Alzheimer's Research & Therapy最新文献

{"title":"Timing of risk factors, prodromal features, and comorbidities of dementia from a large health claims case-control study.","authors":"Stefan Teipel, Manas Akmatov, Bernhard Michalowsky, Steffi Riedel-Heller, Jens Bohlken, Jakob Holstiege","doi":"10.1186/s13195-024-01662-x","DOIUrl":"10.1186/s13195-024-01662-x","url":null,"abstract":"<p><strong>Background: </strong>Many risk factors for dementia have been identified, but the timing of risk is less well understood. Here, we analyzed risk factors in a case-control study covering 10 years before an incident dementia diagnosis.</p><p><strong>Methods: </strong>We designed a case-control study using insurance claims of outpatient consultations of patients with German statutory health insurance between January 1, 2012, and December 31, 2022. We included patients with an incident diagnosis of dementia and controls without a diagnosis of dementia matched 1:2 for age, sex, region, and earliest year of outpatient encounter. We selected exposures based on previous systematic reviews, case-control and cohort studies reporting on risk factors, comorbidities, and prodromal features of dementia. We calculated the prevalence of risk factors in cases and controls and odds ratios for each year before the index date, along with Bonferroni-corrected confidence intervals, using conditional logistic regression.</p><p><strong>Results: </strong>We identified a total of 1,686,759 patients with incident dementia (mean (SD) age, 82.15 (6.90) years; 61.70% female) and 3,373,518 matched controls (mean (SD) age, 82.15 (6.90) years; 61.70% female). Study participants were followed up for a mean (SD) of 6.6 (2.3) years. Of the 63 risk factors and prodromal features examined, 56 were associated with an increased risk of dementia in all years during the 10th and the 1st year before the index date. These included established risk factors, such as depression, hypertension, hearing impairment, nicotine and alcohol abuse, obesity, hypercholesterolaemia, traumatic brain injury, and diabetes. The greatest risk, with odds ratios greater than 2.5, was conferred by delirium, memory impairment, mental retardation, personality and behavioral disorders, sensory disorders, schizophrenia, and psychosis. Cancer was associated with a reduced risk of dementia.</p><p><strong>Conclusions: </strong>This large case-control study confirmed established risk factors of dementia. In addition, the study identified non-specific diagnoses that showed a steep increase in risk close to the index date, such as psychosis, conduct disorder, and other sensory disorders. Consideration of these diagnoses, which may represent prodromal features rather than risk factors for dementia, may help to identify people with dementia in routine care.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"22"},"PeriodicalIF":7.9,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11736938/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142998420","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":"Exome sequencing reveals a rare damaging variant in GRIN2C in familial late-onset Alzheimer's disease.","authors":"Elisa Rubino, Maria Italia, Elisa Giorgio, Silvia Boschi, Paola Dimartino, Tommaso Pippucci, Fausto Roveta, Clara Maria Cambria, Gabriella Elia, Andrea Marcinnò, Salvatore Gallone, Ekaterina Rogaeva, Flavia Antonucci, Alfredo Brusco, Fabrizio Gardoni, Innocenzo Rainero","doi":"10.1186/s13195-024-01661-y","DOIUrl":"10.1186/s13195-024-01661-y","url":null,"abstract":"<p><strong>Background: </strong>Alzheimer's disease (AD) is a progressive neurodegenerative disorder with both genetic and environmental factors contributing to its pathogenesis. While early-onset AD has well-established genetic determinants, the genetic basis for late-onset AD remains less clear. This study investigates a large Italian family with late-onset autosomal dominant AD, identifying a novel rare missense variant in GRIN2C gene associated with the disease, and evaluates the functional impact of this variant.