Alzheimer's Research & Therapy最新文献

{"title":"Diagnostic performance of plasma p-tau217 in a memory clinic cohort using the Lumipulse automated platform.","authors":"Francisco Martínez-Dubarbie, Armando Guerra-Ruiz, Sara López-García, Carmen Lage, Marta Fernández-Matarrubia, Álvaro Nevado-Cáceres, María Rivera-Sánchez, Andrea Valera-Barrero, Ana Pozueta-Cantudo, María García-Martínez, Andrea Corrales-Pardo, María Bravo, Marcos López-Hoyos, Juan Irure-Ventura, Enrique Marco de Lucas, Marta Drake-Pérez, Nancy Heidy Cahuana-Santamaría, María Teresa García-Unzueta, Pascual Sánchez-Juan, Eloy Rodríguez-Rodríguez","doi":"10.1186/s13195-025-01719-5","DOIUrl":"10.1186/s13195-025-01719-5","url":null,"abstract":"<p><strong>Background: </strong>Plasma biomarkers for Alzheimer's disease (AD) are a promising tool for accessible and accurate biological diagnostics. However, data in clinical practice are needed to better understand their diagnostic and prognostic ability in memory unit patients.</p><p><strong>Methods: </strong>We analyzed plasma phosphorylated tau at threonine 217 (p-tau217) and neuroflament light chain (NfL) levels and AD cerebrospinal fluid (CSF) biomarkers in a group of 493 subjects using the Lumipulse G600II platform. The sample includes 340 patients from our memory unit (142 dementia, 186 mild cognitive impairment, and 12 with subjective complaints) and 153 cognitively unimpaired volunteers. We have correlated plasma and CSF biomarkers; we have analyzed plasma biomarker levels as a function of clinical diagnosis, cognitive status and amyloid status. We have also studied the ability of p-tau217 to discriminate between amyloid-positive and -negative subjects according to CSF using receiver operating characteristic curves.</p><p><strong>Results: </strong>Plasma p-tau217 correlated significantly with CSF Aβ42/Aβ40 (Rho = -0.75; p-value < 0.001), p-tau181 (r = 0.66; p-value < 0.001), and t-tau (r = 0.59; p-value < 0.001). Plasma NfL correlated with CSF NfL (r = 0.48; p-value < 0.001). By clinical diagnosis, plasma p-tau217 levels showed to be higher in AD patients than in healthy controls (difference = 0.63 pg/ml; p-value < 0.001), FTD (difference = 0.60 pg/ml; p-value < 0.001), and nondegenerative dementias (difference = 0.61 pg/ml; p-value < 0.001). Plasma p-tau217 showed an area under the curve of 0.95 to discriminate between A + and A- subjects (95%CI 0.93-0.97).</p><p><strong>Conclusion: </strong>Plasma p-tau217 shows excellent results for detecting amyloid pathology at brain level in a clinical setting with an AUC of 0.95. It is a highly specific marker of AD and increases progressively along the disease continuum. Using plasma p-tau217 as an initial diagnostic tool with cut-offs at sensitivities and specificities of 95 or 97.5% could save between 57.4-84.8% of LP/PETs with diagnostic accuracies of 95-97%. Plasma NfL increases progressively at different cognitive stages.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"68"},"PeriodicalIF":7.9,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11948696/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143717624","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":"Accelerometer-derived \"weekend warrior\" physical activity, sedentary behavior, and risk of dementia.","authors":"Yuye Ning, Meilin Chen, Hao Yang, Jianping Jia","doi":"10.1186/s13195-024-01657-8","DOIUrl":"10.1186/s13195-024-01657-8","url":null,"abstract":"<p><strong>Background: </strong>Research has shown that sedentary behavior (SB) may increase dementia risk, but it remains unclear whether concentrated moderate to vigorous physical activity (MVPA) can compensate such negative effects. This study aimed to explore the association between different MVPA patterns combined with SB time and the risk of dementia.</p><p><strong>Methods: </strong>This prospective study used data from the UK Biobank cohort, which provided accelerometer-based physical activity data for a full week from February 2013 to December 2015. Participants were categorized into \"weekend warriors (WW)\" group, engaged in more than 50% MVPA (≥ 150 min/week) on 1 to 2 days; inactive group (total MVPA < 150 min/week); and regular group, who met the recommended MVPA (≥ 150 min/week) but not WW. The participants were further divided into six groups based on SB duration (≥ 8.52 h/day or < 8.52 h/day). A multivariable Cox model was used to assess the relationship between these patterns and the risk of dementia, adjusted by age, gender, ethnicity, Townsend deprivation index, education level, employment status, alcohol consumption, smoking, BMI, and baseline comorbidities (including cardiovascular disease, hypertension, and diabetes).