Constance Delaby, Daniel Alcolea, Germain Busto, Audrey Gabelle, Xavier Ayrignac, Karim Bennys, Elena Muiño, Paula Villatoro, Israel Fernández-Cadenas, Nicolas Pradeilles, Shaima El Bounasri, Soraya Torres, Christophe Hirtz, Henrik Zetterberg, Alberto Lleó, Juan Fortea, Sylvain Lehmann
{"title":"Plasma Hepcidin as a potential informative biomarker of Alzheimer disease and vascular dementia.","authors":"Constance Delaby, Daniel Alcolea, Germain Busto, Audrey Gabelle, Xavier Ayrignac, Karim Bennys, Elena Muiño, Paula Villatoro, Israel Fernández-Cadenas, Nicolas Pradeilles, Shaima El Bounasri, Soraya Torres, Christophe Hirtz, Henrik Zetterberg, Alberto Lleó, Juan Fortea, Sylvain Lehmann","doi":"10.1186/s13195-025-01696-9","DOIUrl":"10.1186/s13195-025-01696-9","url":null,"abstract":"<p><strong>Background: </strong>Blood-based assays are expected to be integrated into clinical routines across various contexts, including Alzheimer's disease (AD). Vascular dementia (VaD), which is the second most common cause leading to dementia after AD, could also significantly benefit from this advancement. However, no informative fluid biomarker has been identified for VaD. Given the disruption of iron homeostasis in both AD and VaD, this study aims to characterize the potential of the iron-related hormone Hepcidin as a biomarker for these two conditions. We will compare its added value to established AT(N) blood biomarkers.</p><p><strong>Methods: </strong>Blood biomarkers (amyloid-composite, p-Tau<sub>181</sub>, Neurofilament Light Chain [NfL] and Hepcidin) levels in blood were analyzed in two independent cohorts and compared between AD patients and non-AD individuals. Additionally, blood Hepcidin and NfL were evaluated in the contexts of VaD and CADASIL, with their relative diagnostic value assessed.</p><p><strong>Results: </strong>Blood Hepcidin and NfL do not significantly increase the AUC obtained with both p-Tau<sub>181</sub> and amyloid composite in the context of AD. In contrast, AUC for VaD diagnosis is significantly higher when combining these two blood biomarkers compared to NfL alone. Hepcidin was not significantly modified in CADASIL patients compared to control subjects.</p><p><strong>Conclusion: </strong>Blood Hepcidin and NfL have limited interest in the clinical context of AD but determination of these biomarkers shows to be highly informative for the diagnosis of VaD. This result could have important implications for diagnosis and implementation of clinical trials.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"42"},"PeriodicalIF":7.9,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11823057/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143412880","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}
Siyu Yang, Xintong Zhang, Xinyu Du, Peng Yan, Jing Zhang, Wei Wang, Jing Wang, Lei Zhang, Huaiqing Sun, Yin Liu, Xinran Xu, Yaxuan Di, Jin Zhong, Caiyun Wu, Jan D Reinhardt, Yu Zheng, Ting Wu
{"title":"Prediction of cognitive conversion within the Alzheimer's disease continuum using deep learning.","authors":"Siyu Yang, Xintong Zhang, Xinyu Du, Peng Yan, Jing Zhang, Wei Wang, Jing Wang, Lei Zhang, Huaiqing Sun, Yin Liu, Xinran Xu, Yaxuan Di, Jin Zhong, Caiyun Wu, Jan D Reinhardt, Yu Zheng, Ting Wu","doi":"10.1186/s13195-025-01686-x","DOIUrl":"10.1186/s13195-025-01686-x","url":null,"abstract":"<p><strong>Background: </strong>Early diagnosis and accurate prognosis of cognitive decline in Alzheimer's disease (AD) is important to timely assignment to optimal treatment modes. We aimed to develop a deep learning model to predict cognitive conversion to guide re-assignment decisions to more intensive therapies where needed.</p><p><strong>Methods: </strong>Longitudinal data including five variable sets, i.e. demographics, medical history, neuropsychological outcomes, laboratory and neuroimaging results, from the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort were analyzed. We first developed a deep learning model to predicted cognitive conversion using all five variable sets. We then gradually removed variable sets to obtained parsimonious models for four different years of forecasting after baseline within acceptable frames of reduction in overall model fit (AUC remaining > 0.8).