Topic/methods
Treatment Outcome
*Alzheimer Disease/therapy/psychology
*Parkinson Disease/therapy/complications/psychology

@article {pmid40676466,
year = {2025},
author = {Hu, H and Brys, M and Ruberg, SJ and Qu, Y},
title = {Estimand Endpoints for Longitudinal Measures of Continuous Disease Progression with an Alzheimer's Disease Example.},
journal = {Therapeutic innovation & regulatory science},
volume = {},
number = {},
pages = {},
pmid = {40676466},
issn = {2168-4804},
abstract = {The ICH E9 (R1) Addendum provides a framework to define an estimand and perform sensitivity analysis. The clinical endpoint (i.e., variable, response, outcome) is one of the important estimand attributes. In our opinion, the selection of the endpoint in Alzheimer's disease requires more exploration beyond what is used currently. The change in a cognitive and functional assessment scale from baseline to a specific time point of interest is often used as a primary or key secondary endpoint in clinical trials. However, such a change from baseline to the time point of interest may not reflect the benefit of the treatment over the course of treatment duration and may be difficult to intuitively understand by patients and clinicians. For two patients with the same change from baseline, the patient with rapid disease progression in the beginning is considered to have overall worse quality of life compared to the other patient with slow disease progression in the beginning but rapid progression toward the end. We explore time-averaged measurement (TAM) as a new endpoint and propose using the relative change to quantify the treatment difference. Estimands under the ICH E9 (R1) Addendum were considered by using various strategies in handling intercurrent events and used corresponding methods for handling missing data. We illustrate the use of TAM and compare the results with other commonly used estimand endpoints (the change from baseline, the relative disease progression model, and the slope of disease progression) for different estimands and imputation methods from retrospective analyses of a historical study.},
}

@article {pmid40675957,
year = {2025},
author = {Vaghari, D and Mohankumar, G and Tan, K and Lowe, A and Shering, C and Tino, P and Kourtzi, Z},
title = {AI-guided patient stratification improves outcomes and efficiency in the AMARANTH Alzheimer's Disease clinical trial.},
journal = {Nature communications},
volume = {16},
number = {1},
pages = {6244},
pmid = {40675957},
issn = {2041-1723},
support = {INF\R2\202107//Royal Society/ ; 221633/Z/20/Z//Wellcome Trust (Wellcome)/ ; },
mesh = {Humans ; *Alzheimer Disease/drug therapy/metabolism/diagnosis ; Male ; Female ; Aged ; Amyloid beta-Peptides/metabolism ; Treatment Outcome ; Amyloid Precursor Protein Secretases/antagonists & inhibitors ; Aspartic Acid Endopeptidases/antagonists & inhibitors ; Aged, 80 and over ; Prognosis ; Cognitive Dysfunction/drug therapy ; Patient Selection ; Cognition/drug effects ; },
abstract = {Alzheimer's Disease (AD) drug discovery has been hampered by patient heterogeneity, and the lack of sensitive tools for precise stratification. Here, we demonstrate that our robust and interpretable AI-guided tool (predictive prognostic model, PPM) enhances precision in patient stratification, improving outcomes and decreasing sample size for a AD clinical trial. The AMARANTH trial of lanabecestat, a BACE1 inhibitor, was deemed futile, as treatment did not change cognitive outcomes, despite reducing β-amyloid. Employing the PPM, we re-stratify patients precisely using baseline data and demonstrate significant treatment effects; that is, 46% slowing of cognitive decline for slow progressive patients at earlier stages of neurodegeneration. In contrast, rapid progressive patients did not show significant change in cognitive outcomes. Our results provide evidence for AI-guided patient stratification that is more precise than standard patient selection approaches (e.g. β-amyloid positivity) and has strong potential to enhance efficiency and efficacy of future AD trials.},
}

Humans
*Alzheimer Disease/drug therapy/metabolism/diagnosis
Male
Female
Aged
Amyloid beta-Peptides/metabolism
Treatment Outcome
Amyloid Precursor Protein Secretases/antagonists & inhibitors
Aspartic Acid Endopeptidases/antagonists & inhibitors
Aged, 80 and over
Prognosis
Cognitive Dysfunction/drug therapy
Patient Selection
Cognition/drug effects

@article {pmid40675659,
year = {2025},
author = {Singla, P and Argoff, CE},
title = {How Common Is Pain in Neurologic Disorders and Why Should Neurologists Care?.},
journal = {Neurologic clinics},
volume = {43},
number = {3},
pages = {457-465},
doi = {10.1016/j.ncl.2025.04.001},
pmid = {40675659},
issn = {1557-9875},
mesh = {Humans ; *Neurologists ; *Nervous System Diseases/complications/therapy ; *Pain Management/methods ; *Pain/etiology ; *Chronic Pain/therapy/etiology ; },
abstract = {This article explores the link between chronic pain and neurologic disorders, focusing on how pain affects conditions like Alzheimer's disease, Parkinson's disease, multiple sclerosis, and post-stroke pain. The article highlights the need to recognize pain as an important symptom in these conditions and encourages neurologists to take an active role in managing pain. By understanding how pain works and using a team approach, health care providers can improve the quality of life for patients and create better treatment plans for chronic pain related to neurologic disorders.},
}

Humans
*Neurologists
*Nervous System Diseases/complications/therapy
*Pain Management/methods
*Pain/etiology
*Chronic Pain/therapy/etiology

@article {pmid40675372,
year = {2025},
author = {Afrin, LB and Weinstock, LB and Dempsey, TT and Aschenbrenner, K and Blitshteyn, S and Schofield, JR},
title = {Utility of Glucagon-Like-Peptide-1-Receptor Agonists in Mast Cell Activation Syndrome.},
journal = {The American journal of the medical sciences},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.amjms.2025.07.006},
pmid = {40675372},
issn = {1538-2990},
abstract = {INTRODUCTION: Mast cell (MC) activation syndrome (MCAS) is a collection of illnesses rooted in inappropriate MC activation with little to no neoplastic MC proliferation, distinguishing it from mastocytosis. Due to great heterogeneity in the underlying MC regulatory gene mutational profiles present in most cases and resulting great heterogeneity in aberrant expression of the hundreds of potent mediators known to be expressed by MCs, MCAS presents with great heterogeneity but dominantly manifests as chronic multisystem polymorbidity of generally inflammatory, allergic, and dystrophic behaviors. MCAS's heterogeneity at multiple levels poses challenges for identifying optimal individual treatment. Targeting commonly affected downstream effectors of the disease's various symptoms may yield clinical benefit independent of the root/upstream mutational profile in the individual patient. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) engage with GLP-1 receptors present on many types of cells, including MCs. These drugs are already approved for management of a few chronic inflammatory diseases (e.g., diabetes mellitus type 2, obesity, obstructive sleep apnea) but are increasingly being appreciated to help in a wide range of other inflammatory diseases (e.g., Alzheimer's disease).

METHODS: We present the first case series showing utility of a variety of GLP-1RAs for managing refractory MCAS in a diverse assortment of such patients.

RESULTS: Among 47 cases (age range 15-71, 89% female), 89% demonstrated clinical benefit with GLP-1RAs for a broad range of problems associated with MCAS.

