Alzheimer's Research & Therapy最新文献

{"title":"Post-marketing safety concerns with lecanemab: a pharmacovigilance study based on the FDA Adverse Event Reporting System database.","authors":"Xiaoxuan Xing, Xiaotong Zhang, Ke Wang, Zhizhou Wang, Yingnan Feng, Xiaoxi Li, Yiming Hua, Lan Zhang, Xianzhe Dong","doi":"10.1186/s13195-024-01669-4","DOIUrl":"10.1186/s13195-024-01669-4","url":null,"abstract":"<p><strong>Background: </strong>The safety data of lecanemab in the post-marketing period has yet to be fully investigated in the current literature. We aimed to identify and characterise the safety profile of lecanemab in the post-marketing period.</p><p><strong>Methods: </strong>We searched and reviewed the reports submitted to the FDA's Adverse Event Reporting System (FAERS). We used a case/non-case approach to estimate the reporting odds ratio (ROR) and information component (IC) with 95% confidence intervals (CI) for lecanemab-related adverse events (AEs) reported at least four counts. We compared the difference between serious and non-serious reports using non-parametric tests.</p><p><strong>Results: </strong>The FAERS recorded 1,986 lecanemab-related AEs affecting 868 patients. Two hundred and three patients experienced serious AEs, including 22 deaths. The most frequently reported AEs were headache (n = 193), chills (n = 100), fatigue (n = 93), and amyloid-related imaging abnormality-oedema/effusion (ARIA-E) (n = 91). Safety signals were detected, such as headache (ROR: 10.4, 95%CI: 8.97, 12.07; IC: 3.25, 95%CI: 2.97, 3.40), ARIA-E (ROR: 18,299.69, 95%CI: 14,001.27, 23,917.73; IC: 13.37, 95%CI: 6.15, 6.87), and infusion-related reaction (ROR: 35.25, 95CI 27.58, 45.07; IC: 5.09, 95CI 4.15, 4.87). We also identified several new AEs, such as migraine and pancreatic carcinoma. Patients with serious AEs were more likely to be on polypharmacy for Alzheimer's disease and use aspirin, acid-suppressing medications, statins, antidepressants, or benzodiazepines compared to those with non-serious AEs.</p><p><strong>Conclusions: </strong>Lecanemab may have a significant potential for AEs. Our results provide evidence for healthcare professionals and patients to weigh the risks and benefits of lecanemab treatment. Further prospective studies are needed to explore rare and unexpected AEs.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"15"},"PeriodicalIF":7.9,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11708074/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142942494","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":"evoke and evoke+: design of two large-scale, double-blind, placebo-controlled, phase 3 studies evaluating efficacy, safety, and tolerability of semaglutide in early-stage symptomatic Alzheimer's disease.","authors":"Jeffrey L Cummings, Alireza Atri, Howard H Feldman, Oskar Hansson, Mary Sano, Filip K Knop, Peter Johannsen, Teresa León, Philip Scheltens","doi":"10.1186/s13195-024-01666-7","DOIUrl":"10.1186/s13195-024-01666-7","url":null,"abstract":"<p><strong>Background: </strong>Disease-modifying therapies targeting the diverse pathophysiology of Alzheimer's disease (AD), including neuroinflammation, represent potentially important and novel approaches. The glucagon-like peptide-1 receptor agonist semaglutide is approved for the treatment of type 2 diabetes and obesity and has an established safety profile. Semaglutide may have a disease-modifying, neuroprotective effect in AD through multimodal mechanisms including neuroinflammatory, vascular, and other AD-related processes. Large randomized controlled trials are needed to assess the efficacy and safety of semaglutide in early-stage symptomatic AD.</p><p><strong>Methods: </strong>evoke and evoke+ are randomized, double-blind, placebo-controlled phase 3 trials investigating the efficacy, safety, and tolerability of once-daily oral semaglutide versus placebo in early-stage symptomatic AD. Eligible participants were men or women aged 55-85 years with mild cognitive impairment or mild dementia due to AD with confirmed amyloid abnormalities (assessed by positron emission tomography or cerebrospinal fluid [CSF] analysis). After a maximum 12-week screening phase, an anticipated 1840 patients in each trial are randomized (1:1) to semaglutide or placebo for 156 weeks (104-week main treatment phase and 52-week extension). Randomized participants follow an 8-week dose escalation regimen (3 mg [weeks 0-4], 7 mg [weeks 4-8], and 14 mg [weeks 8-156]). The primary endpoint is the semaglutide-placebo difference on change from baseline to week 104 in the Clinical Dementia Rating - Sum of Boxes score. Analyses of plasma biomarkers, collected from all participants, and a CSF sub-study (planned n = 210) will explore semaglutide effects on AD biomarkers and neuroinflammation.