Alzheimer's Research & Therapy最新文献

{"title":"Increased cerebrospinal fluid and plasma apoE glycosylation is associated with reduced levels of Alzheimer's disease biomarkers.","authors":"Dobrin Nedelkov, Zoe E Tsokolas, Matheus Scarpatto Rodrigues, Isabel Sible, S Duke Han, Bilal E Kerman, Michael Renteln, Wendy J Mack, Tharick A Pascoal, Hussein N Yassine","doi":"10.1186/s13195-025-01795-7","DOIUrl":"10.1186/s13195-025-01795-7","url":null,"abstract":"<p><p>The apolipoprotein E (APOE) ε4 allele is the strongest genetic risk factor for late-onset Alzheimer's disease (AD). ApoE is glycosylated with an O-linked Core-1 sialylated glycan at several sites; however, the impact and function of this glycosylation on AD biomarkers remain unclear. We examined apoE glycosylation (total and secondary) in a cohort of cerebrospinal fluid (CSF, n = 181) and plasma (n = 178) samples from the Alzheimer's Disease Neuroimaging Initiative (ADNI) stratified into 4 groups: cognitively normal (CN), Mild Cognitive Impairment (MCI), progressors, and non-progressors based on delayed word recall performance over 4 years. We observed decreasing glycosylation (reduced % of apoE being glycosylated) from apoE2 > apoE3 > apoE4 in the CSF and in plasma (apoE3 > apoE4), with stronger effect sizes for secondary glycosylation in CSF (total glycosylation in CSF: E2 > E3 (4.6%), E3 > E4 (5.1%), E2 > E4 (9.4%); secondary glycosylation in CSF: E2 > E4 (33.1%), E3 > E4 (25.4%); total glycosylation in plasma: E3 > E4 (24.2%). Secondary ApoE glycosylation was reduced (8%, p = 0.009) in the MCI group compared with the CN group and in the progressor group compared with the non-progressor group (7%, p = 0.01). In CSF, higher apoE glycosylation was cross-sectionally associated with lower total tau (t-tau) and p-tau181. In CSF, greater apoE4 glycosylation was associated with lower t-tau and p-tau181 levels. These results indicate strong associations between apoE glycosylation and biomarkers of AD pathology independent of apoE genotype, warranting a deeper understanding of the functional role of apoE glycosylation in AD tau pathology.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"151"},"PeriodicalIF":7.9,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12243426/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144599095","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prospective evaluation of plasma pTau₂₁₇ stability for the detection of Alzheimer's disease in a tertiary memory clinic.","authors":"Javier Arranz, Rosa Ferrer, Nuole Zhu, Sara Rubio-Guerra, Íñigo Rodríguez-Baz, José Enrique Arriola-Infante, Lucía Maure-Blesa, Jesús Garcia-Castro, Judit Selma-González, María Carmona-Iragui, Isabel Barroeta, Ignacio Illán-Gala, Miguel Santos-Santos, Juan Fortea, Alberto Lleó, Mireia Tondo, Daniel Alcolea","doi":"10.1186/s13195-025-01779-7","DOIUrl":"10.1186/s13195-025-01779-7","url":null,"abstract":"<p><strong>Background: </strong>Knowledge on the effect of analytical variability and storage conditions are essential for the successful implementation of plasma pTau₂₁₇ in prospective settings.</p><p><strong>Aims: </strong>To investigate the performance of plasma pTau₂₁₇, measured in consecutive samples with LUMIPULSE, for detecting Alzheimer's disease in a prospective memory clinic setting, along with evaluating its pre-analytical and analytical stability.</p><p><strong>Methods: </strong>We prospectively measured pTau₂₁₇ using the LUMIPULSE automated platform in consecutive patient plasma samples collected between May and November 2024 at the Sant Pau Memory Unit (Barcelona). A subset of participants also underwent paired lumbar puncture for CSF AD biomarkers. We compared biomarker concentrations under different short-term storage conditions (4ºC vs -20ºC) and different protocol pipelines, and assessed lot-to-lot variability. In the subset with available CSF biomarkers, logistic regression was used to evaluate the association between plasma pTau217 and the likelihood of a positive (A +) or a negative (A-) CSF amyloid status. Using ROC analysis, in this prospective cohort we evaluated the accuracy of previously established thresholds derived from historical samples.</p><p><strong>Results: </strong>We included 280 participants, divided into two groups: those with (n = 109) and without CSF data (n = 171). Among the subset with CSF, 48% were A + , with a plasma pTau₂₁₇ fold-change of 4.5 × compared to A-. We found no differences in plasma pTau₂₁₇ concentrations between either short-term storage conditions. The overall coefficients of analytical variation ranged from 1.8% to 3.2%. Plasma pTau₂₁₇ concentrations were slightly higher in paired samples of the clinical protocol. Following a two-threshold approach, the need of confirmatory tests (grey zones) after measuring plasma pTau₂₁₇ ranged between 45.9% and 18.3% using our previously reported strict or lenient cutoffs (overall accuracy 96.6% and 92.1%, respectively).