{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,4]],"date-time":"2026-05-04T20:31:43Z","timestamp":1777926703776,"version":"3.51.4"},"reference-count":47,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,7,6]],"date-time":"2022-07-06T00:00:00Z","timestamp":1657065600000},"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>Fibrinogen is reportedly associated with neurodegenerative diseases (NDs), but the underlying causality remains controversial. Using Mendelian randomization (MR), this study aimed to assess the causal association between fibrinogen and Alzheimer\u2019s disease (AD), Parkinson\u2019s disease (PD), and Lewy body dementia (LBD). Genetic variants associated with fibrinogen and \u03b3-fibrinogen were selected and used as instrumental variables. The effect estimates of the main analysis were obtained by inverse-variance weighting (IVW), complemented by sensitivity analyses to verify model assumptions, and multivariable MR was conducted to control for potential pleiotropic effect. Two-step MR was performed to assess the causal association through mediators. The main analysis suggested no causal association between genetically predicted plasma fibrinogen and \u03b3-fibrinogen levels and the risk of AD, PD, and LBD. The effect estimates did not change in the follow-up sensitivity analyses and MVMR. However, the two-step MR analysis provides evidence that fibrinogen may contribute to the risk of AD via CRP levels. There was an inverse effect of adult height levels on the risk of AD. Our results support the effects of fibrinogen on the risk of AD through increasing plasma CRP levels. Our study found no evidence to support the effects of genetically determined fibrinogen and \u03b3-fibrinogen levels on the risk of PD and LBD. Additionally, our findings suggested an inverse association between genetically determined adult height levels and the risk of AD. Future studies are needed to elucidate the underlying mechanisms and their clinical applications.<\/jats:p>","DOI":"10.3389\/fnagi.2022.847583","type":"journal-article","created":{"date-parts":[[2022,7,7]],"date-time":"2022-07-07T01:04:42Z","timestamp":1657155882000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":4,"title":["Fibrinogen in Alzheimer\u2019s Disease, Parkinson\u2019s Disease and Lewy Body Dementia: A Mendelian Randomization Study"],"prefix":"10.3389","volume":"14","author":[{"given":"Hanyu","family":"Zhang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zengyuan","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2022,7,6]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"2925","DOI":"10.2174\/092986707782360015","article-title":"Fibrinogen signal transduction as a mediator and therapeutic target in inflammation: lessons from multiple sclerosis.","volume":"14","author":"Adams","year":"2007","journal-title":"Curr. Med. Chem."},{"key":"B2","doi-asserted-by":"publisher","first-page":"151","DOI":"10.1111\/imm.12233","article-title":"Inflammation in neurodegenerative diseases\u2013an update.","volume":"142","author":"Amor","year":"2014","journal-title":"Immunology"},{"key":"B3","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1097\/00019442-200502000-00005","article-title":"Relationship between body height and dementia.","volume":"13","author":"Beeri","year":"2005","journal-title":"Am. J. Geriatr. Psychiatry"},{"key":"B4","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1038\/ng.2606","article-title":"Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture.","volume":"45","author":"Berndt","year":"2013","journal-title":"Nat. Genet."},{"key":"B5","doi-asserted-by":"publisher","first-page":"512","DOI":"10.1093\/ije\/dyv080","article-title":"Mendelian randomization with invalid instruments: effect estimation and bias detection through Egger regression.","volume":"44","author":"Bowden","year":"2015","journal-title":"Int. J. Epidemiol."},{"key":"B6","doi-asserted-by":"publisher","first-page":"304","DOI":"10.1002\/gepi.21965","article-title":"Consistent estimation in mendelian randomization with some invalid instruments using a weighted median estimator.","volume":"40","author":"Bowden","year":"2016","journal-title":"Genet. Epidemiol."