CONCLUSION: GLP-1RAs may have substantial benefit in MCAS. Randomized controlled trials are needed to assess the efficacy, and identify optimal dosing, of GLP-1RA treatment in MCAS.},
}

@article {pmid40675338,
year = {2025},
author = {Shtilbans, A},
title = {Combination Supplement Therapy: A New Frontier in Treatment of Neurodegenerative Diseases.},
journal = {The Journal of nutrition},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.tjnut.2025.07.004},
pmid = {40675338},
issn = {1541-6100},
abstract = {This review highlights the importance and potential beneficial effects of dietary supplements, including taurine, tauroursodeoxycholic acid (TUDCA), curcumin, coenzyme Q10 (CoQ10), creatine, and N-acetylcysteine (NAC) in the management of neurodegenerative diseases. Studies in preclinical models have consistently shown significant potential of these supplements in mitigating neurodegenerative pathology. Through a range of mechanisms targeting different molecular pathways, these supplements demonstrate therapeutic outcomes in preclinical models of such conditions such as Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, and Huntington's disease. This review discusses published data on each of these supplements in the context of neurodegenerative diseases. It also discusses a combination therapy concept and proposes a strategy to formulate an optimal blend of these supplements. This combination approach will target key processes, including mitochondrial dysfunction, protein misfolding, neuroinflammation, and oxidative stress responsible for neurodegenerative conditions. Additionally, this review examines various models used for both the initial screening and subsequent assessment of candidate supplement combinations.},
}

@article {pmid40674898,
year = {2025},
author = {Sikirzhytskaya, A and Tyagin, I and Sutton, SS and Wyatt, MD and Safro, I and Shtutman, M},
title = {AI-based mining of biomedical literature: Applications for drug repurposing for the treatment of dementia.},
journal = {Artificial intelligence in medicine},
volume = {168},
number = {},
pages = {103218},
doi = {10.1016/j.artmed.2025.103218},
pmid = {40674898},
issn = {1873-2860},
abstract = {Neurodegenerative diseases like Alzheimer's, Parkinson's, and HIV-associated neurocognitive disorder severely impact patients and healthcare systems. While effective treatments remain limited, researchers are actively developing ways to slow progression and improve patient outcomes, requiring innovative approaches to handle huge volumes of new scientific data. To enable the automatic analysis of biomedical data we introduced AGATHA, an effective AI-based literature mining tool that can navigate massive scientific literature databases. The overarching goal of this effort is to adapt AGATHA for drug repurposing by revealing hidden connections between FDA-approved medications and a health condition of interest. Our tool converts the abstracts of peer-reviewed papers from PubMed into multidimensional space where each gene and health condition are represented by specific metrics. We implemented advanced statistical analysis to reveal distinct clusters of scientific terms within the virtual space created using AGATHA-calculated parameters for selected health conditions and genes. Partial Least Squares Discriminant Analysis was employed for categorizing and predicting samples (122 diseases and 20,889 genes) fitted to specific classes. Advanced statistics were employed to build a discrimination model and extract lists of genes specific to each disease class. We focused on repurposing drugs for dementia by identifying dementia-associated genes highly ranked in other disease classes. The method was developed for detection of genes that shared across multiple conditions and classified them based on their roles in biological pathways. This led to the selection of six primary drugs for further study.},
}

@article {pmid40672883,
year = {2025},
author = {Zammit, AR and Capuano, AW and Barnes, LL and Schneider, JA and Sperling, RA and Bennett, DA and Grodstein, F},
title = {Cognitive decline across five cognitive batteries: Sample size implications for clinical trials.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {11},
number = {3},
pages = {e70137},
pmid = {40672883},
issn = {2352-8737},
abstract = {INTRODUCTION: We evaluated the statistical power for a theoretical randomized trial of anti-amyloid treatment in preclinical Alzheimer's Disease across five cognitive composites in preclinical Alzheimer's Disease across five cognitive composites: Alzheimer's Prevention Initiative Preclinical Composite Cognitive Test (APCC); Preclinical Alzheimer's Composite with Semantic Processing (PACC5); Preclinical Alzheimer's Cognitive Composite (PACC); and global and episodic memory composites.

METHODS: We utilized annual cognitive assessments from 517 decedents (78.2 ± 4.7years; 72% female) with post mortem pathologic Alzheimer's disease (AD) to represent amyloid positivity. We calculated sample sizes to detect 30% reduction in 5-year slopes of cognitive decline for equal size treatment versus placebo groups across composites.

RESULTS: Estimated sample sizes for APCC (n = 1633, 95% confidence interval [CI] 1400-1823), PACC (n = 1822, 95% CI 1612-2122), and episodic memory (n = 3141 95%CI 2563-3732) were larger than for PACC5 (n = 1424, 95% CI 1249-1575). Sample size estimates were similar between PACC5 and the global composite (n = 1267, 95%CI 1336-1407).

DISCUSSION: Small changes in composites, such as addition of semantic fluency in PACC5, could be considered as part of approaches to improve statistical power.

HIGHLIGHTS: We evaluated statistical power of a theoretical 5-year randomized trial testing anti-amyloid treatments in early Alzheimer's across five cognitive composite endpoints.We leveraged annual cognitive assessment in Rush Alzheimer's Disease Center cohorts and used post mortem pathologic AD to represent amyloid positivity.Preclinical Alzheimer's Composite with Semantic Processing (PACC5) required significantly lower sample size to achieve power for a 30% reduction in cognitive slope than Alzheimer's Disease Cooperative Study-Preclinical Alzheimer's Cognitive Composite (PACC).PACC5 had better statistical power than Alzheimer's Prevention Initiative Preclinical Composite Cognitive Test (APCC) and an episodic memory composite.Small changes in cognitive composites can improve detection of cognitive decline.},
}

@article {pmid40672873,
year = {2025},
author = {Xu, Q and An, L and Yang, H and Hong, KS},
title = {A multi-graph convolutional network method for Alzheimer's disease diagnosis based on multi-frequency EEG data with dual-mode connectivity.},
journal = {Frontiers in neuroscience},
volume = {19},
number = {},
pages = {1555657},
pmid = {40672873},
issn = {1662-4548},
abstract = {OBJECTIVE: Alzheimer's disease (AD) is mainly identified by cognitive function deterioration. Diagnosing AD at early stages poses significant challenges for both researchers and healthcare professionals due to the subtle nature of early brain changes. Currently, electroencephalography (EEG) is widely used in the study of neurodegenerative diseases. However, most existing research relies solely on functional connectivity methods to infer inter-regional brain connectivity, overlooking the importance of spatial connections. Moreover, many existing approaches fail to fully integrate multi-frequency EEG features, limiting the comprehensive understanding of dynamic brain activity across different frequency bands. This study aims to address these limitations by developing a novel graph-based deep learning model that fully utilizes both functional and structural information from multi-frequency EEG data.

METHODS: This paper introduces a Multi-Frequency EEG data-based Multi-Graph Convolutional Network (MF-MGCN) model for AD diagnosis. This method integrates both functional and structural connectivity to more thoroughly capture the relationships among brain regions. By extracting differential entropy (DE) features from five distinct frequency bands of EEG signals for each segment and using graph convolutional networks (GCNs) to aggregate these features, the model effectively distinguishes between AD and healthy controls (HC).

