@article {pmid40812500,
year = {2025},
author = {Su, WS and Wu, MT and Cheng, IH and Yang, FY},
title = {Low-intensity pulsed ultrasound enhances microglial-mediated Aβ clearance and synaptic preservation in an APP transgenic mouse model of Alzheimer's disease.},
journal = {Experimental neurology},
volume = {},
number = {},
pages = {115420},
doi = {10.1016/j.expneurol.2025.115420},
pmid = {40812500},
issn = {1090-2430},
abstract = {Alzheimer's disease (AD) is characterized by amyloid-β (Aβ) plaque accumulation and neurofibrillary tangles, leading to neuroinflammation, synaptic dysfunction, and cognitive decline. Despite extensive research, current therapies for AD show limited efficacy. Low-intensity pulsed ultrasound (LIPUS) has emerged as a promising non-invasive therapeutic approach due to its neuroprotective and immunomodulatory properties. This study investigates the effects of LIPUS on Aβ pathology, neuroinflammation, and cognitive deficits in a transgenic AD mouse model. Twelve-month-old J20 transgenic mice expressing human amyloid precursor protein (APP) were used to model middle-to-late-stage AD. LIPUS was administered for 30 days, targeting the bilateral hippocampus. Spatial memory was assessed via the Morris water maze (MWM). Aβ plaque burden and synaptic integrity were quantified using immunofluorescence and Thioflavin-S staining. Western blot analysis evaluated neurotrophic factors, inflammatory markers, and synaptic proteins (PSD95). LIPUS treatment significantly improved spatial learning and memory deficits in APP transgenic mice, as evidenced by reduced escape latency and increased platform crossings in the MWM test. LIPUS significantly reduced hippocampal amyloid plaque burden and promoted microglial recruitment to Aβ plaques. Importantly, LIPUS downregulated TNF-α expression without affecting IL-6 levels, suggesting enhanced Aβ clearance without inducing neuroinflammation. Furthermore, LIPUS increased synaptophysin expression in the CA3-mossy fiber and dentate gyrus (DG) regions, while PSD95 levels remained unchanged. Our findings demonstrate that LIPUS enhances microglial-mediated Aβ clearance, preserves synaptic integrity, and improves cognitive function in a transgenic AD model. As a non-invasive modality capable of targeting deep brain structures, LIPUS holds promise as a potential therapeutic strategy for AD.},
}

@article {pmid40812427,
year = {2025},
author = {Wu, J and Chai, K and Tu, Y and Fang, K and Shi, S and Hu, X and Liu, J and Yao, T},
title = {Multifunctional Molecular Agent for Tau-targeted Combinational Therapy of Alzheimer's Disease.},
journal = {The Journal of biological chemistry},
volume = {},
number = {},
pages = {110583},
doi = {10.1016/j.jbc.2025.110583},
pmid = {40812427},
issn = {1083-351X},
abstract = {Tau aggregation inhibitors or neurotoxic-metal chelators have been extensively studied as potential treatment for Alzheimer's disease. However, it is a great challenge to improve their therapeutic effects while reducing neurotoxicity. Herein, we designed and synthesized two new compounds, (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl)tetrakis((3,4,5-trihydroxyphenyl)methanone) (4GA) and (4,10-dimethyl-1,4,7,10-tetraazacyclododecane-1,7-diyl)bis((3,4,5-trihydroxyphenyl)methanone) (2GA). Each molecule is composed of a 1,4,7,10-tetraazacyclododecane (cyclen) core as the supramolecular chelator to copper ions, attached by 2 or 4 gallic acid polyphenol arms to capture tau peptide chain like a molecular hairpin. We interestingly found 4GA and 2GA could inhibit self-aggregation through blocking the misfolding of tau peptide, suppress the promotion of Cu[2+] on tau aggregation by removing Cu[2+] from dyshomeostasis, and clear reactive oxygen species (ROS) triggered by Cu[2+] using their reductive gallic acid groups. More significantly, the synthesized compounds exhibit remarkable efficiency on both in vitro and at cellular level. Our rational design of multifunctional therapeutic agent that simultaneously targets tau misfolding process, copper dyshomeostasis and oxidative stress of ROS, may hold considerable implications for the treatment of AD.},
}

@article {pmid40811673,
year = {2025},
author = {Goodland, MN and Banerjee, S and Niehoff, ML and Young, BJ and Macarthur, H and Butler, AA and Morley, JE and Farr, SA},
title = {Cannabidiol improves learning and memory deficits and alleviates anxiety in 12-month-old SAMP8 mice.},
journal = {PloS one},
volume = {20},
number = {8},
pages = {e0296586},
doi = {10.1371/journal.pone.0296586},
pmid = {40811673},
issn = {1932-6203},
abstract = {Cannabidiol (CBD) has gained a lot of interest in recent years for its purported medicinal properties. CBD has been investigated for the treatment of anxiety, depression, epilepsy, neuroinflammation, and pain. Recently there has been an interest in CBD as a possible treatment for age-related disorders such as Alzheimer's disease and related disorders (ADRD). Here we tested the hypothesis that chronic CBD administration would improve learning and memory in the SAMP8 mouse model of Alzheimer's disease. SAMP8 mice aged 11 months (at the start of the study) were administered vehicle or CBD (3 or 30 mg/Kg) daily via oral gavage for 2 months. Vehicle-treated young SAMP8 mice (age 3 months at the start of the study) served as unimpaired controls. After 30 days of treatment (4 and 12 months of age), learning and memory, activity, anxiety, strength and dexterity were assessed. High dose CBD treatment significantly improved learning and memory of the 12-month-old mice in the T maze. Novel object recognition memory was also improved by CBD in aged CBD treated mice. Aged CBD treated mice also displayed less anxiety in the elevated plus maze test compared to controls. However, activity and strength levels were similar between groups. Biochemical analysis revealed decreased markers of oxidative stress, providing a possible mechanism by which CBD treatment impacts learning, memory, and anxiety. These results highlight the potential use of CBD as a therapeutic for age related cognitive impairment and dementia.},
}

@article {pmid40811499,
year = {2025},
author = {Fernandez-Mendoza, J},
title = {Insomnia Phenotypes, Cardiovascular Risk and Their Link to Brain Health.},
journal = {Circulation research},
volume = {137},
number = {5},
pages = {727-745},
pmid = {40811499},
issn = {1524-4571},
abstract = {About 30% to 40% of the general population experiences insomnia symptoms of difficulty initiating or maintaining sleep, and another 10% to 15% of the general population experiences chronic insomnia disorder. The prevalence of insomnia is disproportionately higher in people with cardiometabolic risk factors, cardiovascular diseases, cerebrovascular diseases, and neurocognitive disorders, including vascular cognitive impairment. In fact, recent meta-analytic evidence from epidemiological studies has demonstrated that insomnia, especially when accompanied by objective short sleep duration, is a risk factor for incident hypertension, type 2 diabetes, heart failure, stroke, cognitive impairment, Alzheimer disease, and all-cause mortality. Insomnia should, thus, be part of the prevention and management of these adverse health outcomes. However, randomized clinical trials have not demonstrated whether treatment with cognitive-behavioral therapy for insomnia, the first-line guideline-recommended treatment, or hypnotics/sedatives improves heart- or brain-related outcomes. Studies have also failed to consider insomnia a heterogeneous disorder consisting of distinct phenotypes that result from the relative contribution of biological versus cognitive-behavioral perpetuating factors. Objective short sleep duration has emerged as a marker of physiological hyperarousal in insomnia (ie, dysregulation of the hypothalamic-pituitary axis, increased sympathetic nervous system activation, and increased inflammation), as a predictor of insomnia-related adverse heart and brain health outcomes and, potentially, poor response to cognitive-behavioral therapy for insomnia. This review summarizes the meta-analytic evidence on the association of insomnia with cardiometabolic risk factors, cardiovascular diseases, cerebrovascular diseases, and neurocognitive disorders, including current knowledge on the heterogeneity of the disorder. This review also summarizes the potential pathophysiologic mechanisms that lead to heart and brain morbidity, which vary across insomnia phenotypes based on objective sleep duration. This review suggests that basic and clinical sciences need to unveil the molecular, cellular, and behavioral mechanisms at play across insomnia phenotypes, as the public health and clinical implications of their association with adverse heart and brain health are demanding immediate attention.},
}

@article {pmid40810748,
year = {2025},
author = {Nabizadeh, A and Rafati, A and Karbalaei, N and Namavar, MR and Hosseinzadeh, S and Moatamed Jahromi, H and Rahimi, A and Naseh, M},
title = {Probiotic effects on cognitive performance, hippocampal oxidative stress, and structural damage induced by icv STZ in Alzheimer-like rat model.},
journal = {Brain structure & function},
volume = {230},
number = {7},
pages = {135},
pmid = {40810748},
issn = {1863-2661},
abstract = {Alzheimer's disease (AD) is a deteriorating neurodegenerative disorder defined by cognitive decline and neuronal damage, with oxidative stress and neuroinflammation as central pathological features. Emerging evidence suggests the gut-brain axis is a key modulator in neurodegeneration, highlighting probiotics' potential in mitigating AD progression. This study investigates the effects of Lactobacillus acidophilus ATCC4356, Lactobacillus reuteri DSM 17938, and their combination on cognitive performance, oxidative stress, and hippocampal structure in a streptozotocin (STZ)-induced AD-like rat model. Thirty-Five male Sprague-Dawley rats were randomly assigned to five groups: Sham, AD-like model (STZ), STZ + Ac, STZ + Re, and STZ + Comb. The AD-like model was induced via intracerebroventricular (icv) injection of STZ. Probiotics were administered by gavage for 35 days. Behavioral assessments, including the open field test and Morris water maze, were conducted to evaluate cognitive and anxiety-like behaviors. Hippocampal oxidative stress markers, including malondialdehyde (MDA), glutathione, superoxide dismutase, and catalase , were analyzed biochemically. Additionally, stereological techniques were used to assess hippocampal volume and cellular densities. Behavioral results demonstrated significant improvement in anxiety-like behavior and spatial memory in probiotic-treated groups compared to the STZ group. Biochemical analysis revealed reduced MDA levels and enhanced antioxidant markers following probiotic intervention. Histological and stereological analyses indicated increased neuronal density and reduced glial cell activation in hippocampal subregions (CA1, CA3, DG), though hippocampal volume loss remained unaltered. These findings underscore the neuroprotective potential of probiotics in alleviating AD-related neurodegeneration, possibly through antioxidative and anti-inflammatory mechanisms. Further pre-clinical studies are warranted to optimize probiotic regimens for AD prevention and treatment.},
}

@article {pmid40810239,
year = {2025},
author = {Jinglei, J and Tao, YU and Yulin, Q and Meng, W},
title = {Understanding the role of microglia in Alzheimer's disease: insights into mechanisms, acupuncture, and potential therapeutic targets.},
journal = {Journal of traditional Chinese medicine = Chung i tsa chih ying wen pan},
volume = {45},
number = {4},
pages = {922-936},
pmid = {40810239},
issn = {2589-451X},
abstract = {Microglia (MG) are immune effector cells in the central nervous system (CNS) and play a pivotal role in the pathogenesis of various CNS diseases. Alzheimer's disease (AD) is defined as a severe chronic degenerative neurological disease in humans. The amyloid cascade hypothesis is a hypothesis on the pathogenesis of AD that suggests that abnormal extracellular aggregation of β-amyloid (Aβ) peptides is the main cause of the disease. Although this hypothesis has been found to be convincing, a growing body of evidence suggests that it does not fully explain the pathogenesis of AD. Neuroinflammation is a crucial element in the pathogenesis of AD, as evidenced by elevated levels of inflammatory markers and the identification of AD risk genes associated with innate immune function. This paper will first summarize the impact of microglia-mediated neuroinflammation on AD, exploring the phenotypic changes that follow microglia activation. Secondly, the interactions between microglia, Aβ, microtubule-associated protein, apolipoprotein E and neurons are thoroughly investigated, with particular focus on the interactive mechanisms. Furthermore, the recent progress and prospects of microglia as a diagnostic and therapeutic target for AD are analysed. A review of the literature on the mechanisms regulating MG for AD at home and abroad revealed that acupuncture modulation of microglia could help to delay the progression of AD. This was followed by an extensive discussion of the clinical possibilities and scientific validity of acupuncture treatment for AD, with the aim of providing new insights for acupuncture modulation of MG targeting for the treatment of AD.},
}

@article {pmid40810165,
year = {2025},
author = {Jeon, MT and Sung, B and Lee, JW and Hwang, DW and Lee, E and Kim, HK and Kim, DK and Kim, DG and Chang, Y},
title = {Therapeutic Potential of a Gadolinium Chelate Complex Conjugated with Vanillic Acid for Alzheimer's Disease.},
journal = {ACS pharmacology & translational science},
volume = {8},
number = {8},
pages = {2725-2735},
pmid = {40810165},
issn = {2575-9108},
abstract = {Magnetic resonance imaging (MRI) is a widely used diagnostic tool for neurodegenerative diseases, including Alzheimer's disease. A gadolinium chelate conjugated with vanillic acid (Gd-DO3A-Va) serves as a contrast agent that specifically targets activated microglia in the brains of Alzheimer's disease animal models, such as the 5XFAD mouse. In this study, we evaluated the therapeutic potential of Gd-DO3A-Va in this model. The 5XFAD mouse exhibits neuroinflammation, characterized by activation of the c-Jun N-terminal kinase signaling pathway, inflammasome activation, and increased amyloid-β (Aβ) production(?)all of which are pathological features of Alzheimer's disease. Treatment with Gd-DO3A-Va reduced inflammatory responses and Aβ deposits. Additionally, the peri-plaque dendritic loss observed in the brains of 5XFAD mice was attenuated following Gd-DO3A-Va treatment. Moreover, Gd-DO3A-Va treatment prevented memory loss, as indicated by the Y-maze test. Taken together, these findings suggest that Gd-DO3A-Va, an MR contrast agent that provides disease-specific signal enhancement in the brains of animal models of Alzheimer's disease, shows promising therapeutic potential for preventing disease progression by suppressing inflammation and inhibiting Aβ production. Therefore, Gd-DO3A-Va could serve as a theranostic agent for Alzheimer's disease.},
}

@article {pmid40810164,
year = {2025},
author = {Alo, B and Lamers, C},
title = {Crossing Barriers: Advancements in Macromolecular Therapeutics for Neurodegenerative Diseases and Strategies to Overcome the Blood-Brain Barrier.},
journal = {ACS pharmacology & translational science},
volume = {8},
number = {8},
pages = {2353-2383},
pmid = {40810164},
issn = {2575-9108},
abstract = {Neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, present considerable challenges for our societies and health systems due to their progressive nature, the demographic shift toward older populations, and limited treatment options. Recent advances in macromolecular therapeutics, including antibodies, peptides, and proteins, offer novel therapeutic modalities for a broad range of diseases. Their high potency and specificity hold promise for disease-modifying therapies to combat neurodegenerative diseases. However, the blood-brain barrier poses a significant challenge for the effective delivery of these large molecules to the central nervous system. This review discusses the physiological role of the blood-brain barrier and its influence on restricting the exposure of macromolecules in the brain. Furthermore, emerging strategies for enhancing blood-brain barrier permeability to macromolecules are highlighted. This review summarizes modifications designed to utilize receptor-mediated uptake, adsorptive-mediated transcytosis, carrier-mediated transport, and nanoparticle-based delivery systems to overcome the blood-brain barrier. Additionally, we emphasize the importance of testing macromolecular therapeutics for their blood-brain barrier permeability and review the methods for such in vitro and in vivo testing. Finally, we shed light on therapeutics in preclinical and clinical development for neurodegenerative diseases and their challenges.},
}

@article {pmid40810098,
year = {2025},
author = {Cao, H and Zhong, J and Chen, L},
title = {Alterations of the oral microbiota in mild Alzheimer's disease and the appropriate application of chlorhexidine gluconate.},
journal = {JAR life},
volume = {14},
number = {},
pages = {100024},
pmid = {40810098},
issn = {2534-773X},
abstract = {OBJECTIVE: This study investigated the effect of 0.2 % chlorhexidine gluconate on oral microbiota dysbiosis in Alzheimer's disease (AD) and explored potential links between oral microbiota and cognition, offering new insights into its role in AD treatment.

STUDY DESIGN: We assessed the impact of 0.2 % chlorhexidine gluconate on the oral microbiota of patients with AD. One hundred patients were divided into two groups based on oral health score (using a cut-off of 8). Subgingival plaque samples were analyzed using 16S rRNA sequencing; no significant differences in bacterial composition were observed between groups at baseline.

RESULTS: Poor oral health correlated with higher oral health scores (P = 0.000), fewer teeth (P = 0.002), lower cognitive levels (P = 0.048), and a higher proportion of patients with diabetes (P = 0.032). After 24 weeks of treatment with 0.2 % chlorhexidine gluconate in a randomized controlled trial, subgingival plaques from 66 patients showed changes in Porphyromonas, Filifactor, Desulfobulbus, Anaeroglobus, Pyramidobacter, Mycoplasma, Dialister, Fretibacterium, and Tannerella (P < 0.05). Treponema and Porphyromonas gingivalis were identified as potential interventional targets.

CONCLUSION: Chlorhexidine gluconate effectively alters oral flora, reducing harmful bacteria. Targeting specific microbiota disturbances may offer a promising strategy to delay AD onset or slow its progression.

TRIAL REGISTRATION: This research was registered with the Chinese Clinical Trial Registry (ChiCTR; Reference: ChiCTR2000032876). Registered: 14th of May 2020; http://www.chictr.org.cn/showprojen.aspx?proj=53555.},
}

@article {pmid40809903,
year = {2025},
author = {Koch, G and Assogna, M and Gadola, Y and Alberici, A and Di Lorenzo, F and Bonnì, S and Borghi, I and Cerulli Irelli, E and Mencarelli, L and Maiella, M and Esposito, R and Casula, EP and Pezzopane, V and D'Acunto, A and Candeo, F and Ferraresi, M and Guerrera, G and Battistini, L and Premi, E and Bracca, V and Lucchini, S and Bertagna, F and Romano, P and Ludovici, A and Daniele, A and Motta, C and Ferrari, C and Martorana, A and Borroni, B},
title = {Safety and efficacy of rotigotine in patients with frontotemporal dementia: a phase 2, double-blind, randomized, placebo-controlled, multicenter trial.},
journal = {The Lancet regional health. Europe},
volume = {57},
number = {},
pages = {101409},
pmid = {40809903},
issn = {2666-7762},
abstract = {BACKGROUND: Frontotemporal dementia (FTD) is a common form of dementia with no approved pharmacological treatment. Clinical and experimental evidence suggest that dopaminergic transmission is impaired in FTD. Here we aimed at investigating the clinical impact of treatment with dopaminergic agonists in FTD.

METHODS: This was a phase IIa 24-week randomized, double-blind, multicenter, placebo-controlled study, conducted in Italy from June 16th 2021 to April 30th 2023. Patients with a diagnosis of probable behavioral variant FTD (bvFTD) were randomly assigned in a 1:1:1 ratio to receive rotigotine transdermal patches at 4 mg/24 h, rotigotine transdermal patches at 6 mg/24 h, or placebo transdermal patches for 24 weeks. Randomization was centralized and performed using a double-blind covariate-adaptive scheme. The primary outcome was analyzed in the intention-to treat (ITT) population. The primary efficacy outcome measure was the change at 24-weeks from baseline in the Frontal Assessment Battery (FAB). The trial is completed and was registered on the clinicaltrial.gov website (NCT04937452).

FINDINGS: A total of 128 patients were screened, of which 75 were randomized. 25 patients were randomized to receive Rotigotine 4 mg, 26 patients to Rotigotine 6 mg, and 24 patients to placebo. The mean age of patients was 66.5 ± 8 of which 31 (41%) were female. A total of 69 patients (92%) completed the study. The estimated mean change from baseline at 24 weeks in the FAB score in the ITT population was 0.18 (95% confidence interval [CI] -0.79 to 1.15) in the rotigotine 4 mg group, 0.89 (95% CI -0.09 to 1.88) in the rotigotine 6 mg group and 1.08 (95% CI 0.19-1.98) in the placebo group (rotigotine 4 mg vs placebo, -0.90; 95% CI -2.22 to 0.42; p = 0.18; rotigotine 6 mg vs placebo, -0.19; 95% CI -1.52 to 1.14; p = 0.77). No significant effect was found on secondary outcome measures. Adverse events were mild in all groups and more common in the rotigotine (4 mg: 4/25; 6 mg: 3/26) than in the placebo (1/24) group.

INTERPRETATION: Rotigotine administration may not be a viable therapeutic option for enhancing frontal function, slowing disease progression, mitigating functional decline or ameliorating behavioral disturbances in bvFTD patients. The current findings provide data in a large sample of bvFTD that might be useful for the design of future clinical trials.

FUNDING: This trial was funded by a joint grant from the Alzheimer Drug Discovery Foundation (ADDF) and the Association for Frontotemporal Degeneration (AFTD) grant to GK and BB (GFTD-201902-2017958).},
}

@article {pmid40808707,
year = {2025},
author = {Aydın, B and Aydın, AS and Çeçen, Ö and Yuca, H and Bona, GE and Demirci, B and Bona, M and Karakaya, S},
title = {From Herbal Tea to Science: Phytochemical and Biological Investigation of Ajuga chamaepitys subsp. chia (Lamiaceae) With Molecular Docking Analysis.},
journal = {Food science & nutrition},
volume = {13},
number = {8},
pages = {e70749},
pmid = {40808707},
issn = {2048-7177},
abstract = {The hypothesis that insulin resistance and impaired insulin-like growth factor signaling contribute to Alzheimer's disease (AD) has led to the designation of AD as "type 3 diabetes." Ajuga chamaepitys subsp. chia is traditionally used in Türkiye as an analgesic, tonic, and for the external treatment of hemorrhoids and wound healing. This study evaluates antioxidant, antidiabetic, and anticholinesterase activities of methanolic, aqueous extracts, and essential oils from the flowering aerial parts of A. chamaepitys subsp. chia, along with their phytochemical profiles (GC-MS/MS), morphological-anatomical characteristics, and molecular docking analysis. The essential oil yield was 0.002%, comprising 45 compounds (92.5%), with β-pinene (19.8%), α-pinene (12.8%), and germacrene D (10.0%) as major constituents, dominated by monoterpene (39.8%) and sesquiterpene hydrocarbons (23.5%). The methanolic extract exhibited moderate bioactivity, achieving 28.36% α-amylase inhibition at 5000 μg/mL and 21.85% acetylcholinesterase inhibition at 100 μg/mL, while also demonstrating notable antioxidant activity with 23.013% ABTS[•+] and 8.114% DPPH[•] scavenging. It showed the highest total phenolic (14.261 μg GAE/mg) and tannin content (34.444 μg TAE/mg) among the tested extracts. Morphologically, the plant features hairy stems and tripartite leaves with a cuticle, trichomes, and diacytic stomata, while anatomically, it presents collenchyma, starch-filled parenchyma, and a distinct cambium in the stem. Molecular docking studies revealed that germacrene D exhibited strong binding affinities to acetylcholinesterase, butyrylcholinesterase, α-amylase, and α-glucosidase, suggesting multitarget inhibition potential. These findings support the traditional use of A. chamaepitys subsp. chia and highlight its promise as a natural source for therapeutic agents targeting oxidative stress, diabetes, and neurodegenerative diseases.},
}

@article {pmid40808471,
year = {2025},
author = {Zhang, L and Cai, L and Lin, H and Wu, W and Zhu, Y and Cai, J and Hu, C and Lin, X and Sun, H and Wei, X},
title = {Two Birds With One Stone: The Protective Role of the Antidiabetic Drug Sodium-Glucose Cotransporter-2 Inhibitor in Neurodegenerative Diseases.},
journal = {The European journal of neuroscience},
volume = {62},
number = {3},
pages = {e70221},
doi = {10.1111/ejn.70221},
pmid = {40808471},
issn = {1460-9568},
support = {2021J01397//Natural Science Foundation of Fujian, China/ ; 2022GGA010//Fujian Provincial Health Technology Project/ ; 2023Y9347//Fujian Provincial Joint Funding Project of Scientific and Technological Innovation/ ; 2023Y9298//Fujian Provincial Joint Funding Project of Scientific and Technological Innovation/ ; 2023Y9343//Fujian Provincial Joint Funding Project of Scientific and Technological Innovation/ ; },
abstract = {The neuroprotective role of sodium-glucose cotransporter-2 inhibitor (SGLT2i) has attracted considerable interest. The purpose of this study was to investigate the role of SGLT2i in several common neurodegenerative diseases (NDs), including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS). Utilizing drug-target Mendelian randomization (MR) and colocalization, we used single nucleotide polymorphisms (SNPs) proximal to the SLC5A2 gene to analyze the influence of SGLT2i on AD, PD, ALS, and MS. Sensitivity analyses were performed to assess heterogeneity and pleiotropy. Phenome-wide association study (PheWAS) was used to probe the relationship of SGLT2i with other characteristics. Protein-protein interaction (PPI) networks were used to explore how SLC5A2 affects other proteins, and enrichment analysis was used to explore possible biological processes. The MR analysis showed that SGLT2i was negatively associated with AD (OR = 0.77, p = 0.01), PD (OR = 0.52, p = 0.04), ALS (OR = 0.60, p = 0.01), and MS (OR = 0.33, p = 0.027), indicating that SGLT2i could reduce the risk of AD by 23%, PD by 48%, ALS by 40%, and MS by 67%. The colocalization supported this conclusion. The PheWAS showed that SGLT2i was associated with body mass index and systolic blood pressure. SGLT2i is biologically closely related to the development of NDs. This study suggested that SGLT2i was able to reduce the risk of NDs. SGLT2i may perform this process through many mechanisms. This study provides a new perspective on the treatment of NDs; clinical trials and relevant experiments are necessary to further validate the neuroprotective effects of SGLT2i.},
}