},{"key":"B7","doi-asserted-by":"publisher","first-page":"1264","DOI":"10.1093\/ije\/dyy101","article-title":"Improving the visualization, interpretation and analysis of two-sample summary data mendelian randomization via the radial plot and radial regression.","volume":"47","author":"Bowden","year":"2018","journal-title":"Int. J. Epidemiol."},{"key":"B8","doi-asserted-by":"publisher","first-page":"1497","DOI":"10.1093\/ije\/dyt179","article-title":"Calculating statistical power in mendelian randomization studies.","volume":"42","author":"Brion","year":"2013","journal-title":"Int. J. Epidemiol."},{"key":"B9","doi-asserted-by":"publisher","first-page":"D1005","DOI":"10.1093\/nar\/gky1120","article-title":"The NHGRI-EBI GWAS catalog of published genome-wide association studies, targeted arrays and summary statistics 2019.","volume":"47","author":"Buniello","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.12688\/wellcomeopenres.15555.2","article-title":"Guidelines for performing mendelian randomization investigations.","volume":"4","author":"Burgess","year":"2019","journal-title":"Wellcome open Res."},{"key":"B11","doi-asserted-by":"publisher","first-page":"4603","DOI":"10.1182\/blood-2009-08-236240","article-title":"Elevated fibrinogen gamma\u2019 ratio is associated with cardiovascular diseases and acute phase reaction but not with clinical outcome.","volume":"114","author":"Cheung","year":"2009","journal-title":"Blood"},{"key":"B12","doi-asserted-by":"publisher","first-page":"294","DOI":"10.1038\/s41588-021-00785-3","article-title":"Genome sequencing analysis identifies new loci associated with lewy body dementia and provides insights into its genetic architecture.","volume":"53","author":"Chia","year":"2021","journal-title":"Nat. Genet."},{"key":"B13","doi-asserted-by":"publisher","first-page":"303","DOI":"10.3233\/JAD-140816","article-title":"Are blood-based protein biomarkers for Alzheimer\u2019s disease also involved in other brain disorders? A systematic review.","volume":"43","author":"Chiam","year":"2015","journal-title":"J. Alzheimers Dis."},{"key":"B14","doi-asserted-by":"publisher","first-page":"668","DOI":"10.1038\/s41416-018-0371-8","article-title":"Adult height in relation to risk of cancer in a cohort of 22,809,722 Korean adults.","volume":"120","author":"Choi","year":"2019","journal-title":"Br. J. Cancer"},{"key":"B15","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1007\/s00281-011-0290-8","article-title":"Fibrinogen as a key regulator of inflammation in disease.","volume":"34","author":"Davalos","year":"2012","journal-title":"Semin. Immunopathol."},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1101\/2020.08.10.244293","article-title":"The MRC IEU OpenGWAS data infrastructure.","author":"Elsworth","year":"2020","journal-title":"bioRxiv"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1038\/s41398-021-01400-z","article-title":"Circulating biomarkers of immunity and inflammation, risk of Alzheimer\u2019s disease, and hippocampal volume: a mendelian randomization study.","volume":"11","author":"Fani","year":"2021","journal-title":"Transl. Psychiatry"},{"key":"B18","doi-asserted-by":"publisher","first-page":"877","DOI":"10.1016\/S1474-4422(17)30299-5","article-title":"Global, regional, and national burden of neurological disorders during 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015.","volume":"16","year":"2017","journal-title":"Lancet Neurol."},{"key":"B19","doi-asserted-by":"publisher","first-page":"691","DOI":"10.1093\/ije\/dyy202","article-title":"Contextualizing selection bias in mendelian randomization: how bad is it likely to be?","volume":"48","author":"Gkatzionis","year":"2019","journal-title":"Int. J. Epidemiol."},{"key":"B20","doi-asserted-by":"publisher","first-page":"918","DOI":"10.1016\/j.cell.2010.02.016","article-title":"Mechanisms underlying inflammation in neurodegeneration.","volume":"140","author":"Glass","year":"2010","journal-title":"Cell"},{"key":"B21","doi-asserted-by":"publisher","first-page":"2926","DOI":"10.1002\/sim.6522","article-title":"Detecting pleiotropy in mendelian randomisation studies with summary data and a continuous outcome.","volume":"34","author":"Greco","year":"2015","journal-title":"Stat. Med."