</p><p><strong>Results: </strong>We included 91,948 participants without dementia at baseline. During a median follow-up of 7.93 years, 736 participants developed all-cause dementia. When the MVPA threshold was set at 150 min per week, 16,149 participants (17.5%) were classified as WW with long SB, 19,055 (20.7%) as regular with long SB, and 21,909 (23.8%) as inactive with long SB. Compared to inactive and long SB time, the WW group showed a reduction in dementia risk (WW with long SB time: HR = 0.69, 95% CI: 0.54-0.87, P = 0.002; WW with short SB time: HR = 0.74, 95% CI: 0.56-0.97, P = 0.029). And regular group with shorter SB time was associated with a lower dementia risk (HR = 0.75, 95% CI: 0.59-0.96, P = 0.021), but not in the group with longer SB time.</p><p><strong>Conclusions: </strong>The WW pattern may help mitigate the dementia risk associated with prolonged SB, suggesting that the quality and intensity of physical activity are also important factors.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"67"},"PeriodicalIF":7.9,"publicationDate":"2025-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11929323/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143690679","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":"Impact of effective connectivity within the Papez circuit on episodic memory: moderation by perivascular space function.","authors":"Ling-Ling Li, Jie Ma, Jia-Jia Wu, Xin Xue, Mou-Xiong Zheng, Xu-Yun Hua, Qi-Hao Guo, Jian-Guang Xu","doi":"10.1186/s13195-025-01717-7","DOIUrl":"10.1186/s13195-025-01717-7","url":null,"abstract":"<p><strong>Background and objectives: </strong>The formation and retrieval of episodic memory is dependent on the coordinated activity of multiple brain regions and neural networks, with the Papez circuit playing a critical role in this process. Recently, the role of the perivascular space (PVS) in cognitive function has garnered increasing attention. However, the role of PVS function between neural circuits and cognitive function in amnestic mild cognitive impairment (aMCI) patients remains unknown. Therefore, this study aims to (1) investigate alterations in the effective connectivity of the Papez circuit and PVS function in patients with aMCI and (2) explore the role of PVS function between the effective connectivity of the Papez circuit and episodic memory.</p><p><strong>Methods: </strong>Sixty participants, all of whom underwent multimodal MRI (fMRI, dMRI, and sMRI) and neuropsychological testing, were recruited for this case‒control study. General linear models were used to compare the effective connectivity within the Papez circuit and PVS function between aMCI patients and healthy controls (HCs) and further explore the role of PVS function between the effective connectivity within the Papez circuit and episodic memory.</p><p><strong>Results: </strong>The effective connectivity between multiple critical regions within the Papez circuit, notably in the hippocampus, anterior cingulate cortex, and parahippocampal gyrus, was significantly weakened in aMCI patients. Moreover, a significant reduction in the along the perivascular space (ALPS) index was observed among aMCI patients, accompanied by a marked increase in PVS volume, indicating significant PVS dysfunction. Further moderation analysis revealed that PVS function moderated the relationship between effective connectivity within the Papez circuit and episodic memory.</p><p><strong>Conclusions: </strong>The effective connectivity within the Papez circuit and PVS function are closely related to cognitive function, particularly episodic memory, and enhancing PVS function may serve as a novel therapeutic target for slowing cognitive decline.