RESULTS: The outcomes show that the developed model outperforms existing methods, achieving 96.15% accuracy and 98.74% AUC in AD and HC classification.

CONCLUSION: These findings highlight the potential of the MF-MGCN model as a clinical tool for Alzheimer's disease diagnosis. This approach could help clinicians detect Alzheimer's at earlier stages, enabling timely intervention and personalized treatment plans.},
}

@article {pmid40672508,
year = {2025},
author = {, and Cao, H and Song, Z and Duggan, MR and Erus, G and Srinivasan, D and Tian, YE and Bai, W and Rafii, MS and Aisen, P and Belsky, DW and Walker, KA and Zalesky, A and Ferrucci, L and Davatzikos, C and Wen, J},
title = {Multi-organ MRI digitizes biological aging clocks across proteomics, metabolomics, and genetics.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.07.10.25331263},
pmid = {40672508},
abstract = {Leveraging clinical phenotypes [1,2] , neuroimaging [3] , proteomics [4] , metabolomics [5] , and epigenetics [6] , biological aging clocks across organ systems and tissues have advanced our understanding of human aging and disease. In this study, we expand this biological aging clock framework to multi-organ magnetic resonance imaging (MRI) by developing 7 organ-specific MRI-based biological age gaps (MRIBAGs), including the brain, heart, liver, adipose tissue, spleen, kidney, and pancreas. Leveraging imaging, genetic, proteomic, and metabolomic data from 313,645 individuals curated by the MULTI consortium, we link the 7 MRIBAGs to 2,923 plasma proteins, 327 metabolites, and 6,477,810 common genetic variants. These associations reveal organ-specific and cross-organ interconnection landscapes, identifying distinct molecular signatures related to organ aging. Genome-wide associations identify 53 MRIBAG-locus pairs (P<5×10 [D8]). Genetic correlation and Mendelian randomization analyses further support organ-specific and cross-organ interconnections with 9 phenotype-based [1,2] , 11 proteome-based [7] , and 5 metabolome-based aging clocks [5] , as well as 525 disease endpoints. Through functional gene mapping and Bayesian colocalization analysis linking evidence from genetics, proteomics, and metabolomics, we prioritize 9 druggable genes as targets for future anti-aging treatments. Finally, we demonstrate the clinical relevance of the 7 MRIBAGs in predicting disease endpoints (e.g., diabetes mellitus), all-cause mortality, and capturing differential and heterogeneous cognitive decline trajectories over 240 weeks of treatment with the Alzheimer's disease drug (Solanezumab). Sex differences are evident across multiple organ systems, manifesting at structural, molecular, and genetic levels. In summary, we developed 7 MRI-based aging clocks that enhance the existing multi-organ biological aging framework, offer multi-scale insights into aging biology, and demonstrate clinical potential to advance future aging research.},
}

@article {pmid40672452,
year = {2025},
author = {Mei, X and Zhao, Z and Wang, J and Qiu, C and Li, L and Xiong, C and Zhu, S and Zheng, C},
title = {Synergistic effects of surface-enhanced Raman spectroscopy and enzyme-linked immunoassays in diagnosis of Alzheimer's disease, mild cognitive impairment, and late-life depression.},
journal = {Frontiers in neurology},
volume = {16},
number = {},
pages = {1615457},
pmid = {40672452},
issn = {1664-2295},
abstract = {BACKGROUND: Objective tests that can be used to identify neurodegenerative diseases and neuropsychiatric disorders are urgently needed. The primary objective of this study is to evaluate the diagnostic accuracy of surface-enhanced Raman spectroscopy (SERS), a novel blood-based detection method, in differentiating neurodegenerative diseases and neuropsychiatric disorders. Additionally, we aim to assess the synergistic diagnostic performance of combining SERS with enzyme-linked immunosorbent assay (ELISA) technology for Alzheimer's disease (AD), mild cognitive impairment (MCI), and late-life depression (LLD).

METHODS: In total, 23 patients with AD, 24 with MCI, 20 with LLD, and 20 cognitively normal (control) individuals were enrolled. ELISA and SERS were used to test various biomarkers in the AD, MCI, LLD, and control groups.

RESULTS: Amyloid-β, tau, brain-derived neurotrophic factor, proinflammatory cytokine IL-1β, and growth differentiation factor-15 levels as measured using ELISA significantly differed among the four groups (P < 0.05). SERS peaks at 592 (P = 0.038), 725 (P = 0.001), 1,003 (P = 0.010), 1,331 (P = 0.000), and 165 cm[-1] (P = 0.000) likewise significantly differed among the four groups. The area under the curve was significantly higher after combining multiple blood indicators than that with single-blood indicators.

CONCLUSIONS: Combining SERS and ELISA can significantly increase diagnostic accuracy for AD, MCI, and LLD. The findings are expected to provide potential therapeutic targets for precise intervention in these diseases, thereby contributing to improved clinical stratification and personalized treatment strategies.

ChiCTR2300076307 (30/09/2023).},
}

@article {pmid40671844,
year = {2025},
author = {Mohammed, O and Kelemu, T},
title = {Incretin-Based Therapies in Alzheimer's and Parkinson's Disease: Advancing Neuroprotection With Dual and Triple Agonists-A Review.},
journal = {Health science reports},
volume = {8},
number = {7},
pages = {e71065},
pmid = {40671844},
issn = {2398-8835},
abstract = {BACKGROUND: Alzheimer's disease (AD) and Parkinson's disease (PD) are progressive neurodegenerative disorders with significant cognitive and motor impairments, affecting millions globally. Current treatments offer limited efficacy, prompting the exploration of new therapeutic approaches.

AIM: To discuss the intricate relationship between incretin and insulin signaling pathways and their relevance to the pathogenesis and treatment of Alzheimer's and Parkinson's diseases.

METHODS: A comprehensive literature review was conducted using a variety of search engines, including Google Scholar, PubMed Central, Scopus, Web of Science, and others.

RESULTS: Emerging evidence highlights disrupted insulin signaling in AD and, to a lesser extent, in PD, suggesting that insulin plays a key neuroprotective role. Incretins, such as GLP-1 and GIP, which enhance insulin signaling, have shown potential in preclinical and clinical studies. Incretin-based therapies, particularly GLP-1/GIP receptor agonists, have demonstrated promising effects by addressing several pathological processes, including oxidative stress, inflammation, misfolded protein aggregation, and insulin resistance. Dual agonists like DA-CH3, DA5-CH, and DA4-JC have proven superior in crossing the blood-brain barrier and offering improved neuroprotection in comparison with conventional GLP-1 agonists. Triple agonists provide even greater neuroprotective benefits, highlighting their potential as disease-modifying therapies for AD and PD.

CONCLUSION: While GLP-1 and GIP analogs hold promise in modulating early neurodegenerative processes, their efficacy likely depends on timely intervention before permanent neuronal damage occurs.},
}

@article {pmid40671224,
year = {2025},
author = {Wen, J and Hu, J and Yang, X and Luo, F and Zou, G},
title = {Effective Analysis of Alzheimer's Disease and Mechanisms of Methyl-4- Hydroxybenzoate using Network Toxicology, Molecular Docking, and Machine Learning Strategies.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050399031250623062112},
pmid = {40671224},
issn = {1875-5828},
abstract = {INTRODUCTION: Nowadays, the large increase in environmental pollutants has led to the occurrence and development of an increasing number of diseases. Studies have shown that exposure to environmental pollutants, such as methyl-4-hydroxybenzoate (MEP) may lead to Alzheimer's disease (AD). Therefore, the purpose of this study was to elucidate the complex effects and potential molecular mechanisms of environmental pollutants MEP on AD.