</p><p><strong>Results: </strong>Enrollment was undertaken between May 18, 2021, and September 8, 2023. Completion of the trials' main phase is expected in September 2025, and the 52-week extension (in which participants and investigators remain blinded to treatment assignment) will continue to October 2026.</p><p><strong>Conclusion: </strong>evoke and evoke+ are the first large-scale trials to investigate the disease-modifying potential of semaglutide in participants with early-stage symptomatic AD, including exploration of effects on AD biomarkers and neuroinflammation. The trials will provide data on the potential disease-modifying effects of semaglutide and will be important in evaluating its utility in the treatment of early-stage symptomatic AD.</p><p><strong>Trial registration: </strong>Clinicaltrials.gov, NCT04777396 and NCT04777409. Date: 02/03/2021.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"14"},"PeriodicalIF":7.9,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11708093/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142941550","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":"Uncovering the epigenetic regulatory clues of PRRT1 in Alzheimer's disease: a strategy integrating multi-omics analysis with explainable machine learning.","authors":"Fang Wang, Ying Liang, Qin-Wen Wang","doi":"10.1186/s13195-024-01646-x","DOIUrl":"https://doi.org/10.1186/s13195-024-01646-x","url":null,"abstract":"<p><strong>Background: </strong>Alzheimer's disease (AD) is a complex neurodegenerative disorder with a largely unexplored epigenetic landscape.</p><p><strong>Objective: </strong>This study employs an innovative approach that integrates multi-omics analysis and explainable machine learning to explore the epigenetic regulatory mechanisms underlying the epigenetic signature of PRRT1 implicated in AD.</p><p><strong>Methods: </strong>Through comprehensive DNA methylation and transcriptomic profiling, we identified distinct epigenetic signatures associated with gene PRRT1 expression in AD patient samples compared to healthy controls. Utilizing interpretable machine learning models and ELMAR analysis, we dissected the complex relationships between these epigenetic signatures and gene expression patterns, revealing novel regulatory elements and pathways. Finally, the epigenetic mechanisms of these genes were investigated experimentally.</p><p><strong>Results: </strong>This study identified ten epigenetic signatures, constructed an interpretable AD diagnostic model, and utilized various bioinformatics methods to create an epigenomic map. Subsequently, the ELMAR R package was used to integrate multi-omics data and identify the upstream transcription factor MAZ for PRRT1. Finally, experiments confirmed the interaction between MAZ and PRRT1, which mediated apoptosis and autophagy in AD.</p><p><strong>Conclusion: </strong>This study adopts a strategy that integrates bioinformatics analysis with molecular experiments, providing new insights into the epigenetic regulatory mechanisms of PRRT1 in AD and demonstrating the importance of explainable machine learning in elucidating complex disease mechanisms.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"12"},"PeriodicalIF":7.9,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11706112/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142942499","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":"Variables associated with cognitive function: an exposome-wide and mendelian randomization analysis.","authors":"Yong-Li Zhao, Yi-Ning Hao, Yi-Jun Ge, Yi Zhang, Lang-Yu Huang, Yan Fu, Dan-Dan Zhang, Ya-Nan Ou, Xi-Peng Cao, Jian-Feng Feng, Wei Cheng, Lan Tan, Jin-Tai Yu","doi":"10.1186/s13195-025-01670-5","DOIUrl":"https://doi.org/10.1186/s13195-025-01670-5","url":null,"abstract":"<p><strong>Background: </strong>Evidence indicates that cognitive function is influenced by potential environmental factors. We aimed to determine the variables influencing cognitive function.