@article {pmid40808466,
year = {2025},
author = {Martinez, B and Peplow, PV},
title = {Amelioration of behavioral and neural deficits in animal models of neurodegenerative disease by nanoformulations of curcumin and quercetin.},
journal = {Neural regeneration research},
volume = {},
number = {},
pages = {},
doi = {10.4103/NRR.NRR-D-25-00343},
pmid = {40808466},
issn = {1673-5374},
abstract = {Neurodegenerative diseases are increasing in prevalence due largely to aging populations worldwide and improved medical care for the elderly. Currently approved drugs can reduce some of the symptoms of neurodegenerative diseases but cannot cure them. Inflammation is involved in the development and progression of neurodegenerative diseases, and oxidative stress is implicated in neurodegeneration associated with cognitive decline and age-related cognitive impairment. Polyphenols such as curcumin, quercetin, and resveratrol possess potent anti-inflammatory and antioxidant properties. Nanoformulations of curcumin and quercetin can optimize their pharmacological effects in the treatment of neurodegenerative diseases. Nanocarriers play a crucial role in delivering drugs across the blood-brain barrier, thereby lowering the risk of peripheral side effects. Various nanoforms have been developed to induce bioavailability and solubility of curcumin and quercetin, including nanoparticles and nanoemulsions. The studies reviewed included 17 using curcumin nanoformulations and seven with quercetin nanoformulations and were tested in widely used animal models of Alzheimer's disease, Parkinson's disease, Huntington's disease, and multiple sclerosis. Many of the curcumin and quercetin nanoformulations brought about improvements in learning and memory in behavioral tests of Alzheimer's disease models and were effective in reducing oxidative stress in the brain. Both nanocurcumin and nanoquercetin decreased the levels of inflammatory markers in the brain. Nanocurcumin formulations improved motor behavior, gait, and memory in Parkinson's disease models and increased dopaminergic neurons in the striatum and substantia nigra. Furthermore, nanocurcumin improved locomotor activity, memory, and learning, and the number of dendrites of medium spiny neurons in Huntington's disease models. Nanocurcumin formulations decreased oxidative stress and inflammation in a model of demyelination. Several important limitations were identified in the studies reviewed and these need to be considered in future studies. Also, clinical trials could be performed using the currently available nanoforms of curcumin and quercetin.},
}

@article {pmid40808416,
year = {2025},
author = {Figueiredo-Pereira, ME and Serrano, PA and Rockwell, P},
title = {Six promising drug repurposing candidates for Alzheimer's disease and their sex-specific mechanisms and efficacy.},
journal = {Neural regeneration research},
volume = {},
number = {},
pages = {},
doi = {10.4103/NRR.NRR-D-25-00256},
pmid = {40808416},
issn = {1673-5374},
abstract = {Alzheimer's disease is a neurodegenerative disorder that leads to progressive memory loss, cognitive decline, and behavioral changes. Despite ongoing research, its exact causes and effective treatments remain elusive. Traditional approaches have focused on symptom management, but breakthroughs in bioinformatics and high-throughput drug screening are offering new pathways to potential therapies. This review highlights our recent efforts to identify novel drug candidates for Alzheimer's disease by leveraging computational methods and large-scale biological datasets. Our work introduces two key innovations in Alzheimer's disease research: addressing sex-specific differences and leveraging drug repurposing for accelerated treatment discovery. By combining sex-stratified preclinical data with machine learning and in vivo validation, we improve translational relevance and support precision medicine. Using the TgF344-AD rat model, which mimics human Alzheimer's disease spatial memory deficits and pathology, we explored the efficacy of various US Food and Drug Administration- approved and investigational drugs. These included ibudilast, timapiprant, RG2833, diazoxide/ dibenzoylmethane (combined), and BT-11, which targeted key Alzheimer's disease-related molecular pathways such as amyloid-beta plaques, Tau tangles, and neuroinflammation. These drugs, at various stages of development, offer hope for not only managing symptoms but also addressing the underlying mechanisms of Alzheimer's disease. This review underscores the need for a multifaceted approach to Alzheimer's disease treatment, combining symptom relief with disease modification.},
}

@article {pmid40808358,
year = {2025},
author = {Shelton, M and Kerns, KA and Shirali, S and Castora, FJ and Coleman, RA},
title = {Integrating mitochondrial gene expression data to model the effects of respirasome supercomplex formation on reactive oxygen species production in Alzheimer's disease models.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251362889},
doi = {10.1177/13872877251362889},
pmid = {40808358},
issn = {1875-8908},
abstract = {BackgroundIn the past decade, Alzheimer's disease (AD) researchers have found that the formation of amyloid aggregates occurs after dysregulation of respiratory chain activity.ObjectiveUsing our developing mathematical model to identify potential therapeutic targets for AD treatment.MethodsWe have constructed a mathematical model for AD that incorporates enzyme activities and kinetics, and protein and mRNA expression levels.ResultsOur analyses of gene expression in AD brains provide complimentary evidence that changes in mitochondrial energy production and biogenesis accompany AD pathogenesis. Using this data, we created a mitochondrial model of electron transport chain supercomplex assembly.ConclusionsBy carrying out sensitivity analyses of responses to oxidative stress and effects of gene expression on energy production, we demonstrate how oxidative stress and energy deficits change the initial antioxidant defense system and impact the progression of AD. We investigated the impact of gene expression changes in 9 genes as new therapeutic options via metabolic flux analysis of supercomplex assembly. Through careful analysis, we propose that UQCRC1 may be an effective therapy option for in vitro AD treatment testing.},
}

@article {pmid40808348,
year = {2025},
author = {Bhushan, B and Singh, NK and Singh, R},
title = {An Overview of Neuroprotective Effects of Erythropoietin Against Neurological Disorders: Beyond Erythropoiesis.},
journal = {Journal of biochemical and molecular toxicology},
volume = {39},
number = {9},
pages = {e70442},
doi = {10.1002/jbt.70442},
pmid = {40808348},
issn = {1099-0461},
support = {//The authors received no specific funding for this work./ ; },
abstract = {Brain related disorders are a set of medical ailments that cause motor incoordination, cognitive and memory problems due to neurodegeneration in the brain. Although current therapies alleviate symptoms, they fail to target the fundamental pathological processes driving the disorders. A hematopoietic growth factor, Erythropoietin, stimulates erythroid cell formation and is therapeutically applied for the treatment of anemia. Furthermore, Erythropoietin has shown improved neurological outcomes in preclinical models and is being investigated as a potential therapeutic agent for neurodegenerative disorders. Erythropoietin is potential target for the regulation of numerous cellular signal pathways to enhance the neuronal survival, promote neuronal differentiation via binding of Erythropoietin-to-Erythropoietin receptor to stimulate the protein Janus-tyrosine kinase 2 followed by regulation of protein kinase B, signal transducer and stimulators of transcription 5, protein tyrosine phosphatases, mitogen-activated protein kinases, nuclear factor kB and Wnt1. Numerous research studies have evaluated the therapeutic potential of Erythropoietin against several neurological disorders including Alzheimer's disease, Parkinson's disease, neuroinflammation and epilepsy and highlight that Erythropoietin exhibits significant neuroprotective effects by counteracting apoptosis, neuroinflammatory process, reactive oxygen species overburden and neuronal death, consequently, prevent the progression of such diseases. However, two major challenges in developing erythropoietin as a neuroprotective agent include optimizing its therapeutic window and addressing safety concerns, particularly its adverse interaction with tissue plasminogen activator, which has been shown to increase the risk of hemorrhagic complications in ischemic stroke patients. In present review, we discuss the neurotherapeutic applications of Erythropoietin against brain related disorders beyond erythropoiesis. In conclusion, it can be assumed that Erythropoietin could be an alternative therapeutic option for the management of neurological disorders.},
}

@article {pmid40807333,
year = {2025},
author = {Godela, A and Rogacz, D and Pawłowska, B and Biczak, R},
title = {Natural Neuroinflammatory Modulators: Therapeutic Potential of Fungi-Derived Compounds in Selected Neurodegenerative Diseases.},
journal = {Molecules (Basel, Switzerland)},
volume = {30},
number = {15},
pages = {},
doi = {10.3390/molecules30153158},
pmid = {40807333},
issn = {1420-3049},
abstract = {Neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis remain incurable. Current therapeutic strategies primarily focus on slowing disease progression, alleviating symptoms, and improving patients' quality of life, including the management of comorbid conditions. Over the past few decades, the incidence of diagnosed neurodegenerative disorders has risen significantly. As the number of affected individuals continues to grow, so does the urgent need for effective treatments that can halt or mitigate the progression of these diseases. Among the most promising therapeutic resources are bioactive compounds derived from fungi. The high quality of proteins, polysaccharides, unsaturated fatty acids, triterpenoids, sterols, and secondary metabolites found in fungi have attracted growing interest from researchers across multiple disciplines. One intensively studied direction involves the use of naturally occurring fungi-derived nutraceuticals in the treatment of various diseases, including neurodegenerative conditions. This article provides an overview of recent findings on fungal compounds-such as phenolic compounds, carbohydrates, peptides and proteins, and lipids-that may have potential applications in the treatment of neurodegenerative diseases and the alleviation of their symptoms.},
}

@article {pmid40807232,
year = {2025},
author = {Chávez-Castillo, M and Gotera, MP and Duran, P and Díaz, MP and Nava, M and Cano, C and Díaz-Camargo, E and Cano, G and Cano, R and Rivera-Porras, D and Bermúdez, V},
title = {Neuroprotective Role of Omega-3 Fatty Acids: Fighting Alzheimer's Disease.},
journal = {Molecules (Basel, Switzerland)},
volume = {30},
number = {15},
pages = {},
doi = {10.3390/molecules30153057},
pmid = {40807232},
issn = {1420-3049},
abstract = {Alzheimer's disease (AD) is one of the main causes of dementia, with an exponential increment in its incidence as years go by. However, since pathophysiological mechanisms are complex and multifactorial, therapeutic strategies remain inconclusive and only provide symptomatic relief to patients. In order to solve this problem, new strategies have been investigated over recent years for AD treatment. This field has been reborn due to epidemiological and preclinical findings that demonstrate the fact that omega-3 polyunsaturated fatty acids (ω-3 PUFAs) can be promising therapeutic agents because of their anti-inflammatory, antioxidant, and neurogenic-promoting activities, thus allowing us to classify these molecules as neuroprotectors. Similarly, ω-3 PUFAs perform important actions in the formation of characteristic AD lesions, amyloid-β plaques (Aβ) and neurofibrillary tangles, reducing the development of these structures. Altogether, the aforementioned actions hinder cognitive decline and possibly reduce AD development. In addition, ω-3 PUFAs modulate the inflammatory response by inhibiting the production of pro-inflammatory molecules and promoting the synthesis of specialised pro-resolving mediators. Consequently, the present review assesses the mechanisms by which ω-3 PUFAs can act as therapeutic molecules and the effectiveness of their use in patients. Clinical evidence so far has shown promising results on ω-3 PUFA effects, both in animal and epidemiological studies, but remains contradictory in clinical trials. More research on these molecules and their neuroprotective effects in AD is needed, as well as the establishment of future guidelines to obtain more reproducible results on this matter.},
}

@article {pmid40806766,
year = {2025},
author = {Rebolledo-Pérez, L and Hernández-Bello, J and Martínez-Ramos, A and Castañeda-Arellano, R and Fernández-Quezada, D and Sandoval-García, F and Aguilar-García, IG},
title = {Substance Abuse and Cognitive Decline: The Critical Role of Tau Protein as a Potential Biomarker.},
journal = {International journal of molecular sciences},
volume = {26},
number = {15},
pages = {},
doi = {10.3390/ijms26157638},
pmid = {40806766},
issn = {1422-0067},
abstract = {Tau protein is essential for the structural stability of neurons, particularly through its role in microtubule assembly and axonal transport. However, when abnormally hyperphosphorylated or cleaved, Tau can aggregate into insoluble forms that disrupt neuronal function, contributing to the pathogenesis of neurodegenerative diseases such as Alzheimer's disease (AD). Emerging evidence suggests that similar Tau-related alterations may occur in individuals with chronic exposure to psychoactive substances. This review compiles experimental, clinical, and postmortem findings that collectively indicate a substance-specific influence on Tau dynamics. Alcohol and opioids, for instance, promote Tau hyperphosphorylation and fragmentation through the activation of kinases such as GSK-3β and CDK5, as well as proteases like caspase-3, leading to neuroinflammation and microglial activation. Stimulants and dissociatives disrupt insulin signaling, increase oxidative stress, and impair endosomal trafficking, all of which can exacerbate Tau pathology. In contrast, cannabinoids and psychedelics may exert protective effects by modulating kinase activity, reducing inflammation, or enhancing neuroplasticity. Psychedelic compounds such as psilocybin and harmine have been demonstrated to decrease Tau phosphorylation and facilitate cognitive restoration in animal models. Although the molecular mechanisms differ across substances, Tau consistently emerges as a convergent target altered in substance-related cognitive disorders. Understanding these pathways may provide not only mechanistic insights into drug-induced neurotoxicity but also identify Tau as a valuable biomarker and potential therapeutic target for the prevention or treatment of cognitive decline associated with substance use.},
}

@article {pmid40806624,
year = {2025},
author = {Șerban, M and Toader, C and Covache-Busuioc, RA},
title = {The Redox Revolution in Brain Medicine: Targeting Oxidative Stress with AI, Multi-Omics and Mitochondrial Therapies for the Precision Eradication of Neurodegeneration.},
journal = {International journal of molecular sciences},
volume = {26},
number = {15},
pages = {},
doi = {10.3390/ijms26157498},
pmid = {40806624},
issn = {1422-0067},
abstract = {Oxidative stress is a defining and pervasive driver of neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). As a molecular accelerant, reactive oxygen species (ROS) and reactive nitrogen species (RNS) compromise mitochondrial function, amplify lipid peroxidation, induce protein misfolding, and promote chronic neuroinflammation, creating a positive feedback loop of neuronal damage and cognitive decline. Despite its centrality in promoting disease progression, attempts to neutralize oxidative stress with monotherapeutic antioxidants have largely failed owing to the multifactorial redox imbalance affecting each patient and their corresponding variation. We are now at the threshold of precision redox medicine, driven by advances in syndromic multi-omics integration, Artificial Intelligence biomarker identification, and the precision of patient-specific therapeutic interventions. This paper will aim to reveal a mechanistically deep assessment of oxidative stress and its contribution to diseases of neurodegeneration, with an emphasis on oxidatively modified proteins (e.g., carbonylated tau, nitrated α-synuclein), lipid peroxidation biomarkers (F2-isoprostanes, 4-HNE), and DNA damage (8-OHdG) as significant biomarkers of disease progression. We will critically examine the majority of clinical trial studies investigating mitochondria-targeted antioxidants (e.g., MitoQ, SS-31), Nrf2 activators (e.g., dimethyl fumarate, sulforaphane), and epigenetic reprogramming schemes aiming to re-establish antioxidant defenses and repair redox damage at the molecular level of biology. Emerging solutions that involve nanoparticles (e.g., antioxidant delivery systems) and CRISPR (e.g., correction of mutations in SOD1 and GPx1) have the potential to transform therapeutic approaches to treatment for these diseases by cutting the time required to realize meaningful impacts and meaningful treatment. This paper will argue that with the connection between molecular biology and progress in clinical hyperbole, dynamic multi-targeted interventions will define the treatment of neurodegenerative diseases in the transition from disease amelioration to disease modification or perhaps reversal. With these innovations at our doorstep, the future offers remarkable possibilities in translating network-based biomarker discovery, AI-powered patient stratification, and adaptive combination therapies into individualized/long-lasting neuroprotection. The question is no longer if we will neutralize oxidative stress; it is how likely we will achieve success in the new frontier of neurodegenerative disease therapies.},
}

@article {pmid40806521,
year = {2025},
author = {Szablewski, L},
title = {Human Glucose Transporters in Health and Selected Neurodegenerative Diseases.},
journal = {International journal of molecular sciences},
volume = {26},
number = {15},
pages = {},
doi = {10.3390/ijms26157392},
pmid = {40806521},
issn = {1422-0067},
abstract = {Glucose is the main source of energy and the source of carbon for the biosynthesis of several molecules, such as neurotransmitters, for most mammalian cells. Therefore, the transport of glucose into cells is very important. There are described three distinct families of glucose transporters: facilitative glucose transporters (GLUTs), sodium-dependent glucose cotransporters (SGLTs), and a uniporter, the SWEET protein. Impaired function and/or expression of these transporters due to, for example, mutations in their genes, may cause severe diseases. Associations with the impaired function of glucose transporters have been described in the case of neurodegenerative diseases (NDs) such as Alzheimer's disease, Parkinson's disease, Huntington's disease, GLUT1-deficiency syndrome, stroke, and traumatic brain injury. Changes in the presence of glucose transporters may be a cause of NDs, and they may be the effect of NDs. On the other hand, in many cases of neurodegenerative diseases, changes in the expression of glucose transporters may be a targeted therapy in the treatment of patients with these diseases.},
}

@article {pmid40806469,
year = {2025},
author = {Wang, J and Shen, Y and Liao, P and Yang, B and Jiang, R},
title = {Roles of Ion Channels in Oligodendrocyte Precursor Cells: From Physiology to Pathology.},
journal = {International journal of molecular sciences},
volume = {26},
number = {15},
pages = {},
doi = {10.3390/ijms26157336},
pmid = {40806469},
issn = {1422-0067},
support = {82401445//National Natural Science Foundation of China/ ; 82271249//National Natural Science Foundation of China/ ; 2024M752251//China Postdoctoral Science Foundation/ ; 2024NSFSC1636//Sichuan Science and Technology Program/ ; 2024HXBH013//Post doctor Research Fund of West China Hospital of Sichuan University/ ; ZYYC23002//1-3-5 Project for Disciplines of Excellence of West China Hospital of Sichuan University/ ; GZC20241141//Postdoctoral Fellowship Program of CPSF/ ; },
abstract = {Oligodendrocyte precursor cells (OPCs) are a distinct and dynamic glial population that retain proliferative and migratory capacities throughout life. While traditionally recognized for differentiating into oligodendrocytes (OLs) and generating myelin to support rapid nerve conduction, OPCs are now increasingly appreciated for their diverse and non-canonical roles in the central nervous system (CNS), including direct interactions with neurons. A notable feature of OPCs is their expression of diverse ion channels that orchestrate essential cellular functions, including proliferation, migration, and differentiation. Given their widespread distribution across the CNS, OPCs are increasingly recognized as active contributors to the development and progression of various neurological disorders. This review aims to present a detailed summary of the physiological and pathological functions of ion channels in OPCs, emphasizing their contribution to CNS dysfunction. We further highlight recent advances suggesting that ion channels in OPCs may serve as promising therapeutic targets across a broad range of disorders, including, but not limited to, multiple sclerosis (MS), spinal cord injury, amyotrophic lateral sclerosis (ALS), psychiatric disorders, Alzheimer's disease (AD), and neuropathic pain (NP). Finally, we discuss emerging therapeutic strategies targeting OPC ion channel function, offering insights into potential future directions in the treatment of CNS diseases.},
}

@article {pmid40806404,
year = {2025},
author = {Yu, Y and Wang, C and Wang, B and Wang, X and Zhao, Q and Yan, Y and Liu, X},
title = {Clusterin Regulates the Mechanisms of Neuroinflammation and Neuronal Circuit Impairment in Alzheimer's Disease.},
journal = {International journal of molecular sciences},
volume = {26},
number = {15},
pages = {},
doi = {10.3390/ijms26157271},
pmid = {40806404},
issn = {1422-0067},
support = {H2024206232//Natural Science Foundation of Hebei Province/ ; ZF2024142//The Hebei Provincial Department of Finance and the Health Commission will fund the 2024 government-funded clinical medicine excellent talent training project/ ; 20252051//Hebei Provincial Health Commission Medical Science Research Project Project/ ; },
abstract = {Alzheimer's disease (AD) is a neurodegenerative disease with a multifaceted pathogenesis, which remains elusive, seriously affecting the quality of life of elderly patients and placing a heavy burden on affected individuals, their families, and society. As third-party synapses in brain networks, astrocytes play an important role in maintaining the normal function of neural networks, which contribute to the abnormal function of networks in AD. In recent years, numerous studies have shown that clusterin, a protein expressed by astrocytes, can participate in the progression of AD. Clusterin plays a significant role in many pathological processes of AD, such as lipid metabolism, AD pathological features, the imbalance in neural circuit excitatory inhibition, and neuroinflammation. Therefore, delving deeper into the association between clusterin and AD will help us to understand the mechanisms of disease better and provide a theoretical basis for early diagnosis and the development of treatment strategies for AD.},
}

@article {pmid40806401,
year = {2025},
author = {Nunkoo, VS and Jurcau, A and Les, M and Cristian, A and Militaru, M and Marge, C and Iovanovici, DC and Jurcau, MC},
title = {Circulating Biomarkers for the Early Diagnosis of Alzheimer's Disease.},
journal = {International journal of molecular sciences},
volume = {26},
number = {15},
pages = {},
doi = {10.3390/ijms26157268},
pmid = {40806401},
issn = {1422-0067},
abstract = {With a rapidly growing incidence and prevalence, Alzheimer's disease (AD) is rapidly becoming one of the most disabling, lethal, and expensive diseases of the century. To diagnose AD as early as possible, the scientific world struggles to find reliable and non-invasive biomarkers that could predict the conversion of mild cognitive impairment to AD and delineate the ongoing pathogenic vicious pathways to be targeted with therapy. Research supports the use of blood biomarkers, such as Aβ1-42/Aβ1-40 ratio, phosphorylated tau181, and p-tau217 for diagnostic purposes, although the cut-offs are not clearly established and can depend on the assays used. For more accurate diagnosis, markers of neurodegeneration (neurofilament light) and neuroinflammation (glial fibrillary acidic protein) could be introduced in the biomarker panel. The recent approval of the Lumipulse G p-tau217/Aβ1-42 plasma ratio by the FDA for the early detection of amyloid plaques associated with Alzheimer's disease in adult patients, aged 55 years and older, exhibiting signs and symptoms of the disease represents a significant advancement in the diagnosis of Alzheimer's disease, offering a more accessible and less invasive way to diagnose this devastating disease and allow potentially earlier access to treatment options.},
}

@article {pmid40805906,
year = {2025},
author = {Fereshtehnejad, SM and Lökk, J},
title = {Healthcare Complexities in Neurodegenerative Proteinopathies: A Narrative Review.},
journal = {Healthcare (Basel, Switzerland)},
volume = {13},
number = {15},
pages = {},
doi = {10.3390/healthcare13151873},
pmid = {40805906},
issn = {2227-9032},
abstract = {Background/Objectives: Neurodegenerative proteinopathies, such as Alzheimer's disease (AD), Parkinson's disease (PD), and dementia with Lewy bodies (DLB), are increasingly prevalent worldwide mainly due to population aging. These conditions are marked by complex etiologies, overlapping pathologies, and progressive clinical decline, with significant consequences for patients, caregivers, and healthcare systems. This review aims to synthesize evidence on the healthcare complexities of major neurodegenerative proteinopathies to highlight current knowledge gaps, and to inform future care models, policies, and research directions. Methods: We conducted a comprehensive literature search in PubMed/MEDLINE using combinations of MeSH terms and keywords related to neurodegenerative diseases, proteinopathies, diagnosis, sex, management, treatment, caregiver burden, and healthcare delivery. Studies were included if they addressed the clinical, pathophysiological, economic, or care-related complexities of aging-related neurodegenerative proteinopathies. Results: Key themes identified include the following: (1) multifactorial and unclear etiologies with frequent co-pathologies; (2) long prodromal phases with emerging biomarkers; (3) lack of effective disease-modifying therapies; (4) progressive nature requiring ongoing and individualized care; (5) high caregiver burden; (6) escalating healthcare and societal costs; and (7) the critical role of multidisciplinary and multi-domain care models involving specialists, primary care, and allied health professionals. Conclusions: The complexity and cost of neurodegenerative proteinopathies highlight the urgent need for prevention-focused strategies, innovative care models, early interventions, and integrated policies that support patients and caregivers. Prevention through the early identification of risk factors and prodromal signs is critical. Investing in research to develop effective disease-modifying therapies and improve early detection will be essential to reducing the long-term burden of these disorders.},
}