METHODS: Through exhaustive exploration of databases, such as ChEMBL, STITCH, SwissTarget- Prediction, and Gene Expression Omnibus DataSets (GEO DataSets), we have identified a comprehensive list of 46 potential targets closely related to MEP and AD. After rigorous screening using the STRING platform and Cytoscape software, we narrowed the list to nine candidate targets and ultimately identified six hub targets using three proven machine learning methods (LASSO, RF, and SVM): CREBBP, BCL6, CXCR4, GRIN1, GOT2, and ITGA5. The "clusterProfiler" R package was used to conduct GO and KEGG enrichment analysis. At the same time, we also constructed disease prediction models for core genes. At last, six hub targets were executed molecular docking.

RESULTS: We derived 46 key target genes related to MEP and AD and conducted gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. MEP might play a role in AD by affecting the pathways of neuroactive ligand-receptor interaction. Nine genes were screened as pivotal targets, followed by machine learning methods to identify six hub targets. Molecular docking analysis showed a good binding ability between MEP and CREBBP, BCL6, CXCR4, GRIN1, GOT2 and ITGA5. In addition, changes in the immune microenvironment revealed a significant impact of immune status on AD.

DISCUSSIONS: This study revealed that MEP may induce AD through multiple mechanisms, such as oxidative stress, neurotoxicity, and immune regulation, and identified six core targets (CREBBP, BCL6, etc.) and found that they are related to changes in the immune microenvironment, such as T cells and B cells, providing new molecular targets for AD intervention.

CONCLUSION: Overall, CREBBP, BCL6, CXCR4, GRIN1, GOT2, and ITGA5 have been identified as the crucial targets correlating with AD. Our findings provide a theoretical framework for understanding the complex molecular mechanisms underlying the effects of MEP on AD and provide insights for the development of prevention and treatment of AD caused by exposure to MEP.},
}

@article {pmid40671162,
year = {2025},
author = {Rodríguez, A and Calero, O and Veiga, S and Menacho-Román, M and Arribas, I and Cano, L and García-Ribas, G and Calero, M},
title = {A novel biochemical analysis for ApoE4 quantification in plasma and discrimination of homozygous and heterozygous APOE ε4 carriers.},
journal = {Alzheimer's research & therapy},
volume = {17},
number = {1},
pages = {163},
pmid = {40671162},
issn = {1758-9193},
support = {AB-SER1-19-025//Servicio Gallego de Salud (SERGAS) and Fondo Europeo de Desarrollo Regional (FEDER)/ ; CB06/05/0085//CIBER - Consorcio Centro de Investigación Biomédica en Red/ ; },
mesh = {Humans ; *Apolipoprotein E4/blood/genetics ; *Heterozygote ; Homozygote ; Male ; Female ; Aged ; Alzheimer Disease/genetics/blood ; Middle Aged ; ROC Curve ; Genotype ; Aged, 80 and over ; },
abstract = {BACKGROUND: The APOE ε4 allele is the strongest genetic risk factor for late-onset Alzheimer's disease (AD) and is associated with increased risk of amyloid-related imaging abnormalities (ARIA) during anti-amyloid therapy. Accurate identification of ε4 carriers, particularly APOE ε4/ε4 individuals, is clinically relevant. This study outlines the development and validation of e4Quant, a novel turbidimetric assay for quantifying plasma ApoE4 as a non-genetic alternative to APOE genotyping.

METHODS: The e4Quant test utilizes a proprietary particle-enhanced immunoturbidimetry method, employing an isoform-specific anti-ApoE4 antibody on standard chemistry analyzers. Plasma samples from 160 individuals of known APOE genotype (35 APOE ε4/ε4 homozygotes, 115 APOE ε4 heterozygotes, and 10 APOE ε4 non-carriers) were analyzed for ApoE4 and total ApoE levels. The test's discriminatory performance was assessed by ROC analysis and two-threshold classification algorithms.

RESULTS: ApoE4 levels ascertained by the e4Quant test exhibited clear genotype-dependent stratification. ROC analysis indicated 100% sensitivity and specificity in distinguishing APOE ε4 carriers from non-carriers, and 88.6% sensitivity and 90.4% specificity for discriminating homozygous from heterozygous carriers. Normalizing ApoE4 to total ApoE improved classification (sensitivity 94.3%, specificity 93.9%). A combined ratio-plus-concentration approach further enhanced discrimination (sensitivity 91.4%, specificity 100%). Three ε4 homozygous samples with low ApoE4/total ApoE ratios were misclassified.

DISCUSSION: The e4Quant assay offers a rapid, cost-effective, and highly accurate biochemical alternative to APOE genotyping, suitable for clinical and research settings, particularly in assessing AD risk and optimizing anti-amyloid therapeutic strategies. One subgroup of APOE ε4/ε4 subjects had unexpectedly low ApoE4 levels, raising questions about potential biological heterogeneity and its impact on Alzheimer's disease biology.

CONCLUSION: The e4Quant assay is a novel alternative for genotyping to determine APOE ε4 carrier status, while also providing quantitative measurements of ApoE4 levels. Its high diagnostic accuracy, ease of use in standard clinical laboratories, and potential utility for personalized medicine in AD treatment highlight its translational value. Further studies are warranted to investigate the clinical significance of APOE ε4 expression variability and its impact on disease progression and treatment response.},
}

Humans
*Apolipoprotein E4/blood/genetics
*Heterozygote
Homozygote
Male
Female
Aged
Alzheimer Disease/genetics/blood
Middle Aged
ROC Curve
Genotype
Aged, 80 and over

@article {pmid40670451,
year = {2025},
author = {Ali, ZH and Hassan, E and Elgamal, S and El-Rashidy, N},
title = {Developing an explainable machine learning and fog computing-based visual rating scale for the prediction of dementia progression.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {25872},
pmid = {40670451},
issn = {2045-2322},
mesh = {Humans ; *Machine Learning ; Aged ; Male ; Female ; *Dementia/diagnosis ; Disease Progression ; Cognitive Dysfunction/diagnosis ; Magnetic Resonance Imaging ; Mental Status and Dementia Tests ; Aged, 80 and over ; Neuropsychological Tests ; Middle Aged ; },
abstract = {Recently, dementia research has primarily concentrated on using Magnetic Resonance Imaging (MRI) to develop learning models in processing and analyzing brain data. However, these models often cannot provide early detection of affected brain regions. Alternatively, mental test scores such as the Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) offer valuable insights into the likelihood of dementia and cognitive impairments. The main objective of this study is to introduce an innovative and dependable context-aware health monitoring system based on fog computing to measure mental impairment in the elderly population. The framework provides screening tests utilizing MMSE and MoCA to achieve accurate and real-time monitoring of cognitive function, allowing for early detection and treatment of mental disorders. To assess the effectiveness of our screening test, we evaluated a dataset comprising 450 subjects with Mild Cognitive Impairment (MCI) from Kaferelshikh University. The aggregated dataset is categorized into three classes: (1) 150 patients with MCI, (2) 150 subjects with subcortical diseases, Parkinson's Disease (PD), and (3) 150 subjects with cortical diseases, Alzheimer's Disease (AD). To accurately determine health risks, we employ an ensemble AdaBoost model, providing superior performance in accuracy, precision, recall, F-score, and Area Under the Curve (AUC). To validate the effectiveness of our Machine Learning (ML) model on unseen data, we evaluate an additional 18 subjects using the proposed scoring test, with six subjects from each class. The results indicate that our proposed ML model achieves an impressive accuracy of 0.93, outperforming the MoCA score (0.90) and MMSE score (0.83). Through our research, we demonstrate the potential of our context-aware fog computing approach in significantly enhancing early diagnosis of dementia, leveraging mental test scores as valuable indicators.},
}