</p><p><strong>Methods: </strong>Affected and unaffected members from a Northern Italian family were included. Genomic DNA from family members was extracted and initially screened for pathogenic mutations in APP, PSEN1, and PSEN2, and screened for 77 genes associated with neurodegenerative conditions using NeuroX array assay. Exome sequencing was performed on three affected individuals and two healthy relatives. Bioinformatics analyses were conducted. Functional analysis was performed using primary neuronal cultures, and the impact of the variant was assessed through immunocytochemistry and electrophysiology.</p><p><strong>Results: </strong>Pathogenic variants were not identified in APP, PSEN1, or PSEN2, nor in the 77 genes in NeuroX array assay. Exome Sequencing revealed the c.3215C > T p.(A1072V) variant in GRIN2C gene (NM 000835.6), encoding for the glutamate ionotropic receptor N-methyl-D-aspartate receptor (NMDA) type subunit 2C (GluN2C). This variant segregated in 6 available AD patients in the family and was absent in 9 healthy relatives. Primary rat hippocampal neurons overexpressing GluN2C^A1072V showed an increase in NMDAR-induced currents, suggesting altered glutamatergic transmission. Surface expression assays demonstrated an elevated surface/total ratio of the mutant GluN2C, correlating with the increased NMDAR current. Additionally, immunocytochemistry revealed in neurons expressing the mutant variant a reduced colocalization between the GluN2C subunit and 14-3-3 proteins, which are known to facilitate membrane trafficking of NMDARs.</p><p><strong>Discussion: </strong>We identified a rare missense variant in GRIN2C associated with late-onset autosomal dominant Alzheimer's disease. These findings highlight the role of GluN2C-containing NMDARs in glutamatergic signaling and their potential contribution to AD pathogenesis.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"21"},"PeriodicalIF":7.9,"publicationDate":"2025-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11730494/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142982492","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":"CEST imaging combined with ¹H-MRS reveal the neuroprotective effects of riluzole by improving neurotransmitter imbalances in Alzheimer's disease mice.","authors":"Yuanyu Shen, Xiaolei Zhang, Siqi Liu, Lijing Xin, Wentao Xuan, Caiyu Zhuang, Yue Chen, Beibei Chen, Xinhui Zheng, Renhua Wu, Yan Lin","doi":"10.1186/s13195-025-01672-3","DOIUrl":"10.1186/s13195-025-01672-3","url":null,"abstract":"<p><strong>Background: </strong>The imbalance of glutamate (Glu) and gamma-aminobutyric acid (GABA) neurotransmitter system plays a crucial role in the pathogenesis of Alzheimer's disease (AD). Riluzole is a Glu modulator originally approved for amyotrophic lateral sclerosis that has shown potential neuroprotective effects in various neurodegenerative disorders. However, whether riluzole can improve Glu and GABA homeostasis in AD brain and its related mechanism of action remain unknown. This study utilized chemical exchange saturation transfer (CEST) imaging combined with proton magnetic resonance spectroscopy (¹H-MRS) to monitor the dynamic changes of Glu and GABA in riluzole-treated AD mice, aiming to evaluate the efficacy and mechanism of riluzole in AD treatment.</p><p><strong>Methods: </strong>GluCEST, GABACEST and ¹H-MRS were used to longitudinally monitor Glu and GABA levels in 3xTg AD mice treated with riluzole (12.5 mg/kg/day) or vehicle for 20 weeks. Magnetic resonance measurements were performed at baseline, 6, 12, and 20 weeks post-treatment. Cognitive performance was assessed using the Morris Water Maze (MWM) at baseline, 10, and 20 weeks. At the study endpoint, immunohistochemistry, Nissl staining, and Western blot were used to evaluate the brain pathology, neuronal survival, and protein expression.</p><p><strong>Results: </strong>GluCEST, GABACEST and ¹H-MRS consistently revealed higher levels of Glu and GABA in the brain of riluzole-treated AD mice compared to untreated controls, which were associated with improvements in spatial learning and memory. The cognitive improvements significantly correlated with the increased GluCEST signals and Glu levels. Immunohistochemistry and Nissl staining demonstrated that riluzole treatment reduced amyloid-beta (Aβ) deposition, tau hyperphosphorylation, GFAP-positive astrocyte activation, and prevented neuronal loss. Moreover, riluzole upregulated the expression of excitatory amino acid transporter 2 (EAAT2), glutamic acid decarboxylase 65/67 (GAD65/67), and glutamine synthetase (GS), suggesting enhanced neurotransmitter metabolism.