@article {pmid40804109,
year = {2025},
author = {Jia, M and Liu, Z and Fan, X and Ahmad, S and Wang, Z and Zhu, X and Ai, H},
title = {Conformation-Dependent Binding Affinity of Small Molecules to Aβ42 Fibrils: Mechanistic Insights into Tracer Design.},
journal = {The journal of physical chemistry. B},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.jpcb.5c04444},
pmid = {40804109},
issn = {1520-5207},
abstract = {The β-amyloid (Aβ) deposits in Alzheimer's disease (AD) are primarily composed of Aβ42-derived fibrils, and Aβ42 fibrils exhibit polymorphism with diverse molecular structures. While small-molecule-based targeting strategies have achieved phased progress in AD diagnosis and treatment, the distribution and quantity of binding sites on Aβ42 fibrils, as well as the dynamic interaction mechanisms between these sites and different tracers, remain unclear. Additionally, the binding efficacy of small molecules to Aβ42 fibrils with distinct structures and their conformational dependence have not yet been elucidated. In this study, five novel ligands were selected as tracers to investigate their interactions with four representative Aβ42 fibril conformations. The results demonstrated significant differences in the capacities of these molecules to bind Aβ fibrils with varying conformations, revealing a pronounced conformation-dependent relationship. Notably, small molecule 1 (SM1) and SM3 exhibited robust binding affinities across all four Aβ fibril conformations, highlighting their potential as tracers. Furthermore, the binding sites of the υ-type (8EZE) Aβ fibril accommodating small molecules were first identified, and U-type (2BEG), S-type (2NAO), and LS-type (5OQV) Aβ fibrils were found to align with the ones reported previously for other ligands. Notably, strongly bound molecules induce structural deformation of the fibril. These findings provide critical insights for the rational design and modification of existing Aβ42 fibril-targeting ligands, facilitating the development of tracers with enhanced specificity and selectivity.},
}

@article {pmid40803539,
year = {2025},
author = {Ji, Y and Wang, M and Yang, C},
title = {Neurosteroids for the treatment of neurodegenerative disorders: We still have a long way to go.},
journal = {The Journal of steroid biochemistry and molecular biology},
volume = {254},
number = {},
pages = {106841},
doi = {10.1016/j.jsbmb.2025.106841},
pmid = {40803539},
issn = {1879-1220},
}

@article {pmid40803248,
year = {2025},
author = {Esparza-Moltó, PB and Goswami, AV and Bozkurt, S and Münch, C and Newman, LE and Moyzis, AG and Rojas, GR and Guan, D and Jones, JR and Gage, FH and Shadel, GS},
title = {ROS-dependent localization of glycolytic enzymes to mitochondria.},
journal = {Redox biology},
volume = {86},
number = {},
pages = {103812},
doi = {10.1016/j.redox.2025.103812},
pmid = {40803248},
issn = {2213-2317},
abstract = {Mitochondrial reactive oxygen species (mtROS) regulate cellular signaling pathways, but also cause oxidative stress when de-regulated during aging and pathological conditions such as neurodegenerative diseases. The dynamic redistribution of proteins between cellular compartments is a common mechanism to control their stability and biological activities. By targeting the BirA∗ biotin ligase to the outer mitochondrial membrane in HEK293 cells, we identified proteins whose labeling increased or decreased in response to treatment with menadione, consistent with a dynamic change in their mitochondrial localization in response to increased mtROS production. These proteins represent potential candidates for future studies of mitochondrial oxidative stress signaling. A subset of glycolytic enzymes was found in this screen and confirmed, by mitochondrial fractionation and imaging, to increase localization to mitochondria in response to menadione, despite no change in their overall abundance. Submitochondrial fractionation studies are consistent with import of a pool of these enzymes to the mitochondrial intermembrane space. Localization of glycolytic enzymes to mitochondria was also increased in cells grown under hypoxia or that express a mitochondria-targeted d-amino-acid oxidase (conditions that induce increased mtROS production), and inhibited basally under normal growth conditions by the mitochondrial antioxidant MnTBAP. Finally, primary Alzheimer's disease fibroblasts also had glycolytic enzymes associated with mitochondria that was reduced by antioxidants, consistent with increased mtROS altering their relative distribution between the cytoplasm and mitochondria. We speculate that the increased mitochondrial localization of glycolytic enzymes is an adaptive response to mtROS that alters glucose flux toward the antioxidant pentose phosphate pathway, creates distinct regulatory pools of mitochondrial metabolites or new metabolic circuits, and/or provides cytoprotection or other adaptive responses via moonlighting functions unrelated to their enzymatic activity.},
}

@article {pmid40803039,
year = {2025},
author = {Erickson, RP and Bernas, MJ and Witte, MH},
title = {Manual Lymph Drainage for Alzheimer's Dementia: A Clinical Trial Whose Time Has Come?.},
journal = {Lymphology},
volume = {58},
number = {2},
pages = {43-45},
pmid = {40803039},
issn = {2522-7963},
abstract = {Mounting evidence implicates brain lymphatic drainage in the pathogenesis of Alzheimer's disease and other dementias. Several recent basic and clinical science discoveries have suggested the impact of lymphatic therapy to stimulate lymph flow in the head and neck including improvement in cognition. Manual lymphatic drainage has potential as a simple inexpensive way to promote brain lymph drainage and is worthy of a well-designed clinical trial to evaluate its potential as a primary or adjunctive treatment of Alzheimer's disease at this time.},
}

@article {pmid40802200,
year = {2025},
author = {Talib, M and Siddiqui, N and Tripathi, PN and Chaudhary, A},
title = {Ameliorative Role of Phosphodiesterase-5 (PDE-5) Inhibitor "Avanafil" via Modulating cAMP & cGMP Pathway Against Alzheimer's Disease.},
journal = {Neurochemical research},
volume = {50},
number = {4},
pages = {258},
pmid = {40802200},
issn = {1573-6903},
abstract = {Alzheimer's disease (AD) is the utmost age-linked neuro-degenerative conditions, marked via gradual deterioration of cognitive abilities and continues to be a significant worldwide health issue. Etiology of AD is linked to neurobehavioral variations, deposition of Aβ, p-Tau, activations of glycogen synthase kinase-3 (GSK-3β), and fluctuations in cyclic nucleotides including cAMP & cGMP. As per evidence, PDE-5 inhibitors are able to boost cAMP & cGMP levels and other etiological hallmarks, which could be a novel AD cure. The main objective of present study was to examine therapeutic potential of Avanafil in a rat model of AD induced by administering 60 mg/kg of D-galactose (D-galac) and 10 mg/kg of Aluminium chloride (AlCl3) for a period of 42 days. Following this, 28 days of therapy with two different doses of Avanafil (3 mg/kg and 6 mg/kg) was given. Towards end of treatment, locomotor activity & Morris water maze were performed. Rats were then euthanized and hippocampus was isolated for biochemical parameters & histological investigation. Results revealed that both neurobehavioral parameters exhibits significant difference in treatment group as compared to toxic group. Alterations in level of AchE, Aβ (1-42), GSK-3β, p-Tau, tumor necrosis factor- alpha (TNF-α), IL-1β, & IL-6, cAMP, cGMP & BDNF, and oxidative stress were significantly reversed towards normal level in the treatment group when compared to toxic rats. Histopathological changes by H&E staining showed significant difference in treatment vs. toxic rats. The current investigation suggested that Avanafil improves memory by improving cAMP and cGMP pathways, implying that it may have therapeutic prospective in cognitive deficiencies linked with Alzheimer's disease.},
}

@article {pmid40801914,
year = {2025},
author = {Liguori, C},
title = {Sleep disturbances impact cognition and are highly prevalent in memory clinics.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251366660},
doi = {10.1177/13872877251366660},
pmid = {40801914},
issn = {1875-8908},
abstract = {Sleep questionnaires may help understand sleep habits and screen for sleep disorders. However, they can fail in diagnosing obstructive sleep apnea or identifying the chronotype and the total sleep time of patients admitted to a specialized memory clinic. Lam et al. showed the high prevalence of sleep disturbances in patients with cognitive impairment. They also highlighted the importance of combining subjective questionnaires with objective tests to identify sleep problems associated with poor cognitive performance, particularly in women. Consequently, recognizing sleep problems can help clinicians set personalized treatment strategies for improving sleep and preventing or slowing cognitive impairment.},
}

@article {pmid40801842,
year = {2025},
author = {Xie, F and Ye, Y and Hao, J and Liu, H and Richard, SA and He, S},
title = {Surgical advances in the treatment of Alzheimer's disease: A comprehensive review.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251364397},
doi = {10.1177/13872877251364397},
pmid = {40801842},
issn = {1875-8908},
abstract = {Alzheimer's disease (AD), a progressive neurodegenerative disorder, represents a significant global health challenge with profound implications for patients and their families. Despite decades of intensive research efforts, no curative treatment for AD currently exists. In recent years, surgical interventions have emerged as a promising therapeutic avenue, offering potential for disease modification and symptom management. This comprehensive review critically evaluates the evolving landscape of surgical approaches in AD treatment, encompassing deep brain stimulation, focused ultrasound, gene therapy delivery systems, neural grafting techniques, and lymphatic-venous anastomosis. We systematically analyze the neurobiological mechanisms, clinical efficacy, safety profiles, and technical challenges associated with these interventions. Drawing upon an extensive review of 112 recent studies, this article provides a rigorous assessment of the current state of surgical therapies for AD, while identifying key knowledge gaps and future research directions that could advance the field toward more effective therapeutic strategies.},
}

@article {pmid40801602,
year = {2025},
author = {de Munter, J and Chaprov, K and Lang, E and Sitdikova, K and Wolters, EC and Svirin, E and Kassenova, A and Tsoy, A and Kramer, BW and Askarova, S and Schroeter, CA and Anthony, DC and Strekalova, T},
title = {Neuro-Cells Mitigate Amyloid Plaque Formation and Behavioral Deficits in the APPswe/PS1dE9 Model of Alzheimer Disease While Also Reducing IL-6 Production in Human Monocytes.},
journal = {Cells},
volume = {14},
number = {15},
pages = {},
pmid = {40801602},
issn = {2073-4409},
support = {101007642//HORIZON, EU/ ; AP23485236, BR24992841//the Ministry of Higher Education and Science of the Republic of Kazakhstan/ ; },
abstract = {Neuroinflammation is a key feature of Alzheimer's disease (AD), and stem cell therapies have emerged as promising candidates due to their immunomodulatory properties. Neuro-Cells (NC), a combination of unmodified mesenchymal stem cells (MSCs) and hematopoietic stem cells (HSCs), have demonstrated therapeutic potential in models of central nervous system (CNS) injury and neurodegeneration. Here, we studied the effects of NC in APPswe/PS1dE9 mice, an AD mouse model. Twelve-month-old APPswe/PS1dE9 mice or their wild-type littermates were injected with NC or vehicle into the cisterna magna. Five to six weeks post-injection, cognitive, locomotor, and emotional behaviors were assessed. The brain was stained for amyloid plaque density using Congo red, and for astrogliosis using DAPI and GFAP staining. Gene expression of immune activation markers (Il-1β, Il-6, Cd45, Tnf) and plasticity markers (Tubβ3, Bace1, Trem2, Stat3) was examined in the prefrontal cortex. IL-6 secretion was measured in cultured human monocytes following endotoxin challenge and NC treatment. Untreated APPswe/PS1dE9 mice displayed impaired learning in the conditioned taste aversion test, reduced object exploration, and anxiety-like behavior, which were improved in the NC-treated mutants. NC treatment normalized the expression of several immune and plasticity markers and reduced the density of GFAP-positive cells in the hippocampus and thalamus. NC treatment decreased amyloid plaque density in the hippocampus and thalamus, targeting plaques of <100 μm[2]. Additionally, NC treatment suppressed IL-6 secretion by human monocytes. Thus, NC treatment alleviated behavioral deficits and reduced amyloid plaque formation in APPswe/PS1dE9 mice, likely via anti-inflammatory mechanisms. The reduction in IL-6 production in human monocytes further supports the potential of NC therapy for the treatment of AD.},
}

@article {pmid40801286,
year = {2025},
author = {Huang, J and Perrin, NA and Spira, AP and Szanton, SL and Rebok, GW and Budhathoki, C and Gooneratne, NS and Li, J},
title = {Sleep Disturbance and Cognitive Trajectories Among Older Adults with Subjective Cognitive Decline: The Roles of Age and Sleep Treatment.},
journal = {Sleep},
volume = {},
number = {},
pages = {},
doi = {10.1093/sleep/zsaf234},
pmid = {40801286},
issn = {1550-9109},
abstract = {STUDY OBJECTIVES: Growing evidence indicates that subjective cognitive decline (SCD), characterized by self-reported cognitive deterioration without measurable cognitive impairment, may be an early indicator of Alzheimer's Disease. This study investigated the association between baseline sleep disturbance and a 10-year trajectory of global cognitive performance in adults with SCD and examined if this association was moderated by age (50-64 years and ≥65 years) and sleep treatment.

METHODS: Using six waves (2010-2020) of the Health and Retirement Study, we included individuals aged ≥50 years who reported SCD but had no objective cognitive impairment at baseline (2010) and had final wave of cognitive data (n=1,372). Latent growth curve modeling was employed to examine the associations between self-reported sleep disturbance and cognitive trajectories from 2010 to 2020, controlling for sociodemographic and health-related factors.

RESULTS: In the full sample, baseline sleep disturbance was not significantly associated with cognitive change. However, a significant interaction between sleep disturbance and age group was found (β=-0.04, 95% CI [-0.08, -0.003]). Stratified analyses showed that poorer sleep was associated with faster cognitive decline in those aged ≥65 years (β=-0.04, 95% CI [-0.07, -0.005]; n=558), and receiving sleep treatment was associated with a reduced impact of sleep disturbance on cognitive decline (β=0.31, 95% CI [0.02, 0.60]). These associations were not significant in those aged 50-64 years (n=814).

CONCLUSIONS: Sleep disturbance was an independent risk factor of future cognitive decline in older adults ≥65 years with SCD. Sleep treatment may mitigate this decline, offering a potential intervention strategy.},
}

@article {pmid40801268,
year = {2025},
author = {Ikanga, J and Patel, SS and Schwinne, M and Obenauf, C and Gikelekele, G and Epenge, E and Tshengele, N and Kavugho, I and Mampunza, S and Mananga, L and Teunissen, CE and Rojas, JC and Yohe, EO and Alonso, A and Gross, AL},
title = {Association between neuropsychiatric symptoms and neurodegeneration-related plasma biomarkers in older adults with and without clinical dementia in the Democratic Republic of the Congo.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {8},
pages = {e70530},
pmid = {40801268},
issn = {1552-5279},
support = {//Emory Goizueta Alzheimer's disease Research Center (ADRC)/ ; P30AG066511/AG/NIA NIH HHS/United States ; RF1AG088003 to AG/AG/NIA NIH HHS/United States ; R01AG070953 to AG/AG/NIA NIH HHS/United States ; R01AG030153 to AG/AG/NIA NIH HHS/United States ; UL1TR002378//National Center for Advancing Translational Sciences/ ; //National Institutes of Health/ ; },
abstract = {INTRODUCTION: Neuropsychiatric symptoms (NPS) are prevalent in dementia, but most studies focus on Western populations. This study examines the association between NPS and neurodegeneration-related plasma biomarkers in older adults with and without dementia in the Democratic Republic of the Congo (DRC).

METHODS: Eighty-five individuals (≥65 years) underwent dementia adjudication using the Community Screening Instrument for Dementia (CSID) and Alzheimer's Questionnaire (AQ). Plasma biomarkers (amyloid β [Aβ] 42/40, phosphorylated-tau181 [p-tau181], neurofilament light [NfL], glial fibrillary acidic protein (GFAP), interleukin-1β [IL-1β], tumor necrosis factor-α [TNF-α]) were measured. NPS were assessed using the Geriatric Depression Scale (GDS), Beck Anxiety Inventory (BAI), and Neuropsychiatric Inventory Questionnaire (NPI) (for dementia cases). Logistic regressions examined associations between NPS and biomarkers, adjusting for age, sex, and education.

RESULTS: NPS were common in dementia cases, with irritability (57.8%) and depression (90.7%) most frequent. GFAP was linked to irritability (odds ratio [OR] = 3.34, p = 0.01), and NfL and GFAP were associated with depressive symptoms (OR = 0.76, p = 0.04; OR = 1.98, p = 0.02, respectively).

DISCUSSION: These findings highlight the burden of NPS in the DRC and suggest biomarker-driven mechanisms, emphasizing the need for further research in diverse populations.

HIGHLIGHTS: Identifies neuropsychiatric symptoms as early indicators of Alzheimer's disease (AD) progression. Examines associations between depression and AD biomarkers in preclinical and prodromal stages. Highlights the role of amyloid and tau pathology in depression-related cognitive decline. Discusses implications for early intervention and personalized treatment strategies.},
}

@article {pmid40801241,
year = {2025},
author = {Jin, Z and Lu, Y and Tang, H and Cui, H},
title = {Integrating neuroinflammation biomarkers into the ATN(X) framework: Advances in Alzheimer's pathogenesis, diagnosis, and insights from non-human primate models.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {8},
pages = {e70472},
pmid = {40801241},
issn = {1552-5279},
support = {82074535//National Natural Science Foundation of China/ ; },
abstract = {The amyloid/tau/neurodegeneration (ATN) biomarker framework has greatly progressed the diagnosis and staging of Alzheimer's disease (AD). However, recent research highlights neuroinflammation as an equally critical factor in AD pathology across humans, rodents, and non-human primates (NHPs). This review evaluates the combined use of ATN and neuroinflammatory biomarkers-such as glial fibrillary acidic protein (GFAP) (astrocytic marker) and triggering receptor expressed on myeloid cells 2 (TREM2)/ ionized calcium-binding adapter molecule 1 (IBA-1) (microglial markers)-in elucidating AD mechanisms, promoting early diagnosis, and shaping therapeutic strategies. It also summarizes the key features and translational potential of NHP models that closely mimic human AD pathology, highlighting the promising prospects of integrating these models with the ATN(X) biomarker system. These insights strengthen the link between biomarkers, NHP research, and clinical practice, opening new avenues for the early detection and treatment strategies of AD. HIGHLIGHTS: Neuroinflammation biomarkers, including glial fibrillary acidic protein (GFAP), triggering receptor expressed on myeloid cells 2 (TREM2)/sTREM2, and YKL-40, show strong clinical potential in Alzheimer's disease (AD). Incorporating neuroinflammation biomarkers into the ATN(X) framework may enhance diagnostic precision. Advanced non-human primate (NHP) models closely replicate human brain pathology, addressing key limitations of mouse models. Measuring ATN(X) biomarkers in NHPs may improve clinical translation and support early diagnosis of AD. Optimizing NHP models-including ApoE4 status, injection protocols, and gene-editing approaches-is crucial for reproducibility and efficiency.},
}

@article {pmid40797227,
year = {2025},
author = {Liang, J and Li, R and Wong, G and Huang, X},
title = {Lewy body dementia: exploring biomarkers and pathogenic interactions of amyloid β, tau, and α-synuclein.},
journal = {Molecular neurodegeneration},
volume = {20},
number = {1},
pages = {90},
pmid = {40797227},
issn = {1750-1326},
support = {32400781//National Natural Science Foundation of China/ ; No. BYYZ25014//President Foundation of Baiyun District People's Hospital of Guangzhou/ ; },
abstract = {Lewy body dementia (LBD) is a neurodegenerative disorder characterized by a combination of progressive dementia and spontaneous parkinsonian symptoms. As the second most prevalent form of neurodegenerative dementia after Alzheimer’s disease (AD), LBD necessitates a deeper understanding of its pathogenesis to enable the development of targeted therapeutic interventions. While numerous reviews focus on documenting the clinical manifestations and therapeutic modalities for LBD, animal models provide valuable insights into the underlying mechanisms and potential therapeutic strategies. In this review, we systematically analyze the hallmarks of LBD pathogenesis, genetic risk factors, clinical features, and treatment strategies. Importantly, we emphasize and critically evaluate the pivotal role of animal models in LBD research in advancing our understanding of this disorder, offering a comprehensive framework to elucidate the interactions among misfolded proteins and their role in LBD pathogenesis. Our review proposes new directions for LBD therapeutic management and facilitates the development of innovative pharmacological interventions.},
}

@article {pmid40800505,
year = {2024},
author = {Dong, M and Xie, L and Das, SR and Wang, J and Wisse, LEM and deFlores, R and Wolk, DA and Yushkevich, PA},
title = {Regional deep atrophy: Using temporal information to automatically identify regions associated with Alzheimer's disease progression from longitudinal MRI.},
journal = {Imaging neuroscience (Cambridge, Mass.)},
volume = {2},
number = {},
pages = {},
pmid = {40800505},
issn = {2837-6056},
abstract = {Longitudinal assessment of brain atrophy, particularly in the hippocampus, is a well-studied biomarker for neurodegenerative diseases, such as Alzheimer's disease (AD). Estimating brain progression patterns can be applied to understanding the therapeutic effects of amyloid-clearing drugs in research and detecting the earliest sign of accelerated atrophy in clinical settings. However, most state-of-the-art measurements calculate changes directly by segmentation and/or deformable registration of MRI images, and may misreport head motion or MRI artifacts as neurodegeneration, impacting their accuracy. In our previous study, we developed a deep learning method DeepAtrophy that uses a convolutional neural network to quantify differences between longitudinal MRI scan pairs that are associated with time. DeepAtrophy has high accuracy in inferring temporal information from longitudinal MRI scans, such as temporal order or relative interscan interval. DeepAtrophy also provides an overall atrophy score that was shown to perform well as a potential biomarker of disease progression and treatment efficacy. However, DeepAtrophy is not interpretable, and it is unclear what changes in the MRI contribute to progression measurements. In this paper, we propose Regional Deep Atrophy (RDA), which combines the temporal inference approach from DeepAtrophy with a deformable registration neural network and attention mechanism that highlights regions in the MRI image where longitudinal changes are contributing to temporal inference. RDA has similar prediction accuracy as DeepAtrophy, but its additional interpretability makes it more acceptable for use in clinical settings, and may lead to more sensitive biomarkers for disease monitoring and progression understanding in preclinical AD.},
}

@article {pmid40799992,
year = {2025},
author = {Chu, J and Hu, H and Xu, W and Lu, X and Zhou, H and Hao, M and Wang, L and Li, S and Ji, W and Li, G and Luo, Y and Gao, J and Huang, D and Liu, Y and Yin, Y},
title = {Top-down engineered micron-cell derived nanovesicles encapsulating curcumin targeting the 3R strategy (remove, remodel, repair) for Alzheimer's disease therapy.},
journal = {Materials today. Bio},
volume = {34},
number = {},
pages = {102157},
pmid = {40799992},
issn = {2590-0064},
abstract = {Alzheimer's disease (AD), a global health crisis exacerbated by aging populations, demands innovative therapeutic strategies. Curcumin, a natural compound with anti-aging and anti-inflammatory properties, holds promise for AD treatment but is hindered by poor bioavailability. Here, we developed curcumin-loaded nanovesicles (NV-CUR) derived from brain-homing B16 melanoma cells to overcome these limitations. NV-CUR enhanced the solubility, stability, and blood‒brain barrier (BBB) penetration of curcumin, enabling systemic delivery in aged 3 × Tg AD mice. Our 3R strategy for removing senescent cells, remodeling the neuroinflammatory microenvironment, and repairing neuronal damage was comprehensively validated. NV-CUR effectively cleared p16[INK4a] (P16)-positive senescent microglia, suppressed senescence-associated secretory phenotypes (SASP), and reduced neuroinflammation (IL-1β, IL-6, and TNF-α). Concurrently, NV-CUR diminished amyloid-beta plaques, attenuated Tau hyperphosphorylation, and restored hippocampal neuronal integrity. Cognitive assessments revealed significant improvements in memory and exploratory behavior, whereas biosafety evaluations confirmed that there was no systemic toxicity. This study establishes NV-CUR as a mechanistically innovative, clinically translatable nanomedicine that aligns with the 3R paradigm, offering a multifaceted approach to combat AD pathogenesis.},
}

