{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T00:38:08Z","timestamp":1788482288683,"version":"build-2803163510"},"reference-count":51,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,7,21]],"date-time":"2021-07-21T00:00:00Z","timestamp":1626825600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Aging Neurosci."],"abstract":"<jats:p><jats:bold>Background and Objective<\/jats:bold>: Plasma biomarkers for the diagnosis and stratification of Alzheimer\u2019s disease (AD) are intensively sought. However, no plasma markers are well established so far for AD diagnosis. Our group has identified and validated various blood-based proteomic biomarkers relating to AD pathology in multiple cohorts. The study aims to conduct a meta-analysis based on our own studies to systematically assess the diagnostic performance of our previously identified blood biomarkers.<\/jats:p><jats:p><jats:bold>Methods<\/jats:bold>: To do this, we included seven studies that our group has conducted during the last decade. These studies used either Luminex xMAP or ELISA to measure proteomic biomarkers. As proteins measured in these studies differed, we selected protein based on the criteria that it must be measured in at least four studies. We then examined biomarker performance using random-effect meta-analyses based on the mean difference between biomarker concentrations in AD and controls (CTL), AD and mild cognitive impairment (MCI), MCI, and CTL as well as MCI converted to dementia (MCIc) and non-converted (MCInc) individuals.<\/jats:p><jats:p><jats:bold>Results<\/jats:bold>: An overall of 2,879 subjects were retrieved for meta-analysis including 1,053 CTL, 895 MCI, 882 AD, and 49 frontotemporal dementia (FTD) patients. Six proteins were measured in at least four studies and were chosen for meta-analyses for AD diagnosis. Of them, three proteins had significant difference between AD and controls, among which alpha-2-macroglobulin (A2M) and ficolin-2 (FCN2) increased in AD while fibrinogen gamma chain (FGG) decreased in AD compared to CTL. Furthermore, FGG significantly increased in FTD compared to AD. None of the proteins passed the significance between AD and MCI, or MCI and CTL, or MCIc and MCInc, although complement component 4 (CC4) tended to increase in MCIc individuals compared to MCInc.<\/jats:p><jats:p><jats:bold>Conclusions<\/jats:bold>: The results suggest that A2M, FCN2, and FGG are promising biomarkers to discriminate AD patients from controls, which are worthy of further validation.<\/jats:p>","DOI":"10.3389\/fnagi.2021.712545","type":"journal-article","created":{"date-parts":[[2021,7,21]],"date-time":"2021-07-21T15:27:32Z","timestamp":1626881252000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":24,"title":["Plasma Proteomic Biomarkers Relating to Alzheimer\u2019s Disease: A Meta-Analysis Based on Our Own Studies"],"prefix":"10.3389","volume":"13","author":[{"given":"Liu","family":"Shi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noel J.","family":"Buckley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabelle","family":"Bos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sebastiaan","family":"Engelborghs","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristel","family":"Sleegers","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovanni B.","family":"Frisoni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anders","family":"Wallin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alberto","family":"Ll\u00e9o","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julius","family":"Popp","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pablo","family":"Martinez-Lage","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina","family":"Legido-Quigley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frederik","family":"Barkhof","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henrik","family":"Zetterberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pieter