</p><p><strong>Conclusions: </strong>CEST imaging combined with ¹H-MRS demonstrated the effectiveness of riluzole in modulating Glu- and GABA-related changes and improving cognitive function in 3xTg AD mice, potentially through regulating key proteins involved in neurotransmitter metabolism. These findings suggest riluzole as a therapeutic agent for Alzheimer's disease and highlight the utility of multimodal MR imaging in monitoring treatment response and exploring disease mechanisms.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"20"},"PeriodicalIF":7.9,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11726951/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142977101","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":"Association and multimodal model of retinal and blood-based biomarkers for detection of preclinical Alzheimer's disease.","authors":"Swetha Ravichandran, Peter J Snyder, Jessica Alber, Charles F Murchison, Lauren E Chaby, Andreas Jeromin, Edmund Arthur","doi":"10.1186/s13195-024-01668-5","DOIUrl":"10.1186/s13195-024-01668-5","url":null,"abstract":"<p><strong>Background: </strong>The potential diagnostic value of plasma amyloidogenic beta residue 42/40 ratio (Aβ42/Aβ40 ratio), neurofilament light (NfL), tau phosphorylated at threonine-181 (p-tau181), and threonine-217 (p-tau217) has been extensively discussed in the literature. We have also previously described the association between retinal biomarkers and preclinical Alzheimer's disease (AD). The goal of this study was to evaluate the association, and a multimodal model of, retinal and plasma biomarkers for detection of preclinical AD.</p><p><strong>Methods: </strong>We included 82 cognitively unimpaired (CU) participants (141 eyes; mean age: 67 years; range: 56-80) from the Atlas of Retinal Imaging in Alzheimer's Study (ARIAS). Blood samples were assessed for concentrations of Aβ42/Aβ40 ratio, NfL, p-tau181, and p-tau217 (ALZpath, Inc.) using Single molecule array (SIMOA) technology. The Spectralis II system (Heidelberg Engineering) was used to acquire macular centered Spectral Domain Optical Coherence Tomography (SD-OCT) images for evaluation of putative retinal gliosis surface area and macular retinal nerve fiber layer (mRNFL) thickness. For all participants, correlations (adjusted for age and correlation between eyes) were assessed between retinal and blood-based biomarkers. A subgroup cohort of 57 eyes from 32 participants with recent Aβ positron emission tomography (PET) results, comprising 18 preclinical patients (Aβ PET + ve, 32 eyes) and 14 controls (Aβ PET -ve, 25 eyes) with a mean age of 69 vs. 66, p = 0.06, was included for the assessment of a multimodal model to distinguish between the two groups. For this subgroup cohort, receiver operating characteristic (ROC) analysis was performed to compare the multimodal model of retinal and plasma biomarkers vs. each biomarker alone to distinguish between the two groups.</p><p><strong>Results: </strong>Significant correlation was found between putative retinal gliosis and p-tau217 in the univariate mixed model (β = 0.48, p = 0.007) but not for the other plasma biomarkers (p > 0.05). This positive correlation was also retained in the multivariate mixed model (β = 0.43, p = 0.022). The multimodal ROC model based on retinal (gliosis area, inner inferior RNFL thickness, inner superior RNFL thickness, and inner nasal RNFL thickness) and plasma biomarkers (p-tau217 and Aβ42/Aβ40 ratio) had an excellent AUC of 0.97 (95% CI = 0.93-1.01; p < 0.001) compared to unimodal models of retinal and plasma biomarkers.</p><p><strong>Conclusions: </strong>Our analyses show the potential of integrating retinal and blood-based biomarkers for improved detection and screening of preclinical AD.