@article {pmid40799764,
year = {2025},
author = {Chakkarai, S and Sadowski, M and Yang, Q and Ray, A and Wang, R and Thomas, LF and Fuentes, RP and Tabar, MS and Cui, B and Jian, X and Nyquist, PA and Gill, D and Aiello, AE and Montine, TJ and Bukhari, S and Rogalski, E and Edland, SE and Haan, ME and Kawas, CH and Corrada, MM and Salardini, A and Chen, ZZ and Himali, JJ and Satizabal, CL and Gerszten, RE and Åsvold, BO and Fornage, M and Cruchaga, C and Habes, M and Chasman, DI and Launer, LJ and Flanagan, ME and Brumpton, BM and Georgakis, MK and Zaitlen, N and Ruiz, A and Debette, S and Seshadri, S and Sargurupremraj, M},
title = {Cross-tissue omics-guided drug repurposing triangulates novel targetable mechanisms for Alzheimer's disease and candidate genetic biomarkers for treatment stratification.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-7279662/v1},
pmid = {40799764},
issn = {2693-5015},
abstract = {White matter hyperintensities (WMH) are covert magnetic resonance imaging (MRI) - markers of microvascular dysfunction and are primary vascular contributors to dementia, emphasizing its importance in prevention strategies. Here, we integrate gene expression and protein levels measured across plasma, cerebrospinal fluid (CSF), brain and multiple other tissues from population-based and biobank-scale data to triangulate druggable genes influencing WMH-burden and Alzheimer's disease (AD) and to map their spatial localization specifically in brain-cell types. Lowering the expression levels of CALCRL, MAP3K11 , PKN2 and EPHB4 shows putative causal associations with reduced WMH-burden, and AD risk. These targets of clinically approved drugs, enriched in key cell types of the neurovascular unit and exhibiting cell-type specific effects in peripheral CD4 + T cell subsets, are implicated in regulating neuroimmune interactions and amyloid-β homeostasis. Gene-drug interaction analysis identifies higher levels of GLTPD2 modifying the antidepressants associated increase in dementia risk contributing to a 73.3% risk reduction relative to the use of drugs. Furthermore, pharmagenic pathway studies identify the coagulation cascade as a targetable pathway associated with AD risk (HR: 2.23, 95% CI:1.85-2.69), providing orthogonal support to emerging therapies targeting coagulation components in treating neurodegenerative disorders.},
}

@article {pmid40799393,
year = {2025},
author = {Araya, P and Niemeyer, B and Schade, K and Dunn, LN and Waugh, K and Busquet, N and Brindley, C and Brown, C and Winkler, C and Lyford, HR and Britton, EC and Ludwig, M and Siegenthaler, J and Galbraith, MD and Espinosa, JM and Sullivan, KD},
title = {Interferon signaling modulates Down syndrome-associated Alzheimer's disease pathology in a mouse model.},
journal = {iScience},
volume = {28},
number = {8},
pages = {113130},
pmid = {40799393},
issn = {2589-0042},
abstract = {Individuals with Down syndrome (DS), caused by trisomy of chromosome 21 (chr21, T21), are strongly predisposed to Alzheimer's disease (AD), due to triplication of the APP gene, with ∼100% penetrance of AD brain pathology by age 40 and variable onset of dementia thereafter. It remains unclear what role other triplicated genes play in the pathophysiology of DS-associated AD (DS-AD). Using mouse models of DS-AD, we demonstrate that triplication of other chr21 genes has paradoxical effects on learning and memory in DS-AD mice, exacerbating some phenotypes and attenuating others. Spatial transcriptomic analysis revealed genome-wide alterations typified by upregulation of interferon (IFN) signatures and elevated levels of disease-associated microglia with concomitant decreases in neurons in DS-AD animals. Finally, systemic treatment with a JAK inhibitor improved cognition and rescued gene expression changes in DS-AD animals, indicating that IFN may be a driver of pathophysiology in DS-AD that could be amenable to therapeutic intervention.},
}

@article {pmid40798958,
year = {2025},
author = {Zhang, Y and Ke, Z and Luo, J and Chen, Q and Jiang, X and Xiong, J and Deng, L},
title = {Betaine: A Promising Natural Product for Neurological and Psychiatric Diseases.},
journal = {Current neuropharmacology},
volume = {},
number = {},
pages = {},
doi = {10.2174/011570159X375540250718094903},
pmid = {40798958},
issn = {1875-6190},
abstract = {Neurological and psychiatric diseases pose a considerable global burden. Exploring additional potential prevention strategies and therapies is ongoing. As a prevalent natural product and nutraceutical from food, betaine's pharmaceutical applications suggest benefits for both health and disease in multiple organs. Recently, its efficacy on neurological and psychiatric health has been proposed and has drawn considerable attention. This review aims to provide an updated, critical, and comprehensive profile of the promising medicinal roles of betaine in these diseases. In addition to its well-known osmotic protection, due to methyl donation, it regulates metabolism, alleviates oxidative stress, and reduces inflammation. To manifest neurological and psychiatric health benefits, betaine acts by affecting gamma-aminobutyric acid associated with its transporters, related neurotransmitters, downstream and neurological pathways, and other specific mechanisms in the nervous system. Betaine demonstrates therapeutic potential against various neurological and psychiatric diseases, such as epilepsy, neurocognitive disorders (including Alzheimer's disease), Parkinson's disease, stroke, multiple sclerosis, traumatic brain injury, depression, anxiety, schizophrenia, autism spectrum disorder, sleep disorders, fetal alcohol syndrome, syringomyelia, neonatal brain injury, neuropathic pain, and motor dysfunction. Despite the promising role of betaine in the treatment, diagnosis, and prevention of neuropsychiatric disorders, much of the present evidence appears to be fragmentary. Further studies elucidating the underlying mechanisms and direct clinical applications are required to obtain a deeper understanding of betaine and its underutilized potential. Overall, this review highlights the potential of betaine as a promising agent with benefits for neurological and psychiatric diseases, aiming to offer clues to advance this field.},
}

@article {pmid40796907,
year = {2025},
author = {Choi, J and Kim, D and Jeong, H and Hwang, J and Ramalingam, M and Han, S and Cho, HH and Kim, BC and Jeong, HS and Jang, S},
title = {A novel miR-4536-3p inhibition ameliorates Alzheimer's disease by reducing Aβ accumulation and tau phosphorylation.},
journal = {Alzheimer's research & therapy},
volume = {17},
number = {1},
pages = {189},
pmid = {40796907},
issn = {1758-9193},
support = {RS-2020-KH088567//Korea Health Industry Development Institute/Republic of Korea ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is characterized by cognitive decline, amyloid-beta (Aβ) accumulation, and tau hyperphosphorylation. Effective therapies remain limited; therefore, recent studies have explored microRNAs as potential therapeutic targets.

METHODS: miR-4536-3p inhibition was investigated using in vitro (SH-SY5Y cells) and in vivo (5xFAD mouse) AD models. Apoptosis, neuronal markers, and signaling pathways were assessed through functional assays. Cognitive effects were evaluated via the Morris water maze.

RESULTS: miR-4536-3p inhibition increased an expression of Drebrin1 (DBN1), a key regulator of synaptic plasticity, but it reduced Aβ deposition, tau phosphorylation, and apoptosis. The treatment improved neuronal marker levels and significantly enhanced the spatial learning and memory of 5xFAD mice. Mechanistically, miR-4536-3p inhibition activated the PI3K/Akt/GSK3β signaling pathway, suppressing apoptosis and mitigating AD pathology.

CONCLUSION: miR-4536-3p inhibition offers a promising therapeutic strategy for AD by restoring the DBN1 expression, reducing neurodegeneration, and improving cognitive outcomes through PI3K/Akt pathway modulation.},
}

@article {pmid40796687,
year = {2025},
author = {Kashiyama, R and Watanabe, H and Akasaka, T and Fujimoto, H and Murakami, M and Ooe, K and Toyoshima, A and Nakashima, K and Ono, M},
title = {Feasibility of targeted alpha therapy for Alzheimer's disease using [211]At-labeled agent targeting amyloid-β aggregates.},
journal = {Annals of nuclear medicine},
volume = {},
number = {},
pages = {},
pmid = {40796687},
issn = {1864-6433},
support = {JP24wm0625512h//Japan Agency for Medical Research and Development/ ; JP25wm0625512h//Japan Agency for Medical Research and Development/ ; },
abstract = {OBJECTIVE: Amyloid-β (Aβ) aggregates have been recognized as therapeutic targets for Alzheimer's disease (AD). Targeted alpha therapy (TAT) using α-particles has the potential to be applied as a novel treatment approach for AD by reducing the quantity of Aβ aggregates. In this study, we developed a novel astatine-211-labeled pyridyl benzofuran (PBF) derivative, [[211]At]APBF-2, as a small molecule-based Aβ-TAT agent and evaluated its potential for in vivo use.

METHODS: [[211]At]APBF-2 was synthesized in a one-step astatination process using the tributyltin precursor. In the Aβ aggregation inhibition assay, [[211]At]APBF-2 was added to a sample containing Aβ1-42 monomers and thioflavin-T (ThT) and the mixture was incubated for 24 h. The quantity of Aβ aggregates was evaluated by measuring ThT fluorescence intensity. The biodistribution of [[211]At]APBF-2 (25 kBq/100 μL) was evaluated using ddY mice (n = 5).

RESULTS: [[211]At]APBF-2 was synthesized in radiochemical yield of 57% with a radiochemical purity of over 95%. In the in vitro assay, [[211]At]APBF-2 showed a dose-dependent decrease in ThT fluorescence intensity, suggesting the ability of [[211]At]APBF-2 to inhibit Aβ aggregation. In the biodistribution study using normal mice, the initial brain uptake of [[211]At]APBF-2 was observed (2.95% injected dose/g at 2 min), demonstrating favorable Blood-brain barrier permeability.

CONCLUSIONS: These results suggest the feasibility of using [[211]At]APBF-2 as an Aβ-TAT agent for in vivo applications.},
}

@article {pmid40795635,
year = {2025},
author = {Zhou, W and Tian, L and Wang, X and Hou, G and Yu, J and Chen, M and Xu, C and Xue, L and Tan, X and Dai, R},
title = {Integrated untargeted and targeted metabolomics to reveal the mechanisms of herbal medicine HLXLD on Alzheimer's disease.},
journal = {Journal of chromatography. B, Analytical technologies in the biomedical and life sciences},
volume = {1265},
number = {},
pages = {124746},
doi = {10.1016/j.jchromb.2025.124746},
pmid = {40795635},
issn = {1873-376X},
abstract = {Huo-Luo-Xiao-Ling-Dan (HLXLD), a Chinese herbal medicine consisting of 11 herbs, has been shown to be effective in alleviating cognitive and memory impairment in Alzheimer's disease (AD). However, the underlying mechanisms require further investigation. This study aimed to clarify potential therapeutic mechanisms of HLXLD in the treatment of AD from a metabolic perspective. A rat model of AD induced by AlCl3 and D-gal was established, the Morris water maze (MWM) test and hippocampal histopathology were used to evaluate the pharmacological effect of the HLXLD on AD. Subsequently, untargeted metabolomics of brain tissues samples was performed by UHPLC-Q-Exactive-Orbitrap-MS, followed by multivariate statistical analysis. Targeted metabolomics by UHPLC-QQQ-MS was further employed to validate and supplement the untargeted metabolomics finding, involving neurotransmitters, amino acids, arachidonic acid and lipids, to elucidate the relationship between disease, herbal medicine and metabolism pathway. The study found that HLXLD could relieve the progression of AD and regulate metabolic imbalances. The levels of 26 metabolites decreased and 6 increased in brain tissues including lysine, taurine, fumaric acid, prostaglandin E2, choline and so on, these altered metabolites were primarily associated with amino acid metabolism, TCA cycle, arachidonic acid metabolism and lipid metabolism. The targeted metabolomics results showed that compared with the model group, the levels of 8 neurotransmitters, 21 amino acids, 7 arachidonic acids and 16 lipids in brain tissue, 9 neurotransmitters, 20 amino acids, 6 arachidonic acids and 2 lipids in plasma were changed. In summary, HLXLD could improve the levels of endogenous metabolites by regulating multiple metabolic pathways and play a role in energy supply, anti-neuroinflammatory and neuroprotective effects in AD treatment.},
}

@article {pmid40794901,
year = {2025},
author = {Tavakoli, E and Niciforos, E and Amid, P and Cuperfain, AB and Burhan, AM and Colman, S and Chu, L and Davies, SJC and Derkach, P and Gerretsen, P and Graff-Guerrero, A and Hussain, M and Ismail, Z and Kim, D and Krisman, L and Mulsant, BH and Pollock, BG and Rej, S and Rostas, A and Rajji, TK and Van Bussel, L and Kumar, S and Elmi, S},
title = {The impact of lifetime excessive alcohol use on behavioural and psychological symptoms of dementia.},
journal = {Alcohol and alcoholism (Oxford, Oxfordshire)},
volume = {60},
number = {5},
pages = {},
doi = {10.1093/alcalc/agaf048},
pmid = {40794901},
issn = {1464-3502},
support = {//The Standardizing Care for Neuropsychiatric Symptoms and Quality of Life in Dementia (StaN)/ ; //Brain Canada Foundation/ ; //Centre for Aging and Brain Health Innovation/ ; },
mesh = {Aged ; Aged, 80 and over ; Female ; Humans ; Male ; *Alcoholism/psychology/epidemiology/complications ; Alzheimer Disease/psychology ; Cross-Sectional Studies ; *Dementia/psychology/epidemiology ; Randomized Controlled Trials as Topic ; },
abstract = {INTRODUCTION: Excessive alcohol use (EAU) elevates the risk of dementia through various mechanisms, yet its impact on the behavioural and psychological symptoms of dementia (BPSDs) remains uncertain.

METHODS: In this exploratory cross-sectional analysis of baseline data from the Standardizing Care for Neuropsychiatric Symptoms and Quality of Life in Dementia (StaN) study (ClinicalTrials.gov/NCT03672201), we included individuals with Alzheimer's disease and related dementias requiring BPSD treatment. We compared demographic characteristics and presentation of BPSDs (using the total and domain scores on the Neuropsychiatric Inventory-Clinician) in those with and without a lifetime history of EAU.

RESULTS: Among 193 participants [mean (SD) age: 80.6 (9.7) years, male: 48.4%], those in the EAU group (n = 17) and in the comparator group (n = 176) had severe and comparable cognitive impairment, with a median Functional Assessment Staging Tool for Dementia score of 6e. Participants with EAU were significantly younger than comparators [mean age (SD): 72.9 (7.1) years vs. 81.4 (9.5) years] (t = -3.678, df = 181, P < .001), and were more frequently male (76.5% [13 of 17] vs. 46.6% [82 of 176]; P = .036). In a sensitivity analysis, there were no differences in the Neuropsychiatric Inventory-Clinician total or individual domain scores between those with EAU and a subsample of those without EAU matched for age, sex, and recruitment site.

CONCLUSION: This exploratory study found that among individuals with Alzheimer's disease and related dementias and BPSDs, lifetime history of EAU is more frequent in younger males. Future studies may further examine the impact of EAU in individuals with BPSDs.},
}

Aged
Aged, 80 and over
Female
Humans
Male
*Alcoholism/psychology/epidemiology/complications
Alzheimer Disease/psychology
Cross-Sectional Studies
*Dementia/psychology/epidemiology
Randomized Controlled Trials as Topic

@article {pmid40794806,
year = {2025},
author = {Yoon, DM and Plante, D and Fleming, V and Handen, B and Lao, P and Peven, J and Christian, B and Okonkwo, O and Laymon, C and Ances, B and Hom, C and Helsel, B and Hartley, SL and , },
title = {Preliminary Investigation of Obstructive Sleep Apnea and Alzheimer's Disease in Down Syndrome.},
journal = {Sleep},
volume = {},
number = {},
pages = {},
doi = {10.1093/sleep/zpaf044},
pmid = {40794806},
issn = {1550-9109},
abstract = {This study provided a preliminary examination of indices of obstructive sleep apnea (OSA) and sleep disruptions in adults with Down syndrome (DS), and their associations with Alzheimer's disease (AD) pathology and symptomatology. Ninety-three adults with DS (aged 25-61 years) from the Alzheimer Biomarker Consortium - Down Syndrome completed cognitive assessments, MRI and PET scans (assessing amyloid-beta [Aβ] and tau), and a one-night home sleep study using the WatchPAT-300 device. Study partners also reported on depressive symptoms and diagnoses. Correlational analyses examined relationships between sleep variables, PET biomarkers, and AD symptomatology (cognitive functioning and depressive mood), controlling for sociodemographics. Eighty-one participants (87%) completed valid WatchPAT data. Of these, 60 (74%) screened positive for OSA, and an additional 11 had a prior OSA diagnosis and used CPAP during the test night. Nearly half (45%) of those screening positive for OSA had no prior diagnosis, indicating under-detection. Among the 22 participants using OSA treatment, 50% continued to show sleep-disordered breathing, suggesting suboptimal treatment effectiveness. Higher wake percentage and shorter total sleep time were associated with greater Aβ and tau burden. Cognitive performance was negatively associated with wake percentage, total sleep time, and oxygenation indices (minimum oxygen, desaturation, and time ≤ 88% oxygen). Depressive symptoms were negatively related to total sleep time. These findings add preliminary evidence linking sleep disruption and OSA with AD-related pathology and symptomatology. Larger, longitudinal studies are needed to confirm these associations and evaluate whether improving sleep quality and treating OSA may help delay AD onset in this high-risk population.},
}

@article {pmid40794238,
year = {2025},
author = {Jellinger, KA},
title = {Comorbid pathologies and their impact on progressive supranuclear palsy: current view.},
journal = {Journal of neural transmission (Vienna, Austria : 1996)},
volume = {},
number = {},
pages = {},
pmid = {40794238},
issn = {1435-1463},
support = {Society for the Promotion of Research in Experimental Neurology, Vienna, Austria//Society for the Promotion of Research in Experimental Neurology, Vienna, Austria/ ; },
abstract = {Progressive supranuclear palsy, a four-repeat tauopathy, is clinically characterized by early postural instability and falls, vertical supranuclear palsy, levodopa poorly-responsive parkinsonism, pseudobulbar palsy, and cognitive impairment. It is morphologically featured by accumulation of hyperphosphorylated tau protein in neurons and glia predominantly in the basal ganglia, brainstem tegmentum and frontal cortex, associated with degeneration of the extrapyramidal system and cortical atrophy. Isolated PSP neuropathology is uncommon, with nearly 70% showing co-neuropathologies including Alzheimer-type, Lewy body, TDP-43 pathologies, argyrophilic grains, and other tauopathies and neurodegenerative disorders (Parkinson disease, amyotrophic lateral sclerosis). The most common comorbid conditions are hypertension, cardiovascular and cerebrovascular diseases, diabetes mellitus, polyneuropathies, muscular and urological disorders. Due the increased prevalence of comorbidities and their eminent impact on the progress and outcome of the disease, clinical trials should account for them in their design and selection. However, currently little is known about co-pathologies in these patients. In view of the eminent burden of comorbidities and resulting therapeutic consequences, the frequency of the different co-pathologies in PSP and their clinical impact will be discussed. It should provide insight into their pathogenic backgrounds as a basis for adequate treatment procedures to improve the quality of life of patients with this fatal disease.},
}

@article {pmid40792123,
year = {2025},
author = {Zhi, N and Ren, R and Qi, J and Liu, X and Yun, Z and Lin, S and Hu, Y and Li, H and Xie, X and Wang, J and Li, J and Zhu, Y and Gao, M and Yang, J and Wang, Y and Jing, Y and Geng, J and Cao, W and Xu, Q and Yu, X and Zhu, Y and Zhou, Y and Wang, L and Gao, C and Li, B and Chen, S and Yuan, F and Dou, R and Liu, X and Li, X and Yin, Y and Chang, Y and Xu, G and Zhong, Y and Li, C and Wang, Y and Zhou, M and Wang, G},
title = {The China Alzheimer Report 2025.},
journal = {General psychiatry},
volume = {38},
number = {4},
pages = {e102020},
pmid = {40792123},
issn = {2517-729X},
abstract = {With the sustained growth of the economy and significant changes in social demographics, the issue of elderly-related diseases has increasingly drawn attention, particularly. Alzheimer's disease (AD), as a representative disease of neurodegenerative diseases, has become a major challenge, affecting the health and quality of life of the elderly population severely. In recent years, the incidence, prevalence and mortality rates of AD have increased in China, imposing substantial economic burdens on families, society and the entire healthcare system. To proactively address this challenge and respond to the national 'Healthy China Action' initiative, leading experts from authoritative institutions jointly authored the China Alzheimer Report 2025. Building on previous editions, this report updates epidemiological data on AD in China, thoroughly analyses the latest economic burdens of the disease and comprehensively evaluates the current status of AD diagnosis and treatment services, as well as the allocation of public health resources in our country. Its release reflects China's progress in AD research and prevention, underscores societal concern for elderly health and aims to provide scientific guidance and data support for AD prevention, diagnosis and treatment. It also facilitates academic exchanges and cooperation, enhancing public awareness and promoting active participation in elderly healthcare, towards achieving 'healthy ageing' in China.},
}

@article {pmid40792047,
year = {2025},
author = {Mannai, A and Ressaissi, A and Merghni, A and Chahdoura, H and Mnif, W and Alelyani, Z and Ben-Attia, M and El-Bok, S and Serralheiro, ML},
title = {Phytochemical Profile and Evaluation of Antioxidant Activity, Enzyme Inhibition and Cell Viability of Leaves Extracts of Three Tunisian Varieties of Diospyros kaki L.},
journal = {Food science & nutrition},
volume = {13},
number = {8},
pages = {e70775},
pmid = {40792047},
issn = {2048-7177},
abstract = {Because of their biological qualities, the leaves of Diospyros kaki L., also known as persimmon, have long been used in traditional Chinese medicine for the treatment of ischemic stroke, angina, internal hemorrhage, hypertension, atherosclerosis, and some infectious diseases. It has also been used in cosmetics, as well as in refreshing drink preparations. In the present study, we have compared the aqueous extract effects of the leaves of the three Tunisian varieties of D. kaki, namely Triumph, Jiro, and Rojo Brillante, prepared by decoction and then filtered. The obtained filtrates were lyophilized and kept cold until analysis. Phytochemical profile and biological activities were performed on the freeze-dried fractions of the different varieties of D. kaki. Analysis of the results shows that the leaf extracts of the three varieties are rich in total phenols and flavonoids (ranking: Rojo Brillante > Triumph > Jiro) and have a high antioxidant activity (EC50 values of 3.8, 8.0 and 12.1 μg/mL respectively for Rojo Brillante, Triumph and Jiro). Using a quadrupole time-of-flight interface and high-resolution tandem liquid chromatography, 29 secondary metabolites of D. kaki leaf decoctions were identified in the three varieties, including several polyphenols such as flavonoids, tannins, organic acids, and others. In addition, these extracts were found to inhibit the function of two key enzymes, acetylcholinesterase (IC50 values of 58, 96 and 210 μg/mL respectively for Rojo Brillante, Triumph and Jiro) and inhibition percentages of 3-hydroxy-3-methylglutaryl-CoA reductase were 61.44%, 57.35%, and 46.28% for Jiro, Triumph, and Rojo Brillante, respectively. However, we noted that these different extracts had no cytotoxic effect on human liver or breast cancer cells in culture until 10 μg/mL. The results reveal that the D. kaki leaves are a potential matrix for the launch of future nutraceuticals, cosmetics, and pharmaceutical specialties such as drugs to combat Alzheimer's disease or to reduce cholesterol levels, as well as an attractive source of ingredients beneficial to health. Comparative analysis of D. kaki leaves showed that the Rojo Brillante variety has a higher content of secondary metabolites than the other two varieties, thus increasing its antioxidant activity and enzyme inhibitory effect, although it is not as cytotoxic as the other two varieties.},
}

@article {pmid40791780,
year = {2025},
author = {Mahendrarajan, V and Lazarus, HPS and Muthukaliannan, GK and Varghese, S and Easwaran, N},
title = {Membrane vesicles from Red Complex bacteria: key players in oral pathogenesis, immune disruption, systemic diseases, and therapeutic insights.},
journal = {Frontiers in oral health},
volume = {6},
number = {},
pages = {1607931},
pmid = {40791780},
issn = {2673-4842},
abstract = {The oral cavity serves as a habitat for a diverse array of microorganisms, each performing distinct functions, thereby constituting a vibrant and intricate ecological community. The most common pathogenic bacteria in the oral ecosystem are the Red Complex group, which includes Porphyromonas gingivalis, Treponema denticola, and Tannerella forsythia. These bacteria have several ways to inflict damage, such as creating biofilms and secreting nano-sized vesicles from their outer membrane, called Outer Membrane Vesicles (OMV). OMVs are nano structures that carry proteins, lipids, and toxins from the outer membrane of Gram-negative bacteria. The OMVs of Red Complex bacteria play a role in the onset and development of oral pathological conditions such as gingivitis and periodontitis. Additionally, a substantial body of evidence supports the notion that these OMVs may exert influence on systemic pathologies, including atherosclerosis, alzheimer's, rheumatoid arthritis, and diabetes mellitus. This review will discuss the formation and composition of Red Complex bacterial OMVs, their impacts on the oral environment, the immune response, and their correlations with various systemic diseases. The suggested treatment approach by probiotics and bioactives focuses on the genetic elements that induce the production of OMVs by the Red Complex bacteria, offering a potent means to hinder the advancement of diseases propagated through these OMVs.},
}

@article {pmid40791767,
year = {2025},
author = {Wang, X and Li, J and Fu, Q and Zheng, H and Duan, S and Gao, Y and Luo, H and Xu, Y},
title = {Cerebral Amyloid Angiopathy-Related Inflammation: Clinical Characteristics and Treatment Experience.},
journal = {Clinical interventions in aging},
volume = {20},
number = {},
pages = {1181-1190},
pmid = {40791767},
issn = {1178-1998},
mesh = {Humans ; *Cerebral Amyloid Angiopathy/complications/diagnosis/diagnostic imaging/therapy/drug therapy ; Male ; Female ; Aged ; Middle Aged ; Retrospective Studies ; Aged, 80 and over ; Adult ; *Inflammation/etiology ; Neuroimaging ; Cognitive Dysfunction/etiology ; },
abstract = {OBJECTIVE: The present study aims to analyze the clinical manifestations, laboratory results, neuroimaging features, treatment interventions, and outcomes in a cohort of patients with cerebral amyloid angiopathy-related inflammation (CAA-ri), providing a deeper understanding of this rare subtype of CAA and enhancing diagnostic precision in clinical practice.