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"66"},"PeriodicalIF":7.9,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11927174/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143668848","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-PET pathology in the subregions of the amygdala and its associations with cognitive performance and neuropsychiatric symptoms in autosomal dominant Alzheimer's disease.","authors":"Catarina Tristão-Pereira, Stephanie Langella, Justin S Sanchez, Vincent Malotaux, Bing He, Jorge Alcina, Jairo E Martinez, Zoe Rubinstein, Ana Baena, Clara Vila-Castelar, Averi Giudicessi, Liliana Ramirez Gomez, Claudia Ramos, Daniel Vasquez, David Aguillon, Heidi I L Jacobs, Reisa A Sperling, Keith Johnson, Jennifer R Gatchel, Yakeel T Quiroz","doi":"10.1186/s13195-025-01711-z","DOIUrl":"10.1186/s13195-025-01711-z","url":null,"abstract":"<p><strong>Background: </strong>The amygdala plays a role in behavior and emotional response and is vulnerable to Alzheimer's disease (AD) pathology, yet little is known about amygdala tau accumulation before clinical symptom onset. To investigate whether certain amygdala nuclei are particularly vulnerable to degeneration and might underlie early neuropsychiatric symptoms in AD, we aimed to characterize subregional amygdala tau pathology and its correlates associations with established biomarkers of early AD and cognitive-behavioral measures in Presenilin-1 E280A mutation carriers of autosomal dominant AD.</p><p><strong>Methods: </strong>Participants included 25 cognitively unimpaired mutation carriers and 37 non-carrier family members from the Colombia-Boston (COLBOS) Biomarker Study. Measures included 18F-flortaucipir, 11C-Pittsburgh compound B, Consortium to Establish a Registry for Alzheimer's Disease Word List Learning, Trail Making Test, Geriatric Depression Scale, and Geriatric Anxiety Inventory. We examined group differences in amygdala tau levels (whole amygdala, lateral nucleus and basal nucleus) and analyzed tau associations with disease markers and clinical measures.</p><p><strong>Results: </strong>Amygdala tau levels were higher in unimpaired carriers compared to non-carriers. Among carriers, the basal nucleus showed a greater tau burden than the lateral nucleus, and tau accumulation correlated with closer estimated age to clinical onset and increased cortical amyloid. Additionally, tau in both the basal and lateral amygdala was associated with poorer working memory, lower executive function and greater depressive symptoms. However, amygdala tau did not correlate with symptoms of anxiety. Notably, tau levels in the basal amygdala differentiated carriers from non-carriers, with higher predictive accuracy when neuropsychiatric measures were included.</p><p><strong>Conclusions: </strong>These findings suggest that in autosomal dominant AD, tau accumulation in the amygdala begins early in the basal nucleus, while both the basal and the lateral nuclei are associated with early cognitive deficits and depressive symptoms. The nuclei's differential vulnerability to pathology underscores the importance of investigating tau spread within amygdala-associated networks, relative to the early clinical manifestations of AD. This study reinforces the potential of amygdala tau burden as a valuable biomarker for preclinical AD.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"64"},"PeriodicalIF":7.9,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11924723/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143661956","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":"Impact of sleep apnea on alzheimer's disease in relation to sex: an 8-year longitudinal follow-up study of a nationwide cohort.","authors":"Su Jin Chung, Sung Hoon Kang, Minwoong Kang, Yunjin Choi, Yu Jeong Park, Hayom Kim, Kyungmi Oh, Seong-Beom Koh, Jung Bin Kim","doi":"10.1186/s13195-024-01667-6","DOIUrl":"10.1186/s13195-024-01667-6","url":null,"abstract":"<p><strong>Background: </strong>We aimed to investigate the association between sleep apnea and incident dementia (dementia of the Alzheimer type [DAT] and vascular dementia) and whether differences in the effects of sleep apnea on dementia depend on sex. Furthermore, we sought to determine whether obesity affects the sex-specific relationship between sleep apnea and dementia.</p><p><strong>Methods: </strong>We used de-identified data on patients with sleep apnea and a control group aged ≥ 50 years from the Korean National Health Insurance Service. After propensity score matching to balance age and sex between the patient and control groups, 30,111 individuals with sleep apnea (patient group) and 121,528 individuals without sleep apnea (control group) were included. To investigate the impact of sleep apnea on the development of dementia, we used Cox proportional hazards regression after controlling for potential confounders.