Jelle","family":"Visser","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lars","family":"Bertram","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simon","family":"Lovestone","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alejo J.","family":"Nevado-Holgado","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,7,21]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"21812","DOI":"10.1073\/pnas.1010373107","article-title":"Alzheimer\u2019s disease peptide beta-amyloid interacts with fibrinogen and induces its oligomerization","volume":"107","author":"Ahn","year":"2010","journal-title":"Proc. Natl. Acad. Sci. U S A"},{"key":"B2","doi-asserted-by":"publisher","first-page":"48","DOI":"10.1016\/j.dadm.2014.11.005","article-title":"Blood protein predictors of brain amyloid for enrichment in clinical trials?","volume":"1","author":"Ashton","year":"2015","journal-title":"Alzheimers Dement."},{"key":"B3","doi-asserted-by":"publisher","first-page":"236","DOI":"10.3389\/fneur.2015.00236","article-title":"Blood-based proteomic biomarkers of Alzheimer\u2019s disease pathology","volume":"6","author":"Baird","year":"2015","journal-title":"Front. Neurol."},{"key":"B4","doi-asserted-by":"publisher","first-page":"1711","DOI":"10.2967\/jnumed.116.185017","article-title":"Clinical use and utility of amyloid imaging","volume":"58","author":"Barthel","year":"2017","journal-title":"J. Nucl. Med."},{"key":"B5","doi-asserted-by":"publisher","first-page":"e20200861","DOI":"10.1084\/jem.20200861","article-title":"Blood plasma phosphorylated-tau isoforms track CNS change in Alzheimer\u2019s disease","volume":"217","author":"Barth\u00e9lemy","year":"2020","journal-title":"J. Exp. Med."},{"key":"B6","doi-asserted-by":"publisher","first-page":"266","DOI":"10.1097\/NEN.0b013e31824b211b","article-title":"Accuracy of the clinical diagnosis of Alzheimer disease at National Institute on Aging Alzheimer Disease Centers, 2005\u20132010","volume":"71","author":"Beach","year":"2012","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"B7","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1007\/s40120-017-0073-9","article-title":"A review of fluid biomarkers for Alzheimer\u2019s disease: moving from CSF to blood","volume":"6","author":"Blennow","year":"2017","journal-title":"Neurol. Ther."},{"key":"B8","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1038\/s41398-020-01137-1","article-title":"Plasma glial fibrillary acidic protein is elevated in cognitively normal older adults at risk of Alzheimer\u2019s disease","volume":"11","author":"Chatterjee","year":"2021","journal-title":"Transl. Psychiatry"},{"key":"B9","doi-asserted-by":"publisher","first-page":"256","DOI":"10.1093\/jmcb\/mjs032","article-title":"Low serum levels of the innate immune component ficolin-3 is associated with insulin resistance and predicts the development of type 2 diabetes","volume":"4","author":"Chen","year":"2012","journal-title":"J. Mol. Cell Biol."},{"key":"B10","doi-asserted-by":"publisher","first-page":"68","DOI":"10.1186\/s13195-021-00804-9","article-title":"Plasma glial fibrillary acidic protein detects Alzheimer pathology and predicts future conversion to Alzheimer dementia in patients with mild cognitive impairment","volume":"13","author":"Cicognola","year":"2021","journal-title":"Alzheimers Res. Ther."},{"key":"B11","doi-asserted-by":"publisher","first-page":"65","DOI":"10.1186\/s13195-021-00805-8","article-title":"Plasma neurofilament light and phosphorylated tau 181 as biomarkers of Alzheimer\u2019s disease pathology and clinical disease progression","volume":"13","author":"Clark","year":"2021","journal-title":"Alzheimers Res. Ther."},{"key":"B12","doi-asserted-by":"publisher","first-page":"1503","DOI":"10.1111\/j.1526-4610.2011.01959.x","article-title":"Incidence of post-dural puncture headache in research volunteers","volume":"51","author":"de Almeida","year":"2011","journal-title":"Headache"},{"key":"B13","doi-asserted-by":"publisher","first-page":"185","DOI":"10.1111\/j.0105-2896.2004.0123.x","article-title":"The lectin-complement pathway\u2013its role in innate immunity and evolution","volume":"198","author":"Fujita","year":"2004","journal-title":"Immunol. Rev."