</p><p><strong>Methods: </strong>Our study included 164,463 non-demented adults (89,644 [54.51%] female; mean [SD] age, 56.69 [8.14] years) from the UK Biobank who completed four cognitive assessments at baseline. 364 variables were finally extracted for analysis through a rigorous screening process. We performed univariate analyses to identify variables significantly associated with each cognitive function in two equal-sized split discovery and replication datasets. Subsequently, the identified variables in univariate analyses were further assessed in a multivariable model. Additionally, for the variables identified in multivariable model, we explored the associations with longitudinal cognitive decline. Moreover, one- and two- sample Mendelian randomization (MR) analyses were conducted to confirm the genetic associations. Finally, the quality of the pooled evidence for the associations between variables and cognitive function was evaluated.</p><p><strong>Results: </strong>252 variables (69%) exhibited significant associations with at least one cognitive function in the discovery dataset. Of these, 231 (92%) were successfully replicated. Subsequently, our multivariable analyses identified 41 variables that were significantly associated with at least one cognitive function, spanning categories such as education, socioeconomic status, lifestyle factors, body measurements, mental health, medical conditions, early life factors, and household characteristics. Among these 41 variables, 12 were associated with more than one cognitive domain, and were further identified in all subgroup analyses. And LASSO, rigde, and principal component analysis indicated the robustness of the primary results. Moreover, among these 41 variables, 12 were significantly associated with a longitudinal cognitive decline. Furthermore, 22 were supported by one-sample MR analysis, and 5 were further confirmed by two-sample MR analysis. Additionally, the quality of the pooled evidence for the associations between 10 variables and cognitive function was rated as high. Based on these 10 identified variables, adopting a more favorable lifestyle was significantly associated with 38% and 34% decreased risks of dementia and Alzheimer's disease (AD).</p><p><strong>Conclusion: </strong>Overall, our study constructed an evidence database of variables associated with cognitive function, which could contribute to the prevention of cognitive impairment and dementia.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"13"},"PeriodicalIF":7.9,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11706180/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142942502","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":"Neuronal CD59 isoforms IRIS-1 and IRIS-2 as regulators of neurotransmitter release with implications for Alzheimer's disease.","authors":"Ewelina Golec, Robin Olsson, Emre Can Tuysuz, Maja Karlsson, Yasmin Serjieh, Ben C King, Malin Wennström, Anna M Blom","doi":"10.1186/s13195-024-01660-z","DOIUrl":"https://doi.org/10.1186/s13195-024-01660-z","url":null,"abstract":"<p><p>We have previously demonstrated that the intracellular, non-GPI anchored CD59 isoforms IRIS-1 and IRIS-2 (Isoforms Rescuing Insulin Secretion 1 and 2) are necessary for insulin secretion from pancreatic β-cells. While investigating their expression across human tissues, we identified IRIS-1 and IRIS-2 mRNA in the human brain, though their protein expression and function remained unclear. This study shows the presence of both IRIS-1 and 2 proteins in the human brain, specifically in neurons and astrocytes. In the neuroblastoma cell line (SH-SY5Y), both isoforms are intracellular, and their expression increases upon differentiation into mature neurons. Silencing IRIS-1 and 2 in SH-SY5Y cells reduces the SNARE complex formation, essential for synaptic vesicle exocytosis, leading to a reduction in noradrenaline secretion. Notably, we observed diminished expression of neuronal IRIS-1 and 2 in patients with Alzheimer's disease (AD) and non-demented individuals with type 2 diabetes (T2D). In SH-SY5Y cells, knockdown of all isoforms of CD59 including IRIS-1 and 2 not only elevates phosphorylated tau but also increases cyclin-dependent kinase 5 (CDK5) expression, known promoter of hyperphosphorylation and accumulation of tau, a key pathological feature of AD. Additionally, we found that prolonged exposure to high glucose or cytokines markedly reduces the expression of IRIS-1 and 2 in SH-SY5Y cells, suggesting a link between AD pathology and metabolic stress through modulation of these isoforms.