Melissa E. Petersen, Lisi Flores-Aguilar, Elizabeth Head, Laia Montoliu-Gaya, Andre Strydom, Sarah E. Pape, Juan Fortea, Nicholas J. Ashton, Chinedu Udeh-Momoh, Sid E. O'Bryant, Dwight German, Florin Despa, Mark Mapstone, Henrik Zetterberg
Blood-based biomarkers continue to be explored for disease detection, monitoring of progression, and therapeutic outcomes as the diagnostic determination of Alzheimer's Disease in Down Syndrome (DS-AD) remains challenging in clinical settings. This perspective highlights the current status of this effort. Overall, amyloid (A), tau (T), and neurodegeneration (AT[N]) blood-based biomarkers have been shown to increase with disease pathology for individuals with DS. Phosphorylated tau biomarkers (p-tau217, p-tau181) have been consistently shown to track disease progression for DS-AD and are likely good candidates for use in clinical settings. Biomarkers of inflammation (glial fibrillary acidic protein) also show promise; however, additional work is needed. Findings from stability work of blood-based biomarkers conducted among non-DS also support the potential longitudinal utility of biomarkers such as neurofilament light chain and p-tau181 in DS. Gaps in our knowledge are highlighted, and a potential role for sex differences in biomarker outcomes is noted, along with recommendations for determining the appropriate context of use when translating biomarkers into clinical applications.
由于唐氏综合征阿尔茨海默病（DS-AD）的诊断确定在临床环境中仍具有挑战性，因此人们继续探索基于血液的生物标志物，以用于疾病检测、进展监测和治疗结果。本视角重点介绍了这一工作的现状。总体而言，淀粉样蛋白（A）、tau（T）和神经变性（AT[N]）血液生物标志物已被证明会随着唐氏综合征患者的疾病病理变化而增加。磷酸化 tau 生物标志物（p-tau217、p-tau181）已被证实可追踪 DS-AD 的疾病进展，并有可能被用于临床。炎症生物标志物（神经胶质纤维酸性蛋白）也显示出良好的前景；但是，还需要做更多的工作。在非DS患者中开展的基于血液的生物标志物稳定性研究结果也支持神经丝轻链和p-tau181等生物标志物在DS中的潜在纵向用途。报告强调了我们的知识空白，指出了性别差异在生物标记物结果中的潜在作用，并建议在将生物标记物转化为临床应用时确定适当的使用环境。
{"title":"Blood biomarkers in Down syndrome: Facilitating Alzheimer's disease detection and monitoring","authors":"Melissa E. Petersen, Lisi Flores-Aguilar, Elizabeth Head, Laia Montoliu-Gaya, Andre Strydom, Sarah E. Pape, Juan Fortea, Nicholas J. Ashton, Chinedu Udeh-Momoh, Sid E. O'Bryant, Dwight German, Florin Despa, Mark Mapstone, Henrik Zetterberg","doi":"10.1002/alz.14364","DOIUrl":"https://doi.org/10.1002/alz.14364","url":null,"abstract":"Blood-based biomarkers continue to be explored for disease detection, monitoring of progression, and therapeutic outcomes as the diagnostic determination of Alzheimer's Disease in Down Syndrome (DS-AD) remains challenging in clinical settings. This perspective highlights the current status of this effort. Overall, amyloid (A), tau (T), and neurodegeneration (AT[N]) blood-based biomarkers have been shown to increase with disease pathology for individuals with DS. Phosphorylated tau biomarkers (p-tau217, p-tau181) have been consistently shown to track disease progression for DS-AD and are likely good candidates for use in clinical settings. Biomarkers of inflammation (glial fibrillary acidic protein) also show promise; however, additional work is needed. Findings from stability work of blood-based biomarkers conducted among non-DS also support the potential longitudinal utility of biomarkers such as neurofilament light chain and p-tau181 in DS. Gaps in our knowledge are highlighted, and a potential role for sex differences in biomarker outcomes is noted, along with recommendations for determining the appropriate context of use when translating biomarkers into clinical applications.","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"310 1","pages":""},"PeriodicalIF":14.0,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142601396","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Anna Volkmer, Emily Viega Alves, Hagit Bar-Zeev, Elena Barbieri, Petronilla Battista, Ashleigh Beales, Barbara Costa Beber, Emilie Brotherhood, Ines Ribeiro Cadorio, Maria Teresa Carthery-Goulart, Jade Cartwright, Sebastian Crutch, Karen Croot, Maria Isabel d´Ávila Freitas, Jeanne Gallée, Stephanie M. Grasso, Katarina Haley, Heleen Hendriksen, Shalom Henderson, Lize Jiskoot, Isabel Junqueira Almeida, Jackie Kindell, Rachel Kingma, Lorinda LY Kwan-Chen, Monica Lavoie, Adi Lifshitz-Ben-Basat, Regina Jokel, Aurore Mahut-Dubos, Jordi A. Matias-Guiu, Michèle Masson-Trottier, Marcus Meinzer, Ellen McGowan, Carolina Mendez-Orellana, Aaron M. Meyer, Carly Millanski, Núria Montagut, Aimee Mooney, Darby J. Morhardt, Lyndsey Nickels, Monica Norvik, Iris Edda Nowenstein, Avanthi Paplikar, Margaret Pozzebon, Antoine Renard, Leanne Ruggero, Emily Rogalski, Anna U. Rysop, Fredrik Sand Aronsson, Aida Suárez-González, Sharon Savage, Mai Tran Thi, Kyriana Tsapkini, Cathleen Taylor-Rubin, Donna C. Tippett, Nina Unger, Lizet van Ewijk, Sandra Wielaert, Ingvild Elisabeth Winsnes, Anne Whitworth, Ibrahim Can Yasa, David Copland, Maya L. Henry, Jason D. Warren, Rosemary Varley, Sarah J. Wallace, Chris J. D. Hardy
Interventions to treat speech-language difficulties in primary progressive aphasia (PPA) often use word accuracy as a highly comparable outcome. However, there are more constructs of importance to people with PPA that have received less attention.
