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However, because of the confounding and reverse causality, the findings could be biased. We aimed to determine whether circulating amino acid levels have potential effects on the risk of neurodegenerative diseases through a more robust analysis. So, we performed a total of two MR analyses, a discovery two\u2010sample MR analysis, and a replication test, using summary\u2010level genome\u2010wide association study (GWAS) data, both with circulating levels of amino acids as exposure and risk of neurodegenerative diseases as an outcome. The potential causalities between nine amino acids (Glutamine [Glu], Leucine [Leu], Isoleucine [Ile], Phenylalanine [Phe], Valine [Val], Alanine [Ala], Tyrosine [Tyr], Histidine [His], and Glycine [Gly]) and six neurodegenerative disorders (Alzheimer's disease [AD], Parkinson's disease [PD], Multiple sclerosis [MS], Frontotemporal dementia [FTD], Lewy body dementia [DLB], Amyotrophic lateral sclerosis [ALS]) were explored in this study. According to the discovery MR analysis, 1 SD. increase in circulating levels of Gln was genetically determined to result in a 13% lower risk of AD (IVW OR<jats:sub>SD<\/jats:sub> [95% CI]\u2009=\u20090.872 [0.822, 0.926]; FDR\u2009=\u20097.46\u2009\u00d7\u200910<jats:sup>\u22125<\/jats:sup>) while PD risk was decreased to 63% per SD. increase of circulating Leu levels (IVW OR<jats:sub>SD<\/jats:sub> [95% CI]\u2009=\u20090.628 [0.467, 0.843]; FDR\u2009=\u20090.021). Results from the replication test provide further evidence of the potential association between circulating Gln levels and AD risk (IVW OR<jats:sub>SD<\/jats:sub> [95% CI]\u2009=\u20090.094 [0.028, 0.311]; FDR\u2009=\u20099.98\u2009\u00d7\u200910<jats:sup>\u22124<\/jats:sup>). Meanwhile, sensitivity analysis demonstrated that the significant relationships revealed by our two\u2010sample MR outcomes were reliable. Our analyses provided robust evidence of causal associations between circulating levels of Gln and AD risk as well as circulating Leu levels and risk of PD. However, the underlying mechanisms remain to be further investigated.<jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc15937-fig-0004-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text><\/jats:p>","DOI":"10.1111\/jnc.15937","type":"journal-article","created":{"date-parts":[[2023,8,11]],"date-time":"2023-08-11T14:41:25Z","timestamp":1691764885000},"page":"972-981","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["The causal role of circulating amino acids on neurodegenerative disorders: A two\u2010sample Mendelian randomization study"],"prefix":"10.1111","volume":"166","author":[{"given":"Ji\u2010Yun","family":"Cheng","sequence":"first","affiliation":[{"name":"Department of Neurology and National Center for Neurological Disorders, Huashan Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science Shanghai Medical College, Fudan University  Shanghai China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yue\u2010Ting","family":"Deng","sequence":"additional","affiliation":[{"name":"Department of Neurology and National Center for Neurological Disorders, Huashan Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science Shanghai Medical College, Fudan University  Shanghai China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7686-0547","authenticated-orcid":false,"given":"Jin\u2010Tai","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Neurology and National Center for Neurological Disorders, Huashan Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science Shanghai Medical College, Fudan 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