Humans
*Machine Learning
Aged
Male
Female
*Dementia/diagnosis
Disease Progression
Cognitive Dysfunction/diagnosis
Magnetic Resonance Imaging
Mental Status and Dementia Tests
Aged, 80 and over
Neuropsychological Tests
Middle Aged

@article {pmid40668823,
year = {2025},
author = {Castelli, V and Cesare, P and Bej, E and d'Angelo, M and Volpe, AR},
title = {Mechanistic insights into the anti-aging effects of Crocus sativus in a D-Gal-induced in vitro neural senescence model.},
journal = {PloS one},
volume = {20},
number = {7},
pages = {e0320572},
pmid = {40668823},
issn = {1932-6203},
mesh = {*Crocus/chemistry ; *Galactose/pharmacology ; *Cellular Senescence/drug effects ; Animals ; *Plant Extracts/pharmacology ; Reactive Oxygen Species/metabolism ; *Aging/drug effects ; Lipid Peroxidation/drug effects ; Cell Proliferation/drug effects ; Endoplasmic Reticulum Stress/drug effects ; *Neurons/drug effects/metabolism/cytology ; beta-Galactosidase/metabolism ; Glycation End Products, Advanced/metabolism ; Malondialdehyde/metabolism ; Cell Cycle/drug effects ; Humans ; Oxidative Stress/drug effects ; Rats ; },
abstract = {BACKGROUND: The increasing number of elderly individuals has made age-related disorders a significant health concern. Aging is a natural, progressive and gradual phenomenon that leads to irreversible modifications in all molecules, cells, tissues and organs of an organism. Brain senescence is associated with increased risk of developing various neurological diseases, such as Alzheimer's disease, Parkinson's disease, and stroke. Therefore, finding effective strategies to counteract or delay brain senescence is of great importance for improving the quality of life and health span of the elderly population. Previous studies demonstrated that D-galactose is an appropriate agent to induce aging effects in in vivo and in vitro models.

PURPOSE: In the present study, we evaluated anti-aging effects of a local Saffron extract (SE from Central Italy) on D-GAL-induced aging model in vitro. Based on promising preliminary results, future studies will focus on testing this specific Crocus sativus stigma preparation in animal models of aging.

METHODS: The potential anti-aging effect was evaluated using assessment of cell proliferation, live-cell cytotoxicity, Beta-Galactosidase (β-GAL), lipid peroxidation, intracellular reactive oxygen species (ROS), advanced glycation end products (AGEs) and malondialdehyde (MDA) levels. Additionally, the effects of SE pretreatment were examined on cell cycle and endoplasmic reticulum stress. Additionally, we employed a novel approach to analyze deeper changes upon saffron extract treatment, which is label-free holotomography.

RESULTS: Overall, our findings suggested that pretreatment with SE was protective against D-GAL-induced senescence, by counteracting oxidative and endoplasmic reticulum stress and proteins that regulate cell death.

CONCLUSION: We obtained interesting results since pre-treatment with SE ameliorated overall condition, and for the first time we observed the strong anti-aging effect of SE not only in term of morphology, but also dynamics and total dry mass of cells. Overall, our work introduces a novel and promising approach to counteract or delay brain senescence, potentially improving the quality of life and health span of the elderly population.},
}

*Crocus/chemistry
*Galactose/pharmacology
*Cellular Senescence/drug effects
Animals
*Plant Extracts/pharmacology
Reactive Oxygen Species/metabolism
*Aging/drug effects
Lipid Peroxidation/drug effects
Cell Proliferation/drug effects
Endoplasmic Reticulum Stress/drug effects
*Neurons/drug effects/metabolism/cytology
beta-Galactosidase/metabolism
Glycation End Products, Advanced/metabolism
Malondialdehyde/metabolism
Cell Cycle/drug effects
Humans
Oxidative Stress/drug effects
Rats

@article {pmid40668694,
year = {2025},
author = {Padliya, T},
title = {Breaking Barriers With Sound: Focused Ultrasound in the Brain.},
journal = {IEEE pulse},
volume = {16},
number = {3},
pages = {30-35},
doi = {10.1109/MPULS.2025.3572600},
pmid = {40668694},
issn = {2154-2317},
mesh = {Humans ; *Brain/diagnostic imaging ; Magnetic Resonance Imaging ; *Ultrasonic Therapy/methods ; },
abstract = {Focused ultrasound (FUS) is rapidly redefining the landscape of brain therapy, offering a noninvasive, highly precise alternative to traditional neurosurgical techniques. Enabled by advances in phased-array transducer technology, MRI-guided targeting and thermometry, and sophisticated treatment planning software, FUS delivers sub-millimeter accuracy through the skull while sparing surrounding tissue. This article provides a comprehensive yet accessible overview of the core technologies that make FUS possible, including phase correction for skull variability and real-time imaging for safety. We survey the broadening spectrum of clinical applications, from FDA-approved treatments for essential tremor and Parkinson's disease to investigational uses in Alzheimer's, glioblastoma, obsessive-compulsive disorder, and targeted drug delivery. Pioneering trials have demonstrated not only durable tremor control and motor improvement, but also the unique ability to deliver drugs directly to the brain and noninvasively target deep neuropsychiatric circuits.},
}

Humans
*Brain/diagnostic imaging
Magnetic Resonance Imaging
*Ultrasonic Therapy/methods

@article {pmid40668687,
year = {2025},
author = {Kern, R},
title = {Restoring the Brain's Rhythm: A Physics-Driven Approach to Treating Alzheimer's Disease.},
journal = {IEEE pulse},
volume = {16},
number = {3},
pages = {56-59},
doi = {10.1109/MPULS.2025.3572591},
pmid = {40668687},
issn = {2154-2317},
mesh = {Humans ; *Alzheimer Disease/therapy/physiopathology ; *Brain/physiopathology ; *Gamma Rhythm/physiology ; },
abstract = {Alzheimer's disease (AD) has traditionally been addressed through biochemical interventions targeting amyloid and tau pathologies. However, these approaches are constrained by high costs, limited accessibility, and suboptimal efficacy. This article introduces a novel, physics-based therapeutic modality: noninvasive neuromodulation via synchronized visual and auditory stimulation to restore gamma frequency brain rhythms. The Spectris AD device, developed by Cognito Therapeutics, leverages principles of signal processing and systems engineering to drive gamma oscillations in patients with mild to moderate AD. Early clinical studies, including the OVERTURE and FLICKER trials, demonstrate promising results, such as a 77% reduction in functional decline [Alzheimer's disease co-operative study ADL (ADCS-ADL)], a 76% slowing of cognitive decline [mini mental-state exam (MMSE)], and structural brain preservation without the safety risks associated with monoclonal antibodies. The ongoing HOPE pivotal trial aims to validate these findings in a diverse U.S. population. Spectris AD exemplifies a shift from molecular to network-level interventions, offering a scalable, home-based solution that reimagines neurodegenerative treatment as a systems-engineering challenge. This article presents the engineering, clinical data, and broader implications of this pioneering approach to neurotherapeutics.},
}