{"title":"An international core outcome set for primary progressive aphasia (COS-PPA): Consensus-based recommendations for communication interventions across research and clinical settings","authors":"Anna Volkmer, Emily Viega Alves, Hagit Bar-Zeev, Elena Barbieri, Petronilla Battista, Ashleigh Beales, Barbara Costa Beber, Emilie Brotherhood, Ines Ribeiro Cadorio, Maria Teresa Carthery-Goulart, Jade Cartwright, Sebastian Crutch, Karen Croot, Maria Isabel d´Ávila Freitas, Jeanne Gallée, Stephanie M. Grasso, Katarina Haley, Heleen Hendriksen, Shalom Henderson, Lize Jiskoot, Isabel Junqueira Almeida, Jackie Kindell, Rachel Kingma, Lorinda LY Kwan-Chen, Monica Lavoie, Adi Lifshitz-Ben-Basat, Regina Jokel, Aurore Mahut-Dubos, Jordi A. Matias-Guiu, Michèle Masson-Trottier, Marcus Meinzer, Ellen McGowan, Carolina Mendez-Orellana, Aaron M. Meyer, Carly Millanski, Núria Montagut, Aimee Mooney, Darby J. Morhardt, Lyndsey Nickels, Monica Norvik, Iris Edda Nowenstein, Avanthi Paplikar, Margaret Pozzebon, Antoine Renard, Leanne Ruggero, Emily Rogalski, Anna U. Rysop, Fredrik Sand Aronsson, Aida Suárez-González, Sharon Savage, Mai Tran Thi, Kyriana Tsapkini, Cathleen Taylor-Rubin, Donna C. Tippett, Nina Unger, Lizet van Ewijk, Sandra Wielaert, Ingvild Elisabeth Winsnes, Anne Whitworth, Ibrahim Can Yasa, David Copland, Maya L. Henry, Jason D. Warren, Rosemary Varley, Sarah J. Wallace, Chris J. D. Hardy","doi":"10.1002/alz.14362","DOIUrl":"https://doi.org/10.1002/alz.14362","url":null,"abstract":"Interventions to treat speech-language difficulties in primary progressive aphasia (PPA) often use word accuracy as a highly comparable outcome. However, there are more constructs of importance to people with PPA that have received less attention.","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"80 1","pages":""},"PeriodicalIF":14.0,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142601401","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The pathogenesis of two major pathogenic characters—amyloid beta (Aβ) accumulation and hyperphosphorylated tau protein—in the brains of patients with Alzheimer's disease (AD) remains unclear.