</p><p><strong>Conclusions: </strong>The robust stability and low lot-to-lot variability of plasma pTau₂₁₇ measurement in an automated platform result in high diagnostic performance of this biomarker in the prospective evaluation of patients in a memory clinic setting. These findings support its implementation into clinical routine, offering clinicians an accessible biomarker for AD diagnosis.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"150"},"PeriodicalIF":7.9,"publicationDate":"2025-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12228402/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144566989","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Predicting brain amyloid load with digital and blood-based biomarkers.","authors":"Weineng Chen, Yu Liao, Xinchong Shi, Fengjuan Su, Haifan Kong, Yingying Fang, Yifan Zheng, Jiayi Zhou, Ganqiang Liu, Xianbo Zhou, Xiaoli Yao, Curtis B Ashford, Feng Li, Long Yang, Michael F Bergeron, J Wesson Ashford, Xiangsong Zhang, Zhong Pei","doi":"10.1186/s13195-025-01801-y","DOIUrl":"10.1186/s13195-025-01801-y","url":null,"abstract":"<p><strong>Background: </strong>With the recent approval of anti-β-amyloid (Aβ) treatment for Alzheimer's disease (AD), a demand has emerged for scalable, convenient and accurate estimations of brain Aβ burden for the detection of AD that would enable timely, accurate and reliable diagnosis in one's primary care physician's (PCPs) office as called for recently by World Health Organization (WHO).</p><p><strong>Methods: </strong>MemTrax, a 2-minute online memory test, was selected as the digital biomarker of cognitive impairment, and blood-based biomarkers (BBMs) including Aβ42, Aβ40, P-tau181, GFAP and NfL were used to estimate AD-related metrics in different groups of elderly individuals (n = 349) for comparison with Aβ PET scans of brain Aβ burden. The correlations between MemTrax, MoCA, BBMs and brain Aβ burden, expressed in centiloid (CL) values, were analyzed for predicting CL value alone or in combinations using machine-learning (ML).</p><p><strong>Results: </strong>Both MemTrax and the MoCA were able to differentiate Aβ status similarly. Integration of MemTrax and BBMs using ML, however, significantly improved the AUCs (over the same with MoCA) for differentiating Aβ status. MemTrax and p-Tau181/Aβ42 composite showed the strongest relationship with CL value among other BBMs. Most importantly, regression analyses of MemTrax and p-Tau181/Aβ42 aptly predicted CL values.</p><p><strong>Conclusion: </strong>The combination of MemTrax and BBMs provides an accurate, convenient, non-invasive, cost-effective and scalable way to estimate Aβ load, which provides an opportunity for mass screening and timely and accurate diagnosis of AD. Our findings could also facilitate more effective AD clinical management in the PCPs office worldwide for more equitable access to current standard of care.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"149"},"PeriodicalIF":7.9,"publicationDate":"2025-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12228144/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144566988","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Machine-learning based strategy identifies a robust protein biomarker panel for Alzheimer's disease in cerebrospinal fluid.","authors":"Xiaosen Hou, Yunjie Qiu, Hui Li, Yan Yan, Dongxu Zhao, Simei Ji, Junjun Ni, Jun Zhang, Kefu Liu, Hong Qing, Zhenzhen Quan","doi":"10.1186/s13195-025-01789-5","DOIUrl":"10.1186/s13195-025-01789-5","url":null,"abstract":"<p><strong>Background: </strong>The complex pathogenesis of Alzheimer's disease (AD) has resulted in limited current biomarkers for its classification and diagnosis, necessitating further investigation into reliable universal biomarkers or combinations.</p><p><strong>Methods: </strong>In this work, we collect multiple CSF proteomics datasets and build a universal diagnose model by SVM-RFECV method combined with equal sample size and standard normalization design. The model was training in 297_CSF and then test the effect in other datasets.