</p><p><strong>Results: </strong>Sleep apnea was predictive of developing DAT in both women (hazard ratio [HR] = 1.30, 95% confidence interval [CI] 1.16-1.44, p < 0.001) and men (HR = 1.13, 95% CI 1.03-1.24, p = 0.012). The adverse effects of sleep apnea on DAT were more prominent in women than in men (p = 0.015 for sleep apnea×sex). Furthermore, obesity affected the sex-specific relationship between sleep apnea and DAT. Specifically, the adverse effects of obese sleep apnea on the DAT were more pronounced in women than in men (p = 0.002 for obese sleep apnea×sex). In contrast, there were no differences in the effects of non-obese sleep apnea on DAT between women and men (p = 0.667 for non-obese sleep apnea×sex).</p><p><strong>Conclusions: </strong>Our results highlight sex differences in the adverse effects of sleep apnea on DAT. Furthermore, these results suggest that sex-specific strategies for controlling sleep apnea are necessary to prevent DAT.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"65"},"PeriodicalIF":7.9,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11924715/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143668850","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":"Correction: Cornuside alleviates cognitive impairments induced by Aβ_1-42 through attenuating NLRP3-mediated neurotoxicity by promoting mitophagy.","authors":"Fulin Zhou, Wenwen Lian, Xiaotang Yuan, Zexing Wang, Congyuan Xia, Yu Yan, Wenping Wang, Zhuohang Tong, Yungchi Cheng, Jiekun Xu, Jun He, Weiku Zhang","doi":"10.1186/s13195-025-01715-9","DOIUrl":"10.1186/s13195-025-01715-9","url":null,"abstract":"","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"63"},"PeriodicalIF":7.9,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11921720/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143661953","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":"Perivascular space and white matter hyperintensities in Alzheimer's disease: associations with disease progression and cognitive function.","authors":"Philine Marie Schirge, Robert Perneczky, Toshiaki Taoka, Adriana L Ruiz-Rizzo, Ersin Ersoezlue, Robert Forbrig, Selim Guersel, Carolin Kurz, Matthias Brendel, Julian Hellmann-Regen, Josef Priller, Anja Schneider, Frank Jessen, Emrah Düzel, Katharina Buerger, Stefan Teipel, Christoph Laske, Oliver Peters, Eike Spruth, Klaus Fliessbach, Ayda Rostamzadeh, Wenzel Glanz, Daniel Janowitz, Ingo Kilimann, Sebastian Sodenkamp, Michael Ewers, Boris-Stephan Rauchmann","doi":"10.1186/s13195-025-01707-9","DOIUrl":"10.1186/s13195-025-01707-9","url":null,"abstract":"<p><strong>Background: </strong>Alzheimer's disease (AD) is the leading cause of dementia, characterized by the accumulation of amyloid-beta (Aβ) and neurofibrillary tangles. Recent studies emphasize the role of vascular factors, including the glymphatic system, in AD pathogenesis, particularly in Aβ clearance. The diffusion tensor image analysis along the perivascular space (DTI-ALPS; ALPS-Index) has emerged as a novel, non-invasive method to evaluate the glymphatic system in vivo, showing glymphatic insufficiency in AD. This study aimed to investigate alterations in the function of the glymphatic system in individuals with AD versus healthy controls (HC), and to explore its association with Aβ, cerebrovascular disease (CVD), white matter hyperintensities (WMH), and cognitive function.</p><p><strong>Methods: </strong>DTI MRI data from three independent study cohorts (ActiGliA: AD n = 16, Controls n = 18; DELCODE: AD n = 54, Controls n = 67; ADNI: AD n = 43, Controls n = 49) were used to evaluate the perivascular space (PVS) integrity; a potential biomarker for glymphatic activity. The DTI-Along the Perivascular Space technique was used to measure water diffusion along PVS providing an index to assess the efficiency of the glymphatic system's waste clearance function. WMH load was quantified in FLAIR MRI using the lesion segmentation tool. We quantified WMHs volume within our defined region of interest (ROI) and excluded participants with any WMHs to avoid confounding the ALPS-Index. Associations with cerebrospinal fluid (CSF) AD hallmark biomarkers, cognitive performance (MMSE) and clinical severity (CDR) were assessed.