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"11"},"PeriodicalIF":7.9,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11705862/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142942469","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":"Subjective cognitive decline predicts longitudinal neuropsychological test performance in an unsupervised online setting in the Brain Health Registry.","authors":"Jae Myeong Kang, Manchumad Manjavong, Chengshi Jin, Adam Diaz, Miriam T Ashford, Joseph Eichenbaum, Emily Thorp, Elizabeth Wragg, Kenton H Zavitz, Francesca Cormack, Anna Aaronson, R Scott Mackin, Rachana Tank, Bernard Landavazo, Erika Cavallone, Diana Truran, Sarah Tomaszewski Farias, Michael W Weiner, Rachel L Nosheny","doi":"10.1186/s13195-024-01641-2","DOIUrl":"https://doi.org/10.1186/s13195-024-01641-2","url":null,"abstract":"<p><strong>Backgrounds: </strong>Digital, online assessments are efficient means to detect early cognitive decline, but few studies have investigated the relationship between remotely collected subjective cognitive change and cognitive decline. We hypothesized that the Everyday Cognition Scale (ECog), a subjective change measure, predicts longitudinal change in cognition in the Brain Health Registry (BHR), an online registry for neuroscience research.</p><p><strong>Methods: </strong>This study included BHR participants aged 55 + who completed both the baseline ECog and repeated administrations of the CANTAB^® Paired Associates Learning (PAL) visual learning and memory test. Both self-reported ECog (Self-ECog) and study partner-reported ECog (SP-ECog), and two PAL scores (first attempt memory score [FAMS] and total errors adjusted [TEA]) were assessed. We estimated associations between multiple ECog scoring outputs (ECog positive [same or above cut-off score], ECog consistent [report of consistent decline in any item], and total score) and longitudinal change in PAL. Additionally we assessed the ability of ECog to identify 'decliners', who exhibited the worst PAL progression slopes corresponding to the fifth percentile and below.</p><p><strong>Results: </strong>Participants (n = 16,683) had an average age of 69.07 ± 7.34, 72.04% were female, and had an average of 16.66 ± 2.26 years of education. They were followed for an average of 2.52 ± 1.63 visits over a period of 11.49 ± 11.53 months. Both Self-ECog positive (estimate = -0.01, p < 0.001, R²m = 0.56) and Self-ECog consistent (estimate=-0.01, p = 0.002, R²m = 0.56) were associated with longitudinal change in PAL FAMS after adjusting demographics and clinical confounders. Those who were Self-ECog total (Odds ratio [95% confidence interval] = 1.390 [1.121-1.708]) and SP-ECog consistent (2.417 [1.591-3.655]) had higher probability of being decliners based on PAL FAMS.</p><p><strong>Conclusion: </strong>In the BHR's unsupervised online setting, baseline subjective change was feasible in predicting longitudinal decline in neuropsychological tests. Online, self-administered measures of subjective cognitive change might have a potential to predict objective subjective change and identify individuals with cognitive impairments.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"10"},"PeriodicalIF":7.9,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11706033/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142942497","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":"Integrative multiomics reveals common endotypes across PSEN1, PSEN2, and APP mutations in familial Alzheimer's disease.","authors":"Phoebe Valdes, Andrew B Caldwell, Qing Liu, Michael Q Fitzgerald, Srinivasan Ramachandran, Celeste M Karch, Douglas R Galasko, Shauna H Yuan, Steven L Wagner, Shankar Subramaniam","doi":"10.1186/s13195-024-01659-6","DOIUrl":"10.1186/s13195-024-01659-6","url":null,"abstract":"<p><strong>Background: </strong>PSEN1, PSEN2, and APP mutations cause Alzheimer's disease (AD) with an early age at onset (AAO) and progressive cognitive decline. PSEN1 mutations are more common and generally have an earlier AAO; however, certain PSEN1 mutations cause a later AAO, similar to those observed in PSEN2 and APP.</p><p><strong>Methods: </strong>We examined whether common disease endotypes exist across these mutations with a later AAO (~ 55 years) using hiPSC-derived neurons from familial Alzheimer's disease (FAD) patients harboring mutations in PSEN1^A79V, PSEN2^N141I, and APP^V717I and mechanistically characterized by integrating RNA-seq and ATAC-seq.