</p><p><strong>Results: </strong>Utilizing machine learning, we identify a 12-protein panel from cerebrospinal fluid proteomic datasets. The universal diagnosis model demonstrated strong diagnostic capability and high accuracy across ten different AD cohorts across different countries and different detection technologies. These proteins involved in various biological processes related to AD and shows a tight correlation with established AD pathogenic biomarkers, including amyloid-β, tau/p-tau, and the Montreal Cognitive Assessment score. The high accuracy in the model may due to multiple protein combination based on comprehensive pathogenesis and different AD progress. Furthermore, it effectively differentiates AD from mild cognitive impairment (MCI) and other neurodegenerative disorders, especially the frontotemporal dementia (FTD), which share similar pathogenesis as AD.</p><p><strong>Conclusion: </strong>This study highlights a high accuracy, robustness and compatibility model of 12-protein panel whose detection is even based on label-free, TMT and DIA mass spectrometry or ELISA technologies, implicating its potential prospect in clinical application.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"147"},"PeriodicalIF":7.9,"publicationDate":"2025-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12232211/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144564245","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Rescue of protein dyshomeostasis in hippocampal astrocytes from an Alzheimer's disease mouse model by stabilizing ER-mitochondrial interactions at a 20 nm distance.","authors":"Giulia Dematteis, Chunmei Gong, Justyna Malecka, Elisa Tonelli, Armando Genazzani, Laura Tapella, Anna Maria Eleuteri, Dmitry Lim, Laura Bonfili","doi":"10.1186/s13195-025-01793-9","DOIUrl":"10.1186/s13195-025-01793-9","url":null,"abstract":"<p><strong>Background: </strong>Alzheimer's disease (AD) is the major age-related form of dementia in which dysfunctional ubiquitin-proteasome system (UPS) and autophagy represent primary mechanisms leading to accumulation of misfolded proteins, dysfunction of astroglial cells, neuroinflammation and neurodegeneration. Alterations of the endoplasmic reticulum (ER)-mitochondria contact sites (MERCS), specifically the shortening of the distance between the organelles, was proposed as a key mechanism of cell dysfunction in AD. However, its link to the impairment of the proteolytic system in AD remains unexplored.</p><p><strong>Methods: </strong>We used, as a model, hippocampal astrocytes from 3xTg-AD mice expressing either control plasmid or synthetic linkers stabilizing ER-mitochondrial interaction at 10 nm (10 nm-EML) or at 20 nm (20 nm-EML). Alternatively, astrocytes were treated with mitochondrial Ca²⁺ uptake inhibitor benzethonium chloride or activator amorolfine. We used Western blot to assess protein expression and specific enzymatic activity tests for the analysis of proteasomal, autophagic and lysosomal activities. Single cell fluorescent Ca²⁺ imaging, using 4mtD3cpv probe targeted to the mitochondrial matrix, was used to assess mitochondrial Ca²⁺ uptake.</p><p><strong>Results: </strong>Stabilization of MERCS at 20 nm (20 nm-MERCS), which promotes mitochondrial Ca²⁺ uptake, rescued protein ubiquitination, UPS composition and activity. Immunoproteasome components β2i and β5i, upregulated in AD astrocytes, and INFγ, a master-regulator of UPS remodelling in inflammatory conditions, were also rescued. Autophagic markers beclin 1, LC3II and p62, and lysosome-related marker cathepsin B, all upregulated in AD astrocytes, were significantly reduced, while autophagic flux was rescued, by stabilizing 20 nm-MERCS. Furthermore, stabilization of 20 nm-MERCS fully rescued previously reported deficit of mitochondrial Ca²⁺ uptake. Strikingly, application of a mitochondrial Ca²⁺ uptake positive modulator, amorolfine, partially rescued pathological remodelling of UPS and autophagy, suggesting that both mitochondrial Ca²⁺-related and Ca²⁺-unrelated mechanisms play a role in the beneficial effect of 20 nm-MERCS stabilization on protein dyshomeostasis.</p><p><strong>Conclusions: </strong>Our results suggest that disruption of ER-mitochondrial interaction is a key factor for AD-related dysregulation of protein degradation and provide a proof that stabilization of MERCS at a defined distance and/or pharmacological rescue of mitochondrial Ca²⁺ uptake represent valuable strategies for the development of future anti-AD therapy.