</p><p><strong>Results: </strong>A total of 607 individuals were included at baseline, of whom 538 participants were followed up at 12 months, 482 at 24 months, 268 at 36 months and 280 at 48 months. Predictive performance was excellent with AUCs ranging from 0.87 to 0.92 when all variable sets were considered. Parsimonious prediction models that still had a good performance with AUC 0.80-0.84 were established, each only including two variable sets. Neuropsychological outcomes were included in all parsimonious models. In addition, biomarker was included at year 1 and year 2, imaging data at year 3 and demographics at year 4. Under our pre-set threshold, the rate of upgrade to more intensive therapies according to predicted cognitive conversion was always higher than according to actual cognitive conversion so as to decrease the false positive rate, indicating the proportion of patients who would have missed upgraded treatment based on prognostic models although they actually needed it.</p><p><strong>Conclusions: </strong>Neurophysiological tests combined with other indicator sets that vary along the AD continuum can improve can provide aid for clinical treatment decisions leading to improved management of the disease.</p><p><strong>Trail registration information: </strong>ClinicalTrials.gov Identifier: NCT00106899 (Registration Date: 31 March 2005).</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"41"},"PeriodicalIF":7.9,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11823042/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143412884","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}
Clemente Humberto Zúñiga, Blanca Isaura Acosta, Rufino Menchaca, Cesar A Amescua, Sean Hong, Lucia Hui, Minchan Gil, Yong-Hee Rhee, Sangwook Yoon, Minji Kim, Paul Y Chang, Yong Man Kim, Paul Y Song, Katia Betito
{"title":"Treatment of Alzheimer's Disease subjects with expanded non-genetically modified autologous natural killer cells (SNK01): a phase I study.","authors":"Clemente Humberto Zúñiga, Blanca Isaura Acosta, Rufino Menchaca, Cesar A Amescua, Sean Hong, Lucia Hui, Minchan Gil, Yong-Hee Rhee, Sangwook Yoon, Minji Kim, Paul Y Chang, Yong Man Kim, Paul Y Song, Katia Betito","doi":"10.1186/s13195-025-01681-2","DOIUrl":"10.1186/s13195-025-01681-2","url":null,"abstract":"<p><strong>Background: </strong>The importance of natural killer (NK) cells of the innate immune system in neurodegenerative disease has largely been overlooked despite studies demonstrating their ability to reduce neuroinflammation (thought to be mediated by the elimination of activated T cells, degradation of protein aggregates and secretion of anti-inflammatory cytokines). SNK01 is an autologous non-genetically modified NK cell product showing increased activity in vitro. We hypothesized that SNK01 can be safely infused to reduce neuroinflammation in Alzheimer's Disease (AD) patients.</p><p><strong>Methods: </strong>SNK01 was produced and characterized for its ability to eliminate activated T cells, degrade protein aggregates and secrete anti-inflammatory cytokines. In this phase 1 study, SNK01 was administered intravenously every three weeks for a total of 4 treatments using a 3 + 3 dose escalation design (1, 2 and 4 × 10<sup>9</sup> cells) in subjects with either mild, moderate, or severe AD (median CDR-SB 10.0). Cognitive assessments and cerebrospinal fluid biomarkers associated with protein aggregation, neurodegeneration and neuroinflammation including amyloid-β42 and 42/40, α-synuclein, total Tau, pTau217 and pTau181, neurofilament light, GFAP and YKL-40 analyses were performed at baseline, at 1 and 12 weeks after the last dose. The primary endpoint was safety; secondary endpoints included changes in cognitive assessments and biomarker levels.