</p><p><strong>Results: </strong>AD patients had a significantly lower ALPS-Index vs. healthy controls (ActiGliA: AD: mean = 1.22, SD = 0.12; Controls: mean = 1.36, SD = 0.14, p = 0.004; DELCODE: AD: mean = 1.26, SD = 0.18; Controls: mean = 1.34, SD = 0.2, p = 0.035; ADNI: AD: mean = 1.08, SD = 0.24; Controls: mean = 1.19, SD = 0.13, p = 0.008). The ALPS-Index was associated with CSF Aβ concentration, WMH number and MMSE and CDR. WMH, found in the ROIs correlated negatively with the ALPS-Index.</p><p><strong>Conclusions: </strong>This study highlights the potential of the DTI-ALPS-Index as a biomarker for glymphatic dysfunction in AD. It underscores the importance of considering vascular factors and the glymphatic system in the pathogenesis and diagnosis of AD as WMHs in the ROI could cause disturbances and inaccurate indices.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"62"},"PeriodicalIF":7.9,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11917016/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143646833","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":"Adherence and intensity in multimodal lifestyle-based interventions for cognitive decline prevention: state-of-the-art and future directions.","authors":"Natalia Soldevila-Domenech, Amaia Ayala-Garcia, Mariagnese Barbera, Jenni Lehtisalo, Laura Forcano, Ana Diaz-Ponce, Marissa Zwan, Wiesje M van der Flier, Tiia Ngandu, Miia Kivipelto, Alina Solomon, Rafael de la Torre","doi":"10.1186/s13195-025-01691-0","DOIUrl":"10.1186/s13195-025-01691-0","url":null,"abstract":"<p><p>Preventing dementia and Alzheimer's disease (AD) is a global priority. Multimodal interventions targeting several risk factors and disease mechanisms simultaneously are currently being tested worldwide under the World-Wide FINGERS (WW-FINGERS) network of clinical trials. Adherence to these interventions is crucial for their success, yet there is significant heterogeneity in adherence reporting across studies, hindering the understanding of adherence barriers and facilitators. This article is a narrative review of available evidence from multimodal dementia prevention trials. A literature search was conducted using medical databases (MEDLINE via PubMed and SCOPUS) to select relevant studies: nonpharmacological multimodal interventions (i.e., combining three or more intervention domains), targeting individuals without dementia, and using changes in cognitive performance and/or incident mild cognitive impairment or dementia as primary outcomes. Based on the findings, we propose future adherence reporting to encompass both participation (average attendance to each intervention component) and lifestyle change using dementia risk scores (e.g., the LIBRA index). Moreover, we provide an estimation of the expected intensity of multimodal interventions, defined as the ratio of the expected dose (i.e., the overall amount of the intervention offered specified in the trial protocol) to duration (in months). Adjusting the expected dose by average adherence enables estimation of the observed dose and intensity, which could be informative for identifying optimal dosage thresholds that maximize cognitive benefits across different populations. Finally, this article provides an overview of the determinants of adherence to multimodal interventions, emphasizing the need for improved adherence reporting to inform the design and implementation of precision prevention interventions.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"61"},"PeriodicalIF":7.9,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11912746/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143646823","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":"Beyond expectations: investigating nilotinib's potential in attenuating neurodegeneration in alzheimer's disease.","authors":"Darcy Tocci, Maiah Fogel, Vanya Gupta, Peter Kim, Jean Latimer, Aida Adlimoghaddam, Lisa S Robison, Benedict C Albensi","doi":"10.1186/s13195-025-01706-w","DOIUrl":"10.1186/s13195-025-01706-w","url":null,"abstract":"<p><p>Neurodegenerative diseases, such as Alzheimer's disease (AD), pose a formidable global challenge. While therapeutic options are available, their limitations are significant, necessitating the development of innovative treatment approaches. Here, we highlight the importance of repurposing drugs and discuss the future of drug treatments for AD. We review the potential of tyrosine kinase inhibitors (TKI) for mitigating AD pathology