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"148"},"PeriodicalIF":7.9,"publicationDate":"2025-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12228274/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144564246","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Low-dose interleukin-2 in patients with mild to moderate Alzheimer's disease: a randomized clinical trial.","authors":"Alireza Faridar, Nazaret Gamez, Daling Li, Yanling Wang, Reena Boradia, Aaron D Thome, Weihua Zhao, David R Beers, Jason R Thonhoff, Mohammad O Nakawah, Gustavo C Román, John J Volpi, Jon B Toledo, Michael George, Charles S Davis, Belen Pascual, Michael Grundman, Joseph C Masdeu, Stanley H Appel","doi":"10.1186/s13195-025-01791-x","DOIUrl":"10.1186/s13195-025-01791-x","url":null,"abstract":"<p><strong>Background: </strong>We previously documented that regulatory T cells (Tregs) immunomodulatory mechanisms are compromised in Alzheimer's disease (AD), shifting the immune system toward a pro-inflammatory response. However, Tregs are a potentially restorable therapeutic target in AD. In this study, we evaluated the safety and efficacy of two dosing frequencies of low-dose Interleukin-2 (IL-2) in expanding Tregs to modify disease progression in AD individuals.</p><p><strong>Methods: </strong>In this phase 2a, randomized, double-blind, placebo-controlled study, 38 participants were assigned to receive subcutaneous IL-2 (10^6 IU/day) for five days, administered either every 4 weeks (IL-2 q4wks) or every 2 weeks (IL-2 q2wks), versus placebo, for 21 weeks, followed by 9 weeks of observation. The primary endpoints were the incidence and severity of adverse events. For the secondary endpoints, changes in Treg numbers and suppressive functions were evaluated. Exploratory endpoints included changes in plasma inflammatory mediators, CSF AD-related biomarkers, and clinical scales.</p><p><strong>Results: </strong>Of the 38 participants, 9 received IL-2 q4wks, 10 received IL-2 q2wks, and 19 received placebo. All participants completed the trial with no serious adverse events or deaths. Both IL-2 dosing regimens increased Treg numbers and suppressive function, but IL-2 q4wks treatment exhibited superiority in enhancing Treg percentage and Foxp3 mean fluorescent intensity. In longitudinal analysis of 45 inflammatory mediators, IL-2 q4wks administration demonstrated greater efficacy in alleviating the plasma inflammatory mediators CCL2, CCL11, and IL-15, while enhancing IL-4 and CCL13 levels. A significant improvement in CSF Aβ42 levels (p = 0.045 vs. placebo) on Day 148 was observed following IL-2 q4wks administration, compared to placebo. While CSF NfL increased by 217 pg/ml in placebo recipients, it remained stable in the IL-2 q4wks group (p = 0.060, IL-2 q4wks vs. placebo). The adjusted mean change from baseline in the ADAS-cog score at week 22 indicated a trend toward slower clinical progression in IL-2 q4wks recipients compared to placebo (p = 0.061).</p><p><strong>Conclusions: </strong>The IL-2 immunotherapeutic strategy was safe and well-tolerated. IL-2 q4wks effectively expanded Treg populations, leading to modification in inflammatory mediators and CSF Aβ42 levels, while also showing promising trends on clinical scales. These findings provide a foundation for further investigation of low-dose IL-2 as a potential treatment for Alzheimer's Disease.</p><p><strong>Trial registration: </strong>ClinicalTrials.gov Identifier: NCT06096090, Registration Date: 10-17-2023.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"146"},"PeriodicalIF":7.9,"publicationDate":"2025-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12231701/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144564244","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tau seeding activity in the cerebrospinal fluid of Alzheimer disease patients predicts short-term cognitive decline.","authors":"Ludivine Houzé, Marc Dhenain, Suzanne Lam, Fanny Petit, Stéphane Haïk, François Mouton-Liger, Jacques Hugon, Julie Dam, Claire Paquet, Ralf Jockers, Erika Cecon","doi":"10.1186/s13195-025-01792-w","DOIUrl":"10.1186/s13195-025-01792-w","url":null,"abstract":"<p><strong>Background: </strong>Alzheimer disease (AD) clinical progression is highly heterogeneous, making its prediction essential for the development of effective therapies. The advancement of cognitive decline in AD is tightly linked to the spread of pathological tau protein aggregates in the brain, through tau seeding properties.</p><p><strong>Methods: </strong>We developed a cellular biosensor to measure tau seeding activity from cerebrospinal fluid (CSF) and human brain lysates. Longitudinal analysis of cognitive function was correlated with biosensor response.</p><p><strong>Results: </strong>Individuals with CSF exhibiting high or intermediate seeding activity experienced more rapid cognitive decline compared to those with low seeding. High tau seeding was associated with total and phosphorylated tau biomarkers in AD. The biosensor also predicts the potential of human AD brain lysates to induce tau aggregation upon experimental transmission in animal models.