{"title":"Thorase deficiency causes both Aβ accumulation and tau hyperphosphorylation in mouse brain","authors":"Han Zhang, Menghua Cai, Fei Gao, Jia Yang, Chao Li, Jingyi Han, Yue Wang, Yi Xu, Yu Hu, Hui Chen, Wei He, Jianmin Zhang","doi":"10.1002/alz.14329","DOIUrl":"https://doi.org/10.1002/alz.14329","url":null,"abstract":"The pathogenesis of two major pathogenic characters—amyloid beta (Aβ) accumulation and hyperphosphorylated tau protein—in the brains of patients with Alzheimer's disease (AD) remains unclear.","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"20 1","pages":""},"PeriodicalIF":14.0,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142601450","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Paul Aisen, Randall J. Bateman, Damian Crowther, Jeff Cummings, John Dwyer, Takeshi Iwatsubo, Marie Kosco-Vilbois, Eric McDade, Richard Mohs, Philip Scheltens, Reisa Sperling, Dennis Selkoe
Decades of research have provided evidence that Alzheimer's disease (AD) is caused in part by cerebral accumulation of amyloid beta-protein (Aβ). In 2023, the US Food and Drug Administration gave full regulatory approval to a disease-modifying Aβ antibody for early AD. Secondary prevention trials with Aβ antibodies are underway. We summarize peer-reviewed evidence for targeting Aβ and argue that regulators should consider approving new agents working by similar mechanisms (Aβ antibodies and vaccines) based on robust amyloid lowering and reasonable safety. The urgent need to provide treatments to millions of mildly symptomatic patients suggests that AD should join other diseases for which standard approval is based on significant changes in mechanistically meaningful biomarkers coupled with safety. Robust amyloid lowering in secondary prevention trials of people who have amyloid plaques but are asymptomatic could also provide evidence of a change in the pathophysiological progression of AD as a basis for regulatory approval.
数十年的研究证明，阿尔茨海默病（AD）的部分病因是淀粉样β蛋白（Aβ）在大脑中的积累。2023 年，美国食品和药物管理局全面批准了一种可改变疾病的 Aβ 抗体用于早期 AD 的治疗。Aβ抗体的二级预防试验正在进行中。我们总结了针对 Aβ 的同行评审证据，并认为监管机构应考虑批准通过类似机制发挥作用的新药（Aβ 抗体和疫苗），这些新药应具有强有力的淀粉样蛋白降低作用和合理的安全性。为数百万症状轻微的患者提供治疗的迫切需要表明，注意力缺失症也应加入其他疾病的行列，这些疾病的标准审批依据是机理上有意义的生物标志物的显著变化以及安全性。在对有淀粉样蛋白斑块但无症状的患者进行的二级预防试验中，降低淀粉样蛋白水平的药物也能提供证据，证明AD的病理生理进展发生了变化，从而为监管机构批准提供依据。
{"title":"The case for regulatory approval of amyloid-lowering immunotherapies in Alzheimer's disease based on clearcut biomarker evidence","authors":"Paul Aisen, Randall J. Bateman, Damian Crowther, Jeff Cummings, John Dwyer, Takeshi Iwatsubo, Marie Kosco-Vilbois, Eric McDade, Richard Mohs, Philip Scheltens, Reisa Sperling, Dennis Selkoe","doi":"10.1002/alz.14342","DOIUrl":"https://doi.org/10.1002/alz.14342","url":null,"abstract":"Decades of research have provided evidence that Alzheimer's disease (AD) is caused in part by cerebral accumulation of amyloid beta-protein (Aβ). In 2023, the US Food and Drug Administration gave full regulatory approval to a disease-modifying Aβ antibody for early AD. Secondary prevention trials with Aβ antibodies are underway. We summarize peer-reviewed evidence for targeting Aβ and argue that regulators should consider approving new agents working by similar mechanisms (Aβ antibodies and vaccines) based on robust amyloid lowering and reasonable safety. The urgent need to provide treatments to millions of mildly symptomatic patients suggests that AD should join other diseases for which standard approval is based on significant changes in mechanistically meaningful biomarkers coupled with safety. Robust amyloid lowering in secondary prevention trials of people who have amyloid plaques but are asymptomatic could also provide evidence of a change in the pathophysiological progression of AD as a basis for regulatory approval.","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"3 1","pages":""},"PeriodicalIF":14.0,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142601250","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ariel Caviedes, Paulina Orellana, Cristian Ávila-Rincón, Agustín Ibáñez, Michael J. Corley, Hernando Santamaría-García, Claudia Duran-Aniotz, Carolina Ochoa-Rosales
<p>Dementia is a major health issue in Latin America and the Caribbean (LAC), with a prevalence of 9.5% and an incidence of 26.0 per 1000 among people over 60 years. With cases expected to triple by 2050, there is an urgent need for more extensive local research in this field.<span><sup>1</sup></span> Despite advancements in neuroimaging and protein biomarkers, significant gaps remain in understanding how biological mechanisms that interact with LAC-specific environmental exposures influence dementia risk, presentation, and treatment. Interactions between genetic and environmental factors, mainly through epigenetic changes including DNA methylation (DNAm), noncoding RNA, and histone modifications, can modulate gene expression, altering molecular traits and health outcomes.