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"19"},"PeriodicalIF":7.9,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11720872/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142963338","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":"Association of antihypertensive drug target genes with alzheimer's disease: a mendelian randomization study.","authors":"He Zheng, Chaolei Chen, Yingqing Feng","doi":"10.1186/s13195-025-01671-4","DOIUrl":"10.1186/s13195-025-01671-4","url":null,"abstract":"<p><strong>Background: </strong>Epidemiological and genetic studies have elucidated associations between antihypertensive medication and Alzheimer's disease (AD), with the directionality of these associations varying upon the specific class of antihypertensive agents.</p><p><strong>Methods: </strong>Genetic instruments for the expression of antihypertensive drug target genes were identified using expression quantitative trait loci (eQTL) in blood, which are associated with systolic blood pressure (SBP). Exposure was derived from existing eQTL data in blood from the eQTLGen consortium and in the brain from the PsychENCODE and subsequently replicated in GTEx V8 and BrainMeta V2. We performed two-sample Mendelian randomization (MR) to estimate the potential effect of different antihypertensive drug classes on AD using summary statistics from a meta-analysis (111,326 cases and 677,663 controls) and further replicated in FinnGen cohorts (9301 cases and 367,976 controls). The reverse causality detection, assessing horizontal pleiotropy, Bayesian co-localization, phenotype scanning, and protein quantitative trait loci (pQTL) analysis were implemented to consolidate the MR findings further.</p><p><strong>Results: </strong>A 1-standard deviation (SD) lower expression of the angiotensin-converting enzyme (ACE) gene in blood was associated with a lower SBP of 3.92 (95% confidence interval (CI), 2.69-5.15) mmHg but an increased risk of AD (odds ratio (OR), 2.46; 95% CI, 1.82-3.33). A similar direction of association was also observed between ACE expression in prefrontal cortex (OR, 1.19; 95% CI, 1.10-1.28), frontal cortex (OR, 1.19; 95% CI, 1.11-1.27), cerebellum (OR, 1.13; 95% CI, 1.09-1.17), cortex (OR, 1.59; 95% CI, 1.33-1.28) and ACE protein levels in plasma (OR, 1.13; 95% CI, 1.09-1.17) and AD risk. Colocalization supports these results. Similar results were found in external validation. We found no evidence for an association between genetically estimated blood pressure (BP) and AD risk.</p><p><strong>Conclusions: </strong>There findings suggest an adverse association of lower ACE messenger RNA and protein levels with an elevated risk of AD, irrespective of its BP-lowering effects. These findings warrant greater pharmacovigilance and further investigation into the effect of ACE inhibitors, particularly those that are centrally acting, on neurodegenerative symptoms in patients with AD.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"18"},"PeriodicalIF":7.9,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11720623/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142963345","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":"Neuropathological contributions to grey matter atrophy and white matter hyperintensities in amnestic dementia.","authors":"Diana Ortega-Cruz, Alberto Rabano, Bryan A Strange","doi":"10.1186/s13195-024-01633-2","DOIUrl":"10.1186/s13195-024-01633-2","url":null,"abstract":"<p><strong>Background: </strong>Dementia patients commonly present multiple neuropathologies, worsening cognitive function, yet structural neuroimaging signatures of dementia have not been positioned in the context of combined pathology. In this study, we implemented an MRI voxel-based approach to explore combined and independent effects of dementia pathologies on grey and white matter structural changes.</p><p><strong>Methods: </strong>In 91 amnestic dementia patients with post-mortem brain donation, grey matter density and white matter hyperintensity (WMH) burdens were obtained from pre-mortem MRI and analyzed in relation to Alzheimer's, vascular, Lewy body, TDP-43, and hippocampal sclerosis (HS) pathologies. After exploring co-occurrence profiles of these pathologies, voxel-based morphometry was implemented to determine their joint and independent effects on grey matter loss. The impact of these pathologies on WMH burden was then evaluated both in spatial and quantitative combined analyses, using voxel-based and generalized linear models respectively.