Vijay R Varma, Yang An, Przemek R Kac, Murat Bilgel, Abhay Moghekar, Tina Loeffler, David Amschl, Magdalena Daurer, Manuela Prokesch, Juan Troncoso, Kaj Blennow, Henrik Zetterberg, Nicholas J Ashton, Luigi Ferrucci, Susan M Resnick, Madhav Thambisetty
{"title":"血液生物标志物的纵向进展揭示了反应性星形细胞增生在临床前阿尔茨海默病中的关键作用。","authors":"Vijay R Varma, Yang An, Przemek R Kac, Murat Bilgel, Abhay Moghekar, Tina Loeffler, David Amschl, Magdalena Daurer, Manuela Prokesch, Juan Troncoso, Kaj Blennow, Henrik Zetterberg, Nicholas J Ashton, Luigi Ferrucci, Susan M Resnick, Madhav Thambisetty","doi":"10.1016/j.medj.2025.100724","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Defining the progression of blood biomarkers in Alzheimer's disease (AD) is essential for targeting treatments in patients most likely to benefit from early intervention. We delineated the temporal ordering of blood biomarkers a decade prior to the onset of AD, explored associations with AD brain pathology, and examined the relationship between reactive astrocytosis in the brain and plasma in a transgenic mouse model.</p><p><strong>Methods: </strong>We analyzed plasma blood biomarkers using the Quanterix HD-X instrument in case-control and postmortem cohorts from the Baltimore Longitudinal Study on Aging (BLSA). We assessed plasma and cortical reactive astrocytosis, measured by glial fibrillary acidic protein (GFAP), in 5xFAD transgenic and wild-type mice.</p><p><strong>Findings: </strong>In AD-converters (N = 158, 377 samples), higher plasma GFAP levels are observed 10 years prior to the onset of cognitive impairment due to AD compared with individuals who remain cognitively unimpaired (N = 160, 379 samples). Plasma GFAP levels are highest in neuropathologically confirmed AD, intermediate in asymptomatic AD, and lowest in cognitively unimpaired and associated with severity of neuritic plaques and neurofibrillary tangles. GFAP-labeled immunoreactive astrocytes in the cortex of 3- and 7-month-old 5xFAD transgenic mice increased relative to wild-type mice and higher blood GFAP concentration was associated with more GFAP-expressing astrocytes.</p><p><strong>Conclusions: </strong>Reactive astrocytosis, assessed by elevated GFAP levels, is an early event in the progression of blood biomarker changes in preclinical AD, may be an early marker of AD pathogenesis, and a promising therapeutic target.</p><p><strong>Funding: </strong>Intramural Research Program, NIA.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":" ","pages":"100724"},"PeriodicalIF":11.8000,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Longitudinal progression of blood biomarkers reveals a key role of reactive astrocytosis in preclinical Alzheimer's disease.\",\"authors\":\"Vijay R Varma, Yang An, Przemek R Kac, Murat Bilgel, Abhay Moghekar, Tina Loeffler, David Amschl, Magdalena Daurer, Manuela Prokesch, Juan Troncoso, Kaj Blennow, Henrik Zetterberg, Nicholas J Ashton, Luigi Ferrucci, Susan M Resnick, Madhav Thambisetty\",\"doi\":\"10.1016/j.medj.2025.100724\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>Defining the progression of blood biomarkers in Alzheimer's disease (AD) is essential for targeting treatments in patients most likely to benefit from early intervention. We delineated the temporal ordering of blood biomarkers a decade prior to the onset of AD, explored associations with AD brain pathology, and examined the relationship between reactive astrocytosis in the brain and plasma in a transgenic mouse model.</p><p><strong>Methods: </strong>We analyzed plasma blood biomarkers using the Quanterix HD-X instrument in case-control and postmortem cohorts from the Baltimore Longitudinal Study on Aging (BLSA). We assessed plasma and cortical reactive astrocytosis, measured by glial fibrillary acidic protein (GFAP), in 5xFAD transgenic and wild-type mice.</p><p><strong>Findings: </strong>In AD-converters (N = 158, 377 samples), higher plasma GFAP levels are observed 10 years prior to the onset of cognitive impairment due to AD compared with individuals who remain cognitively unimpaired (N = 160, 379 samples). Plasma GFAP levels are highest in neuropathologically confirmed AD, intermediate in asymptomatic AD, and lowest in cognitively unimpaired and associated with severity of neuritic plaques and neurofibrillary tangles. GFAP-labeled immunoreactive astrocytes in the cortex of 3- and 7-month-old 5xFAD transgenic mice increased relative to wild-type mice and higher blood GFAP concentration was associated with more GFAP-expressing astrocytes.