<span><sup>2</sup></span> Adverse environmental exposures in LAC, including socioeconomic disparities, pollutants, unhealthy habits, and comorbidities, have been associated with higher dementia risk,<span><sup>1</sup></span> potentially through epigenetic mechanisms. Most existing knowledge on epigenetics is derived from studies conducted in Europe and the United States, which limits the generalization of these findings to underrepresented regions,<span><sup>3</sup></span> including LAC. To understand state-of-the-art epigenetic studies on dementia in LAC, we conducted a systematic review following the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) protocols. Our search focused on chemical modifications of the DNA or histones able to regulate chromatin's structure. We reviewed the literature up to May 2024 in MEDLINE, Web of Science, PubMed, and Scopus databases (research strategy and findings in Table 1). Surprisingly, we found only five case-control studies comparing late-onset Alzheimer's disease (LOAD)<span><sup>4-6</sup></span> or mild cognitive impairment (MCI)<span><sup>7, 8</sup></span> versus healthy controls, revealing a disparity in published studies on epigenetics and dementia in LAC. Further epigenetics research is needed in the region, including the use of cutting-edge methods, target tissues, and systematic approaches. Studies have investigated global DNAm (<i>LINE-1</i>).<span><sup>4</sup></span> DNAm in candidate genes.<span><sup>5, 6</sup></span> or genome-wide DNAm<span><sup>7, 8</sup></span> assessed in peripheral blood. Two studies were conducted in Colombian,<span><sup>4, 5</sup></span> two in Mexican-American (MA),<span><sup>7, 8</sup></span> and one in Costa Rican populations.<span><sup>6</sup></span> Three studies addressed sex<span><sup>4, 5</sup></span> or ethnic<span><sup>8</sup></span> differences in DNAm. The study conducted by Hernández et al. found no significant differences in <i>LINE-1</i> methylation across LOAD patients and controls, even after stratification by sex or <i>APOE4</i> genotypes.<span><sup>4</sup></span> Further, Salcedo-Tacuma et al. identified significantly lower DNAm levels at three CpGs at <i>BIN1<
{"title":"Epigenetics of dementia remains unraveled in Latin American and Caribbean populations: A call for collaborative efforts","authors":"Ariel Caviedes, Paulina Orellana, Cristian Ávila-Rincón, Agustín Ibáñez, Michael J. Corley, Hernando Santamaría-García, Claudia Duran-Aniotz, Carolina Ochoa-Rosales","doi":"10.1002/alz.14295","DOIUrl":"https://doi.org/10.1002/alz.14295","url":null,"abstract":"<p>Dementia is a major health issue in Latin America and the Caribbean (LAC), with a prevalence of 9.5% and an incidence of 26.0 per 1000 among people over 60 years. With cases expected to triple by 2050, there is an urgent need for more extensive local research in this field.<span><sup>1</sup></span> Despite advancements in neuroimaging and protein biomarkers, significant gaps remain in understanding how biological mechanisms that interact with LAC-specific environmental exposures influence dementia risk, presentation, and treatment. Interactions between genetic and environmental factors, mainly through epigenetic changes including DNA methylation (DNAm), noncoding RNA, and histone modifications, can modulate gene expression, altering molecular traits and health outcomes.<span><sup>2</sup></span> Adverse environmental exposures in LAC, including socioeconomic disparities, pollutants, unhealthy habits, and comorbidities, have been associated with higher dementia risk,<span><sup>1</sup></span> potentially through epigenetic mechanisms. Most existing knowledge on epigenetics is derived from studies conducted in Europe and the United States, which limits the generalization of these findings to underrepresented regions,<span><sup>3</sup></span> including LAC. To understand state-of-the-art epigenetic studies on dementia in LAC, we conducted a systematic review following the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) protocols. Our search focused on chemical modifications of the DNA or histones able to regulate chromatin's structure. We reviewed the literature up to May 2024 in MEDLINE, Web of Science, PubMed, and Scopus databases (research strategy and findings in Table 1). Surprisingly, we found only five case-control studies comparing late-onset Alzheimer's disease (LOAD)<span><sup>4-6</sup></span> or mild cognitive impairment (MCI)<span><sup>7, 8</sup></span> versus healthy controls, revealing a disparity in published studies on epigenetics and dementia in LAC. Further epigenetics research is needed in the region, including the use of cutting-edge methods, target tissues, and systematic approaches. Studies have investigated global DNAm (<i>LINE-1</i>).<span><sup>4</sup></span> DNAm in candidate genes.<span><sup>5, 6</sup></span> or genome-wide DNAm<span><sup>7, 8</sup></span> assessed in peripheral blood. Two studies were conducted in Colombian,<span><sup>4, 5</sup></span> two in Mexican-American (MA),<span><sup>7, 8</sup></span> and one in Costa Rican populations.<span><sup>6</sup></span> Three studies addressed sex<span><sup>4, 5</sup></span> or ethnic<span><sup>8</sup></span> differences in DNAm. The study conducted by Hernández et al. found no significant differences in <i>LINE-1</i> methylation across LOAD patients and controls, even after stratification by sex or <i>APOE4</i> genotypes.<span><sup>4</sup></span> Further, Salcedo-Tacuma et al. identified significantly lower DNAm levels at three CpGs at <i>BIN1<","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"72 1","pages":""},"PeriodicalIF":14.0,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142601254","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Yini Chen, Yiwei Qi, Yiying Hu, Xinhui Qiu, Tao Qiu, Song Li, Meichen Liu, Qiqi Jia, Bo Sun, Cong Liu, Tianbai Li, Weidong Le
Pathological and neuroimaging alterations in the cerebellum of Alzheimer's disease (AD) patients have been documented. However, the role of cerebellum-derived radiomic and structural connectome modeling in the prediction of AD progression remains unclear.
