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However, it remains largely unclear about the link between AD and COVID\u201019 outcomes. ACE2 is an entry receptor for SARS\u2010CoV\u20102. Circulating ACE2 is a novel biomarker of death and associated with COVID\u201019 outcomes.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Here, we explored the shared genetics and causal association between AD and plasma ACE2 levels using large\u2010scale genome\u2010wide association study, gene expression, expression quantitative trait loci, and high\u2010throughput plasma proteomic profiling datasets.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We found a significant causal effect of genetically increased circulating ACE2 on increased risk of AD. Cross\u2010trait association analysis identified 19 shared genetic variants, and three variants rs3104412, rs2395166, and rs3135344 at chromosome 6p21.32 were associated with COVID\u201019 infection, hospitalization, and severity. We mapped 19 variants to 117 genes, which were significantly upregulated in lung, spleen, and small intestine, downregulated in brain tissues, and involved in immune system, immune disease, and infectious disease pathways. The plasma proteins corresponding to <jats:italic>LST1<\/jats:italic>, <jats:italic>AGER<\/jats:italic>, <jats:italic>TNXB<\/jats:italic>, and <jats:italic>APOC1<\/jats:italic> were predominantly associated with COVID\u201019 infection, ventilation, and death.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Together, our findings suggest the shared genetics and causal association between AD and plasma ACE2 levels, which may partially explain the link between AD and COVID\u201019.<\/jats:p><\/jats:sec>","DOI":"10.1111\/cns.14873","type":"journal-article","created":{"date-parts":[[2024,7,26]],"date-time":"2024-07-26T09:00:02Z","timestamp":1721984402000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Shared genetics and causal association between plasma levels of <scp>SARS<\/scp>\u2010<scp>CoV<\/scp>\u20102 entry receptor <scp>ACE2<\/scp> and Alzheimer's disease"],"prefix":"10.1111","volume":"30","author":[{"given":"Yan","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Pathology The Affiliated Hospital of Weifang Medical University  Weifang China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fang","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Neurology, Xuanwu Hospital, National Center for Neurological Disorders Capital Medical University  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tao","family":"Wang","sequence":"additional","affiliation":[{"name":"Academy for Advanced Interdisciplinary Studies Peking University  Beijing China"},{"name":"Chinese Institute for Brain Research  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhifa","family":"Han","sequence":"additional","affiliation":[{"name":"Center of Respiratory Medicine, China\u2013Japan Friendship Hospital, National Center for Respiratory 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