},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.34408","article-title":"The MR-Base platform supports systematic causal inference across the human phenome.","volume":"7","author":"Hemani","year":"2018","journal-title":"eLife"},{"key":"B23","doi-asserted-by":"publisher","first-page":"404","DOI":"10.1038\/s41588-018-0311-9","article-title":"Genome-wide meta-analysis identifies new loci and functional pathways influencing Alzheimer\u2019s disease risk.","volume":"51","author":"Jansen","year":"2019","journal-title":"Nat. Genet."},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awac035","article-title":"Cancer diagnosis is associated with a lower burden of dementia and less Alzheimer\u2019s-type neuropathology.","author":"Karanth","year":"2022","journal-title":"Brain"},{"key":"B25","doi-asserted-by":"publisher","first-page":"691","DOI":"10.3233\/jad-170528","article-title":"Genetically-predicted adult height and Alzheimer\u2019s Disease.","volume":"60","author":"Larsson","year":"2017","journal-title":"J. Alzheimers Dis."},{"key":"B26","doi-asserted-by":"publisher","first-page":"3062","DOI":"10.1182\/blood.2019004781","article-title":"A Mendelian randomization of \u03b3\u2019 and total fibrinogen levels in relation to venous thromboembolism and ischemic stroke.","volume":"136","author":"Maners","year":"2020","journal-title":"Blood"},{"key":"B27","doi-asserted-by":"publisher","first-page":"1091","DOI":"10.1016\/S1474-4422(19)30320-5","article-title":"Identification of novel risk loci, causal insights, and heritable risk for Parkinson\u2019s disease: a meta-analysis of genome-wide association studies.","volume":"18","author":"Nalls","year":"2019","journal-title":"Lancet Neurol."},{"key":"B28","doi-asserted-by":"publisher","first-page":"283","DOI":"10.1038\/nrn.2018.13","article-title":"Fibrinogen in neurological diseases: mechanisms, imaging and therapeutics.","volume":"19","author":"Petersen","year":"2018","journal-title":"Nat. Rev. Neurosci."},{"key":"B29","doi-asserted-by":"publisher","first-page":"337","DOI":"10.3233\/jad-2007-11310","article-title":"Height and Alzheimer\u2019s disease: findings from a case-control study.","volume":"11","author":"Petot","year":"2007","journal-title":"J. Alzheimers Dis."},{"key":"B30","doi-asserted-by":"publisher","first-page":"1223","DOI":"10.1016\/0895-4356(91)90155-3","article-title":"How independent are \u201cindependent\u201d effects? Relative risk estimation when correlated exposures are measured imprecisely.","volume":"44","author":"Phillips","year":"1991","journal-title":"J. Clin. Epidemiol."},{"key":"B31","doi-asserted-by":"publisher","first-page":"1177","DOI":"10.1093\/aje\/kwt084","article-title":"Efficient design for mendelian randomization studies: subsample and 2-sample instrumental variable estimators.","volume":"178","author":"Pierce","year":"2013","journal-title":"Am. J. Epidemiol."},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-19996-z","article-title":"Genetic architecture of host proteins involved in SARS-CoV-2 infection.","volume":"11","author":"Pietzner","year":"2020","journal-title":"Nat. Commun."},{"key":"B33","doi-asserted-by":"crossref","first-page":"1310","DOI":"10.1161\/CIRCULATIONAHA.113.002251","article-title":"Multiethnic meta-analysis of genome-wide association studies in >100 000 subjects identifies 23 fibrinogen-associated loci but no strong evidence of a causal association between circulating fibrinogen and cardiovascular disease.","volume":"128","author":"Sabater-Lleal","year":"2013","journal-title":"Circulation"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a038984","article-title":"Multivariable mendelian randomization and mediation.","volume":"11","author":"Sanderson","year":"2021","journal-title":"Cold Spring Harb. Perspect. Med."