</p><p><strong>Conclusions: </strong>These results suggest that seeding activity might be a relevant biomarker to forecast AD pathogenicity and clinical progression.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"145"},"PeriodicalIF":7.9,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12220128/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144551696","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Safety, tolerability, pharmacokinetic and pharmacodynamic effects of the muscarinic M₁ positive allosteric modulator VU0467319 for Alzheimer's disease: a single ascending-dose study in healthy participants.","authors":"Alexander C Conley, Alexandra P Key, Jennifer U Blackford, Jason K Russell, Kimberly M Albert, Xuewen Gong, Michael Bubser, Jerri M Rook, P Jeffrey Conn, Craig W Lindsley, Carrie K Jones, Paul A Newhouse","doi":"10.1186/s13195-025-01798-4","DOIUrl":"10.1186/s13195-025-01798-4","url":null,"abstract":"<p><p>The development of cholinergic neurotransmitter based cognitive enhancers for Alzheimer's disease and other neuropsychiatric disorders have focused recently on allosteric modulation of specific muscarinic acetylcholine receptor (mAChR) subtypes to reduce dose-limiting side-effects that have been the hallmark of earlier orthosteric mAChR agonists. VU0467319 (VU319) is an investigational positive allosteric modulator of the M₁ mAChR. A Phase 1 first-in-human study was conducted assessing safety and brain activity utilizing cognitive tasks and event-related potentials (ERPs) in single-ascending dose and food effect studies. VU319 was given orally to 52 healthy volunteers aged 18-55 years. The single ascending dose study tested 40 participants in five dose escalating cohorts (60, 120, 240, 400, 600 mg; 6 VU319/2 placebo per dose). The food effect study involved 12 participants, 10 VU319 (120 mg)/2 placebo. Exploratory cognitive and electrophysiological tasks were examined pre-dosing and at 5 h post-dose. Tolerability was good with no observed dose limiting side effects throughout the full dose range tested. In the single ascending dose study, there were 47 TEAEs reported across the 5 cohorts, 14 in the placebo group and 33 across the 5 active dose cohorts. In the food effect study, there were 20 TEAEs reported, 6 in the placebo group and 14 in the fed and fasted conditions. Drug exposure increased with dose in a less than dose-proportional manner with a half-life ranging from 30 to 55 h. Peak concentration was observed between 5 and 9.5 h across the dosage groups. Absorption was increased with food. Exploratory cognitive/ERP testing showed evidence for drug-induced CNS activity on higher doses of VU319 compared to placebo. Single dose VU319 across five ascending cohorts appeared to have a favorable safety profile and a PK profile consistent with once daily dosing. Target engagement results suggest stimulation of the cholinergic system functioning in healthy adults following a single dose of VU319. These results provide a strong foundation for further studies of positive allosteric modulators of muscarinic M₁ receptors for potential cognitive or behavioral benefits.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"144"},"PeriodicalIF":7.9,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12211128/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144537705","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Arhgef7 as a key target for enriched environment rescuing spatial cognitive deficits and anxiety-like behaviors in a mouse model of Alzheimer's disease following early social isolation.","authors":"Yimiao Wang, Ze Wang, Yue Li, Min Cao, Shuying Zhang, Shixin Ding, Sijia Chen, Yuxi Jin, Yanli Zhang, Junying Gao, Ming Xiao","doi":"10.1186/s13195-025-01797-5","DOIUrl":"10.1186/s13195-025-01797-5","url":null,"abstract":"<p><strong>Background: </strong>Both social and physical environmental factors influence the progression of Alzheimer's disease (AD), but the underlying mechanisms are not yet fully understood. This study aims to investigate how an enriched environment (EE) alleviates the detrimental effects of early social isolation (SI) on AD-like pathophysiology.</p><p><strong>Methods: </strong>Four-week-old 5×FAD transgenic mice were randomly divided into group-housed and isolated groups. After 3 weeks, the mice were further raised in either a physical EE or a standard environment for an additional 3 weeks. Subsequently, these experimental subjects underwent a two-week of behavioral tests while maintaining their original housing conditions unchanged, followed by neuropathological analyses. A series of experiments were conducted on the medial prefrontal cortex (mPFC), including transcriptome sequencing, cellular localization, and knockdown and overexpression of a candidate gene, to identify the key molecules through which physical EE alleviates SI-induced AD-like alterations. The protective effects of the identified gene on cultured forebrain neurons exposed to β-amyloid stimulation, as well as its associated signaling pathways, were also investigated.