},{"key":"B15","doi-asserted-by":"publisher","first-page":"3042","DOI":"10.1093\/brain\/awl279","article-title":"Proteome-based plasma biomarkers for Alzheimer\u2019s disease","volume":"129","author":"Hye","year":"2006","journal-title":"Brain"},{"key":"B14","doi-asserted-by":"publisher","first-page":"799.e2","DOI":"10.1016\/j.jalz.2014.05.1749","article-title":"Plasma proteins predict conversion to dementia from prodromal disease","volume":"10","author":"Hye","year":"2014","journal-title":"Alzheimers Dement."},{"key":"B16","doi-asserted-by":"publisher","first-page":"535","DOI":"10.1016\/j.jalz.2018.02.018","article-title":"NIA-AA research framework: toward a biological definition of Alzheimer\u2019s disease","volume":"14","author":"Jack","year":"2018","journal-title":"Alzheimers Dement."},{"key":"B17","doi-asserted-by":"publisher","first-page":"119","DOI":"10.1016\/S1474-4422(09)70299-6","article-title":"Hypothetical model of dynamic biomarkers of the Alzheimer\u2019s pathological cascade","volume":"9","author":"Jack","year":"2010","journal-title":"Lancet Neurol."},{"key":"B18","doi-asserted-by":"publisher","first-page":"149","DOI":"10.1001\/jamaneurol.2020.4201","article-title":"Associations of plasma phospho-Tau217 levels with tau positron emission tomography in early Alzheimer disease","volume":"78","author":"Janelidze","year":"2021","journal-title":"JAMA Neurol."},{"key":"B19","doi-asserted-by":"publisher","first-page":"474","DOI":"10.2337\/diabetes.53.2.474","article-title":"Increased risk of type 2 diabetes in Alzheimer disease","volume":"53","author":"Janson","year":"2004","journal-title":"Diabetes"},{"key":"B20","doi-asserted-by":"publisher","first-page":"429","DOI":"10.1038\/s41380-020-00923-z","article-title":"Diagnostic performance and prediction of clinical progression of plasma phospho-tau181 in the Alzheimer\u2019s Disease Neuroimaging Initiative","volume":"26","author":"Karikari","year":"2021","journal-title":"Mol. Psychiatry"},{"key":"B21","doi-asserted-by":"publisher","first-page":"422","DOI":"10.1016\/S1474-4422(20)30071-5","article-title":"Blood phosphorylated tau 181 as a biomarker for Alzheimer\u2019s disease: a diagnostic performance and prediction modelling study using data from four prospective cohorts","volume":"19","author":"Karikari","year":"2020","journal-title":"Lancet Neurol."},{"key":"B22","doi-asserted-by":"publisher","first-page":"e44260","DOI":"10.1371\/journal.pone.0044260","article-title":"Plasma based markers of [11C] PiB-PET brain amyloid burden","volume":"7","author":"Kiddle","year":"2012","journal-title":"PLoS One"},{"key":"B23","doi-asserted-by":"publisher","first-page":"138797","DOI":"10.1155\/2012\/138797","article-title":"Human L-ficolin (ficolin-2) and its clinical significance","volume":"2012","author":"Kilpatrick","year":"2012","journal-title":"J. Biomed. Biotechnol."},{"key":"B24","doi-asserted-by":"publisher","first-page":"1705","DOI":"10.1523\/JNEUROSCI.5626-11.2012","article-title":"Contrast-enhanced magnetic resonance microangiography reveals remodeling of the cerebral microvasculature in transgenic ArcA\u03b2 mice","volume":"32","author":"Klohs","year":"2012","journal-title":"J. Neurosci."},{"key":"B25","doi-asserted-by":"publisher","first-page":"473","DOI":"10.1016\/s0531-5565(00)00113-3","article-title":"alpha2-macroglobulin in late-onset Alzheimer\u2019s disease","volume":"35","author":"Kovacs","year":"2000","journal-title":"Exp. Gerontol."},{"key":"B26","doi-asserted-by":"publisher","first-page":"177","DOI":"10.3233\/JAD-200900","article-title":"Blood-based ATN biomarkers of Alzheimer\u2019s disease: a meta-analysis","volume":"79","author":"Koychev","year":"2021","journal-title":"J. Alzheimers Dis."