{"title":"Integrated cerebellar radiomic-network model for predicting mild cognitive impairment in Alzheimer's disease","authors":"Yini Chen, Yiwei Qi, Yiying Hu, Xinhui Qiu, Tao Qiu, Song Li, Meichen Liu, Qiqi Jia, Bo Sun, Cong Liu, Tianbai Li, Weidong Le","doi":"10.1002/alz.14361","DOIUrl":"https://doi.org/10.1002/alz.14361","url":null,"abstract":"Pathological and neuroimaging alterations in the cerebellum of Alzheimer's disease (AD) patients have been documented. However, the role of cerebellum-derived radiomic and structural connectome modeling in the prediction of AD progression remains unclear.","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"34 1","pages":""},"PeriodicalIF":14.0,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142601246","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Selena Wang, Yiting Wang, Frederick H. Xu, Xinyuan Tian, Carolyn A. Fredericks, Li Shen, Yize Zhao
We investigate sex-specific topological structures associated with typical Alzheimer's disease (AD) dementia using a novel state-of-the-art latent space estimation technique.
我们采用最新的潜在空间估计技术，研究了与典型阿尔茨海默病（AD）痴呆症相关的性别拓扑结构。
{"title":"Sex-specific topological structure associated with dementia via latent space estimation","authors":"Selena Wang, Yiting Wang, Frederick H. Xu, Xinyuan Tian, Carolyn A. Fredericks, Li Shen, Yize Zhao","doi":"10.1002/alz.14266","DOIUrl":"https://doi.org/10.1002/alz.14266","url":null,"abstract":"We investigate sex-specific topological structures associated with typical Alzheimer's disease (AD) dementia using a novel state-of-the-art latent space estimation technique.","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"7 1","pages":""},"PeriodicalIF":14.0,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142599914","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Stephen P. Schauer, Balazs Toth, Julie Lee, Lee A. Honigberg, Vidya Ramakrishnan, Jenny Jiang, Gwendlyn Kollmorgen, Anna Bayfield, Norbert Wild, Jennifer Hoffman, Ryan Ceniceros, Michael Dolton, Sandra M. Sanabria Bohórquez, Casper C. Hoogenraad, Kristin R. Wildsmith, Edmond Teng, Cecilia Monteiro, Veronica Anania, Felix L. Yeh
INTRODUCTIONSemorinemab, an anti‐tau monoclonal antibody, was assessed in two Phase II trials for Alzheimer's disease (AD). Plasma and cerebrospinal fluid (CSF) biomarkers provided insights into the drug's potential mechanism of action.METHODSQualified assays were used to measure biomarkers of tau, amyloidosis, glial activity, neuroinflammation, synaptic function, and neurodegeneration from participant samples in Tauriel (NCT03289143) and Lauriet (NCT03828747) Phase II trials.RESULTSPlasma phosphorylated Tau 181 (pTau181) and CSF chitinase‐3‐like protein 1 (YKL‐40) increased following semorinemab treatment in both studies. In Lauriet, increasing plasma glial fibrillary protein (GFAP) concentrations stabilized with semorinemab, while this was not observed in Tauriel. Other AD pathophysiology biomarkers showed no consistent response to semorinemab.DISCUSSIONIncreases in CSF YKL‐40 suggest that semorinemab may stimulate microglia activation in the presence of AD‐associated Tau pathology, but not in healthy controls. Stabilization of plasma GFAP in Lauriet indicates a possible impact on reactive gliosis in mild‐to‐moderate AD.Trial Registration: Tauriel ClinicalTrials.gov Identifier: NCT03289143. Lauriet ClinicalTrials.gov Identifier: NCT03828747. Phase 1 ClinicalTrials.gov Identifier: NCT02820896.HighlightsAD pathophysiology biomarkers were measured to assess the mechanism of action.Semorinemab increased CSF YKL‐40 in participants with AD but not in healthy controls.Semorinemab possibly stabilized plasma GFAP in the Lauriet trial.Semorinemab treatment may activate microglia and moderate reactive gliosis.