Humans
*Alzheimer Disease/therapy/physiopathology
*Brain/physiopathology
*Gamma Rhythm/physiology

@article {pmid40667684,
year = {2025},
author = {Gueorguieva, I and Chow, K and Chua, L and Shcherbinin, S and Zimmer, JA and Evans, CD and Wang, H and Nery, ESM and Brooks, DA and Sims, JR},
title = {Donanemab exposure-response in early symptomatic Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {7},
pages = {e70491},
doi = {10.1002/alz.70491},
pmid = {40667684},
issn = {1552-5279},
support = {//Eli Lilly and Company/ ; },
mesh = {Humans ; *Alzheimer Disease/drug therapy ; Male ; Female ; Dose-Response Relationship, Drug ; Aged ; *Antibodies, Monoclonal, Humanized/therapeutic use/pharmacokinetics ; *Plaque, Amyloid/drug therapy ; Disease Progression ; Treatment Outcome ; },
abstract = {INTRODUCTION: These analyses aimed to identify factors impacting donanemab exposure, amyloid plaque, and clinical efficacy in early symptomatic Alzheimer's disease using a population pharmacokinetic/pharmacodynamic (PK/PD) approach.

METHODS: Analyses included donanemab trial participants (NCT02624778; NCT03367403; NCT04640077; NCT04437511). Dose- and exposure-response relationships were characterized relative to amyloid plaque lowering using indirect response PK/PD and disease progression models.

RESULTS: Donanemab population PK was described by a biphasic distribution with an estimated terminal elimination half-life of approximately 12.1 days for a typical participant (72 kg body weight, 1:2560 maximum antidrug antibody [ADA] titer). Amyloid reduction was associated with maintaining median serum donanemab concentrations over 15 µg/mL (95% confidence interval: 8.54, 18.0). After completing active treatment, simulations showed an estimated plaque reaccumulation rate (median, 95% confidence interval) of 2.8 (2.16, 3.11) Centiloids/year. The donanemab disease progression model showed a clear treatment effect.

DISCUSSION: These donanemab models can inform dosing strategies in future clinical trials.

HIGHLIGHTS: Weight-based and flat dosing had similar exposure metrics; flat dosing was adopted. Donanemab exposure was influenced by weight and titer (not clinically relevant). 2.8 Centiloids/year amyloid reaccumulation rate observed upon donanemab treatment completion. Around 30% reduction in disease progression rate on treatment for integrated Alzheimer's Disease Rating Scale (iADRS) and Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB).},
}

Humans
*Alzheimer Disease/drug therapy
Male
Female
Dose-Response Relationship, Drug
Aged
*Antibodies, Monoclonal, Humanized/therapeutic use/pharmacokinetics
*Plaque, Amyloid/drug therapy
Disease Progression
Treatment Outcome

@article {pmid40667349,
year = {2025},
author = {Young, JI and Varma, A and Gomez, L and Schmidt, MA and Kunkle, B and Wang, L and Martin, ER},
title = {Sex-Stratified Transcriptomic Meta-Analysis of Alzheimer's Disease Reveal Brain Region and Sex Specific Dysregulation.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.06.25.661596},
pmid = {40667349},
issn = {2692-8205},
abstract = {OBJECTIVE: Alzheimer disease (AD) is a neurodegenerative disorder leading to cognitive decline. Despite growing recognition of sex differences in epidemiology, symptomatology, and clinical outcomes of AD, the molecular mechanisms underlying these variations remain poorly defined. We performed transcriptome association studies of AD aiming to identify sex-specific and sex-dependent transcriptomic profiles that could provide insights into the molecular mechanisms underlying sex differences in AD pathogenesis.

METHODS: We conducted a meta-analysis of bulk-RNAseq data derived from human postmortem brain studies. Specifically, we analyzed gene expression differences between individuals diagnosed with AD and non-cognitively impaired (NCI) individuals across two key brain regions: the prefrontal cortex and the temporal lobe. We performed stratified differential expression analyses separately in males and females, alongside combined analyses across sexes. Additionally, we assessed the data in relation to known AD genes, proteomic studies, and drug repurposing opportunities.

RESULTS: Beyond the genes commonly dysregulated across both sexes, our meta-analyses identified multiple differentially expressed genes (DEGs) between AD and NCI that are either altered in only one sex or show different effects between sexes. Some genes are known AD genes from genetic studies, but others are novel. Correlation with proteomic data suggests that these transcriptional differences have functional significance, potentially contributing to the biological mechanisms underlying sex differences observed in AD. Finally, we identify drug compounds that are potential candidates for treatment.

INTERPRETATION: Our findings enhance our understanding of sex-related differences in disease etiology and progression, and underscore the importance of incorporating sex as a critical variable in transcriptomic studies of AD. These insights help pave the way for more precise, personalized medicine approaches that account for sex-specific molecular mechanisms.},
}

@article {pmid40666518,
year = {2025},
author = {Liao, Y and Xu, F and Yan, Y and Zhou, S and Liu, N and Dou, B and Srinivasan, N and Wang, W and Zhu, X and Ye, J and Xu, Y},
title = {Chronic ethanol administration exacerbates memory loss by altering N6-methyladenosine-mediated epigenetic signaling.},
journal = {Frontiers in immunology},
volume = {16},
number = {},
pages = {1455994},
pmid = {40666518},
issn = {1664-3224},
mesh = {Animals ; *Adenosine/analogs & derivatives/metabolism ; *Ethanol/administration & dosage/adverse effects/toxicity ; *Epigenesis, Genetic/drug effects ; Mice ; *Memory Disorders/genetics/metabolism/etiology/chemically induced ; Mice, Transgenic ; Signal Transduction/drug effects ; Disease Models, Animal ; Male ; Alzheimer Disease/genetics/metabolism ; },
abstract = {BACKGROUND: Chronic alcohol use disorder (AUD) is recognized as one of the most critical risk factors for the progression of Alzheimer's disease (AD). Epigenetic and neuroimmune alterations are closely associated with the development of memory impairment related to AUD and AD.

METHODS: Adult APP/PS1 transgenic mice received intermittently intraperitoneal injections of ethanol (EtOH, 2.5 g/kg, i.p.) or vehicle with two "drug" treatment days, and one and two "drug-free" days every 7 days for 10 weeks. The novel object recognition (NOR) and Y-maze tests were performed to determine whether chronic ethanol treatment exacerbated memory impairment in these mice. The brain tissues were collected for pathological changes through MeRIP/RNA-sequence analyses and molecular biological assays.