},{"key":"B27","doi-asserted-by":"publisher","first-page":"e3224","DOI":"10.1371\/journal.pone.0003224","article-title":"Localized-statistical quantification of human serum proteome associated with type 2 diabetes","volume":"3","author":"Li","year":"2008","journal-title":"PLoS One"},{"key":"B28","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.pneurobio.2012.06.007","article-title":"Blood and plasma-based proteomic biomarker research in Alzheimer\u2019s disease","author":"Lista","year":"2013","journal-title":"Prog. Neurobiol."},{"key":"B29","doi-asserted-by":"publisher","first-page":"1300","DOI":"10.2174\/1381612826666200114105515","article-title":"Blood-based biomarkers of Alzheimer\u2019s disease: the long and winding road","volume":"26","author":"Manzine","year":"2020","journal-title":"Curr. Pharm. Des."},{"key":"B30","doi-asserted-by":"publisher","first-page":"3234","DOI":"10.1093\/brain\/awaa286","article-title":"Longitudinal plasma p-tau217 is increased in early stages of Alzheimer\u2019s disease","volume":"143","author":"Mattsson-Carlgren","year":"2020","journal-title":"Brain"},{"key":"B32","doi-asserted-by":"publisher","first-page":"939","DOI":"10.1212\/wnl.34.7.939","article-title":"Clinical diagnosis of Alzheimer\u2019s disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer\u2019s Disease","volume":"34","author":"McKhann","year":"1984","journal-title":"Neurology"},{"key":"B31","doi-asserted-by":"publisher","first-page":"263","DOI":"10.1016\/j.jalz.2011.03.005","article-title":"The diagnosis of dementia due to Alzheimer\u2019s disease: recommendations from the National Institute on Aging-Alzheimer\u2019s association workgroups on diagnostic guidelines for Alzheimer\u2019s disease","volume":"7","author":"McKhann","year":"2011","journal-title":"Alzheimers Dement."},{"key":"B33","doi-asserted-by":"publisher","first-page":"249","DOI":"10.1038\/nature25456","article-title":"High performance plasma amyloid-\u03b2 biomarkers for Alzheimer\u2019s disease","volume":"554","author":"Nakamura","year":"2018","journal-title":"Nature"},{"key":"B34","doi-asserted-by":"publisher","first-page":"2911","DOI":"10.1111\/j.1582-4934.2008.00434.x","article-title":"A leaky blood-brain barrier, fibrinogen infiltration and microglial reactivity in inflamed Alzheimer\u2019s disease brain","volume":"13","author":"Ryu","year":"2009","journal-title":"J. Cell. Mol. Med."},{"key":"B35","doi-asserted-by":"publisher","first-page":"724","DOI":"10.1016\/j.jalz.2013.09.016","article-title":"Alzheimer\u2019s disease biomarker discovery using SOMAscan multiplexed protein technology","volume":"10","author":"Sattlecker","year":"2014","journal-title":"Alzheimers Dement."},{"key":"B36","doi-asserted-by":"publisher","first-page":"327","DOI":"10.1007\/s00702-018-01967-w","article-title":"Comparison of clinical and neuropathological diagnoses of neurodegenerative diseases in two centres from the brains for dementia research (BDR) cohort","volume":"126","author":"Selvackadunco","year":"2019","journal-title":"J. Neural Transm."},{"key":"B37","doi-asserted-by":"publisher","first-page":"1181","DOI":"10.3233\/JAD-170531","article-title":"A decade of blood biomarkers for Alzheimer\u2019s disease research: an evolving field, improving study designs and the challenge of replication","volume":"62","author":"Shi","year":"2018","journal-title":"J. Alzheimers Dis."},{"key":"B38","doi-asserted-by":"publisher","first-page":"60","DOI":"10.1016\/j.neurobiolaging.2020.05.011","article-title":"A longitudinal examination of plasma neurofilament light and total tau for the clinical detection and monitoring of Alzheimer\u2019s disease","volume":"94","author":"Sugarman","year":"2020","journal-title":"Neurobiol. Aging"},{"key":"B39","doi-asserted-by":"publisher","first-page":"1316","DOI":"10.1172\/JCI59903","article-title":"Demonstrated brain insulin resistance in Alzheimer\u2019s disease patients is associated with IGF-1 resistance, IRS-1 dysregulation and cognitive decline","volume":"122","author":"Talbot","year":"2012","journal-title":"J. Clin. Invest."