</p><p><strong>Results: </strong>86.8% of patients in this cohort presented more than one pathology. The combined structural effect of these pathologies was a focal impact on hippocampal grey matter atrophy, primarily driven by HS and Alzheimer's pathology (family-wise error corrected, p < 0.05), which also exhibited the strongest individual effects (uncorrected, p < 0.001). WMHs, predominant in middle and anterior cerebral portions, were most strongly associated with vascular (T = 2.47, p = 0.017) and tau pathologies (T = 2.09, p = 0.041).</p><p><strong>Conclusions: </strong>The mixed associations of these dementia neuroimaging hallmarks are relevant for the fine-tuning of diagnostic protocols and underscore the need for comprehensive pathology evaluations in the study of dementia phenotypes.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"16"},"PeriodicalIF":7.9,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11714914/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142942472","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":"Brain iron deposition and cognitive decline in patients with cerebral small vessel disease : a quantitative susceptibility mapping study.","authors":"Yian Gao, Changhu Liang, Qihao Zhang, Hangwei Zhuang, Chaofan Sui, Nan Zhang, Mengmeng Feng, Haotian Xin, Lingfei Guo, Yi Wang","doi":"10.1186/s13195-024-01638-x","DOIUrl":"10.1186/s13195-024-01638-x","url":null,"abstract":"<p><strong>Background: </strong>Quantitative susceptibility mapping (QSM) can study the susceptibility values of brain tissue which allows for noninvasive examination of local brain iron levels in both normal and pathological conditions.</p><p><strong>Purpose: </strong>Our study compares brain iron deposition in gray matter (GM) nuclei between cerebral small vessel disease (CSVD) patients and healthy controls (HCs), exploring factors that affect iron deposition and cognitive function.</p><p><strong>Materials and methods: </strong>A total of 321 subjects were enrolled in this study. All subjects had cognitive examination including the Stroop color word test (SCWT) and MRI including multiecho gradient echo (mGRE) sequence. The patients with CSVD were divided into mild to moderate group (CSVD-M, total CSVD score ≤ 1) and severe group (CSVD-S, total CSVD score > 1). Morphology-enabled dipole inversion with an automated uniform cerebrospinal fluid zero reference algorithm (MEDI + 0) was used to generate brain QSM maps from mGRE data. Deep gray regional susceptibility values and cognitive function were compared among three groups (CSVD-S, CSVD-M, and HC) using multiple linear regression analysis and mediation effect analysis.</p><p><strong>Results: </strong>There were significant differences in the SCWT scores and mean susceptibility values of the globus pallidus (GP), putamen (Put), and caudate nucleus (CN) among the three groups (P < 0.05, FDR correction). Age had a significant positive impact on the susceptibility values of GP (p = 0.018), Put (p < 0.001), and CN (p < 0.001). A history of diabetes had a significant positive influence on the susceptibility values of Put (p = 0.011) and CN (p < 0.001). A smoking history had a significant positive association with the susceptibility values of CN (p = 0.019). Mediation effect analysis demonstrated that iron deposition in the neostriatum partially mediated the relationship between hypertension and cognitive function. Age, diabetes, and smoking may increase iron deposition in the basal ganglia, associated with cognitive decline. The mean susceptibility values of the neostriatum played a mediating role in the association between hypertension and cognitive scores.</p><p><strong>Conclusions: </strong>Age, diabetes, and smoking are associated with increased iron deposition in the basal ganglia and also linked to cognitive decline. This can help with understanding CSVD and its prevention and treatment.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"17"},"PeriodicalIF":7.9,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11715900/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142942583","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":"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}