</p><p><strong>Conclusions: </strong>Reactive astrocytosis, assessed by elevated GFAP levels, is an early event in the progression of blood biomarker changes in preclinical AD, may be an early marker of AD pathogenesis, and a promising therapeutic target.</p><p><strong>Funding: </strong>Intramural Research Program, NIA.</p>\",\"PeriodicalId\":29964,\"journal\":{\"name\":\"Med\",\"volume\":\" \",\"pages\":\"100724\"},\"PeriodicalIF\":11.8000,\"publicationDate\":\"2025-06-03\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Med\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.1016/j.medj.2025.100724\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"MEDICINE, RESEARCH & EXPERIMENTAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Med","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1016/j.medj.2025.100724","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"MEDICINE, RESEARCH & EXPERIMENTAL","Score":null,"Total":0}
Longitudinal progression of blood biomarkers reveals a key role of reactive astrocytosis in preclinical Alzheimer's disease.
Background: Defining the progression of blood biomarkers in Alzheimer's disease (AD) is essential for targeting treatments in patients most likely to benefit from early intervention. We delineated the temporal ordering of blood biomarkers a decade prior to the onset of AD, explored associations with AD brain pathology, and examined the relationship between reactive astrocytosis in the brain and plasma in a transgenic mouse model.
Methods: We analyzed plasma blood biomarkers using the Quanterix HD-X instrument in case-control and postmortem cohorts from the Baltimore Longitudinal Study on Aging (BLSA). We assessed plasma and cortical reactive astrocytosis, measured by glial fibrillary acidic protein (GFAP), in 5xFAD transgenic and wild-type mice.
Findings: In AD-converters (N = 158, 377 samples), higher plasma GFAP levels are observed 10 years prior to the onset of cognitive impairment due to AD compared with individuals who remain cognitively unimpaired (N = 160, 379 samples). Plasma GFAP levels are highest in neuropathologically confirmed AD, intermediate in asymptomatic AD, and lowest in cognitively unimpaired and associated with severity of neuritic plaques and neurofibrillary tangles. GFAP-labeled immunoreactive astrocytes in the cortex of 3- and 7-month-old 5xFAD transgenic mice increased relative to wild-type mice and higher blood GFAP concentration was associated with more GFAP-expressing astrocytes.
Conclusions: Reactive astrocytosis, assessed by elevated GFAP levels, is an early event in the progression of blood biomarker changes in preclinical AD, may be an early marker of AD pathogenesis, and a promising therapeutic target.
期刊介绍：
Med is a flagship medical journal published monthly by Cell Press, the global publisher of trusted and authoritative science journals including Cell, Cancer Cell, and Cell Reports Medicine. Our mission is to advance clinical research and practice by providing a communication forum for the publication of clinical trial results, innovative observations from longitudinal cohorts, and pioneering discoveries about disease mechanisms. The journal also encourages thought-leadership discussions among biomedical researchers, physicians, and other health scientists and stakeholders. Our goal is to improve health worldwide sustainably and ethically.
Med publishes rigorously vetted original research and cutting-edge review and perspective articles on critical health issues globally and regionally. Our research section covers clinical case reports, first-in-human studies, large-scale clinical trials, population-based studies, as well as translational research work with the potential to change the course of medical research and improve clinical practice.
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