{"title":"Pharmacodynamic effects of semorinemab on plasma and CSF biomarkers of Alzheimer's disease pathophysiology","authors":"Stephen P. Schauer, Balazs Toth, Julie Lee, Lee A. Honigberg, Vidya Ramakrishnan, Jenny Jiang, Gwendlyn Kollmorgen, Anna Bayfield, Norbert Wild, Jennifer Hoffman, Ryan Ceniceros, Michael Dolton, Sandra M. Sanabria Bohórquez, Casper C. Hoogenraad, Kristin R. Wildsmith, Edmond Teng, Cecilia Monteiro, Veronica Anania, Felix L. Yeh","doi":"10.1002/alz.14346","DOIUrl":"https://doi.org/10.1002/alz.14346","url":null,"abstract":"INTRODUCTIONSemorinemab, an anti‐tau monoclonal antibody, was assessed in two Phase II trials for Alzheimer's disease (AD). Plasma and cerebrospinal fluid (CSF) biomarkers provided insights into the drug's potential mechanism of action.METHODSQualified assays were used to measure biomarkers of tau, amyloidosis, glial activity, neuroinflammation, synaptic function, and neurodegeneration from participant samples in Tauriel (NCT03289143) and Lauriet (NCT03828747) Phase II trials.RESULTSPlasma phosphorylated Tau 181 (pTau181) and CSF chitinase‐3‐like protein 1 (YKL‐40) increased following semorinemab treatment in both studies. In Lauriet, increasing plasma glial fibrillary protein (GFAP) concentrations stabilized with semorinemab, while this was not observed in Tauriel. Other AD pathophysiology biomarkers showed no consistent response to semorinemab.DISCUSSIONIncreases in CSF YKL‐40 suggest that semorinemab may stimulate microglia activation in the presence of AD‐associated Tau pathology, but not in healthy controls. Stabilization of plasma GFAP in Lauriet indicates a possible impact on reactive gliosis in mild‐to‐moderate AD.Trial Registration: Tauriel ClinicalTrials.gov Identifier: NCT03289143. Lauriet ClinicalTrials.gov Identifier: NCT03828747. Phase 1 ClinicalTrials.gov Identifier: NCT02820896.Highlights<jats:list list-type=\"bullet\"> <jats:list-item>AD pathophysiology biomarkers were measured to assess the mechanism of action.</jats:list-item> <jats:list-item>Semorinemab increased CSF YKL‐40 in participants with AD but not in healthy controls.</jats:list-item> <jats:list-item>Semorinemab possibly stabilized plasma GFAP in the Lauriet trial.</jats:list-item> <jats:list-item>Semorinemab treatment may activate microglia and moderate reactive gliosis.</jats:list-item> </jats:list>","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"1 1","pages":""},"PeriodicalIF":14.0,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142597088","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Tamina Park, Jiyun Hwang, Shiwei Liu, Soumilee Chaudhuri, Sang Won Han, Dahyun Yi, Min Soo Byun, Yen‐Ning Huang, Thea Rosewood, Gijung Jung, Min Jeong Kim, Hyejin Ahn, Jun‐Young Lee, Yu Kyeong Kim, MinYoung Cho, Paula J. Bice, Hannah Craft, Shannon L. Risacher, Hongyu Gao, Yunlong Liu, SangYun Kim, Young Ho Park, Dong Young Lee, Andrew J. Saykin, Kwangsik Nho
INTRODUCTIONDespite the recognized importance of including ethnic diversity in Alzheimer's disease (AD) research, substantial knowledge gaps remain, particularly in Asian populations.METHODSRNA sequencing was performed on blood samples from the Korean Brain Aging Study for the Early Diagnosis and Prediction of Alzheimer's Disease (KBASE) to perform differential gene expression (DGE), gene co‐expression network, gene‐set enrichment, and machine learning analyses for amyloid beta (Aβ) deposition on positron emission tomography.RESULTSDGE analysis identified 265 dysregulated genes associated with Aβ deposition and replicated three AD‐associated genes in an independent Korean cohort. Network analysis identified two modules related to pathways including a natural killer (NK) cell–mediated immunity. Machine learning analysis showed the classification of Aβ positivity improved with the inclusion of gene expression data.DISCUSSIONOur results in a Korean population suggest Aβ deposition‐associated genes are enriched in NK cell–mediated immunity, providing a better understanding of AD molecular mechanisms and yielding potential diagnostic and therapeutic strategies.HighlightsDysregulated genes were associated with amyloid beta (Aβ) deposition on positron emission tomography in a Korean cohort.Dysregulated genes in Alzheimer's disease were replicated in an independent Korean cohort.Gene network modules were associated with Aβ deposition.Natural killer (NK) cell proportion in blood was associated with Aβ deposition.Dysregulated genes were related to a NK cell–mediated immunity.