</p><p><strong>Results: </strong>In preclinical in vitro studies, SNK01 were able to uptake and degrade the protein aggregates of amyloid-β and α-synuclein, produce anti-inflammatory cytokines and eliminate activated T cells. In the phase 1 clinical study, eleven subjects were enrolled (10 evaluable). No drug-related adverse events were observed. Despite 70% of subjects being treated at relatively low doses of SNK01 (1 and 2 × 10<sup>9</sup> cells), 50-70% of all enrolled subjects had stable/improved CDR-SB, ADAS-Cog and/or MMSE scores and 90% had stable/improved ADCOMS at one-week after the last dose. SNK01 also appeared to have beneficial effects on protein aggregate levels and neuroinflammatory biomarkers in the cerebrospinal fluid, with decreases in pTau181 and GFAP appearing to be dose-dependent.</p><p><strong>Conclusions: </strong>SNK01 was well tolerated and appeared to have clinical activity in AD while also having beneficial effects on cerebrospinal fluid protein and neuroinflammatory biomarker levels. A larger trial with a higher dosing/duration has been initiated in the USA in 2023.</p><p><strong>Trial registration: </strong>www.</p><p><strong>Clinicaltrials: </strong>gov NCT04678453, date of registration: 2020-12-22.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"40"},"PeriodicalIF":7.9,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11817217/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143405455","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}
Bing Xu, Kang Xiao, Xiaoxi Jia, Rundong Cao, Donglin Liang, Ruhan A, Weiwei Zhang, Chunjie Li, Liping Gao, Cao Chen, Qi Shi, Xiaoping Dong
{"title":"β-synuclein in cerebrospinal fluid as a potential biomarker for distinguishing human prion diseases from Alzheimer's and Parkinson's disease.","authors":"Bing Xu, Kang Xiao, Xiaoxi Jia, Rundong Cao, Donglin Liang, Ruhan A, Weiwei Zhang, Chunjie Li, Liping Gao, Cao Chen, Qi Shi, Xiaoping Dong","doi":"10.1186/s13195-025-01688-9","DOIUrl":"10.1186/s13195-025-01688-9","url":null,"abstract":"<p><strong>Background: </strong>β-synuclein (β-syn), mainly expressed in central nerve system, is one of the biomarkers in cerebrospinal fluid (CSF) and blood for synaptic damage, which has been reported to be elevated in CSF and blood of the patients of prion diseases (PrDs).</p><p><strong>Methods: </strong>We analyzed 314 CSF samples from patients in China National Surveillance for CJD. The diagnostic groups of the 223 patients with PrDs included sporadic Creutzfeldt-Jacob disease (sCJD), genetic CJD (gCJD), fatal familial insomnia (FFI) and Gerstmann-Straussler-Scheinker (GSS). 91 patients with non-PrDs comprised Alzheimer's disease (AD), Parkinson's disease (PD), viral encephalitis (VE) or autoimmune encephalitis (AE) were enrolled in the control groups. The CSF β-syn levels were measured by a commercial microfluidic ELISA. The Mann-Whitney U test and Kruskal-Wallis H test were employed to analyze two or more sets of continuous variables. Multiple linear regression was also performed to evaluate the factors for CSF β-syn levels. Receiver operating characteristics (ROC) curves and area under the curve (AUC) values were used to assess the diagnostic performance of β-syn.</p><p><strong>Results: </strong>The median of β-syn levels (2074 pg/ml; IQR: 691 to 4332) of all PrDs was significantly higher than that of non-PrDs group (504 pg/ml; IQR: 126 to 3374). The CSF β-syn values in the cohorts of sCJD, T188K-gCJD, E200K-gCJD and P102L-GSS were remarkably higher than that of the group of AD + PD, but similar as that of the group of VE + AE. The elevated CSF β-syn in sCJD and gCJD cases was statistically associated with CSF 14-3-3 positive and appearance of mutism. ROC curve analysis identified satisfied performance for distinguishing from AD + PD, with high AUC values in sCJD (0.7640), T188K-gCJD (0.8489), E200K-gCJD (0.8548), P102L-GSS (0.7689) and D178N-FFI (0.7210), respectively.</p><p><strong>Conclusion: </strong>Our data here indicate that CSF β-syn is a potential biomarker for distinguishing PrDs (gCJD, sCJD and GSS) from AD and PD, but is much less efficient from VE and AE. These findings have critical implications for early diagnosis and monitoring of synaptic integrity in prion diseases.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"39"},"PeriodicalIF":7.9,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11806663/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143370231","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}