METHODS: We conducted a systematic retrospective review of clinical records from 13 consecutive patients who met the diagnostic criteria for probable CAA-ri and were evaluated at the First Affiliated Hospital of Zhengzhou University between January 2021 and August 2024.

RESULTS: The study cohort comprised 13 patients (7 males, 6 females; mean age 65.2 years, range 42-81), predominantly presenting with subacute onset (53.8%, n=7). Cognitive impairment (61.5%, n=8) emerged as the most frequent clinical manifestation, followed by headache (46.2%, n=6), epileptic seizures (30.8%, n=4), and focal neurological deficits (23.1%, n=3). Neuroimaging findings across all patients demonstrated asymmetric white matter hyperintensities in conjunction with cortical-subcortical cerebral microbleeds. A subset of patients exhibited cortical superficial siderosis lobar hemorrhage, and/or punctate acute infarction. Among the nine patients who underwent lumbar puncture, five showed elevated cerebrospinal fluid (CSF) pressure and protein levels. All four patients assessed for CSF Alzheimer's disease biomarkers showed reduced Aβ42 and Aβ40 levels, alongside elevated total tau and phosphorylated tau levels. Furthermore, over 70% of the patients who treated with immunosuppressive therapy achieved favorable clinical outcomes.

CONCLUSION: Clinical manifestations and neuroimaging abnormalities serve as pivotal non-invasive criteria for guiding clinicians in the diagnosis of CAA-ri. Timely initiation of immunosuppressive therapy in CAA-ri patients can lead to favorable outcomes.},
}

Humans
*Cerebral Amyloid Angiopathy/complications/diagnosis/diagnostic imaging/therapy/drug therapy
Male
Female
Aged
Middle Aged
Retrospective Studies
Aged, 80 and over
Adult
*Inflammation/etiology
Neuroimaging
Cognitive Dysfunction/etiology

@article {pmid40791424,
year = {2025},
author = {Adaikkan, C and Islam, MR and Bozzelli, PL and Sears, M and Parro, C and Pao, PC and Sun, N and Kim, T and Abdelaal, K and Sedgwick, M and Kellis, M and Tsai, LH},
title = {A multimodal approach of microglial CSF1R inhibition and GENUS provides therapeutic effects in Alzheimer's disease mice.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.04.27.648471},
pmid = {40791424},
issn = {2692-8205},
abstract = {The CSF1R inhibitor PLX3397, an FDA-approved treatment for a rare cancer, has been shown to reduce microglia count, lower inflammation, and increase synaptic markers in mouse models of Alzheimer's disease (AD). However, the effects of PLX3397 on neural function in AD remain largely unknown. Here, we characterized the effects of PLX3397 treatment in 5xFAD mice. While PLX3397 increased synaptic density, it reduced the percentage of neurons phase-locked to gamma oscillations. This neural decoupling was closely associated with gene expression changes related to synapse organization. We investigated whether Gamma ENtrainment Using Sensory (GENUS) stimulation could counterbalance the neural circuit alterations induced by PLX3397. GENUS + PLX3397 restored gamma phase-locking, reshaped gene expression signatures, and improved learning and memory better than either treatment alone in 5xFAD mice. These findings suggest that CSF1R inhibitors like PLX3397 may benefit from a multimodal approach combining microglial targeting with non-invasive sensory stimulation to support neural physiology and improve cognitive function in AD.},
}

@article {pmid40791064,
year = {2025},
author = {Rodrigues, CC and Carvalho, V and Sotero, FD and Mulroy, E and Guedes, LC},
title = {Efficacy and safety of cholinesterase inhibitors and memantine for cognitive symptoms in patients with Huntington's disease: A systematic review.},
journal = {Journal of Huntington's disease},
volume = {},
number = {},
pages = {18796397251367689},
doi = {10.1177/18796397251367689},
pmid = {40791064},
issn = {1879-6400},
abstract = {BackgroundHuntington's Disease (HD) is an autosomal dominant neurodegenerative disorder. Clinical features encompass a broad spectrum of movement disorders, psychiatric and cognitive symptoms, often progressing to dementia and imposing a substantial burden on patients and their families. While cholinesterase inhibitors and memantine are often used for symptomatic treatment of Alzheimer's Disease and other dementias, there is currently no approved medication for treating cognitive symptoms in HD.ObjectiveWe aim to review, summarize, and appraise evidence from the literature for the use of cholinesterase inhibitors and memantine in the treatment of cognitive symptoms in patients with HD.MethodsA searched was conducted in PubMed and SCOPUS, from inception until February 2024, for Randomized Clinical Trials (RCTs), open-label, and case-control studies. Quality appraisal was performed using ROBINS-I and ROB2 for non-randomized studies and RCTs, respectively.ResultsFive eligible studies (three RCTs, one extension study, and one retrospective case-control), exploring the use of rivastigmine (n = 3), memantine (n = 1), and donepezil (n = 1) were found. Only two had a follow-up period longer than eight months. Previous cognitive functioning was not specified in three out of five studies. Cognitive measures varied widely, with Unified Huntington's Disease Rating Scale and Mini-Mental State Exam being used more frequently. None of the studies showed a significant improvement in cognitive function. Side effects occurred in up to 50% of patients and were usually considered mild.ConclusionsThere is insufficient evidence in the literature to support the use of cholinesterase inhibitors or memantine for cognitive symptoms in patients with HD.},
}

@article {pmid40790925,
year = {2025},
author = {Dodel, R and Frölich, L},
title = {Donanemab for Alzheimer's disease: from preclinical research to the clinical application.},
journal = {Expert review of neurotherapeutics},
volume = {},
number = {},
pages = {},
doi = {10.1080/14737175.2025.2546868},
pmid = {40790925},
issn = {1744-8360},
abstract = {INTRODUCTION: Donanemab (donanemab; Kisunla) is a humanized IgG1 monoclonal antibody specifically targeting a modified form of β-amyloid found predominantly within plaques (characterized as N-terminal pyroglutamate Aβ). Recently, it has gained approval for the use in early -stage Alzheimer's disease (AD) encompassing mild cognitive impairment due to AD or mild AD with confirmed brain amyloid pathology.

AREAS COVERED: This drug profile discusses donanemab's function, clinical effectiveness, safety, tolerability, health economics, access challenges, and future prospects. This article is based on literature that was derived from PubMed.

EXPERT OPINION: Donanemab is the third monoclonal antibody introduced for the treatment of individuals in the early stage of AD. While critical dialogue continues regarding the potential impacts and role of antibody therapies, its approval signifies considerable progress in addressing the underlying pathology of AD. The authors are confident in the potential of antibodies against Aβ as a promising treatment option and foresee exciting advancements. However, further research is needed on trials extending beyond 18 months of follow-up, postmarketing surveillance, and the application of donanemab in combination with existing treatments and lifestyle interventions. Additionally, significant knowledge gaps and implementation limitations persist and must be addressed.},
}

@article {pmid40790613,
year = {2025},
author = {Li, B and Wang, S and Kerman, B and Hugo, C and Shwab, EK and Shu, C and Chiba-Falek, O and Arvanitakis, Z and N Yassine, H},
title = {Microglial States Are Susceptible to Senescence and Cholesterol Dysregulation in Alzheimer's Disease.},
journal = {Aging cell},
volume = {},
number = {},
pages = {e70189},
doi = {10.1111/acel.70189},
pmid = {40790613},
issn = {1474-9726},
support = {//Tiny Foundation/ ; //Vranos Foundation/ ; P30AG066530/AG/NIA NIH HHS/United States ; P30AG72975/AG/NIA NIH HHS/United States ; R01AG054434/AG/NIA NIH HHS/United States ; R01AG055770/AG/NIA NIH HHS/United States ; R01AG057522/AG/NIA NIH HHS/United States ; R01AG067063/AG/NIA NIH HHS/United States ; R01AG15819/AG/NIA NIH HHS/United States ; R21AG056518/AG/NIA NIH HHS/United States ; RF1AG076124/AG/NIA NIH HHS/United States ; RF1AG077695/AG/NIA NIH HHS/United States ; //Ms. Lynne Nauss/ ; GC-201711-2014197//Alzheimer's Drug Discovery Foundation/ ; AARFD-24-1313939/ALZ/Alzheimer's Association/United States ; },
abstract = {Cellular senescence is a major contributor to aging-related degenerative diseases, including Alzheimer's disease (AD), but much less is known about the key cell types and pathways driving senescence mechanisms in the brain. We hypothesized that dysregulated cholesterol metabolism is central to cellular senescence in AD. We analyzed single-cell RNA-seq data from the ROSMAP and SEA-AD cohorts to uncover cell type-specific senescence pathologies. In ROSMAP snRNA-seq data (982,384 nuclei from postmortem prefrontal cortex), microglia emerged as central contributors to AD-associated senescence phenotypes among non-neuronal cells. Homeostatic, inflammatory, phagocytic, lipid-processing, and neuronal-surveillance microglial states were associated with AD-related senescence in both ROSMAP (152,459 microglia nuclei from six brain regions) and SEA-AD (82,486 microglia nuclei) via integrative analysis. We assessed top senescence-associated bioprocesses and demonstrated that senescent microglia exhibit altered cholesterol-related processes and dysregulated cholesterol metabolism. We identified three gene co-expression modules representing cholesterol-related senescence signatures in postmortem brains. To validate these findings, we applied these signatures to snRNA-seq data from iPSC-derived microglia（iMGs) exposed to myelin, Aβ, apoptotic neurons, and synaptosomes. Treatment with AD-related substrates altered cholesterol-associated senescence signatures in iMGs. This study provides the first human evidence that dysregulated cholesterol metabolism in microglia drives cellular senescence in AD. Targeting cholesterol pathways in senescent microglia is an attractive strategy to attenuate AD progression.},
}

@article {pmid40790282,
year = {2025},
author = {Higuchi, M and Tagai, K and Takahata, K and Endo, H},
title = {Advances in PET imaging of protein aggregates associated with neurodegenerative disease.},
journal = {Nature reviews. Neurology},
volume = {},
number = {},
pages = {},
pmid = {40790282},
issn = {1759-4766},
abstract = {Neurodegenerative diseases such as Alzheimer disease (AD), Parkinson disease, frontotemporal lobar degeneration and multiple system atrophy (MSA) are characterized pathologically by deposition of specific proteins in the brain. Five major neurodegenerative disease-associated proteins - amyloid-β (Aβ), tau, α-synuclein, TAR DNA-binding protein 43 (TDP43) and fused in sarcoma (FUS) - are commonly encountered, and the disease specificity and neurotoxicity of the fibrillar protein assemblies are determined by factors such as the protein type, fibril structure, degree of multimerization and post-translational modifications. This article reviews the latest advances in PET technologies aimed at visualizing neurodegenerative proteinopathies, and highlights the importance of these technologies for emerging diagnostic and therapeutic approaches. PET allows Aβ deposition to be visualized throughout the natural history of AD and following anti-Aβ immunotherapies. However, whether this technology can visualize specific Aβ assembly subspecies primarily targeted by the treatment remains inconclusive. Various PET radiotracers can capture AD-type tau deposits, although only a few are known to react with non-AD tau pathologies, and cryo-electron microscopy has revealed the mode of binding of these compounds to different tau protofibrils. High-contrast PET imaging of α-synuclein lesions in MSA is a recent development in the field, and gradual progress is being made towards visualization of other, less abundant α-synuclein pathologies. Imaging of TDP43 and FUS deposits presents particular challenges, which might be overcome by establishing public-private partnerships focused on biomarker development.},
}

@article {pmid40787376,
year = {2025},
author = {Gebeş-Alperen, B and Evren, AE and Sağlik Özkan, BN and Karaburun, AC and Gundogdu-Karaburun, N},
title = {Novel Benzofuran-3-yl-methyl and Aliphatic Azacyclics: Design, Synthesis, and In Vitro and In Silico anti-Alzheimer Disease Activity Studies.},
journal = {ACS omega},
volume = {10},
number = {30},
pages = {32829-32843},
pmid = {40787376},
issn = {2470-1343},
abstract = {Neurological disorders represent a significant burden on human health, particularly as global life expectancy continues to rise. Among these conditions, Alzheimer's disease is notably prevalent. Of greater concern, if left untreated or unaddressed, Alzheimer's disease can progress to dementia, leading to severe cognitive decline and a substantial reduction in quality of life. In this study, 15 novel benzofuran-azacyclic hybrids were designed and synthesized. The final compounds were evaluated for their inhibitory potency on AChE and BACE-1 enzymes, and in silico studies were performed to clarify their binding modes. Finally, structure-activity relationships (SARs) were proposed for future studies. The results indicated that the most promising compound is 4m, which contains N-(2-hydroxyethyl)-piperazine and benzofuran moieties. These moieties effectively occupied the substrate channel of the AChE enzyme and the catalytic cleft of the BACE-1 enzyme. Additionally, compounds 4e (benzyl piperidine) and 4h (2-furoyl piperazine) showed dual inhibitory activity on both enzymes. In conclusion, the tubular form with a stopper group shows great potential for the treatment of Alzheimer's disease, as it blocks the entrance cavity of the AChE active pocket for the substrate and increases the stability of the inactive BACE-1 enzyme. Moreover, electrolytes, specifically sodium ions in this case, play a crucial role in stabilizing the 4m-BACE-1 protein complex. For further studies, we suggest that the tubular form with a stopper can serve as a potential pharmacophore and an appropriate starting point for drug development.},
}

@article {pmid40786362,
year = {2025},
author = {Chowdhury, A and Bhasin, G and Ganti, L},
title = {Bibliometric Analysis of the Epidemiological Research on Alzheimer's Disease Treatment.},
journal = {Cureus},
volume = {17},
number = {7},
pages = {e87484},
pmid = {40786362},
issn = {2168-8184},
abstract = {Alzheimer's disease presents a complex global health issue. It is characterized by a decline in cognitive function, starting with memory impairment, and extending to impact reasoning, language abilities, and spatial awareness. Despite decades of research, Alzheimer's disease remains a global challenge lacking long-term treatments. Institutions like the Karolinska Institutet, Columbia University, the University of California San Francisco (UCSF), and the University of Pittsburgh contribute significantly to Alzheimer's research, with a growth in publications in 2022 post-COVID-19. While current treatments offer symptomatic relief, there's a need for disease-modifying therapies targeting its mechanisms. This analysis aims to provide a comprehensive overview of the available research and medical literature on Alzheimer's disease by employing bibliometric methods to identify publication trends, leading research institutions, and the evolving focus from symptomatic treatments to disease-modifying therapies. This paper seeks to analyze the research papers on Alzheimer's disease and catalog the metadata associated with each paper.},
}

@article {pmid40785177,
year = {2025},
author = {Varshney, H and Gaur, K and Subhan, I and Fatima, J and Jyoti, S and I, M and Shahid, M and -, R and Siddique, YH},
title = {Neuroprotective Effects of Fenugreek Leaf Extract in a Drosophila Model of Alzheimer's Disease Expressing Human Aβ-42.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050385870250721072643},
pmid = {40785177},
issn = {1875-5828},
abstract = {INTRODUCTION: Much emphasis has been given to the biological activities of Fenugreek against various diseased conditions. This study investigated the effect of fenugreek leaf extract on behavioural and cognitive function of transgenic Drosophila having human Aβ-42 expression in the neurons, herein referred to as Alzheimer's disease model flies (AD flies).

MATERIALS AND METHODS: AD flies were exposed to four different doses of fenugreek leaf extract (FE) containing i.e., 0.005, 0.010, 0.015 and 0.02 g/ml for 30 days. Thereafter, behavioural and cognitive assessment was done using climbing ability, activity pattern, aversive phototaxis and odour choice indexes. The life span of different groups of flies was also recorded. The effect of FE on the oxidative stress markers, acetylcholinesterase, monoamine oxidase (MAO) and caspase 3 and 9 activities was determined. The deposition of Aβ-42 aggregates in the brain tissue of the flies was studied by performing immunostaining. Also, the metabolic profile of different groups of flies was studied by performing LC-MS/MS. Compared with control flies, 22 selected metabolites were found to be upregulated and downregulated among transgenic AD flies and FE exposed AD flies compared to control.

RESULTS: The findings of this study showed the neuroprotective role of fenugreek extract, which could be employed for the treatment of Alzheimer's disease. The AD flies exposed to FE showed a dose-dependent postponement in the decline of climbing ability, activity and cognitive impairments. A significant dose dependent increase in the life span was also noticed in the AD flies exposed to FE. A significant reduction in the oxidative stress, acetylcholinesterase, monoamine oxidase, and caspase-3&9 activities was also observed in a dose dependent manner. The results obtained from the immunostaining suggest the reduction in the deposition of Aβ-42 fibril, which was also confirmed by the docking studies showing the energetically favoured interaction useful for inhibiting the acetylcholinesterase and Aβ-42 aggregates.

DISCUSSION: This study demonstrates the neurological potency of fenugreek leaf extract (FE) in a Drosophila model of AD due to its antioxidantive, anti-cholinesterase, and neuroprotective properties. Using a combination of behavioral, biochemical, histological, and metabolomic approaches, we evaluated the therapeutic potential of FE in mitigating AD-like symptoms in transgenic flies expressing Aβ-42.

CONCLUSION: Fenugreek leaf extract may serve as a potential natural remedy for slowing down or alleviating the progression of AD.},
}

@article {pmid40784967,
year = {2025},
author = {Şener, B and Açıcı, K and Sümer, E},
title = {Improving early detection of Alzheimer's disease through MRI slice selection and deep learning techniques.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {29260},
pmid = {40784967},
issn = {2045-2322},
mesh = {*Alzheimer Disease/diagnostic imaging/diagnosis ; Humans ; *Deep Learning ; *Magnetic Resonance Imaging/methods ; Early Diagnosis ; Cognitive Dysfunction/diagnostic imaging/diagnosis ; Aged ; Brain/diagnostic imaging/pathology ; Male ; Female ; },
abstract = {Alzheimer's disease is a progressive neurodegenerative disorder marked by cognitive decline, memory loss, and behavioral changes. Early diagnosis, particularly identifying Early Mild Cognitive Impairment (EMCI), is vital for managing the disease and improving patient outcomes. Detecting EMCI is challenging due to the subtle structural changes in the brain, making precise slice selection from MRI scans essential for accurate diagnosis. In this context, the careful selection of specific MRI slices that provide distinct anatomical details significantly enhances the ability to identify these early changes. The chief novelty of the study is that instead of selecting all slices, an approach for identifying the important slices is developed. The ADNI-3 dataset was used as the dataset when running the models for early detection of Alzheimer's disease. Satisfactory results have been obtained by classifying with deep learning models, vision transformers (ViT) and by adding new structures to them, together with the model proposal. In the results obtained, while an accuracy of 99.45% was achieved with EfficientNetB2 + FPN in AD vs. LMCI classification from the slices selected with SSIM, an accuracy of 99.19% was achieved in AD vs. EMCI classification, in fact, the study significantly advances early detection by demonstrating improved diagnostic accuracy of the disease at the EMCI stage. The results obtained with these methods emphasize the importance of developing deep learning models with slice selection integrated with the Vision Transformers architecture. Focusing on accurate slice selection enables early detection of Alzheimer's at the EMCI stage, allowing for timely interventions and preventive measures before the disease progresses to more advanced stages. This approach not only facilitates early and accurate diagnosis, but also lays the groundwork for timely intervention and treatment, offering hope for better patient outcomes in Alzheimer's disease. The study is finally evaluated by a statistical significance test.},
}

*Alzheimer Disease/diagnostic imaging/diagnosis
Humans
*Deep Learning
*Magnetic Resonance Imaging/methods
Early Diagnosis
Cognitive Dysfunction/diagnostic imaging/diagnosis
Aged
Brain/diagnostic imaging/pathology
Male
Female

@article {pmid40784648,
year = {2025},
author = {Zhang, F and Gou, J},
title = {Using multiple biomarkers for patient enrichment in two-stage clinical designs.},
journal = {Contemporary clinical trials},
volume = {},
number = {},
pages = {108012},
doi = {10.1016/j.cct.2025.108012},
pmid = {40784648},
issn = {1559-2030},
abstract = {Enrichment strategies play a critical role in modern clinical trial design, especially as precision medicine advances the focus on patient-specific efficacy. By targeting biomarker-defined populations most likely to benefit, these strategies improve efficiency, reduce sample sizes and costs, accelerate timelines, and minimize unnecessary exposure to treatment-related risks and side effects. Recent developments in enrichment design have introduced biomarker randomness and accounted for the correlation structure between treatment effect and biomarker, resulting in a two-stage threshold enrichment design. However, existing methods are limited to a single continuous biomarker. While incorporating multiple biomarkers can improve the accuracy of target population identification, no study has examined how to incorporate multiple continuous biomarkers into enrichment designs due to the challenges in determining multiple thresholds. To fully utilize information from all relevant biomarkers, we propose novel two-stage enrichment designs capable of handling two or more continuous biomarkers. Our framework accommodates two popular treatment effect metrics including average treatment effect (ATE) and the standardized ATE. We illustrate our method using a hypothetical clinical trial involving early-stage Alzheimer's patients and assess the impact of stage one sample size on threshold estimation through a simulation study. Overall, our proposed two-stage enrichment designs offer researchers greater flexibility in integrating multiple continuous biomarkers. The findings from our study provide valuable insights for the advancement of enrichment trial methodology.},
}

@article {pmid40784620,
year = {2025},
author = {Liu, L and Jiang, M and Zhang, Y and Lv, L and Wang, X and Yang, X},
title = {Acori Tatarinowii Rhizoma inhibited neuroinflammation in Alzheimer's disease rats by modulating the intestinal flora.},
journal = {Brain research},
volume = {},
number = {},
pages = {149878},
doi = {10.1016/j.brainres.2025.149878},
pmid = {40784620},
issn = {1872-6240},
abstract = {Alzheimer's disease (AD) is a degenerative disorder causing neuronal loss and cognitive deficits, which is associated with intestinal flora dysbiosis. Acori Tatarinowii Rhizoma (ATR) is the dried rhizome of Acorus tatarinowii Schott., and exhibits neuroprotective effects. We aimed to investigate the therapeutic mechanism of ATR in AD. AD rat models were constructed by intracerebroventricular injection of Aβ1-42, with gavage of ATR water extract (5, 10, and 20 mg/kg) for 21 days. Behavior tests, HE staining, immunohistochemistry, ELISA, immunofluorescence, and 16S rRNA sequencing were performed. In AD rats, ATR improved cognitive dysfunction and brain histopathological damage, with reduced Aβ1-42, interleukin (IL)-1β, IL-6, tumor necrosis factor-α, malondialdehyde, ionized calcium binding adaptor molecule, and glial fibrillary acidic protein expression, and higher superoxide dismutase activity, indicating inhibition of neuroinflammation by ATR. Moreover, Ruminococcus was strongly associated with ATR treatment for AD, which mainly enriched in Carbohydrate metabolism, Amino acid metabolism, and Lipid metabolism. Meanwhile, Dorea was negatively correlated with behavioural indicators and positively correlated with inflammatory factors, whereas g_Adlercreutzia showed the opposite trend. These findings suggested that ATR may attenuate neuroinflammation and improved AD by modulating intestinal flora and inhibiting microglia and astrocyte activation, providing a scientific basis for its clinical application in AD.},
}