简介：尽管阿尔茨海默病（AD）研究中种族多样性的重要性已得到公认，但仍存在大量的知识空白，尤其是在亚洲人群中。结果DGE分析发现了265个与Aβ沉积相关的失调基因，并在一个独立的韩国队列中复制了3个与AD相关的基因。网络分析发现了两个与通路相关的模块，包括自然杀伤（NK）细胞介导的免疫。我们在韩国人群中的研究结果表明，Aβ沉积相关基因富集于 NK 细胞介导的免疫中，这有助于更好地了解 AD 分子机制，并产生潜在的诊断和治疗策略。阿尔茨海默病的失调基因在一个独立的韩国队列中得到了复制。基因网络模块与 Aβ 沉积有关。血液中自然杀伤（NK）细胞的比例与 Aβ 沉积有关。失调基因与 NK 细胞介导的免疫有关。
{"title":"Genome‐wide transcriptome analysis of Aβ deposition on PET in a Korean cohort","authors":"Tamina Park, Jiyun Hwang, Shiwei Liu, Soumilee Chaudhuri, Sang Won Han, Dahyun Yi, Min Soo Byun, Yen‐Ning Huang, Thea Rosewood, Gijung Jung, Min Jeong Kim, Hyejin Ahn, Jun‐Young Lee, Yu Kyeong Kim, MinYoung Cho, Paula J. Bice, Hannah Craft, Shannon L. Risacher, Hongyu Gao, Yunlong Liu, SangYun Kim, Young Ho Park, Dong Young Lee, Andrew J. Saykin, Kwangsik Nho","doi":"10.1002/alz.14348","DOIUrl":"https://doi.org/10.1002/alz.14348","url":null,"abstract":"INTRODUCTIONDespite the recognized importance of including ethnic diversity in Alzheimer's disease (AD) research, substantial knowledge gaps remain, particularly in Asian populations.METHODSRNA sequencing was performed on blood samples from the Korean Brain Aging Study for the Early Diagnosis and Prediction of Alzheimer's Disease (KBASE) to perform differential gene expression (DGE), gene co‐expression network, gene‐set enrichment, and machine learning analyses for amyloid beta (Aβ) deposition on positron emission tomography.RESULTSDGE analysis identified 265 dysregulated genes associated with Aβ deposition and replicated three AD‐associated genes in an independent Korean cohort. Network analysis identified two modules related to pathways including a natural killer (NK) cell–mediated immunity. Machine learning analysis showed the classification of Aβ positivity improved with the inclusion of gene expression data.DISCUSSIONOur results in a Korean population suggest Aβ deposition‐associated genes are enriched in NK cell–mediated immunity, providing a better understanding of AD molecular mechanisms and yielding potential diagnostic and therapeutic strategies.Highlights<jats:list list-type=\"bullet\"> <jats:list-item>Dysregulated genes were associated with amyloid beta (Aβ) deposition on positron emission tomography in a Korean cohort.</jats:list-item> <jats:list-item>Dysregulated genes in Alzheimer's disease were replicated in an independent Korean cohort.</jats:list-item> <jats:list-item>Gene network modules were associated with Aβ deposition.</jats:list-item> <jats:list-item>Natural killer (NK) cell proportion in blood was associated with Aβ deposition.</jats:list-item> <jats:list-item>Dysregulated genes were related to a NK cell–mediated immunity.</jats:list-item> </jats:list>","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"18 1","pages":""},"PeriodicalIF":14.0,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142597226","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Tiffany Ngai, Julian Willett, Mohammad Waqas, Lucas H. Fishbein, Younjung Choi, Georg Hahn, Kristina Mullin, Christoph Lange, Julian Hecker, Rudolph E. Tanzi, Dmitry Prokopenko
INTRODUCTIONAlzheimer's disease (AD) is the most common form of dementia in the elderly. Given that AD neuropathology begins decades before symptoms, there is a dire need for effective screening tools for early detection of AD to facilitate early intervention.METHODSHere, we used tree‐based and deep learning methods to train polyomic prediction models for AD affection status and age at onset, employing genomic, proteomic, metabolomic, and drug use data from UK Biobank. We used SHAP to determine the feature's importance.RESULTSOur best‐performing polyomic model achieved an area under the receiver operating characteristics curve (AUROC) of 0.87. We identified GFAP and CXCL17 proteins to be the strongest predictors of AD, besides apolipoprotein E (APOE) alleles. Increasing the number of cases by including “AD‐by‐proxy” cases did not improve AD prediction.DISCUSSIONAmong the four modalities, genomics, and proteomics were the most informative modality based on AUROC (area under the receiver operating characteristic curve). Our data suggest that two blood‐based biomarkers (glial fibrillary acidic protein [GFAP] and CXCL17) may be effective for early presymptomatic prediction of AD.HighlightsWe developed a polyomic model to predict AD and age‐at‐onset using omics and medication use data from EHR.We identified GFAP and CXCL17 proteins to be the strongest predictors of AD, besides APOE alleles.“AD‐by‐proxy” cases, if used in training, do not improve AD prediction.Proteomics was the most informative modality overall for affection status and AAO prediction.