Deepti Putcha, Yuta Katsumi, Alexandra Touroutoglou, Ani Eloyan, Alexander Taurone, Maryanne Thangarajah, Paul Aisen, Jeffrey L Dage, Tatiana Foroud, Clifford R Jack, Joel H Kramer, Kelly N H Nudelman, Rema Raman, Prashanthi Vemuri, Alireza Atri, Gregory S Day, Ranjan Duara, Neill R Graff-Radford, Ian M Grant, Lawrence S Honig, Erik C B Johnson, David T Jones, Joseph C Masdeu, Mario F Mendez, Erik Musiek, Chiadi U Onyike, Meghan Riddle, Emily Rogalski, Stephen Salloway, Sharon Sha, R Scott Turner, Thomas S Wingo, David A Wolk, Kyle Womack, Maria C Carrillo, Gil D Rabinovici, Bradford C Dickerson, Liana G Apostolova, Dustin B Hammers
{"title":"Heterogeneous clinical phenotypes of sporadic early-onset Alzheimer's disease: a neuropsychological data-driven approach.","authors":"Deepti Putcha, Yuta Katsumi, Alexandra Touroutoglou, Ani Eloyan, Alexander Taurone, Maryanne Thangarajah, Paul Aisen, Jeffrey L Dage, Tatiana Foroud, Clifford R Jack, Joel H Kramer, Kelly N H Nudelman, Rema Raman, Prashanthi Vemuri, Alireza Atri, Gregory S Day, Ranjan Duara, Neill R Graff-Radford, Ian M Grant, Lawrence S Honig, Erik C B Johnson, David T Jones, Joseph C Masdeu, Mario F Mendez, Erik Musiek, Chiadi U Onyike, Meghan Riddle, Emily Rogalski, Stephen Salloway, Sharon Sha, R Scott Turner, Thomas S Wingo, David A Wolk, Kyle Womack, Maria C Carrillo, Gil D Rabinovici, Bradford C Dickerson, Liana G Apostolova, Dustin B Hammers","doi":"10.1186/s13195-025-01689-8","DOIUrl":"10.1186/s13195-025-01689-8","url":null,"abstract":"<p><strong>Background: </strong>The clinical presentations of early-onset Alzheimer's disease (EOAD) and late-onset Alzheimer's disease are distinct, with EOAD having a more aggressive disease course with greater heterogeneity. Recent publications from the Longitudinal Early-Onset Alzheimer's Disease Study (LEADS) described EOAD as predominantly amnestic, though this phenotypic description was based solely on clinical judgment. To better understand the phenotypic range of EOAD presentation, we applied a neuropsychological data-driven method to subtype the LEADS cohort.</p><p><strong>Methods: </strong>Neuropsychological test performance from 169 amyloid-positive EOAD participants were analyzed. Education-corrected normative comparisons were made using a sample of 98 cognitively normal participants. Comparing the relative levels of impairment between each cognitive domain, we applied a cut-off of 1 SD below all other domain scores to indicate a phenotype of \"predominant\" impairment in a given cognitive domain. Individuals were otherwise considered to have multidomain impairment. Whole-cortex general linear modeling of cortical atrophy was applied as an MRI-based validation of these distinct clinical phenotypes.</p><p><strong>Results: </strong>We identified 6 phenotypic subtypes of EOAD: Dysexecutive Predominant (22% of sample), Amnestic Predominant (11%), Language Predominant (11%), Visuospatial Predominant (15%), Mixed Amnestic/Dysexecutive Predominant (11%), and Multidomain (30%). These phenotypes did not differ by age, sex, or years of education. The APOE ɛ4 genotype was enriched in the Amnestic Predominant group, who were also rated as least impaired. Cortical thickness analysis validated these clinical phenotypes with dissociations in atrophy patterns observed between the Dysexecutive and Amnestic Predominant groups. In contrast to the heterogeneity observed from our neuropsychological data-driven approach, diagnostic classifications for this same sample based solely on clinical judgment indicated that 82% of individuals were amnestic-predominant, 9% were non-amnestic, 4% met criteria for Posterior Cortical Atrophy, and 5% met criteria for Primary Progressive Aphasia.</p><p><strong>Conclusion: </strong>A neuropsychological data-driven method to phenotype EOAD individuals uncovered a more detailed understanding of the presenting heterogeneity in this atypical AD sample compared to clinical judgment alone. Clinicians and patients may over-report memory dysfunction at the expense of non-memory symptoms. These findings have important implications for diagnostic accuracy and treatment considerations.