},{"key":"B40","doi-asserted-by":"publisher","first-page":"e28527","DOI":"10.1371\/journal.pone.0028527","article-title":"Plasma biomarkers of brain atrophy in Alzheimer\u2019s disease","volume":"6","author":"Thambisetty","year":"2011","journal-title":"PLoS One"},{"key":"B41","doi-asserted-by":"publisher","first-page":"739","DOI":"10.1001\/archgenpsychiatry.2010.78","article-title":"Association of plasma clusterin concentration with severity, pathology and progression in Alzheimer disease","volume":"67","author":"Thambisetty","year":"","journal-title":"Arch. Gen. Psychiatry"},{"key":"B42","doi-asserted-by":"publisher","first-page":"1099","DOI":"10.3233\/JAD-2010-101350","article-title":"Proteome-based plasma markers of brain amyloid-beta deposition in non-demented older individuals","volume":"22","author":"Thambisetty","year":"","journal-title":"J. Alzheimers Dis."},{"key":"B43","doi-asserted-by":"publisher","first-page":"387","DOI":"10.1038\/s41591-020-0762-2","article-title":"Diagnostic value of plasma phosphorylated tau181 in Alzheimer\u2019s disease and frontotemporal lobar degeneration","volume":"26","author":"Thijssen","year":"2020","journal-title":"Nat. Med."},{"key":"B44","doi-asserted-by":"publisher","first-page":"fcab008","DOI":"10.1093\/braincomms\/fcab008","article-title":"Detection of \u03b2-amyloid positivity in Alzheimer\u2019s Disease Neuroimaging Initiative participants with demographics, cognition, MRI and plasma biomarkers","volume":"3","author":"Tosun","year":"2021","journal-title":"Brain Commun."},{"key":"B45","doi-asserted-by":"publisher","first-page":"1","DOI":"10.18637\/jss.v036.i03","article-title":"Conducting meta-analyses in R with the metafor package","volume":"36","author":"Viechtbauer","year":"2010","journal-title":"J. Stat. Soft."},{"key":"B47","doi-asserted-by":"publisher","first-page":"213","DOI":"10.3233\/JAD-190434","article-title":"Validation of plasma proteomic biomarkers relating to brain amyloid burden in the EMIF-Alzheimer\u2019s disease multimodal biomarker discovery cohort","volume":"74","author":"Westwood","year":"2020","journal-title":"J. Alzheimers Dis."},{"key":"B46","doi-asserted-by":"publisher","first-page":"409","DOI":"10.3389\/fnagi.2018.00409","article-title":"Plasma protein biomarkers for the prediction of csf amyloid and tau and [18F]-flutemetamol PET scan result","volume":"10","author":"Westwood","year":"2018","journal-title":"Front. Aging Neurosci."},{"key":"B49","doi-asserted-by":"publisher","first-page":"561","DOI":"10.3233\/JAD-151155","article-title":"Blood-based biomarker candidates of cerebral amyloid using PiB PET in non-demented elderly","volume":"52","author":"Westwood","year":"2016","journal-title":"J. Alzheimers Dis."},{"key":"B48","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1186\/s13195-017-0258-6","article-title":"The influence of insulin resistance on cerebrospinal fluid and plasma biomarkers of Alzheimer\u2019s pathology","volume":"9","author":"Westwood","year":"2017","journal-title":"Alzheimers Res. Ther."},{"key":"B50","doi-asserted-by":"publisher","first-page":"26","DOI":"10.1186\/s13041-019-0448-1","article-title":"Blood-based molecular biomarkers for Alzheimer\u2019s disease","volume":"12","author":"Zetterberg","year":"2019","journal-title":"Mol. Brain"},{"key":"B51","doi-asserted-by":"publisher","first-page":"295","DOI":"10.1007\/s00592-015-0780-6","article-title":"Low levels of ficolin-3 are associated with diabetic peripheral neuropathy","volume":"53","author":"Zhang","year":"2016","journal-title":"Acta Diabetol."}],"container-title":["Frontiers in Aging Neuroscience"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnagi.2021.712545\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,7,21]],"date-time":"2021-07-21T15:27:35Z","timestamp":1626881255000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnagi.2021.712545\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,7,21]]},"references-count":51,"alternative-id":["10.3389\/fnagi.2021.712545"],"URL":"https:\/\/doi.org\/10.3389\/fnagi.2021.712545","relation":{},"ISSN":["1663-4365"],"issn-type":[{"value":"1663-4365","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,7,21]]},"article-number":"712545"}}