简介阿尔茨海默病（AD）是最常见的老年痴呆症。鉴于老年痴呆症的神经病理学始于症状出现前的几十年，因此迫切需要有效的筛查工具来早期检测老年痴呆症，以便及早干预。方法在此，我们采用基于树和深度学习的方法，利用英国生物库的基因组、蛋白质组、代谢组和药物使用数据，训练老年痴呆症亲和力状态和发病年龄的多组预测模型。我们使用 SHAP 来确定特征的重要性。结果我们表现最好的多组模型的接收者工作特征曲线下面积 (AUROC) 达到了 0.87。除了脂蛋白 E（APOE）等位基因外，我们还发现 GFAP 和 CXCL17 蛋白是预测 AD 的最强指标。通过纳入 "AD-by-proxy "病例来增加病例数并不能提高AD预测能力。讨论根据AUROC（接收者操作特征曲线下面积），在四种模式中，基因组学和蛋白质组学是信息量最大的模式。我们的数据表明，两种基于血液的生物标记物（胶质纤维酸性蛋白 [GFAP] 和 CXCL17）可能对早期症状前预测 AD 非常有效。亮点 我们开发了一个多组学模型，利用 EHR 中的全局组学和药物使用数据预测 AD 和发病年龄。除 APOE 等位基因外，我们还发现 GFAP 和 CXCL17 蛋白是预测 AD 的最强指标。如果在训练中使用 "AD-by-proxy "病例，并不能提高AD预测能力。蛋白质组学是对情感状态和 AAO 预测最有参考价值的方法。
{"title":"Assessing polyomic risk to predict Alzheimer's disease using a machine learning model","authors":"Tiffany Ngai, Julian Willett, Mohammad Waqas, Lucas H. Fishbein, Younjung Choi, Georg Hahn, Kristina Mullin, Christoph Lange, Julian Hecker, Rudolph E. Tanzi, Dmitry Prokopenko","doi":"10.1002/alz.14319","DOIUrl":"https://doi.org/10.1002/alz.14319","url":null,"abstract":"INTRODUCTIONAlzheimer's disease (AD) is the most common form of dementia in the elderly. Given that AD neuropathology begins decades before symptoms, there is a dire need for effective screening tools for early detection of AD to facilitate early intervention.METHODSHere, we used tree‐based and deep learning methods to train polyomic prediction models for AD affection status and age at onset, employing genomic, proteomic, metabolomic, and drug use data from UK Biobank. We used SHAP to determine the feature's importance.RESULTSOur best‐performing polyomic model achieved an area under the receiver operating characteristics curve (AUROC) of 0.87. We identified GFAP and CXCL17 proteins to be the strongest predictors of AD, besides <jats:italic>apolipoprotein E</jats:italic> (<jats:italic>APOE)</jats:italic> alleles. Increasing the number of cases by including “AD‐by‐proxy” cases did not improve AD prediction.DISCUSSIONAmong the four modalities, genomics, and proteomics were the most informative modality based on AUROC (area under the receiver operating characteristic curve). Our data suggest that two blood‐based biomarkers (glial fibrillary acidic protein [GFAP] and CXCL17) may be effective for early presymptomatic prediction of AD.Highlights<jats:list list-type=\"bullet\"> <jats:list-item>We developed a polyomic model to predict AD and age‐at‐onset using omics and medication use data from EHR.</jats:list-item> <jats:list-item>We identified GFAP and CXCL17 proteins to be the strongest predictors of AD, besides <jats:italic>APOE</jats:italic> alleles.</jats:list-item> <jats:list-item>“AD‐by‐proxy” cases, if used in training, do not improve AD prediction.</jats:list-item> <jats:list-item>Proteomics was the most informative modality overall for affection status and AAO prediction.</jats:list-item> </jats:list>","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"23 1","pages":""},"PeriodicalIF":14.0,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142597089","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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