RESULTS: The results suggested that chronic intermittent ethanol (CIE) treatment for 10 weeks exacerbated sporadic and spatial memory deficits in NOR and Y-maze tests in the APP/PS1 mice. The pathological assays revealed that CIE procedure increased Aβ plaque burden in the brain of the AD mice, which were consistent with memory behavioral deficits. The subsequent MeRIP/RNA sequence analyses showed that two genes, e.g. Rbm15b and Hnrnpa2b1, were related to N6-methyladenosine (m[6]A) methylation that plays an important role in the development of memory loss. These results were further supported by molecular biological and mRNA-microRNA-lncRNA ceRNA network analyses that demonstrated that the increased Rbm15b and decreased Hnrnpa2b1 were involved in synaptic dysfunction and neuroinflammation in CIE-induced memory impairment in these AD mice.

CONCLUSIONS: The conclusion is drawn that m[6]A mediated epigenetic dysfunction and immune cells infiltration participate in chronic alcohol use disorder related memory loss in AD mice.},
}

Animals
*Adenosine/analogs & derivatives/metabolism
*Ethanol/administration & dosage/adverse effects/toxicity
*Epigenesis, Genetic/drug effects
Mice
*Memory Disorders/genetics/metabolism/etiology/chemically induced
Mice, Transgenic
Signal Transduction/drug effects
Disease Models, Animal
Male
Alzheimer Disease/genetics/metabolism

@article {pmid40666174,
year = {2025},
author = {Arya, P and Sharma, V and Singh, P and Thapliyal, S and Sharma, M},
title = {Bacterial endotoxin-lipopolysaccharide role in inflammatory diseases: An overview.},
journal = {Iranian journal of basic medical sciences},
volume = {28},
number = {5},
pages = {553-564},
pmid = {40666174},
issn = {2008-3866},
abstract = {Despite advancements in antimicrobial and anti-inflammatory treatments, inflammation and its repercussions continue to pose a considerable challenge in medicine. Acute inflammation may cause life-threatening conditions like septic shock, while chronic inflammation leads to tissue degeneration and impaired function. Lipopolysaccharides (LPS), a well-known pathogenic trigger contributing to several dysfunctions, is a crucial part of the outer membrane of gr-negative bacteria. LPS are well-known for eliciting acute inflammatory responses by activating a pathogen-associated molecular pattern (PAMP), which stimulates the innate immune system and triggers local or systemic inflammatory responses. LPS also activate numerous intracellular molecules that modulate the expression of a wide range of inflammatory mediators. These mediators subsequently initiate or exacerbate various inflammatory processes. Beyond immune cells, LPS can also activate non-immune cells, leading to inflammatory reactions. These excessive inflammatory responses are often detrimental and typically result in chronic and progressive inflammatory diseases, including neurodegenerative, cardiovascular diseases, and cancer. This review delves into the mechanisms by which the bacterial endotoxin LPS contribute to multiple inflammatory diseases. These insights into LPS signaling pathways could inform the design of new treatment strategies such as TLR4, NLRP3, HMGA1, MAPK, and NF-kB inhibitors. This enables precise targeting of inflammation-related processes in disease management.},
}

@article {pmid40665449,
year = {2025},
author = {Chen, BK and Hunsberger, HC and Whye, A and Matthews, LC and Yook, A and Willner, MJ and Logan, RW and Johns, S and Weisblum, E and Denny, CA},
title = {Combinatorial targeting of NMDARs and 5-HT4Rs exerts beneficial effects in a mouse model of Alzheimer's disease.},
journal = {Alzheimer's research & therapy},
volume = {17},
number = {1},
pages = {160},
pmid = {40665449},
issn = {1758-9193},
mesh = {Animals ; *Alzheimer Disease/drug therapy/metabolism/genetics ; Mice ; Male ; Disease Models, Animal ; Female ; *Receptors, Serotonin, 5-HT4/metabolism ; Mice, Transgenic ; *Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors/metabolism ; *Serotonin 5-HT4 Receptor Agonists/pharmacology/administration & dosage ; *Benzofurans/pharmacology/administration & dosage ; *Excitatory Amino Acid Antagonists/pharmacology ; Amyloid beta-Protein Precursor/genetics ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is the leading cause of dementia. There are limited approved medications that delay cognitive decline or lessen neuropsychiatric symptoms. Numerous clinical trials for AD using a single drug administration have failed to meet therapeutic endpoints, which is most likely due to the complexity of AD. A multimodal therapeutic intervention is more likely to improve symptoms by targeting multiple targets implicated in AD. Here, we investigated if targeting both N-Methyl-D-aspartic acid receptors (NMDARs) and serotonin type 4 receptors (5-HT4R) may have beneficial effects in a mouse model of AD, as they have separately been shown to improve cognition and/or mood.

METHODS: Male and female control (Ctrl) or APP/PS1 mice were administered single, intermittent, or chronic administration of 1) saline; 2) (R,S)-ketamine, an NMDAR antagonist; 3) prucalopride, a 5-HT4R agonist; or 4) (R,S)-ketamine + prucalopride to simultaneously target co-morbid neuropsychiatric and cognitive deficits. Behavioral assays were then administered to measure cognition, perseverative behavior, hyponeophagia, and/or sleep. Brains were processed for glial fibrillary acidic protein (GFAP) immunohistochemistry.

RESULTS: Single and chronic administration of (R,S)-ketamine + prucalopride administration improved cognitive decline by increasing memory retrieval in a contextual fear conditioning (CFC) paradigm in APP/PS1 mice. Drug efficacy was less effective in females than in males and was age dependent. Hippocampal GFAP immunoreactivity was decreased by chronic (R,S)-ketamine + prucalopride treatment in females.

CONCLUSIONS: Our results indicate that combined administration of (R,S)-ketamine + prucalopride is a novel multimodal therapeutic strategy to treat cognitive decline in AD. Future work will further characterize these interactions with the goal of clinical development.},
}

Animals
*Alzheimer Disease/drug therapy/metabolism/genetics
Mice
Male
Disease Models, Animal
Female
*Receptors, Serotonin, 5-HT4/metabolism
Mice, Transgenic
*Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors/metabolism
*Serotonin 5-HT4 Receptor Agonists/pharmacology/administration & dosage
*Benzofurans/pharmacology/administration & dosage
*Excitatory Amino Acid Antagonists/pharmacology
Amyloid beta-Protein Precursor/genetics