</p><p><strong>Results: </strong>We identified common disease endotypes, such as dedifferentiation, dysregulation of synaptic signaling, repression of mitochondrial function and metabolism, and inflammation. We ascertained the master transcriptional regulators associated with these endotypes, including REST, ASCL1, and ZIC family members (activation), and NRF1 (repression).</p><p><strong>Conclusions: </strong>FAD mutations share common regulatory changes within endotypes with varying severity, resulting in reversion to a less-differentiated state. The regulatory mechanisms described offer potential targets for therapeutic interventions.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"5"},"PeriodicalIF":7.9,"publicationDate":"2025-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11699654/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142926268","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 cerebral blood flow response to neuroactivation is reduced in cognitively normal men with β-amyloid accumulation.","authors":"Mark Bitsch Vestergaard, Aftab Bakhtiari, Merete Osler, Erik Lykke Mortensen, Ulrich Lindberg, Ian Law, Martin Lauritzen, Krisztina Benedek, Henrik Bo Wiberg Larsson","doi":"10.1186/s13195-024-01652-z","DOIUrl":"10.1186/s13195-024-01652-z","url":null,"abstract":"<p><strong>Background: </strong>Accumulation of β-amyloid (Aβ) in the brain is a hallmark of Alzheimer's Disease (AD). Cerebral deposition of Aβ initiates deteriorating pathways which eventually can lead to AD. However, the exact mechanisms are not known. A possible pathway could be that Aβ affects the cerebral vessels, causing inadequate cerebrovascular function. In the present study, we examined if Aβ accumulation is associated with a reduced cerebral blood flow response (CBF) to neuronal activation by visual stimulation (ΔCBF_Vis.Act.) in cognitively normal subjects from the Metropolit Danish Male Birth Cohort.</p><p><strong>Methods: </strong>64 subjects participated in the present study. ΔCBF_Vis.Act. was measured using arterial spin labelling (ASL) combined with blood-oxygen-level-dependent (BOLD) MRI. Neuronal activation was obtained by visual stimulation by a flickering checkerboard presented on a screen in the MRI-scanner. Brain Aβ accumulation and cerebral glucose metabolism were assessed by PET imaging using the radiotracers [¹¹C]Pittsburgh Compound-B (PiB) and [¹⁸F]Fluorodeoxyglucose (FDG), respectively. Cortical thickness was measured from structural MRI.</p><p><strong>Results: </strong>ΔCBF_Vis.Act. correlated negatively ( <math><mi>β</mi></math> = -32.1 [95% confidence interval (CI): -60.2; -4.1], r = -0.30, p = 0.025) with PiB standardized uptake value ratio (SUVr) in the brain regions activated by visual stimulation. ΔCBF_Vis.Act. did not correlate with FDG SUVr ( <math><mi>β</mi></math> = 1.9 [CI: -23.8; 27.6], r = 0.02, p = 0.88) or cortical thickness ( <math><mi>β</mi></math> = 10.3 [CI: -8.4; 29.0], r = 0.15, p = 0.27) in the activated brain regions. Resting CBF did not correlate with PiB SUVr neither in the regions activated by visual stimulation ( <math><mi>β</mi></math> = -17.8 [CI:-71.9; 36.2], r =- 0.09, p = 0.51) nor in the remaining cortex ( <math><mi>β</mi></math> = 5.2 [CI:-3.9; 14.2], r = 0.15, p = 0.26).</p><p><strong>Conclusion: </strong>We found a correlation between high PiB SUVr and reduced CBF response to neuronal activation, indicating a link between Aβ accumulation and impaired cerebrovascular function. The impairment was not associated with cortical thinning or hypometabolism, suggesting that Aβ accumulation affecting brain vessel function could be a very early pathology leading to neurodegenerative disease.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"4"},"PeriodicalIF":7.9,"publicationDate":"2025-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11699738/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142926198","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":"Transcriptomic predictors of rapid progression from mild cognitive impairment to Alzheimer's disease.","authors":"Yi-Long Huang, Tsung-Hsien Tsai, Zhao-Qing Shen, Yun-Hsuan Chan, Chih-Wei Tu, Chien-Yi Tung, Pei-Ning Wang, Ting-Fen Tsai","doi":"10.1186/s13195-024-01651-0","DOIUrl":"10.1186/s13195-024-01651-0","url":null,"abstract":"<p><strong>Background: </strong>Effective treatment for Alzheimer's disease (AD) remains an unmet need. Thus, identifying patients with mild cognitive impairment (MCI) who are at high-risk of progressing to AD is crucial for early intervention.