@article {pmid40784614,
year = {2025},
author = {Yang, Y and Zhang, L and Zhao, Y and Yang, Z and Wang, P},
title = {Aβ-damaged neural stem cells migration and differentiation through Wnt3a/β-catenin pathway: Protective effects of 17β-E2.},
journal = {Neuroscience letters},
volume = {},
number = {},
pages = {138350},
doi = {10.1016/j.neulet.2025.138350},
pmid = {40784614},
issn = {1872-7972},
abstract = {Alzheimer's disease (AD) is a widespread central nervous system degenerative disease in the elderly population. This study aims to uniquely targets this sex-specific vulnerability by investigating the effects of 17β-E2 on the differentiation and migration capabilities of Aβ-damaged NSCs and its potential mechanisms-a critical gap for female-focused AD therapies. Primary NSCs isolated from neonatal SD rats were treated with Aβ25-35 (60 μM) to mimic AD pathology, followed by 17β-E2 (100 nM) with or without BX795 (a Wnt3a/β-catenin inhibitor). Results showed that Aβ significantly suppressed Wnt3a, LRP6, and β-catenin mRNA/protein levels while increasing GSK-3β expression. 17β-E2 treatment reversed these effects, enhancing phosphorylated GSK-3β (Ser9) and β-catenin, which were abolished by BX795. Transwell assays demonstrated that 17β-E2 rescued Aβ-damaged migration deficits, accompanied by elevated p-MLC and Cdc42 protein levels. Furthermore, 17β-E2 promoted neuronal differentiation, increasing MAP2 + and βIII-tubulin + cells with enhanced dendritic complexity, whereas BX795 counteracted these benefits. These findings indicate that 17β-E2 mitigates Aβ-damaged NSCs dysfunction by activating the Wnt3a/β-catenin pathway via GSK-3β phosphorylation, highlighting its therapeutic potential for AD by enhancing neurogenesis and NSC mobility.},
}

@article {pmid40784611,
year = {2025},
author = {Maurice, T},
title = {Prevention of memory impairment and hippocampal injury with blarcamesine in an Alzheimer's disease model.},
journal = {Neuroscience letters},
volume = {},
number = {},
pages = {138349},
doi = {10.1016/j.neulet.2025.138349},
pmid = {40784611},
issn = {1872-7972},
abstract = {Alzheimer's disease (AD) is the most common dementia, with rising global prevalence, still incomplete pathogenetic understanding and very limited effective therapies. Recent advances in biomarker identification of Aβ peptides and phospho-tau protein, and in anti-Aβ immunotherapy are suggesting that more early intervention will be more effective. Alternative therapeutic strategies to anti-Aß immunotherapy have received comparably less attention, yet one specific approach toward upstream neuroprotection by improvement of intracellular calcium homeostasis, activation of endogenous neuroprotection and restoration of autophagy through sigma-1 receptor activation recently demonstrated positive clinical data with oral blarcamesine in a phase IIb/III trial in 508 patients with early AD. AD-preventive approaches beyond lifestyle interventions become attractive candidates when meeting criteria of: (i) record of effective early intervention in mild disease, (ii) record of human safety, (iii) ease of administration, (iv) scalability to population level, (v) relative cost-effectiveness considering longer-term preventive use at population level. Here, we assessed blarcamesine's efficacy at preventing memory impairment and brain oxidative injury in the mouse preclinical model induced by intracerebroventricular injection of aggregated Aβ25-35 peptide, that permitted a clean preventive approach before administration of the pathology-inducing amyloidogenic Aβ fragment. We observed significant preventions of Aβ25-35-induced memory impairments, for both spatial working and contextual long-term memories, and of Aβ25-35-induced increase in lipid peroxidation in the mouse hippocampi. These new insights, together with blarcamesine's clinical record in early AD render blarcamesine an attractive candidate for AD pharmacological prevention.},
}

@article {pmid40784568,
year = {2025},
author = {Yang, Y and Guan, PP and Wang, P},
title = {Triptolide induces the secretion of insulin, through which it alleviates the tauopathies of Alzheimer's disease via inhibiting the phosphorylation of tau.},
journal = {Biochemical pharmacology},
volume = {242},
number = {Pt 3},
pages = {117223},
doi = {10.1016/j.bcp.2025.117223},
pmid = {40784568},
issn = {1873-2968},
abstract = {Triptolide (TP) has shown its therapeutic effects on Alzheimer's disease (AD) via decreasing the overloading of β-amyloid protein (Aβ). However, the roles and mechanisms of TP in the pathogenesis of tau have not been revealed until now. To this end, the current study aimed to assess the effects of TP on AD via tau-associated mechanisms. In detail, TP treatment decreases the phosphorylation of tau, which results in attenuating the cognitive decline of PS19 mice. In the mechanisms, we found that TP treatment elevates the levels of insulin, which lowers the blood glucose, leading to superior performance in the glucose tolerance test, inhibition of AMP-activated protein kinase (AMPK), and the change of serum triglycerides and cholesterol. The in vitro studies demonstrating that TP increases insulin production via cAMP-response element binding protein (CREB)- and pancreatic-duodenal homeobox factor 1 (PDX-1)-dependent mechanisms in MIN6 cells further supported the in vivo findings. By enhancing insulin production, TP upregulates protein O-GlcNAc modification and inhibits Ca[2+]/calmodulin-dependent protein kinase 2 (CaMK2) activity to reduce tau phosphorylation in both in vivo and in vitro experiments. Additionally, metabolic changes decrease the activity of the CCAAT/enhancer binding protein beta (C/EBPβ)/asparagine endopeptidase (AEP) signaling pathway, significantly reducing the associated neuroinflammation. Guided by these mechanisms, TP shows inhibitory effects on tau phosphorylation via an insulin secretion-dependent pathway.},
}

@article {pmid39950284,
year = {2025},
author = {Zheng, C and Wu, L and Luo, L and Cai, J and Huang, Z and Tian, K},
title = {Therapeutic Effects and Mechanisms of Icaritin in Parkinson's Disease.},
journal = {Current pharmaceutical design},
volume = {31},
number = {25},
pages = {1983-1989},
pmid = {39950284},
issn = {1873-4286},
support = {31960190//National Natural Science Foundation of China/ ; 20192BAB205117//Jiangxi Natural Science Foundation/ ; 202212550//Science and Technology Plan Project of Jiangxi Provincial Health Care Commission/ ; GZ2021ZSF340//Science and Technology Guidance Project of Ganzhou/ ; 2020-2-48//Science and Technology Plan Project of Ganzhou Health Care Commission/ ; },
mesh = {Humans ; *Parkinson Disease/drug therapy/metabolism ; *Flavonoids/pharmacology/therapeutic use/chemistry/isolation & purification ; Animals ; *Neuroprotective Agents/pharmacology/therapeutic use/isolation & purification/chemistry ; Oxidative Stress/drug effects ; },
abstract = {Parkinson's Disease (PD) is a neurodegenerative disorder of the central nervous system (CNS). Given the increasing age of the general population, PD has emerged as a significant public health and societal concern, impacting both individual well-being and socioeconomic progress. The present interventions have proven insufficient in impeding the progressive nature of PD. Consequently, it is imperative to promptly identify efficacious strategies for the prevention and treatment of PD. Icaritin (ICT) is a flavonoid extracted from Epimedium Brevicornu Maxim that is a phytoestrogen with antitumour, anti-inflammatory, antioxidant, antiaging, and neuroprotective properties. This paper reviews the protective effect of ICT on dopaminergic neurons through anti-oxidative stress, improving mitochondrial function, inhibiting neuroinflammatory responses, reducing Lewy body formation, and decreasing apoptosis. The primary objective of this article is to provide valuable insights and serve as a reference for the potential use of ICT in the prevention and treatment of PD.},
}

Humans
*Parkinson Disease/drug therapy/metabolism
*Flavonoids/pharmacology/therapeutic use/chemistry/isolation & purification
Animals
*Neuroprotective Agents/pharmacology/therapeutic use/isolation & purification/chemistry
Oxidative Stress/drug effects

@article {pmid40784411,
year = {2025},
author = {Yang, J and Chen, Y and Dong, G and Ma, Y and Lin, R and Yuan, Y},
title = {Immune-metabolic perspective on the association of seven psychiatric disorders and five common auditory diseases: a bidirectional two-sample Mendelian randomization study and mediation analysis.},
journal = {Journal of affective disorders},
volume = {},
number = {},
pages = {120044},
doi = {10.1016/j.jad.2025.120044},
pmid = {40784411},
issn = {1573-2517},
abstract = {INTRODUCTION: Although the relationship between psychiatric disorders and common auditory diseases has been discovered in observational studies, the causal linkage between them remains inconclusive.

METHODS: The bidirectional two-sample Mendelian randomization (MR) analysis was performed, drawing on the most recent and expansive genome-wide association studies (GWAS) data for seven psychiatric disorders and five common auditory diseases. Additionally, a mediation analysis was conducted using data on 731 immune cell phenotypes and 1400 metabolite levels to explore potential mediating factors influencing the causal pathways.

RESULTS: Autism Spectrum Disorder (ASD) could increase the risk of presbycusis (odds ratio [OR] = 1.161 [95 % confidence interval (CI), 1.042-1.295], P-value = 0.007) through CD25 on CD45RA- CD4 not regulatory T cell (Mediation effect β = 0.017), and Major Depressive Disorder (MDD) could increase the risk of vertigo (OR = 1.215 [95 % CI, 1.043-1.415], P-value = 0.012) through CD33+ HLA DR+ CD14dim Absolute Count (Mediation effect β = 0.007). Alzheimer's Disease (AD) could reduce the risk of presbycusis through four metabolite levels related to lipid metabolism. And Bipolar Disorder I (BD I) could reduce the risk of vertigo, as well as sudden sensorineural hearing loss (SSNHL) could reduce the risk of Post Traumatic Stress Disorder (PTSD).

CONCLUSION: This study underscores the intricate causal links between psychiatric disorders and auditory diseases. Mediation analyses indicate that immune cells are facilitators of positive effects, while metabolite levels play a protective role. These insights offer potential pathways for more effective clinical diagnosis and treatment.},
}

@article {pmid40784409,
year = {2025},
author = {Sing, R and Shikha, D and Goswami, C},
title = {TRPM8 modulation alters uptake of Transferrin-mediated Fe[3+], mitochondrial Fe[2+] and intracellular Ca[2+]-levels in microglia.},
journal = {Neurochemistry international},
volume = {},
number = {},
pages = {106031},
doi = {10.1016/j.neuint.2025.106031},
pmid = {40784409},
issn = {1872-9754},
abstract = {Microglia play an important role in the immunity of the central nervous system, crucial in maintaining homeostasis. However, under diseased conditions, this cell accumulates Fe[2+/3+], triggering inflammatory and neurotoxic effects that contribute to neurodegenerative disorders such as Alzheimer's and Parkinson's. Hence, the study of dysregulated microglial activation and overload of Fe[2+/3+] is crucial in the context of neurodegenerative conditions. Emerging research has identified cold-sensitive ion channels, i.e., TRPM8 in microglia, which can regulate key subcellular functions. This study explores the regulatory function of the TRPM8 in Fe[2+/3+] metabolism and its implications for potential ferroptosis in BV2 microglial cells. We used highly specific fluorescence probes, pharmacological modulators of TRPM8 and performed life cell imaging to understand the uptake of Transferrin-488, mitochondrial Fe[2+]-level, cellular Ca[2+]-levels in live BV2 cells under different experimental conditions. Our findings reveal that TRPM8 activation leads to enhanced Transferrin-488-mediated cytosolic Fe[3+]-uptake, disrupts mitochondrial superoxide levels, and promotes cell death. Interestingly, under inflammatory conditions induced by LPS treatment, TRPM8 exhibits a distinct functional role. These results position TRPM8 as an important regulator of microglial Fe[2+/3+] metabolism. This study indicates the involvement of TRPM8 in overload of Fe[2+/3+] leading to ferroptosis and potential for M1-M2 polarization in microglia. These findings impose TRPM8 as a potential therapeutic target for neurodegenerative diseases, and aging.},
}

@article {pmid40782673,
year = {2025},
author = {Sabbagh, MN and Kennedy, J and Majeed, J and Decourt, B},
title = {Alzheimer's disease: Clinical trials to watch.},
journal = {Med (New York, N.Y.)},
volume = {6},
number = {8},
pages = {100771},
doi = {10.1016/j.medj.2025.100771},
pmid = {40782673},
issn = {2666-6340},
mesh = {*Alzheimer Disease/drug therapy ; Humans ; Clinical Trials as Topic ; Oligonucleotides, Antisense/therapeutic use ; Glucagon-Like Peptide-1 Receptor Agonists ; Amyloid beta-Peptides/antagonists & inhibitors ; tau Proteins/antagonists & inhibitors ; },
abstract = {Second-generation anti-amyloid therapies (ATTs) offer new options for early Alzheimer's disease treatment, but with modest efficacy and documented adverse events. Here we highlight several ongoing clinical trials, aiming to develop therapeutic agents with higher efficacy and better safety profiles including third-generation ATTs, aggregation inhibitors, Sigma-1 receptor agonists, anti-tau antisense oligonucleotides, and GLP-1 receptor agonists.},
}

*Alzheimer Disease/drug therapy
Humans
Clinical Trials as Topic
Oligonucleotides, Antisense/therapeutic use
Glucagon-Like Peptide-1 Receptor Agonists
Amyloid beta-Peptides/antagonists & inhibitors
tau Proteins/antagonists & inhibitors

@article {pmid40782185,
year = {2025},
author = {Bergamo, G and Liguori, C},
title = {Are sleep disturbances modifiable risk factors for mild cognitive impairment and dementia? A systematic review of large studies.},
journal = {Sleep & breathing = Schlaf & Atmung},
volume = {29},
number = {4},
pages = {269},
pmid = {40782185},
issn = {1522-1709},
mesh = {Humans ; *Cognitive Dysfunction/epidemiology/diagnosis/etiology ; *Dementia/epidemiology/etiology/diagnosis ; Risk Factors ; *Sleep Wake Disorders/epidemiology/diagnosis/complications ; Aged ; },
abstract = {Studies have shown a connection between sleep disorders, mild cognitive impairment and dementia. In this context, the present systematic review aimed to determine in large studies whether sleep disturbances are modifiable risk factors for cognitive decline. Following the application of inclusion and exclusion criteria, this systematic review selected 15 studies, with large cohort of subjects included (more than 1000 participants), who were longitudinally observed. Studies predominantly used questionnaires and interviews to collect subjective data on sleep. Eleven studies were based on subjective measurements, one was based on the International Classification of Diseases - 9th Edition diagnosis codes, and three based on objective actigraphic measurements. No study used polysomnographic assessments for the evaluation of sleep disorders.The results of this systematic review showed that extreme sleep durations (either too short or too long), daytime sleepiness, circadian sleep-wake cycle disruption, and variation in sleep patterns are factors associated with an increased risk of developing cognitive decline and dementia. Actigraphy, as an objective instrument for monitoring the sleep-wake rhythm, provided further insights into the association between sleep problems and longitudinal cognitive decline. These findings emphasize the strong connection between sleep disturbances, circadian rhythm, and the risk of developing dementia and Alzheimer's disease (AD). Sleep disorders may serve as an early indicator for cognitive decline, also considering that they may represent a modifiable risk factor for dementia. Therefore, recognition and treatment of sleep problems should be included in the prevention strategies against cognitive decline, opening up new opportunities for the prevention and treatment of cognitive impairment and AD.},
}

Humans
*Cognitive Dysfunction/epidemiology/diagnosis/etiology
*Dementia/epidemiology/etiology/diagnosis
Risk Factors
*Sleep Wake Disorders/epidemiology/diagnosis/complications
Aged

@article {pmid40780474,
year = {2025},
author = {Manzoor, M and Iqbal, MO and Dan, W and Barkat, MQ and Iqbal Khan, MS and Syed, W and Al-Rawi, MBA and Ni, F},
title = {Syringaresinol from Cinnamomum cassia (L.) J.Presl Ameliorates Cognitive Deficits and AD Pathology via AMPK in a DM-AD Mouse Model.},
journal = {Journal of ethnopharmacology},
volume = {},
number = {},
pages = {120374},
doi = {10.1016/j.jep.2025.120374},
pmid = {40780474},
issn = {1872-7573},
abstract = {Syringaresinol (SYR), a major lignan in food analogous TCM (Cinnamomum cassia (L.) J.Presl) possesses antioxidant, anti-inflammatory, antidiabetic, and antiaging effects. However, its protective role and mechanisms in diabetes-related cognitive dysfunction (DM-AD) remain unclear.

AIM OF THE STUDY: We aimed to assess the protective effects of SYR on metabolic dysfunction associated cognitive decline through the modulation of oxidative stress, neuroinflammation and AMPK activation.

MATERIALS AND METHODS: This study involved extraction of C. cassia bark and isolation of SYR, structurally characterized by HR-MS and [1]H NMR. A DM-AD mouse model was established using HFD and STZ. In vivo assessments included body weight, food intake, fasting glucose, GTT, and ITT. Cognitive function was evaluated using Y-maze, MWM, and NOR tests. SYR's interaction with AMPK was examined through western blotting, molecular docking, and AMPK inhibitor experiments. Oxidative stress markers and neuroinflammatory cytokines were analyzed via biochemical assays and RT-PCR.

RESULTS: SYR treatments at 5 and 15 mg/kg significantly improved metabolic parameters by reducing body weight gain, enhancing glucose tolerance and insulin sensitivity, and restoring hepatic lipid balance. It also alleviated cognitive impairments with improved memory and learning. Mechanistically, SYR activated AMPK, supported by phosphorylation and molecular docking (-8.7 kcal/mol). In addition, SYR also enhanced antioxidant defense and suppressed neuroinflammatory and increased anti-inflammatory cytokines in the DM-AD brain. Co-treatment with the AMPK inhibitor abolished SYR's cognitive and anti-inflammatory benefits to confirm AMPK's key role in neuroprotective effects of SYR.

CONCLUSIONS: In conclusion, SYR demonstrates metabolic and neuroprotective effects comparable to metformin, primarily through AMPK activation therefore it could be used as a promising natural therapeutic candidate for DM-associated AD.},
}

@article {pmid40780467,
year = {2025},
author = {Sugandhi, VV and Gattu, K and Mundrathi, V and Khairnar, R and Arshad, T and Kumar, S and Cho, H},
title = {Intranasal delivery of rapamycin via brain-targeting polymeric micelles for Alzheimer's disease treatment.},
journal = {International journal of pharmaceutics},
volume = {},
number = {},
pages = {126011},
doi = {10.1016/j.ijpharm.2025.126011},
pmid = {40780467},
issn = {1873-3476},
abstract = {Alzheimer's disease (AD) is a long-term neurological disorder associated with neuroinflammation and amyloid-beta (Aβ) aggregation, which leads to a decline in cognitive and behavioral changes. Rapamycin (Rapa) is an immunosuppressive drug effective in preventing organ rejection after a kidney transplant. In the last few years, orally delivered Rapa has emerged as a potential candidate for improving cognitive function in patients with AD. However, it is evident that long-term oral treatment of Rapa causes systemic toxicity, and although controversial, it may even trigger the aggregation of Aβ deposition. This study investigated the therapeutic potential of intranasally delivered brain-targeting polymeric micelles carrying Rapa. We successfully prepared Fibronectin CS1 peptide-conjugated poly(ethylene glycol)-block-poly(D, L-lactic acid) (FibCS1-PEG-b-PLA) micelles carrying Rapa, which were 98.08 ± 1.15 nm in particle size with a polydispersity index of 0.21 ± 0.01. FibCS1-PEG-b-PLA micelles showed a significant improvement for nasal permeation of Rapa across RPMI-2650 epithelial cells. Behavioral studies such as corner, novel object recognition and Morris Water Maze tests showed promising results towards the improvement of cognitive function in a 3xTg-AD mice model when treated with intranasal FibCS1-PEG-b-PLA micelles carrying RAPA at a dose of 0.2 mg/kg (q4dx5). The western blot and ELISA results of the brain tissues of 3xTg-AD mice treated with intranasal FibCS1-PEG-b-PLA micelles carrying Rapa showed significant reductions in Aβ and two pro-inflammation markers (e.g. interleukin (IL)-1β, tumor necrosis factor (TNF)-α). Here, we conclude that brain-targeting FibCS1-PEG-b-PLA micelles carrying Rapa were effective in reaching the brain via intranasal route, reduced pro-inflammatory markers and Aβ, and improved cognitive function in AD-induced mice.},
}

@article {pmid40779804,
year = {2025},
author = {Ferjančič Benetik, S and Proj, M and Knez, D and Košak, U and Meden, A and Krajšek, K and Pišlar, A and Horvat, S and Švajger, U and Tešić, N and Pulkrabkova, L and Soukup, O and Skarka, A and Andrys, R and Brazzolotto, X and Igert, A and Nachon, F and Dias, J and Detka, J and Gdula-Argasińska, J and Wyska, E and Szafarz, M and Manik, A and Płachtij, N and Musílek, K and Sałat, K and Obreza, A and Gobec, S},
title = {Targeting Neuroinflammation and Cognitive Decline: First-in-Class Dual Butyrylcholinesterase and p38α Mitogen-Activated Protein Kinase Inhibitors.},
journal = {Journal of medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.jmedchem.5c00933},
pmid = {40779804},
issn = {1520-4804},
abstract = {The currently approved drugs for the treatment of Alzheimer's disease (AD) fail to address its interconnected pathological processes. Inhibition of butyrylcholinesterase (BChE) and p38α mitogen-activated protein kinase (p38α MAPK) offers an innovative dual approach to mitigate two major drivers of neurodegeneration in AD: cholinergic deficit and neuroinflammation. Using structure-based drug design and a library of known p38α MAPK inhibitors, we developed first-in-class, selective dual BChE/p38α MAPK inhibitors with balanced activity against both targets. The X-ray crystal structures of the two most promising molecules bound to both enzymes were solved. Those ligands effectively reduced the production of proinflammatory markers in vitro and ex vivo in phytohemagglutinin/lipopolysaccharide neuroinflammation models. Remarkably, these compounds also significantly improved cognition in scopolamine- and lipopolysaccharide-induced models of cognitive dysfunction in mice. Because our dual-acting inhibitors target both the symptoms and the underlying neuropathology, they offer an innovative and comprehensive strategy to combat AD.},
}

@article {pmid40779063,
year = {2025},
author = {Bulai, IM and Ferraresso, F and Gladiali, F},
title = {Optimal control of monomers and oligomers degradation in an Alzheimer's disease model.},
journal = {Journal of mathematical biology},
volume = {91},
number = {3},
pages = {27},
pmid = {40779063},
issn = {1432-1416},
support = {20227TRY8H//Italian Ministry for Research and Education/ ; ECS 00000038//Italian Ministry for Research and Education/ ; ECS 00000038//Italian Ministry for Research and Education/ ; EU-CUP-J55F21004240001//Università degli Studi di Sassari/ ; EU-CUP-J55F21004240001//Università degli Studi di Sassari/ ; },
mesh = {*Alzheimer Disease/metabolism/therapy ; Humans ; *Amyloid beta-Peptides/metabolism/chemistry/antagonists & inhibitors ; Mathematical Concepts ; Brain/metabolism ; Computer Simulation ; Immunotherapy/methods ; *Models, Biological ; Protein Multimerization ; },
abstract = {The aggregation and accumulation of oligomers of misfolded Aβ-amyloids in the human brain is one of the possible causes for the onset of the Alzheimer's disease in the early stage. We introduce and study a new ODE model for the evolution of Alzheimer's disease based on the interaction between monomers, proto-oligomers, and oligomers of Aβ amyloid protein in a small portion of the human brain, based upon biochemical processes such as polymerization, depolymerization, fragmentation and concatenation. We further introduce the possibility of controlling the evolution of the system via a treatment that targets the monomers and/or the oligomers. We observe that a combined optimal treatment on both monomers and oligomers induces a substantial decrease of the oligomer concentration at the final stage. A single treatment on oligomers performs better than a single treatment on monomers. These results shed a light on the effectiveness of immunotherapy using anti-Aβ antibodies, targeting monomers or oligomers. Several numerical simulations show how the oligomer concentration evolves without treatment, with single monomer/oligomer treatment, or with a combined treatment.},
}

*Alzheimer Disease/metabolism/therapy
Humans
*Amyloid beta-Peptides/metabolism/chemistry/antagonists & inhibitors
Mathematical Concepts
Brain/metabolism
Computer Simulation
Immunotherapy/methods
*Models, Biological
Protein Multimerization

@article {pmid40778542,
year = {2025},
author = {Li, R and Xiong, W and Sun, C},
title = {Hippocampal neural stem cells in Alzheimer's disease: bridging neurogenesis, extracellular vesicles, and multimodal therapeutic paradigms.},
journal = {The International journal of neuroscience},
volume = {},
number = {},
pages = {1-21},
doi = {10.1080/00207454.2025.2540989},
pmid = {40778542},
issn = {1563-5279},
abstract = {Alzheimer's disease (AD) presents a formidable challenge in neurodegenerative medicine because of its complex pathophysiology and the absence of effective disease-modifying therapies. Emerging evidence suggests that impaired adult hippocampal neurogenesis (AHN), a dynamic process essential for cognitive plasticity, is a mechanistic contributor to AD progression. This review highlights the role of hippocampal neural stem cells (NSCs) in the pathogenesis of AD, including the molecular mechanisms underlying the neurogenic decline in AD and their potential impact on cognitive resilience. We summarize current therapeutic approaches, including pharmacological agents and non-pharmacological interventions (e.g. exercise, cognitive training, dietary strategies, and neurostimulation therapies), and explore their influence on neurogenesis. Additionally, we explore the potential application of NSCs in AD treatment, specifically through the use of NSC-derived extracellular vesicles (NSC-EVs) as a novel therapeutic modality. By integrating insights from AHN research and cutting-edge therapeutic advancements, this review emphasizes the therapeutic potential of promoting neurogenesis to address cognitive decline and advance treatment strategies for AD.},
}

@article {pmid40778306,
year = {2025},
author = {Li, S and Huang, N and Wang, M and Huang, W and Shi, J and Luo, Y and Huang, J},
title = {GLP-1R as a potential link between diabetes and Alzheimer's disease.},
journal = {Frontiers in aging neuroscience},
volume = {17},
number = {},
pages = {1601602},
pmid = {40778306},
issn = {1663-4365},
abstract = {There is growing interest in the relationship between Alzheimer's disease (AD) and diabetes mellitus (DM), and the glucagon-like peptide-1 receptor (GLP-1R) may be an important link between these two diseases. The role of GLP-1R in DM is principally to regulate glycemic control by stimulating insulin secretion, inhibiting glucagon secretion, and improving insulin signaling, thereby reducing blood glucose levels. In AD, GLP-1R attenuates the pathological features of AD through mechanisms such as anti-inflammatory effects, the reduction in amyloid-beta (Aβ) deposition, the promotion of Aβ clearance, and improvements in insulin signaling. Notably, AD and DM share numerous pathophysiological mechanisms, most notably the disruption of insulin signaling pathways in the brain. These findings further underscore the notion that GLP-1R plays pivotal roles in both diseases. Taken together, these findings lead us to conclude that GLP-1R not only plays an important role in the treatment of DM and AD but also may serve as a bridge between these two diseases. Future research should focus on elucidating the detailed molecular mechanisms underlying the actions of GLP-1R in both diseases and exploring the development of GLP-1R agonists with dual therapeutic benefits for AD and DM. This could pave the way for innovative integrated treatment strategies to improve outcomes for patients affected by these intertwined conditions.},
}

@article {pmid40778305,
year = {2025},
author = {Zhang, X and Wijenayake, S and Hossain, S and Liu, Q},
title = {Estimating progression of Alzheimer's disease with extracellular vesicle-related multi-omics risk models.},
journal = {Frontiers in aging neuroscience},
volume = {17},
number = {},
pages = {1617611},
pmid = {40778305},
issn = {1663-4365},
abstract = {BACKGROUND: Alzheimer's Disease (AD) is heterogeneous and shows complex interconnected pathways at various biological levels. Risk scores contribute greatly to disease prognosis and biomarker discovery but typically represent generic risk factors. However, large-scale multi-omics data can generate individualized risk factors. Filtering these risk factors with brain-derived extracellular vesicles (EVs) could yield key pathologic pathways and vesicular vehicles for treatment delivery.