</p><p><strong>Results: </strong>EE enhanced cognitive function and alleviated anxiety-like behavior in SI-5×FAD mice, partially reversing dendritic and synaptic loss and glial cell activation in the mPFC. However, it did not mitigate deficits in social and cooperative behaviors, hypomyelination, or β-amyloid deposition. Notably, group-housed 5×FAD mice raised in the EE exhibited alleviation of the aforementioned AD-like phenotypes. Transcriptomic and bioinformatic analyses pinpointed Rho guanine nucleotide exchange factor 7 (Arhgef7) as a pivotal mediator of the beneficial effects of physical EE. Arhgef7 overexpression in mPFC neurons enhanced dendritic and synaptic growth and alleviated spatial cognitive impairments and anxiety-like behavior in SI-5×FAD mice, but it did not correct hypomyelination or social behavior deficits. Consistently, knockdown of Arhgef7 in mPFC neurons of group-housed 5×FAD mice selectively impaired neuronal processes and spatial cognition, and increased anxiety-like behavior. Mechanistically, Arhgef7 protected cortical neurons from β-amyloid toxicity by activating the Wnt signaling pathway.</p><p><strong>Conclusion: </strong>Arhgef7 in mPFC neurons is essential for the physical components of EE selectively alleviating spatial cognitive deficits and anxiety-like behaviors in early isolated AD model mice, serving as a potential target for the prevention and treatment of AD.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"143"},"PeriodicalIF":7.9,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12210992/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144537704","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The economic burden of subjective cognitive decline, mild cognitive impairment and Alzheimer's dementia: excess costs and associated clinical and risk factors.","authors":"Eva Gläser, Ingo Kilimann, Moritz Platen, Wolfgang Hoffmann, Frederic Brosseron, Katharina Buerger, Marie Coenjaerts, Emrah Düzel, Michael Ewers, Klaus Fliessbach, Ingo Frommann, Maria Gemenetzi, Wenzel Glanz, Julian Hellmann-Regen, Enise I Incesoy, Daniel Janowitz, Frank Jessen, Oliver Peters, Josef Priller, Alfredo Ramirez, Anja Schneider, Annika Spottke, Eike Jakob Spruth, Stefan Teipel, Michael Wagner, Bernhard Michalowsky","doi":"10.1186/s13195-025-01785-9","DOIUrl":"10.1186/s13195-025-01785-9","url":null,"abstract":"<p><strong>Background: </strong>With the availability of first disease-modifying treatments, evidence on costs across the entire Alzheimer's Continuum, especially for early disease stages, becomes increasingly important to inform healthcare planning, resource allocation, and policy decisions. This study assessed costs and cost-associated factors in patients with subjective cognitive decline (SCD), mild cognitive impairment (MCI) and Alzheimer's Disease (AD) dementia compared to healthy controls.</p><p><strong>Methods: </strong>The German DELCODE cohort study assessed clinical data, healthcare resource use, and informal care provision. Costs were calculated from payer and societal perspectives using standardized unit costs, and multivariate regression analyses identified cost-associated factors.</p><p><strong>Results: </strong>From a payer perspective, costs were elevated by 26% for SCD (adjusted mean 5,976€ [95%CI 4,598-7,355€]), 85% for MCI (8,795€ [6,200-11,391€]) and 36% for AD (6,454€ [2,796-10,111€]) compared to controls (4,754€ [3,586-5,922€]). Societal costs were elevated by 52% for SCD (adjusted mean 8,377€ [95%CI 6,009-10,746€]), 170% for MCI (14,886€ [9,524-20,248€]) and 307% for AD (22,481€ [9,994-34,969€]) compared to controls (5,522€ [3,814-7,230€]). APOE e4 negative patients showed higher costs compared to APOE e4 positive patients. Hypertension was associated with higher costs.</p><p><strong>Conclusions: </strong>Healthcare costs are already elevated in early subjective and objective cognitive impairment, driven by formal and informal care. The study emphasizes the importance of early interventions to reduce the economic burden and delay progression.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"142"},"PeriodicalIF":7.9,"publicationDate":"2025-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12199487/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144504476","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}