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"38"},"PeriodicalIF":7.9,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11800584/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143363391","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":"A systematic review and meta-analysis of the impact of transcranial direct current stimulation on cognitive function in older adults with cognitive impairments: the influence of dosage parameters.","authors":"Thatchaya Prathum, Thanwarat Chantanachai, Oranich Vimolratana, Chotica Laksanaphuk, Irin Apiworajirawit, Benchaporn Aneksan, Kanthika Latthirun, Cheng-Ta Yang, Wanalee Klomjai","doi":"10.1186/s13195-025-01677-y","DOIUrl":"10.1186/s13195-025-01677-y","url":null,"abstract":"<p><strong>Introduction: </strong>Numerous studies have demonstrated the effects of transcranial direct current stimulation (tDCS) on cognitive function in the older people. This study further explores the impact of tDCS and its dosage parameters on cognitive enhancement in older people with cognitive impairments.</p><p><strong>Methods: </strong>Randomized controlled trials (RCTs) published through November 2023 were retrieved from databases including PubMed, Scopus, EMBASE, EBSCO, and the Cochrane Library. Participants were older adults with cognitive impairments, including Alzheimer's disease (AD), mild cognitive impairment (MCI), and dementia. AD was diagnosed based on the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV), or the National Institute of Neurological and Communicative Disorders and Stroke - Alzheimer' Disease and Related Disorders Association (NINCDS-ADRDA) criteria. Dementia was diagnosed using the DSM-V or NINCDS-ADRDA criteria, while MCI was diagnosed using the DSM-V, the Petersen criteria, or assessments such as Montreal Cognitive Assessment (MoCA) and Clinical Dementia Rating (CDR). Standardized mean difference (SMD) values were analyzed to assess the effects.</p><p><strong>Results: </strong>A total of 19 RCTs were included. tDCS significantly improved the Mini-Mental State Examination score both immediately post-intervention (SMD = 0.51, p = 0.005) and at follow-up (SMD = 2.29, p = 0.0003). Significant effects were observed when tDCS was used alone (SMD = 0.39, p = 0.04), at current densities <math><mo>≤</mo></math> 0.06 mA/cm<sup>2</sup> (SMD = 0.25, p = 0.04), session durations exceeding 20 min (SMD = 0.89, p = 0.01), up to 15 sessions (SMD = 0.28, p = 0.009), and when an active electrode was placed over the temporal area (SMD = 0.33, p = 0.02). People with AD showed greater improvements compared to those with MCI or dementia (SMD = 0.91, p = 0.02). However, tDCS did not significantly improve memory or executive function.</p><p><strong>Conclusion: </strong>tDCS demonstrated efficacy in enhancing global cognition in older people with cognitive impairments, providing insight into optimal parameters for clinical application. However, no improvement were observed in memory or executive function.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"37"},"PeriodicalIF":7.9,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11796231/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143187926","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":"Multi-omics analyses identify gut microbiota-fecal metabolites-brain-cognition pathways in the Alzheimer's disease continuum.","authors":"Han Zhao, Xia Zhou, Yu Song, Wenming Zhao, Zhongwu Sun, Jiajia Zhu, Yongqiang Yu","doi":"10.1186/s13195-025-01683-0","DOIUrl":"10.1186/s13195-025-01683-0","url":null,"abstract":"<p><strong>Background: </strong>Gut microbiota dysbiosis is linked to Alzheimer's disease (AD), but our understanding of the molecular and neuropathological bases underlying such association remains fragmentary.</p><p><strong>Methods: </strong>Using 16S rDNA amplicon sequencing, untargeted metabolomics, and multi-modal magnetic resonance imaging, we examined group differences in gut microbiome, fecal metabolome, neuroimaging measures, and cognitive variables across 30 patients with AD, 75 individuals with mild cognitive impairment (MCI), and 61 healthy controls (HC). Furthermore, we assessed the associations between these multi-omics changes using correlation and mediation analyses.