METHODS: A list of 460 EV-related genes was curated from brain tissue samples in the ExoCarta database. This list was used to select genes from transcriptomics, proteomics, and DNA methylation data. Significant risk factors included demographic features (age, sex) and genes significant for progression in transcriptomics data. These genes were selected using Cox regression, aided by the Least Absolute Shrinkage and Selection Operator (LASSO), and were used to construct three risk models at different omics levels. Gene signatures from the significant risk factors were used as biomarkers for further evaluation, including gene set enrichment analysis (GSEA) and drug perturbation analysis.

RESULTS: Nine EV-related genes were identified as significant risk factors. All three risk models predicted high/low risk groups with significant separation in Kaplan-Meier analysis. Training the transcriptomics risk models on EV-related genes yielded better AD classification results than using all genes in an independent dataset. GSEA revealed Mitophagy and several other significant pathways related to AD. Four drugs showed therapeutic potential to target the identified risk factors based on Connectivity Map analysis.

CONCLUSION: The proposed risk score model demonstrates a novel approach to AD using EV-related large-scale multi-omics data. Potential biomarkers and pathways related to AD were identified for further investigation. Drug candidates were identified for further evaluation in biological experiments, potentially transported to targeted tissues via bioengineered EVs.},
}

@article {pmid40778177,
year = {2025},
author = {Villeneuve, S and Poirier, J and Breitner, JCS and Tremblay-Mercier, J and Remz, J and Raoult, JM and Yakoub, Y and Gallego-Rudolf, J and Qiu, T and Valdez, AF and Mohammediyan, B and Javanray, M and Metz, A and Sanami, S and Ourry, V and Wearn, A and Pastor-Bernier, A and Edde, M and Gonneaud, J and Strikwerda-Brown, C and Tardif, CL and Gauthier, CJ and Descoteaux, M and Dadar, M and Presseau, ÉV and Baril, AA and Ducharme, S and Montembeault, M and Geddes, MR and Soucy, JP and Rajah, N and Laforce, R and Bocti, C and Davatzikos, C and Bellec, L and Rosa-Neto, P and Baillet, S and Evans, AC and Louis Collins, D and Chakravarty, MM and Blennow, K and Zetterberg, H and Spreng, RN and Binette, AP and , },
title = {The PREVENT-AD cohort: accelerating Alzheimer's disease research and treatment in Canada and beyond.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.07.22.25331791},
pmid = {40778177},
abstract = {The PREVENT-AD is an investigator-driven study that was created in 2011 and enrolled cognitively normal older adults with a family history of sporadic AD. Participants are deeply phenotyped and have now been followed annually for more than 12 years [median follow-up 8.0 years,SD 3.1]. Multimodal MRI, genetic, neurosensory, clinical, cerebrospinal fluid and cognitive data collected until 2017 on 348 participants who agreed to open sharing with the neuroscience community were already available. We now share a new release including 6 years of additional follow-up cognitive data, and additional MRI follow-ups, clinical progression, new longitudinal behavioral and lifestyle measures (questionnaires, actigraphy), longitudinal AD plasma biomarkers, amyloid-beta and tau PET, magnetoencephalography, as well as neuroimaging analytic measures from all MRI modalities. We describe the PREVENT-AD study, the data shared with the global research community as well as the model we created to sustain longitudinal follow-ups while also allowing new innovative data collection.},
}

@article {pmid40778159,
year = {2025},
author = {Khorsand, B and Ghanbarian, E and Rabin, L and Sajjadi, SA and Ezzati, A},
title = {Incremental Value of Plasma Biomarkers in Predicting Clinical Decline Among Cognitively Unimpaired Older Adults: Results from the A4 trial.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.07.22.25332015},
pmid = {40778159},
abstract = {OBJECTIVE: To evaluate the predictive utility of baseline plasma biomarkers and neuropsychological measures in identifying cognitively unimpaired older adults at risk of cognitive and functional decline over five years.

BACKGROUND: The clinical and biological heterogeneity observed in Alzheimer's disease (AD) complicates design of trials and the identification of appropriate participants. Identifying practical tools to define more homogenous subgroups could enhance clinical trial enrichment and improve early detection.

METHODS: We analyzed data from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) trial and its companion Evaluation of Amyloid Risk and Neurodegeneration (LEARN) observational study. The sample included 866 cognitively unimpaired, amyloid-positive individuals from the A4 trial (comprising participants randomized to receive Solanezumab or placebo) and 343 cognitively unimpaired, amyloid-negative individuals from LEARN. Cognitive/functional decline was defined as an increase of ≥0.5 in Clinical Dementia Rating-Global Score (CDR-GS) during a 240-week period. Using multiple logistic regression models, we evaluated the predictive value of demographic variables, APOE4 status, amyloid PET SUVR, plasma P-tau217, and Alzheimer's Disease Cooperative Study-Preclinical Alzheimer's Cognitive Composite (ADCS-PACC) in three groups: A4-Solanezumab, A4-placebo and LEARN. In a sub-study including 656 participants with available data, we assessed the incremental value of additional plasma biomarkers (Aβ42/Aβ40 ratio, GFAP, and NfL).

RESULTS: Both plasma P-tau217 and ADCS-PACC significantly improved predictive performance over a base model with demographics and APOE4. The full model combining all predictor variables yielded the highest AUCs across A4 Solanezumab (0.80 ± 0.06), A4 Placebo (0.80 ± 0.06), and LEARN (0.78 ± 0.08). Adding other plasma biomarkers yielded small but consistent improvements in AUC (1-3%).

CONCLUSIONS: Plasma P-tau217 and ADCS-PACC, individually and in combination, improved prediction of cognitive/functional decline in asymptomatic older adults. Predictive models incorporating these scalable and non-invasive measures improved clinical trial enrichment and earlier identification of at-risk individuals preclinical AD.},
}

@article {pmid40778154,
year = {2025},
author = {Guarnier, G and Reinelt, J and Molloy, EN and Mihai, PG and Einaliyan, P and Valk, S and Modestino, A and Ugolini, M and Mueller, K and Wu, Q and Babayan, A and Castellaro, M and Villringer, A and Scherf, N and Thierbach, K and Schroeter, ML and , and , and , },
title = {Cascaded Multimodal Deep Learning in the Differential Diagnosis, Progression Prediction, and Staging of Alzheimer's and Frontotemporal Dementia.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.1101/2024.09.23.24314186},
pmid = {40778154},
abstract = {Dementia is a complex condition whose multifaceted nature poses significant challenges in the diagnosis, prognosis, and treatment of patients. Despite the availability of large open-source data fueling a wealth of promising research, effective translation of preclinical findings to clinical practice remains difficult. This barrier is largely due to the complexity of unstructured and disparate preclinical and clinical data, which traditional analytical methods struggle to handle. Novel analytical techniques involving Deep Learning (DL), however, are gaining significant traction in this regard. Here, we have investigated the potential of a cascaded multimodal DL-based system (TelDem), assessing the ability to integrate and analyze a large, heterogeneous dataset (n=7,159 patients), applied to three clinically relevant use cases. Using a Cascaded Multi-Modal Mixing Transformer (CMT), we assessed TelDem's validity and (using a Cross-Modal Fusion Norm - CMFN) model explainability in (i) differential diagnosis between healthy individuals, AD, and three sub-types of frontotemporal lobar degeneration (ii) disease staging from healthy cognition to mild cognitive impairment (MCI) and AD, and (iii) predicting progression from MCI to AD. Our findings show that the CMT enhances diagnostic and prognostic accuracy when incorporating multimodal data compared to unimodal modeling and that cerebrospinal fluid (CSF) biomarkers play a key role in accurate model decision making. These results reinforce the power of DL technology in tapping deeper into already existing data, thereby accelerating preclinical dementia research by utilizing clinically relevant information to disentangle complex dementia pathophysiology.},
}

@article {pmid40778134,
year = {2025},
author = {Ackley, SF and Flanders, M and Murchland, A and Chen, R and Wang, J and Shah, SJ and Huey, ED and Maria Glymour, M},
title = {Evaluation of Amyloid Removal as a Surrogate for Cognitive Decline: Pilot Analysis in Individual-Level Data from the A4 Study of Solanezumab.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.07.21.25331942},
pmid = {40778134},
abstract = {BACKGROUND: Amyloid removal has been used as a surrogate outcome in Alzheimer's disease trials, allowing accelerated approval of aducanumab and lecanemab. The A4 (Alzheimer's Clinical Trial Consortium A4/LEARN) trial's individual-level data supports novel methods to evaluate amyloid's validity as a surrogate for cognitive decline.

METHODS: In 812 participants, cognitive and functional change was measured using the CDR-SB score. Instrumental-variable analysis estimated the effect of amyloid reduction; mediation analysis quantified solanezumab's cognitive effect mediated by amyloid reduction.

RESULTS: Each 10 centiloid reduction due to randomization to treatment was associated with 0.026 higher CDR-SB (95% CI: -0.013, 0.065) 14.6% of solanezumab's effect on cognition was mediated by amyloid reduction (95% CI: -122%, 208%).

DISCUSSION: Estimates showing near-zero effects of amyloid reduction on cognitive decline suggest minimal impact of amyloid reduction in populations with little disease progression. Replication in anti-amyloid trials with larger treatment effects could guide treatment and regulatory decisions.},
}

@article {pmid40777911,
year = {2025},
author = {Shojapour, M and Asgharzade, S},
title = {Regenerative Medicine in the Treatment of Alzheimer's Disease: A Narrative Review.},
journal = {Iranian journal of public health},
volume = {54},
number = {7},
pages = {1399-1410},
pmid = {40777911},
issn = {2251-6093},
abstract = {Alzheimer's disease (AD) is one of the progressive neurodegenerative diseases, memory impairments and multiple cognitive and behavioral deficits characterize that. We aimed to evaluate the molecular mechanisms involved in the pathogenesis of AD. It introduces the regenerative medicine approach as a novel therapeutic strategy based on the pathogenesis of AD that would be efficient. Our data was collected using databases such as the Web of Science, PubMed, Scopus, and Google Scholar. We summarized the available therapeutic strategies to induce neurodegeneration that can increase the number of neurons and their survival and improve the plasticity of synapses and synaptic activity. There is a different approach to treatment. In first-line treatment, focusing declines the amyloid beta and hypophosphorylated tau protein accumulation. It inhibits acetylcholinesterase, but in regenerative medicine focusing on treatment via gene therapy, cell therapy, and tissue engineering. As a proposed solution for AD in recent years, the use of inhibitors of the pathogenesis of AD is known as a supportive therapeutic approach, but the multi-potential treatment of regenerative medicine has been able to provide promising results in treating neurodegenerative patients.},
}

@article {pmid40777747,
year = {2025},
author = {Mathew, LS and Marathe, A and Aman, A and Vats, A and Joy, T and Rao, YL},
title = {Bridging the molecular and clinical aspects of resveratrol in Alzheimer's disease: a review.},
journal = {3 Biotech},
volume = {15},
number = {9},
pages = {284},
pmid = {40777747},
issn = {2190-572X},
abstract = {Alzheimer's disease (AD) is a progressive brain disorder that affects neurological functioning specifically targeting cognition, memory and behaviour. Pathology starts with the accumulation of tau proteins which on phosphorylation can be destructive for brain function. With gold standard drugs like Donepezil, there have been several attempts made to discover adjuvant therapeutic molecules such as plant-based products that could not only ease the ill-toward effects of these drugs, but also lead to the betterment of the patients suffering from AD. These are crucial in the management of patients of AD, by associations with psychological vulnerabilities and the overall loss of health of such individuals 'Resveratrol' is one such plant-based molecule which is a stilbene polyphenol present in many of the commonly occurring plants. Resveratrol is reported to have anti-oxidant and anti-inflammatory properties which brings about the neuroprotection. Several studies have also been conducted that targets the signalling cascades involved during the progression of AD. This review attempts to give a collective information of its properties, its synthesis, metabolism and mechanisms that could drive researchers forward for its therapeutic applications during the treatment of Alzheimer's disease.},
}

@article {pmid40777460,
year = {2025},
author = {Kehmeier, MN and Famiano, A and Cullen, AE and Leonhardt, T and Ferguson, S and Snyder, M and McCurdy, CE and Tyrrell, D and Alkayed, NJ and Walker, AE},
title = {APOE4 genotype negates the benefits of 17β-estradiol on cerebrovascular endothelial and mitochondrial function.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.07.23.666474},
pmid = {40777460},
issn = {2692-8205},
abstract = {BACKGROUND: Postmenopausal females who carry an APOEε4 allele are at higher risk of late-onset Alzheimer's Disease compared to age-matched APOEε4 males. Estrogen deficiency predisposes females to an increased risk of vascular, cognitive, and metabolic impairments. While estrogen and APOE genotype are known to impact metabolic and mitochondrial function in the brain, their cerebrovascular effects are less understood. Thus, the purpose of this study was to determine the interaction between APOE genotype and estrogen on cerebrovascular endothelial and mitochondrial function.

METHODS: Young female homozygous APOEε3 and APOEε4 mice (n=19-20/group; ~6 months old) fed a high-fat diet were ovariectomized (OVX), OVX and supplemented with 17β-estradiol, or left intact.

RESULTS: In APOEε3 mice, OVX was associated with impaired posterior cerebral artery endothelium-dependent dilation, which was rescued by 17β-estradiol. However, in APOEε4 mice, there was no effect of OVX or 17β-estradiol on cerebral artery endothelial function. Carotid artery passive stiffness was greater with OVX and lower with 17β-estradiol treatment in APOEε3 mice, but there was no impact of OVX or 17β-estradiol in the APOEε4 mice. In cerebral arteries and arterioles, mitochondrial complexes I and I+II respiration were lower in APOEε4 mice compared with APOEε3 mice. 17β-estradiol led to higher mitochondrial complex I respiration in APOEε3 but not APOEε4 mice. These functional differences were concomitant with group differences in mitochondrial DNA copy number, antioxidant enzymes, and pro-inflammatory factors. In contrast to other outcomes, we found that 17β-estradiol treatment was associated with lower cerebral artery stiffness in APOEε4 but not APOEε3 mice.

CONCLUSIONS: Overall, these results indicate that the APOE genotype modulates the impact of estrogen on the cerebral vasculature. We found that 17β-estradiol enhances cerebrovascular endothelial and mitochondrial function in APOEε3 mice but not in APOEε4 mice. The results suggest that 17β-estradiol supplementation has more cerebrovascular benefit for APOEε4 non-carriers.

NOVELTY & SIGNIFICANCE: What is known?: Females have twice the risk of Alzheimer's disease compared with males, and the APOE4 genetic variant is associated with a greater risk for Alzheimer's disease compared with the APOE3 variant. The risk for Alzheimer's disease increases after menopause in females, suggesting that the loss of female sex hormones may play a role. There are highly inconsistent results among past studies examining the interaction of APOE genotype and estrogens on cognitive function and other brain outcomes. What new information does this article contribute?: Vascular outcomes were not measured in previous studies examining the interaction between APOE genotype and estrogens. As such, we aimed to determine the impact of APOE4 genotype on the cerebrovascular response to estradiol. We found that estradiol improved cerebral artery endothelial function and mitochondrial respiration in APOE3 mice following ovariectomy. In contrast, APOE4 mice were refractory to the beneficial effects of estradiol on cerebrovascular endothelial and mitochondrial function. The broader implication of this research is that APOE genotype may be a consideration when prescribing hormone replacement therapy to menopausal females due to the impact on vascular outcomes.},
}

@article {pmid40777445,
year = {2025},
author = {Gu, J and Fuller, C and Carbonetto, P and He, X and Zheng, J and Li, H},
title = {Identifying the genetic basis and molecular mechanisms underlying phenotypic correlation between complex human traits using a gene-based approach.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2021.02.09.430368},
pmid = {40777445},
issn = {2692-8205},
abstract = {Phenotypic correlations between complex human traits have long been observed based on epidemiological studies. However, the genetic basis and underlying mechanisms are largely unknown. Here we developed a gene-based approach to measure genetic overlap between a pair of traits and to delineate the shared genes/pathways, through three steps: 1) translating SNP-phenotype association profile to gene-phenotype association profile by integrating GWAS with eQTL data using a newly developed algorithm called Sherlock-II; 2) measuring the genetic overlap between a pair of traits by a normalized distance and the associated p value between the two gene-phenotype association profiles; 3) delineating genes/pathways involved. Application of this approach to a set of GWAS data covering 59 human traits detected significant overlap between many known and unexpected pairs of traits; a significant fraction of them are not detectable by SNP based genetic similarity measures. Examples include Cancer and Alzheimer's Disease (AD), Rheumatoid Arthritis and Crohn's disease, and Longevity and Fasting glucose. Functional analysis revealed specific genes/pathways shared by these pairs. For example, Cancer and AD are co-associated with genes involved in hypoxia response and P53/apoptosis pathways, suggesting specific mechanisms underlying the inverse correlation between them. Our approach can detect yet unknown relationships between complex traits and generate mechanistic hypotheses and has the potential to improve diagnosis and treatment by transferring knowledge from one disease to another.},
}

@article {pmid40777354,
year = {2025},
author = {Ramanan, S and Johnson, GV},
title = {A Bioinformatic Analysis of BAG Protein Interactors and Pathways in Alzheimer's and Parkinson's Disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.07.18.665492},
pmid = {40777354},
issn = {2692-8205},
abstract = {UNLABELLED: Alzheimer's disease (AD) and Parkinson's disease (PD) are the two most common neurodegenerative disorders. While the symptoms and general etiology may be different, these two diseases share significant common features in terms of their disease pathogenesis. Within the scope of neurodegenerative disorders, the Bcl-2 associated athanogene (BAG) family proteins and associated interactors have been a key area of focus. The BAG family is a group of proteins that contain at least one evolutionarily conserved BAG domain. Despite this similarity, their interactions and functions can vary widely. So far, research has predominantly scrutinized individual BAG proteins, rather than explore potential cooperative actions among family members. Some BAG family members may function together thereby indicating potential interactions within this family. Although connections among BAG members have been observed, their role in neurodegenerative disorders, such as AD and PD, remains largely uncharacterized. This mini review explores the common pathways, intersections, and differences within these interactions as well as their link to AD and PD. Using computational techniques to mine transcriptomic data, several groupings of pathways that these BAG family members are involved in were identified in the context of AD and PD. Understanding these pathways and their relationships may uncover potential gaps in current research and help identify novel therapeutic targets for the treatment of these neurodegenerative diseases.

SIGNIFICANCE STATEMENT: Although distinct diseases, Alzheimer's disease and Parkinson's disease share common features such as protein aggregation and mitochondrial dysfunction. Members of the BAG family of proteins have been implicated in the pathogenesis of both diseases. Computational techniques were used to mine transcriptomic data of Alzheimer's and Parkinson's disease cases to identify common pathways. BAG protein interactors, common to all family members, were analyzed in the context of these common pathways for Alzheimer's and Parkinson's disease. These analyses provide insights into the pathways mediated by these BAG protein interactors that are likely at the intersection of Alzheimer's disease and Parkinson's disease pathologies.},
}

@article {pmid40776985,
year = {2025},
author = {Huang, Y and Lei, W and Shen, J and Sun, J},
title = {Tat-NR2B9c prevent cognitive dysfunction in mice modeling Alzheimer's Disease induced by Aβ1-42 via perturbing PSD-95 interactions with NR2B-subtype receptors.},
journal = {IBRO neuroscience reports},
volume = {19},
number = {},
pages = {317-322},
pmid = {40776985},
issn = {2667-2421},
abstract = {BACKGROUND: Alzheimer's Disease (AD) is one of common progressive and fatal neurodegenerative disorders,and its main clinical symptoms are progressive memory impairment and cognitive dysfunction. The Tat-NR2B9c, a peptide was known as postsynaptic density protein-95(PSD-95) inhibitors, has shown clinical efficacy as a neuroprotective effects in some diseases such as acute stroke and neuropathic pain.The aim of the study is to clarify whether Tat-NR2B9c has the same neuroprotective effects in AD.

METHODS: Studies were performed in mice modeling AD induced by Aβ1-42. Animals were treated with drugs after modeling AD for 14 days,and the spatial learning and memory ability were assessed after drug treatment. Then, mice were euthanized for biochemical tests.

RESULTS: The levels of PSD-95 and NR2B decreased,and the levels of N-methyl-d-aspartate receptor-postsynaptic density protein-95 interaction increased in hippocampus in AD mice. Tat-NR2B9c can improve spatial learning and memory ability in AD mice by perturbing PSD-95 interactions with NR2B-subtype but not inhibiting PSD-95 levels.