</p><p><strong>Methods: </strong>Blood-based transcriptomics analyses were performed using a longitudinal study cohort to compare progressive MCI (P-MCI, n = 28), stable MCI (S-MCI, n = 39), and AD patients (n = 49). Statistical DESeq2 analysis and machine learning methods were employed to identify differentially expressed genes (DEGs) and develop prediction models.</p><p><strong>Results: </strong>We discovered a remarkable gender-specific difference in DEGs that distinguish P-MCI from S-MCI. Machine learning models achieved high accuracy in distinguishing P-MCI from S-MCI (AUC 0.93), AD from S-MCI (AUC 0.94), and AD from P-MCI (AUC 0.92). An 8-gene signature was identified for distinguishing P-MCI from S-MCI.</p><p><strong>Conclusions: </strong>Blood-based transcriptomic biomarker signatures show great utility in identifying high-risk MCI patients, with mitochondrial processes emerging as a crucial contributor to AD progression.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"3"},"PeriodicalIF":7.9,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11697870/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142926305","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":"Cerebrospinal fluid β2-microglobulin promotes the tau pathology through microglia-astrocyte communication in Alzheimer's disease.","authors":"Zehu Sheng, Lanyang Wang, Ming Chen, Fuxin Zhong, Shijing Wu, Shuyu Liang, Jiaqi Song, Lihua Chen, Yingxi Chen, Shiyu Chen, Weihua Yu, Yang Lü","doi":"10.1186/s13195-024-01665-8","DOIUrl":"10.1186/s13195-024-01665-8","url":null,"abstract":"<p><strong>Background: </strong>Cerebrospinal fluid (CSF) β2-microglobulin (β2M) has been demonstrated as an important factor in β-amyloid (Aβ) neurotoxicity and a potential target for Alzheimer's disease (AD). However, more investigation is required to ascertain the relationship between β2M and glial activities in AD pathogenesis.</p><p><strong>Methods: </strong>In this study, 211 participants from the Alzheimer's disease Neuroimaging Initiative (ADNI) with CSF and Plasma β2M, CSF glial fibrillary acidic protein (GFAP), soluble triggering receptor expressed on myeloid cells 2 (sTREM2), Aβ₄₂, phosphorylated-tau (P-tau) and total tau (T-tau) were divided into four groups, stage 0, 1, 2, and suspected non-AD pathology (SNAP) based on the National Institute on Aging- Alzheimer's Association (NIA-AA) criteria. Multiple linear regression, linear mixed effects models, and causal mediation analyses bootstrapped 10,000 iterations were used to investigate the underlying associations among β2M and CSF biomarkers at baseline and during a longitudinal visit.</p><p><strong>Results: </strong>CSF β2M concentration decreased with amyloid in stage 1 compared with stage 0 and increased with tau pathology and neurodegeneration in stage 2 and SNAP compared with stage 1. Moreover, CSF β2M level was positively correlated with the Aβ₄₂ (β = 0.230), P-tau (β = 0.564), T-tau (β = 0.603), GFAP (β = 0.552), and sTREM2 (β = 0.641) (all P < 0.001). CSF β2M was only longitudinally correlated with T-tau change. The correlation of CSF β2M with P-tau (proportion = 25.4%, P < 0.001) and T-tau (proportion = 26.7%, P < 0.001) was partially mediated by GFAP in total participants, reproduced in late-life individuals. Furthermore, the astrocyte cascade also partially mediated the pathological relationship between CSF β2M and tau pathology (β2M → GFAP → YKL-40 → P-tau/T-tau, IE: 0.424-0.435, all P < 0.001). Nevertheless, the mediation effects of sTREM2 were not significant. Additionally, there was no association between plasma β2M and CSF biomarkers.</p><p><strong>Conclusions: </strong>CSF β2M is dynamic in AD pathology and associated with neuroinflammation. CSF GFAP might mediate the association between β2M and tau pathology, complementing the existing research on the effect of β2M in AD pathology and providing a new perspective on treatment.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"2"},"PeriodicalIF":7.9,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11697900/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142920336","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}