</p><p><strong>Results: </strong>There were significant group differences in gut microbial composition, which were driven by 8 microbial taxa (e.g., Staphylococcus and Bacillus) exhibiting a progressive increase in relative abundance from HC to MCI to AD, and 2 taxa (e.g., Anaerostipes) showing a gradual decrease. 26 fecal metabolites (e.g., Arachidonic, Adrenic, and Lithocholic acids) exhibited a progressive increase from HC to MCI to AD. We also observed progressive gray matter atrophy in broadly distributed gray matter regions and gradual micro-structural integrity damage in widespread white matter tracts along the AD continuum. Integration of these multi-omics changes revealed significant associations between microbiota, metabolites, neuroimaging, and cognition. More importantly, we identified two potential mediation pathways: (1) microbiota → metabolites → neuroimaging → cognition, and (2) microbiota → metabolites → cognition.</p><p><strong>Conclusion: </strong>Aside from elucidating the underlying mechanism whereby gut microbiota dysbiosis is linked to AD, our findings may contribute to groundwork for future interventions targeting the microbiota-metabolites-brain-cognition pathways as a therapeutic strategy in the AD continuum.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"36"},"PeriodicalIF":7.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11786436/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143073347","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":"Effects of intensive lifestyle changes on the progression of mild cognitive impairment or early dementia due to Alzheimer's disease: the need for rigor.","authors":"Joshua D Grill, Daniel Gillen","doi":"10.1186/s13195-024-01621-6","DOIUrl":"10.1186/s13195-024-01621-6","url":null,"abstract":"<p><p>We consider the recent publication by Ornish and colleagues and the rigor expected for interventional clinical trials. We contend that lifestyle intervention trials should strive for the same rigor as drug trials and highlight opportunities to improve rigor in this example, particularly in design, data analysis, and publication of results for this and other lifestyle intervention studies.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"32"},"PeriodicalIF":7.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11786341/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143073341","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":"Delta-opioid receptor signaling alleviates neuropathology and cognitive impairment in the mouse model of Alzheimer's disease by regulating microglia homeostasis and inhibiting HMGB1 pathway.","authors":"Yuan Xu, Naiyuan Shao, Feng Zhi, Ronghua Chen, Yilin Yang, Jiahui Li, Ying Xia, Ya Peng","doi":"10.1186/s13195-025-01682-1","DOIUrl":"10.1186/s13195-025-01682-1","url":null,"abstract":"<p><strong>Background: </strong>Recent studies suggest that opioid receptor signaling may differentially affect Alzheimer's disease (AD) pathology and the relevant behavioral dysfunctions. However, the precise roles and mechanisms of opioid receptor subtypes in AD pathologies are still unclear with major controversies.</p><p><strong>Methods: </strong>We compared the delta-opioid receptor (DOR)- and mu-opioid receptor (MOR)-mediated effects on AD-associated cognitive deficits, pathologies, neuroinflammations, cell death using transgenic APP/PS1 mouse model and BV2 cell line at behavioral, molecular, and cellular levels. Unpaired t-test and one/two way analysis for variance (ANOVA) were used to analyze statistical significance of the data.</p><p><strong>Results: </strong>We show a distinct role of DOR and its major difference with MOR in AD injury in an APP/PS1 mouse model. DOR activation by UFP-512, but not MOR activation by DAMGO, attenuated cognitive impairment, reduced beta-amyloid (Aβ) production and aggregation, as well as protected the neurons from apoptosis in APP/PS1 mice. DOR and MOR also differentially modulated microglia in APP/PS1 mice and in vitro AD cell model with a DOR-mediated inhibition on the excessive activation of microglia and the release of pro-inflammatory cytokines in AD pathologies. Gene expression profiling further revealed that the alternations in DOR/MOR are closely associated with microglial homeostatic signatures and high mobility group protein B1 (HMGB1) in AD. DOR activation inhibited HMGB1 secretion and its translocation from nuclear to cytoplasm. Our in-vitro studies further confirmed that DOR overexpression mitigated microglial inflammatory response and rescued neurons from AD injury via HMGB1-NF-κB signaling pathway.