},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1101\/716621","article-title":"Bias from competing risk before recruitment in mendelian randomization studies of conditions with shared etiology.","author":"Schooling","year":"2019","journal-title":"bioRxiv"},{"key":"B36","doi-asserted-by":"crossref","first-page":"605","DOI":"10.1055\/s-2000-13216","article-title":"Fibrin clot formation and lysis: basic mechanisms.","volume":"26","author":"Sidelmann","year":"2000","journal-title":"Semin. Thromb. Hemost."},{"key":"B37","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1093\/ije\/dyg070","article-title":"Mendelian randomization\u2019: can genetic epidemiology contribute to understanding environmental determinants of disease?","volume":"32","author":"Smith","year":"2003","journal-title":"Int. J. Epidemiol."},{"key":"B38","doi-asserted-by":"crossref","first-page":"3207","DOI":"10.1093\/bioinformatics\/btw373","article-title":"PhenoScanner: a database of human genotype-phenotype associations.","volume":"32","author":"Staley","year":"2016","journal-title":"Bioinformatics"},{"key":"B39","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1038\/s41586-018-0175-2","article-title":"Genomic atlas of the human plasma proteome.","volume":"558","author":"Sun","year":"2018","journal-title":"Nature"},{"key":"B40","doi-asserted-by":"publisher","first-page":"274","DOI":"10.1016\/j.parkreldis.2011.11.003","article-title":"Markers of inflammation in prevalent and incident parkinson\u2019s disease in the cardiovascular Health Study.","volume":"18","author":"Ton","year":"2012","journal-title":"Parkinsonism Relat Disord."},{"key":"B41","doi-asserted-by":"publisher","first-page":"761","DOI":"10.1093\/brain\/awu393","article-title":"Vascular and amyloid pathologies are independent predictors of cognitive decline in normal elderly.","author":"Vemuri","year":"2015","journal-title":"Brain"},{"key":"B42","doi-asserted-by":"publisher","first-page":"693","DOI":"10.1038\/s41588-018-0099-7","article-title":"Detection of widespread horizontal pleiotropy in causal relationships inferred from mendelian randomization between complex traits and diseases.","volume":"50","author":"Verbanck","year":"2018","journal-title":"Nat. Genet."},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.15252\/emmm.201810248","article-title":"Inflammasomes in neuroinflammatory and neurodegenerative diseases.","volume":"11","author":"Voet","year":"2019","journal-title":"EMBO Mole. Med."},{"key":"B44","doi-asserted-by":"publisher","first-page":"1173","DOI":"10.1038\/ng.3097","article-title":"Defining the role of common variation in the genomic and biological architecture of adult human height.","volume":"46","author":"Wood","year":"2014","journal-title":"Nat. Genet."},{"key":"B45","doi-asserted-by":"publisher","first-page":"1734","DOI":"10.1093\/ije\/dyx034","article-title":"MendelianRandomization: an R package for performing mendelian randomization analyses using summarized data.","volume":"46","author":"Yavorska","year":"2017","journal-title":"Int. J. Epidemiol."},{"key":"B46","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1016\/j.neurobiolaging.2021.08.010","article-title":"C-reactive protein and risk of Alzheimer\u2019s disease.","volume":"109","author":"Zhang","year":"2022","journal-title":"Neurobiol. Aging"},{"key":"B47","doi-asserted-by":"publisher","first-page":"353","DOI":"10.1016\/j.neubiorev.2020.02.022","article-title":"Fibrinogen and risk of dementia: a systematic review and meta-analysis.","volume":"112","author":"Zhou","year":"2020","journal-title":"Neurosci. Biobehav. Rev."}],"container-title":["Frontiers in Aging Neuroscience"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnagi.2022.847583\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,7,7]],"date-time":"2022-07-07T01:04:50Z","timestamp":1657155890000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnagi.2022.847583\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,7,6]]},"references-count":47,"alternative-id":["10.3389\/fnagi.2022.847583"],"URL":"https:\/\/doi.org\/10.3389\/fnagi.2022.847583","relation":{},"ISSN":["1663-4365"],"issn-type":[{"value":"1663-4365","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,7,6]]},"article-number":"847583"}}