and symptoms, as well as neurodegenerative processes more broadly. We focus on nilotinib, a selective BCR-ABL tyrosine kinase inhibitor, which has unique mechanisms of action involving the modulation of cell responses and removal of toxic proteins associated with AD pathogenesis. Encouraging studies have demonstrated its efficacy, calling for further investigation through clinical trials to assess its potential in various neurodegenerative conditions. However, despite these promising preclinical findings, no clinical studies have yet conclusively demonstrated its efficacy in treating AD. Considering the future directions in AD research, personalized medicine approaches hold promise by incorporating patient-specific factors, including sex and gender differences, to tailor nilotinib treatment for improved efficacy and safety profiles.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"60"},"PeriodicalIF":7.9,"publicationDate":"2025-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11909998/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143633158","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":"Pharmacokinetic and pharmacodynamic assessment of oral nicotinamide in the NEAT clinical trial for early Alzheimer's disease.","authors":"Gabriel L Ketron, Felix Grun, Joshua D Grill, Howard H Feldman, Robert A Rissman, Gregory J Brewer","doi":"10.1186/s13195-025-01693-y","DOIUrl":"10.1186/s13195-025-01693-y","url":null,"abstract":"<p><strong>Background: </strong>Nicotinamide, a form of B3 vitamin, is an NAD⁺ precursor that reduces pTau₂₃₁ levels via histone deacetylase inhibition in murine models of Alzheimer's disease (AD). A recent phase 2a randomized placebo-controlled trial tested high-dose oral nicotinamide for the treatment of early AD. While nicotinamide demonstrated good safety and tolerability, it did not significantly lower CSF pTau₂₃₁, the primary biomarker endpoint of the study. Characterization of nicotinamide's pharmacokinetics and metabolites in the blood and CSF is needed.</p><p><strong>Methods: </strong>In these post hoc, blinded analyses of plasma and CSF samples from the completed two-site placebo controlled randomized trial testing of 1500 mg PO BID oral nicotinamide, we used mass spectroscopy to measure nicotinamide and its inactive metabolite 1-methyl-nicotinamide in plasma at baseline, 6, and 12 months and in CSF at baseline and 12 months from 23 participants on drug and 24 on placebo.</p><p><strong>Results: </strong>Pharmacokinetic analysis found mean 12 month plasma nicotinamide increased > 130-fold to 52 μM while mean methyl-nicotinamide increased > 600-fold to 91 μM in individuals receiving nicotinamide compared to those receiving placebo, whose levels were unchanged from baseline. However, CSF nicotinamide was only measurable in 6 of the 19 available participants (32%) (mean increase of at least 147-fold to 18 μM). These CSF nicotinamide concentrations were 66% of their plasma levels, indicating good CNS bioavailability in only some participants. In contrast to CSF nicotinamide, more treated participants had higher CSF methyl-nicotinamide (n = 9, 43 μM), suggesting high-dosage nicotinamide was sufficient to pass the blood-brain barrier, but 13 of 19 were metabolically inactivated. Treatment favorably decreased mean pTau₂₃₁ levels by 34% in those six participants with elevated CSF levels of nicotinamide, compared to 3% elevation in participants who did not have elevated CSF nicotinamide, and a 3% decrease for placebo. No such relationships were observed for total tau, pTau₁₈₁, or amyloid beta biomarkers.</p><p><strong>Conclusions: </strong>Our findings suggest that oral administration markedly increased mean plasma nicotinamide levels, however CSF levels were below quantitation in a majority of participants and there was extensive metabolic inactivation to methyl-nicotinamide. Both the bioavailability and rapid metabolic methylation need to be addressed if nicotinamide is further developed as a potential intervention for AD.</p><p><strong>Trial registration: </strong>NCT03061474, last updated 2023-10-17. https://clinicaltrials.gov/study/NCT03061474 .</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"59"},"PeriodicalIF":7.9,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11895359/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143603431","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}