</p><p><strong>Conclusions: </strong>These novel findings uncover previously unappreciated roles of DOR in neuroprotection against AD injury via modulating microglia-related inflammatory responses.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"35"},"PeriodicalIF":7.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11786345/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143073338","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}
Zi Jin, Xinmin Wang, Ying Lang, Yufeng Song, Huangxiong Zhan, Wuge Shama, Yingying Shen, Guihua Zeng, Faying Zhou, Hongjian Gao, Shuling Ye, Yanjiang Wang, Fan Lu, Meixiao Shen
{"title":"Retinal optical coherence tomography intensity spatial correlation features as new biomarkers for confirmed Alzheimer's disease.","authors":"Zi Jin, Xinmin Wang, Ying Lang, Yufeng Song, Huangxiong Zhan, Wuge Shama, Yingying Shen, Guihua Zeng, Faying Zhou, Hongjian Gao, Shuling Ye, Yanjiang Wang, Fan Lu, Meixiao Shen","doi":"10.1186/s13195-025-01676-z","DOIUrl":"10.1186/s13195-025-01676-z","url":null,"abstract":"<p><strong>Background: </strong>The nature and severity of Alzheimer's disease (AD) pathologies in the retina and brain correspond. However, retinal biomarkers need to be validated in clinical cohorts with confirmed AD biomarkers and optical coherence tomography (OCT). The main objective of this study was to investigate whether retinal metrics measured by OCT aid in the early screening and brain pathology monitoring for confirmed AD.</p><p><strong>Methods: </strong>This was a case-control study. All participants underwent retinal OCT imaging, and neurological examinations, including amyloid-β (Aβ) positron emission tomography. Participants were subdivided into cognitively normal (CN), mild cognitive impairment (MCI), and AD-derived dementia (ADD). Except retinal thickness, we developed the grey level co-occurrence matrix algorithm to extract retinal OCT intensity spatial correlation features (OCT-ISCF), including angular second matrix (ASM), correlation (COR), and homogeneity (HOM), one-way analysis of variance was used to compare the differences in retinal parameters among the groups, and to analyze the correlation with brain Aβ plaques and cognitive scores. The repeatability and robustness of OCT-ISCF were evaluated using experimental and simulation methods.</p><p><strong>Results: </strong>This study enrolled 82 participants, subdivided into 20 CN, 22 MCI, and 40 ADD. Compared with the CN, the thickness of retinal nerve fiber layer and myoid and ellipsoid zone were significantly thinner (P < 0.05), and ASM, COR, and HOM in several retinal sublayers changed significantly in the ADD (P < 0.05). Notably, the MCI showed significant differences in ASM and COR in the outer segment of photoreceptor compared with the CN (P < 0.05). The changing pattern of OCT-ISCF with interclass correlation coefficients above 0.8 differed from that caused by speckle noise, and was affected by OCT image quality index. Moreover, the retinal OCT-ISCF were more strongly correlated with brain Aβ plaque burden and MoCA scores than retinal thickness. The accuracy using retinal OCT-ISCF (AUC = 0.935, 0.830) was better than that using retinal thickness (AUC = 0.795, 0.705) in detecting ADD and MCI.</p><p><strong>Conclusions: </strong>The study demonstrates that retinal OCT-ISCF enhance the association and detection efficacy of AD pathology compared to retinal thickness, suggesting retinal OCT-ISCF have the potential to be new biomarkers for AD.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"33"},"PeriodicalIF":7.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11786474/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143073425","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}