@article {pmid40665063,
year = {2025},
author = {Yu, L and Yang, X and Lei, HP and Hu, YT and Wu, LN and Zhou, SY and Jin, F},
title = {Multiple Mechanisms and Therapeutic Strategies for the Involvement of AMPK in the Development of Alzheimer's Disease.},
journal = {Molecular neurobiology},
volume = {},
number = {},
pages = {},
pmid = {40665063},
issn = {1559-1182},
support = {ZK [2023]058//the Key Projects of Basic Research Program of the Science and Technology Department of Guizhou Province/ ; ZK [2023]058//the Key Projects of Basic Research Program of the Science and Technology Department of Guizhou Province/ ; ZK [2023]058//the Key Projects of Basic Research Program of the Science and Technology Department of Guizhou Province/ ; ZK [2023]058//the Key Projects of Basic Research Program of the Science and Technology Department of Guizhou Province/ ; ZK [2023]058//the Key Projects of Basic Research Program of the Science and Technology Department of Guizhou Province/ ; ZK [2023]058//the Key Projects of Basic Research Program of the Science and Technology Department of Guizhou Province/ ; ZK [2023]058//the Key Projects of Basic Research Program of the Science and Technology Department of Guizhou Province/ ; 82060727//National Natural Science Foundation of China/ ; 82060727//National Natural Science Foundation of China/ ; 82060727//National Natural Science Foundation of China/ ; 82060727//National Natural Science Foundation of China/ ; 82060727//National Natural Science Foundation of China/ ; 82060727//National Natural Science Foundation of China/ ; 82060727//National Natural Science Foundation of China/ ; },
abstract = {Alzheimer's disease (AD) is a major cause of dementia, a life-threatening condition for which there is currently no cure. Currently, the treatment of AD focuses on reducing the accumulation of amyloid β-protein (Aβ) and the phosphorylation of Tau proteins (Tau). However, simply reducing pathological features does not completely improve AD. Therefore, there is an urgent need to explore a target that regulates AD-related pathologies and highlights its potential as a novel therapeutic target. Recent studies suggest that oxidative stress, neuroinflammation, autophagy dysfunction, and energy metabolism alterations are associated with the development of AD. Reviewing previous data, we found that AMP-activated protein kinase (AMPK) not only acts as a cellular energy sensor to influence the progression of AD, but also activation of AMPK affects the pathologic processes above. In this review, we provide an update on activating the AMPK pathway with targeting in AD therapy. Finally, research has shown that compounds can activate the AMPK pathway to affect a series of cellular processes and improve AD. We propose that AMPK activation represents a paradigm-shifting strategy for AD therapy by simultaneously targeting multiple pathological cascades, although challenges in isoform-specific activation and brain delivery warrant further investigation.},
}

@article {pmid40665048,
year = {2025},
author = {Imam, F and Saloner, R and Vogel, JW and Krish, V and Abdel-Azim, G and Ali, M and An, L and Anastasi, F and Bennett, D and Pichet Binette, A and Boxer, AL and Bringmann, M and Burns, JM and Cruchaga, C and Dage, JL and Farinas, A and Ferrucci, L and Finney, CA and Frasier, M and Hansson, O and Hohman, TJ and Johnson, ECB and Kivimaki, M and Korologou-Linden, R and Ruiz Laza, A and Levey, AI and Liepelt-Scarfone, I and Lu, L and Mattsson-Carlgren, N and Middleton, LT and Nho, K and Oh, HS and Petersen, RC and Reiman, EM and Robinson, O and Rothstein, JD and Saykin, AJ and Shvetcov, A and Slawson, C and Smets, B and Suárez-Calvet, M and Tijms, BM and Timmers, M and Vieira, F and Vilor-Tejedor, N and Visser, PJ and Walker, KA and Winchester, LM and Wyss-Coray, T and Yang, C and Bose, N and Lovestone, S and , },
title = {The Global Neurodegeneration Proteomics Consortium: biomarker and drug target discovery for common neurodegenerative diseases and aging.},
journal = {Nature medicine},
volume = {},
number = {},
pages = {},
pmid = {40665048},
issn = {1546-170X},
abstract = {More than 57 million people globally suffer from neurodegenerative diseases, a figure expected to double every 20 years. Despite this growing burden, there are currently no cures, and treatment options remain limited due to disease heterogeneity, prolonged preclinical and prodromal phases, poor understanding of disease mechanisms, and diagnostic challenges. Identifying novel biomarkers is crucial for improving early detection, prognosis, staging and subtyping of these conditions. High-dimensional molecular studies in biofluids ('omics') offer promise for scalable biomarker discovery, but challenges in assembling large, diverse datasets hinder progress. To address this, the Global Neurodegeneration Proteomics Consortium (GNPC)-a public-private partnership-established one of the world's largest harmonized proteomic datasets. It includes approximately 250 million unique protein measurements from multiple platforms from more than 35,000 biofluid samples (plasma, serum and cerebrospinal fluid) contributed by 23 partners, alongside associated clinical data spanning Alzheimer's disease (AD), Parkinson's disease (PD), frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). This dataset is accessible to GNPC members via the Alzheimer's Disease Data Initiative's AD Workbench, a secure cloud-based environment, and will be available to the wider research community on 15 July 2025. Here we present summary analyses of the plasma proteome revealing disease-specific differential protein abundance and transdiagnostic proteomic signatures of clinical severity. Furthermore, we describe a robust plasma proteomic signature of APOE ε4 carriership, reproducible across AD, PD, FTD and ALS, as well as distinct patterns of organ aging across these conditions. This work demonstrates the power of international collaboration, data sharing and open science to accelerate discovery in neurodegeneration research.},
}

@article {pmid40664126,
year = {2025},
author = {Jangid, K and Devi, B and Kumar, N and Upadhayay, S and Kumar, V and Thareja, S and Kumar, V},
title = {ML-based prediction to experimental validation: Development of dihydroquinazoline based multi-potent ligands as anti-Alzheimer's agents.},
journal = {Computers in biology and medicine},
volume = {196},
number = {Pt A},
pages = {110762},
doi = {10.1016/j.compbiomed.2025.110762},
pmid = {40664126},
issn = {1879-0534},
abstract = {Alzheimer's disease (AD) is a multifactorial neurological disorder accounting for the cognitive decline in the patients. The disease is linked to numerous pathological factors including hyperactivation of acetylcholinesterase (AChE) and monoamine oxidase B (MAO-B), accumulation of amyloid-beta (Aβ) plaques and neurofibrillary tangles in the brain etc. The single-target medications already available in the market are found to be ineffective and the research focus is shifting towards the development of multitargeting agents. In order to find a multi-potent inhibitor against AChE, MAO-B and Aβ1-42, in the present study we employed a machine learning-based tool, PyRMD, to screen an in-house generated library of dihydroquinazoline derivatives. This screening process identified six promising compounds, KV-271, KV-832, KV-968, KV-1131, KV-1159, KV-1234 with dual inhibition potential against AChE and MAO-B enzymes. In the docking studies, these compounds showed good interactions at the active cavity of the AChE and MAO-B comparable to the standard inhibitors donepezil (AChE) and pargyline (MAO-B). To validate these predictions, the six identified compounds were synthesized and subjected to in vitro enzymatic assays. All the six compounds displayed significant inhibitory activity, with IC50 values below 5 μM for both AChE and MAO-B. Amongst these compounds, KV-1131 and KV-1234 were found to be the most potent inhibitors with IC50 values of 0.93 μM and 0.85 μM against AChE and IC50 values of 1.17 μM and 0.79 μM against MAO-B, respectively. In addition, KV-1131 and KV-1234 exhibited inhibitory activity against Aβ1-42 self-aggregation inhibition of 34.79 % and 45.70 %, respectively, after 48 h of incubation. Both KV-1131 and KV-1234 were found to be non-toxic up to 10 μM concentration and showed neuroprotective potential against 6-hydroxydopamine induced neurotoxicity in the SHSY-5Y cells. Thus, KV-1131 and KV-1234 were identified as potent leads that can be developed as drug candidates for the treatment of Alzheimer's disease.},
}