CONCLUSION: Tat-NR2B9c can prevent cognitive dysfunction in mice modeling AD induced by Aβ1-42 via perturbing PSD-95 interactions with NR2B-subtype receptors.},
}

@article {pmid40776228,
year = {2025},
author = {Gao, T and Madanian, S and Templeton, J and Merkin, A},
title = {Clinical Decision Support for Alzheimer's: Challenges in Generalizable Data-Driven Approach.},
journal = {Studies in health technology and informatics},
volume = {329},
number = {},
pages = {1780-1781},
doi = {10.3233/SHTI251211},
pmid = {40776228},
issn = {1879-8365},
mesh = {*Alzheimer Disease/diagnostic imaging/diagnosis ; Humans ; *Decision Support Systems, Clinical/organization & administration ; Magnetic Resonance Imaging/methods ; *Deep Learning ; Neural Networks, Computer ; Brain/diagnostic imaging ; },
abstract = {This paper reviews the current research on Alzheimer's disease and the use of deep learning, particularly 3D-convolutional neural networks (3D-CNN), in analyzing brain images. It presents a predictive model based on MRI and clinical data from the ADNI dataset, showing that deep learning can improve diagnosis accuracy and sensitivity. We also discuss potential applications in biomarker discovery, disease progression prediction, and personalised treatment planning, highlighting the ability to identify sensitive features for early diagnosis.},
}

*Alzheimer Disease/diagnostic imaging/diagnosis
Humans
*Decision Support Systems, Clinical/organization & administration
Magnetic Resonance Imaging/methods
*Deep Learning
Neural Networks, Computer
Brain/diagnostic imaging

@article {pmid40775619,
year = {2025},
author = {Ren, X and Edwards, L and Mann, E and Horiuchi, S and Tsuchiyagaito, A},
title = {Repetitive negative thinking, self-reflection, and perceived cognitive dysfunction in older adults: a cross-sectional study.},
journal = {BMC psychiatry},
volume = {25},
number = {1},
pages = {773},
pmid = {40775619},
issn = {1471-244X},
support = {2P20GM121312-06/GM/NIGMS NIH HHS/United States ; },
mesh = {Humans ; Male ; Female ; Aged ; Cross-Sectional Studies ; *Cognitive Dysfunction/psychology ; *Depression/psychology ; Aged, 80 and over ; *Rumination, Cognitive/physiology ; *Pessimism/psychology ; Japan ; *Thinking ; Middle Aged ; },
abstract = {As the global population ages, understanding cognitive dysfunction, including Alzheimer's Disease and other forms of dementia, is crucial. With the growing prevalence of these disorders, it is essential to identify and understand potential factors that maintain cognitive function and potentially delay severe cognitive dysfunction. This study examined the roles of repetitive negative thinking (RNT) and reflection in subjective cognitive dysfunction among older adults, with an additional consideration of their association with depressive symptoms. RNT, which is common in depression, has been associated with cognitive impairments. However, its unique influence on cognitive dysfunction is unclear. Conversely, reflection, considered to protect against adverse cognitive outcomes, is less explored. Using the Rumination Response Scale (RRS), we hypothesize that RNT may be more strongly linked to cognitive dysfunction than reflection, even when controlling for depressive symptoms. Two-hundred and seventy-six older adults (137 male, 139 female) from Japan participated in the study, providing measures of RRS-brooding (an index of RNT), RRS-reflection (an index of reflection), depressive symptoms, and self-reported cognitive dysfunction. The results showed higher reflection, but not RNT, was associated with greater subjective cognitive dysfunction [β = 0.28, p =.03], even after controlling for depressive symptoms. Importantly, the association between reflection and cognitive dysfunction demonstrated sex differences, with reflection significantly accounting for cognitive dysfunction in female [β = 0.46, p =.01] but not in male. These findings highlight the significance of evaluating specific subtypes of repetitive thoughts and sex differences when investigating the association with perceived cognitive dysfunction. Future research should continue to explore the mechanisms underlying these associations and the prevention and treatment of cognitive dysfunctions.},
}

Humans
Male
Female
Aged
Cross-Sectional Studies
*Cognitive Dysfunction/psychology
*Depression/psychology
Aged, 80 and over
*Rumination, Cognitive/physiology
*Pessimism/psychology
Japan
*Thinking
Middle Aged

@article {pmid40775373,
year = {2025},
author = {Kelleher-Andersson, J and Yoon, E and Green, C and McFarlane, C and Bagheri, D and Thomas, LP and Turner, RS},
title = {First-in-human study of neuron regenerative therapy NNI-362 to evaluate the safety, pharmacokinetics, and pharmacodynamics in healthy aged population.},
journal = {Alzheimer's research & therapy},
volume = {17},
number = {1},
pages = {185},
pmid = {40775373},
issn = {1758-9193},
support = {U01AG082687 (PI-Kelleher-Andersson)/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; Male ; Aged ; Double-Blind Method ; Female ; Middle Aged ; *tau Proteins/blood ; *Nerve Regeneration/drug effects ; Biomarkers/blood ; },
abstract = {BACKGROUND: A placebo-controlled, double-blind Phase 1a trial examined the safety, tolerability, and pharmacokinetics of NNI-362 as well as the pharmacodynamic outcome of plasma phosphorylated tau[181] (p-tau[181]).

METHODS: Oral NNI-362 and placebo were randomized in healthy, cognitively-unimpaired individuals (ages 50-72) at a 3:1 ratio, with sponsor, principal investigator, and subjects all blinded. Plasma levels of p-tau[181] were determined in the placebo and the two highest arms of 120 and 240 mg NNI-362. Plasma biomarker was examined for statistical change from baseline.

RESULTS: NNI-362 treatment was safe and well tolerated in older individuals. NNI-362, at the two highest multiple doses, significantly reduced plasma p-tau[181] levels compared to pretreatment levels (P < 0.0012 to P < 0.0009), while no change occurred in placebo groups.

CONCLUSIONS: These findings suggest in older subjects, oral NNI-362 appeared safe, well tolerated and reduced plasma p-tau[181]. Phase 2 studies of NNI-362 are warranted for Alzheimer's disease and age-related degenerative disorders.

TRIAL REGISTRY NUMBER: NCT04074837. First registered: 2019-08-27.},
}

Humans
Male
Aged
Double-Blind Method
Female
Middle Aged
*tau Proteins/blood
*Nerve Regeneration/drug effects
Biomarkers/blood

@article {pmid40774425,
year = {2025},
author = {Markley, AE and Stratton, KM and Cho, GY and Schmidt, NB and Suhr, J and Sheffler, JL and Nguyen, C and Schubert, FT and Quiles, JRG and Potter, MR and Meynadasy, MA and Irvin, SM and Allan, NP},
title = {Study design and protocol for cognitive anxiety sensitivity treatment for anxiety in adults with mild cognitive impairment or dementia.},
journal = {Contemporary clinical trials},
volume = {},
number = {},
pages = {108044},
doi = {10.1016/j.cct.2025.108044},
pmid = {40774425},
issn = {1559-2030},
abstract = {BACKGROUND: Anxiety is prevalent among older adults with mild cognitive impairment (MCI) and mild Alzheimer's disease and related disorders (ADRD) and may contribute to accelerated cognitive decline and increased care partner burden. Computerized Anxiety Sensitivity Treatment (CAST) is a novel, CBT-based intervention targeting anxiety sensitivity, which has not been widely tested in this population.

METHODS: This randomized controlled trial (NCT05748613) will compare CAST to a health education control (HEC) in 194 dyads consisting of older adults with MCI/mild ADRD and their care partners. Primary outcomes include reductions in anxiety sensitivity and anxiety symptoms. Secondary outcomes include measures of mental health and well-being symptoms, improved cognitive performance, and decreased care partner burden. Participants will be assessed at baseline, during two intervention sessions, and follow-ups at 1-, 3-, and 6-months post-intervention.

EXPECTED OUTCOMES: CAST will significantly lower anxiety sensitivity (AS) post-intervention and reduce anxiety compared to HEC. Secondary hypotheses propose that CAST will reduce other mental symptoms and improve cognitive functioning more effectively than HEC. Additionally, CAST will alleviate care partner distress and improve their quality of life compared to HEC, with the secondary hypothesis suggesting that these effects will be mediated by reductions in AS in older adults. Furthermore, reductions in AS from pre- to post-intervention will account for the effect of CAST on anxiety, and the secondary hypothesis suggesting that reductions in interoceptive fear conditioning will also contribute to the observed anxiety reduction.

CLINICALTRIALS: gov registration: #NCT05748613.},
}

@article {pmid40773904,
year = {2025},
author = {Ahmad, SR and Zeyaullah, M and Zahrani, Y and Khan, MS and Muzammil, K and Dawria, A},
title = {Phytochemicals from Bacopa monnieri as small molecule modulators of MARK4: A multi-modal strategy for preventing Alzheimer's disease-causing tau aggregation.},
journal = {Journal of molecular graphics & modelling},
volume = {140},
number = {},
pages = {109135},
doi = {10.1016/j.jmgm.2025.109135},
pmid = {40773904},
issn = {1873-4243},
abstract = {Neurodegenerative tauopathies, such as Alzheimer's disease, are closely associated with the dysregulation of tau phosphorylation, a process regulated in part by the serine/threonine kinase MARK4. In this study, we explored phytochemicals derived from Bacopa monnieri as potential natural inhibitors of MARK4. Using pressurized liquid extraction with an ethanol-water mixture, we efficiently extracted bioactive compounds from Bacopa leaves. LC-MS analysis identified 25 distinct phytoconstituents spanning flavonoids, triterpenoids, cucurbitacins, sterols, and alkaloids. In silico analysis revealed that several compounds, including oroxindin, cucurbitacin B, and bacosine, bind strongly to the catalytic pocket of MARK4. Molecular dynamics simulations confirmed their stability within the MARK4 active site, with oroxindin demonstrating the most favorable thermodynamic and conformational profile. Principal component and free energy landscape analyses further supported their capacity to stabilize MARK4 in low-energy conformations. Microscale thermophoresis further validated high-affinity binding of MARK4 with oroxindin, while other four compounds also show strong interaction with MARK4. MTT assays in SH-SY5Y cells confirmed the non-cytotoxic nature of all five lead compounds across a concentration range of 10 nM to 10 μM. Cellular assays revealed a significant reduction in Tau-GFP aggregates upon treatment with the compounds, particularly oroxindin. These results highlight oroxindin and other Bacopa monnieri phytochemicals as promising natural inhibitors of MARK4, with potential to attenuate tau pathology in neurodegenerative diseases.},
}

@article {pmid40773726,
year = {2025},
author = {Rajkumar, M and Presley, SID and Govindaraj, P and Girigoswami, K and Meenambigai, K and Deepak, P and Deepika, B and Elbehairi, SEI and Alfaifi, MY and Shati, AA and Menaa, F},
title = {Biomedical Prowess of Clitoria mariana (L.) Flower Methanolic Extract: A Comprehensive In Vitro, Ex Vivo, and In Vivo Evaluation.},
journal = {Chemistry & biodiversity},
volume = {},
number = {},
pages = {e01051},
doi = {10.1002/cbdv.202501051},
pmid = {40773726},
issn = {1612-1880},
abstract = {Clitoria mariana L., a medicinal plant widely distributed in Asia, has long been used in folk medicine. This study investigates the biomedical potential of its methanolic flower extract. Gas chromatography-mass spectrometry (GC-MS) and phytochemical analyses revealed the presence of alkaloids, phenolic compounds, and flavonoids. The phytoextract elicited significant antioxidant activity, as demonstrated by various assays, and displayed broad-spectrum antibacterial effects, producing the largest zones of inhibition (ZI) against Staphylococcus aureus, Micrococcus luteus, Escherichia coli, and Salmonella typhi, supported by MIC/MBC (minimum inhibition concentration/minimum bactericidal concentration) values indicative of bactericidal action. Notably, the phytoextract demonstrated marked cytotoxicity against various cancer cell lines, with the highest potency against MCF-7, followed by HeLa, A549, and PC-3, based on IC50 (concentration required to inhibit 50%) values. Its anti-inflammatory properties, comparable to aspirin (reference standard), increased with concentration. Additionally, the phytoextract showed promise in Alzheimer's disease (AD) treatment by inhibiting AChE (acetylcholinesterase) and BuChE (butyrylcholinesterase) activities more effectively than galantamine (GA), the standard drug. The zebrafish embryo assay evidenced its excellent biocompatibility. Overall, this study offers the first comprehensive phytochemical and pharmacological evaluation of C. mariana's methanolic extract, underscoring its potential relevance in managing inflammatory conditions.},
}

@article {pmid40773100,
year = {2025},
author = {Balki, S and Gautam, AS and Balaji, PG and Yadav, AK and Singh, RK},
title = {Montelukast attenuated memory decline, neuroinflammatory and neurodegenerative biomarkers in Aβ1-42 exposed model of alzheimer's disease in mice.},
journal = {Psychopharmacology},
volume = {},
number = {},
pages = {},
pmid = {40773100},
issn = {1432-2072},
support = {Department of Pharmaceuticals, Ministry of Chemicals and Fertilizers, India//Department of Pharmaceuticals, Ministry of Chemicals and Fertilizers, India/ ; },
abstract = {Alzheimer's disease (AD) represents major cognitive and memory decline in the elderly patients. Although Montelukast has traditionally been used for the treatment of asthma, its role in prevention of neuropathological changes and memory decline in AD have recently been reported in literature. However, the brain availability through oral administration of Montelukast is limited due to its poor blood-brain barrier permeation. This study has highlighted that the intranasal administration of Montelukast can provide a considerable brain bioavailability of Montelukast in mice. In addition, intranasal administration of Montelukast showed a significant improvement of spatial and cognitive memory, prevention of Aβ accumulation, astrocyte activation, along with improved redox balance and neuronal density in the hippocampus and cortex regions in the amyloid-beta1-42 (Aβ1-42)-induced animal model of AD. These neuroprotective effects were found to be better through intranasal administration of Montelukast in comparison to its oral administration at the equivalent dose. These results suggest that Montelukast may be administered through intranasal route to achieve a significant therapeutic effect in the pathophysiology of AD.},
}

@article {pmid40772428,
year = {2025},
author = {French, SR and Arias, JC and Zahra, S and Ally, M and Escareno, C and Heitkamp, E and Vazquez, F and Hillis, M and Wiskoski, H and Ainapurapu, K and Culwell, G and Howell, C and Johnson, K and Kraemer, C and Pacanowski, J and Leon, L and Berman, S and Yanquez, F and Balderman, J and Sabat, J and Hung, O and Lucas, L and Vitali, F and Bedrick, EJ and Mushtaq, R and Altbach, M and Trouard, TP and Elahi, FM and Ashton, NJ and Dage, JL and Reiman, EM and Alexander, GE and Weinkauf, CC},
title = {Cognitive impairment and p-tau217 are high in a vascular patient cohort.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {8},
pages = {e70565},
pmid = {40772428},
issn = {1552-5279},
support = {R01AG070987/AG/NIA NIH HHS/United States ; R01 HL159200/HL/NHLBI NIH HHS/United States ; //Doris Duke Foundation/ ; //University of Arizona Health Sciences Career Development Award/ ; //Arizona Alzheimer's Consortium/ ; P30 AG072980/AG/NIA NIH HHS/United States ; //U24 AG082930 Alzheimer Diagnosis in older Adults with Chronic Conditions ADACC Network/ ; CTR056039//Arizona Biomedical Research Commission/ ; CTR056056//Arizona Biomedical Research Commission/ ; U24 AG021886/AG/NIA NIH HHS/United States ; //Health Sciences, University of Arizona/ ; /DDCF/Doris Duke Charitable Foundation/United States ; },
mesh = {Humans ; Female ; Male ; *Cognitive Dysfunction/blood/diagnosis ; *tau Proteins/blood ; Aged ; Biomarkers/blood ; Cohort Studies ; *Alzheimer Disease/blood ; Mental Status and Dementia Tests/statistics & numerical data ; *Cardiovascular Diseases/complications/blood ; Prospective Studies ; Phosphorylation ; Middle Aged ; Aged, 80 and over ; Neuropsychological Tests ; },
abstract = {INTRODUCTION: Vascular comorbidities are modifiable contributors to cognitive impairment and Alzheimer's disease (AD), yet brain health outcomes are rarely evaluated in cardiovascular patients.

METHODS: This study prospectively evaluated cognition and AD pathology in 162 community-dwelling adults with asymptomatic cardiovascular disease who did not have a clinical diagnosis of dementia or cognitive impairment.

RESULTS: Twenty-nine percent of the cohort had Montreal Cognitive Assessment (MoCA) scores indicative of cognitive impairment or dementia after adjusting for age, sex, and education based on National Alzheimer's Coordinating Center normative data. AD blood biomarker phosphorylated tau217 was elevated in 55% of the cohort, significantly associated with decreased MoCA scores (β = -1.46, 95% confidence interval [CI] -2.53 to -0.39, p < 0.01), and accurately differentiated cognitive impairment (area under the curve 0.94, 95% CI 0.88-0.99).

DISCUSSION: This level of undiagnosed cognitive impairment and AD pathology exceeds what would be expected in the general population and highlights a potential need for screening and future work to better identify treatment options.

HIGHLIGHTS: Brain health outcomes are rarely evaluated in vascular patients. One hundred sixty-two adults with asymptomatic cardiovascular disease but without diagnoses of cognitive impairment or dementia were evaluated. Phosphorylated tau217 accurately differentiated cognitive impairment in patients with cardiovascular disease. High levels of cognitive impairment and Alzheimer's disease pathology are greatly underdiagnosed in the cardiovascular population.},
}

Humans
Female
Male
*Cognitive Dysfunction/blood/diagnosis
*tau Proteins/blood
Aged
Biomarkers/blood
Cohort Studies
*Alzheimer Disease/blood
Mental Status and Dementia Tests/statistics & numerical data
*Cardiovascular Diseases/complications/blood
Prospective Studies
Phosphorylation
Middle Aged
Aged, 80 and over
Neuropsychological Tests

@article {pmid40772264,
year = {2025},
author = {Alrikabi, A and Allahyani, W and Shaghath, A and Alrashdi, J and Almoqhem, R and Alasmari, F and Al-Qerem, W and Albasher, G},
title = {Potential therapeutic effects of Ebixa, Ginkgo biloba, and selenium in a cadmium chloride-induced Alzheimer's disease manifestations in rats.},
journal = {Frontiers in neuroscience},
volume = {19},
number = {},
pages = {1634601},
pmid = {40772264},
issn = {1662-4548},
abstract = {Alzheimer's disease (AD) is a devastating neurodegenerative disorder characterized by cognitive decline and neuronal damage. Cadmium exposure has been implicated in AD pathogenesis. This study aimed to investigate the potential therapeutic effects of Ebixa (memantine), Ginkgo biloba, and selenium in a cadmium-induced rat model of AD. Adult male Wistar rats were divided into six groups: control, control + Ginkgo-treated, cadmium chloride (CdCl2), CdCl2 + Ebixa-treated, CdCl2 + Ginkgo, and CdCl2 + Ginkgo + Selenium. Behavioral tests, including the Morris water maze and passive avoidance learning, were conducted. Additionally, biochemical analysis of acetylcholine (Ach), choline acetyltransferase (AchT), and acetylcholinesterase (AChE) levels in brain homogenates was performed. Histological sections of the cerebral cortex, cerebellum, and medulla were examined. Apoptotic assessment was conducted using the TUNEL assay. CdCl2 exposure resulted in cognitive deficits, reduced Ach levels, and neuronal damage, mirroring AD-like characteristics. Ebixa treatment improved spatial memory behavior as well as Ach, AchT and AChE levels in the brain. Ginkgo biloba and selenium co-administration increased the number of crossings in the Morris water maze test, suggesting memory preservation. Additionally, Ginkgo biloba exhibited potential cholinergic system protective effects. Histological analysis revealed neuroprotection in the cerebral cortex, cerebellum, and medulla. TUNEL assays demonstrated anti-apoptotic effects of both Ebixa and the combination of Ginkgo and selenium. Ebixa, Ginkgo biloba, and selenium showed promise in mitigating cognitive deficits and preserving neuronal structures in a CdCl2-induced AD manifestation in rats. These findings provide insights into potential therapeutic strategies for AD and warrant further investigation.},
}

@article {pmid40771977,
year = {2025},
author = {Park, H and Ni, M and Le, Y},
title = {Neuroinflammation and nutrition in Alzheimer's disease.},
journal = {Frontiers in neurology},
volume = {16},
number = {},
pages = {1622571},
pmid = {40771977},
issn = {1664-2295},
abstract = {The brain contains approximately 100 billion neurons and over 200 billion glial cells, which are integral to the neuronal networks that support normal brain function in the central nervous system. The complexity of the brain makes the diagnosis and treatment of neurodegenerative disease particularly challenging. Neuroinflammation and neuronal cell death contribute to the development of neurodegenerative diseases such as dementia. Dementia refers to a decline in memory and thinking ability, affecting approximately 55 million people worldwide. Owing to the association of multiple factors, including amyloid-β plaque, tau-fibrillary tangles, neuroinflammation, nutritional defects, and genetic mutations, the exact cause of the most common type of dementia, Alzheimer's disease, remains elusive. These multiple factors may cause damage to neurons and glial cells, leading to neurodegeneration. Very few therapeutics are available for neurodegenerative diseases due to the limited understanding of their pathogenesis, resulting in the lack of biomarkers and drug targets. Recent attention has shifted toward addressing modifiable risk factors such as unhealthy diets and lifestyles to delay the onset of Alzheimer's disease. Unhealthy diets that consist of saturated fatty acids and refined sugars, with other multiple risk factors, increase neuroinflammation and oxidative stress, furthering cognitive decline and progression of neurodegeneration. Mitigating these risk factors with antioxidants, anti-inflammatory-based nutrition, and multidomain lifestyle intervention, which may include physical exercise, cognitive stimulation, and social engagement, may delay the development of neurodegenerative diseases and cognitive decline. In this review, we focus on the role of neuroinflammation in contributing to neurodegeneration and dietary influence in Alzheimer's disease.},
}

@article {pmid40771537,
year = {2025},
author = {Sagar, R and Huang, Y and Dong, D and Boyd, RJ and Ahmed, W and Witwer, KW and Mahairaki, V},
title = {Profiling RNA Cargo in Extracellular Vesicles From hiPSC-Derived Neurons of Alzheimer's Disease Patients.},
journal = {Journal of extracellular biology},
volume = {4},
number = {8},
pages = {e70074},
pmid = {40771537},
issn = {2768-2811},
abstract = {Alzheimer's disease (AD) is a major neurodegenerative disorder that affects more than 55 million people, with an incidence that is projected to triple by 2050. Despite continuous advancements in the field, reliable treatment and early detection strategies remain elusive. Extracellular vesicles (EVs) play a major role in cellular communication throughout the body. In this study, we assessed the cargo of neuronal-specific EVs for their potential as AD biomarkers. We isolated EVs released from iPSC-derived excitatory glutamatergic neurons generated from eight AD patients (ADiNEVs) and six healthy controls (iNEVs). We performed RNA-sequencing and identified significant differences in RNA cargo between ADiNEVs and iNEVs. Notably, fewer small nuclear RNAs (snRNAs) were found in ADiNEVs. RNA transcripts significantly more abundant in ADiNEVs included MT-CO1, PRR32 and IGSF8 messenger RNAs. We also observed fewer XIST long noncoding RNAs and miR-7-5p microRNA content in ADiNEVs. These findings suggest that precision medicine approaches, such as characterising the content of EVs from a patient's own cells, could advance early detection and management of AD.},
}

@article {pmid40771353,
year = {2025},
author = {Moravveji, S and Sadia, H and Doyon, N and Duchesne, S},
title = {Sensitivity analysis of a mathematical model of Alzheimer's disease progression unveils important causal pathways.},
journal = {Frontiers in neuroinformatics},
volume = {19},
number = {},
pages = {1590968},
pmid = {40771353},
issn = {1662-5196},
abstract = {INTRODUCTION: Mathematical models serve as essential tools to investigate brain aging, the onset of Alzheimer's disease (AD) and its progression. By studying the representation of the complex dynamics of brain aging processes, such as amyloid beta (Aβ) deposition, tau tangles, neuro-inflammation, and neuronal death. Sensitivity analyses provide a powerful framework for identifying the underlying mechanisms that drive disease progression. In this study, we present the first local sensitivity analysis of a recent and comprehensive multiscale ODE-based model of Alzheimer's Disease (AD) that originates from our group. As such, it is one of the most complex model that captures the multifactorial nature of AD, incorporating neuronal, pathological, and inflammatory processes at the nano, micro and macro scales. This detailed framework enables realistic simulation of disease progression and identification of key biological parameters that influence system behavior. Our analysis identifies the key drivers of disease progression across patient profiles, providing insight into targeted therapeutic strategies.

METHODS: We investigated a recent ODE-based model composed of 19 variables and 75 parameters, developed by our group, to study Alzheimer's disease dynamics. We performed single- and paired-parameter sensitivity analyses, focusing on three key outcomes: neural density, amyloid beta plaques, and tau proteins.

RESULTS: Our findings suggest that the parameters related to glucose and insulin regulation could play an important role in neurodegeneration and cognitive decline. Second, the parameters that have the most important impact on cognitive decline are not completely the same depending on sex and APOE status.

DISCUSSION: These results underscore the importance of incorporating a multifactorial approach tailored to demographic characteristics when considering strategies for AD treatment. This approach is essential to identify the factors that contribute significantly to neural loss and AD progression.},
}