{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T00:12:37Z","timestamp":1789171957613,"version":"build-2803163510"},"posted":{"date-parts":[[2026,9,9]]},"group-title":"Genetics","reference-count":51,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T00:00:00Z","timestamp":1788912000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"award":["DK-52574"],"award-info":[{"award-number":["DK-52574"]}],"id":[{"id":"https:\/\/ror.org\/001d55x84","id-type":"ROR","asserted-by":"publisher"}]},{"award":["DK-119437"],"award-info":[{"award-number":["DK-119437"]}],"id":[{"id":"https:\/\/ror.org\/001d55x84","id-type":"ROR","asserted-by":"publisher"}]},{"award":["HL-151328"],"award-info":[{"award-number":["HL-151328"]}],"id":[{"id":"https:\/\/ror.org\/001d55x84","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,9,9]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Variants in the human\n                  <jats:italic>APOE<\/jats:italic>\n                  gene govern the risk of Alzheimer\u2019s disease and other disorders. Three major\n                  <jats:italic>APOE<\/jats:italic>\n                  variants in humans reflect C\u2192T replacements at two positions in a single exon: an upstream variant (AE4 site) that differs between the ancestral APOE\n                  <jats:italic>\u03b54<\/jats:italic>\n                  allele (\n                  <jats:italic>APOE4<\/jats:italic>\n                  ) (C) and human-specific\n                  <jats:italic>APOE2<\/jats:italic>\n                  \/\n                  <jats:italic>E3<\/jats:italic>\n                  (T), and a downstream variant (AE2 site) that differentiates\n                  <jats:italic>APOE3<\/jats:italic>\n                  \/\n                  <jats:italic>E4<\/jats:italic>\n                  (C)from\n                  <jats:italic>APOE2<\/jats:italic>\n                  (T). It has long been assumed that\n                  <jats:italic>APOE<\/jats:italic>\n                  allelotypes are genomically encoded, but here we report that multiple individuals express brain\n                  <jats:italic>APOE<\/jats:italic>\n                  C or U\/T variant transcripts that differ from genomically templated versions. We demonstrate up to 10% C\u2192U or U\u2192C nucleotide replacement at AE4 and AE2, but not at other sites, and with no corresponding changes in genomic DNA. Single-cell transcriptomic datasets from brain microglia revealed sporadic (up to \u223c8%) C\u2192U replacement at AE2. We found 0.4\u20131.6% of brain transcripts in human\n                  <jats:italic>APOE<\/jats:italic>\n                  knock-in mice harbor selective C\u2192U changes at either AE4 or AE2 sites. Transfection of HepG2 or Huh7 cells with either mouse or human APOBEC1 led to efficient (&gt;90%) C\u2192U editing of\n                  <jats:italic>APOE4<\/jats:italic>\n                  mRNA at the AE4 but not AE2 site, with lower (&lt;10%) C\u2192T editing of genomic DNA at the AE4 site by mouse, but not human, APOBEC1. Furthermore, interrogation of proteomic datasets revealed up to 4% of non-genomically encoded APOE peptides in human plasma, indicating that the edited\n                  <jats:italic>APOE<\/jats:italic>\n                  transcripts are functional\n                  <jats:italic>in vivo<\/jats:italic>\n                  . These data suggest that\n                  <jats:italic>APOE<\/jats:italic>\n                  mRNA is subject to RNA editing that interconverts the different allelic forms of\n                  <jats:italic>APOE<\/jats:italic>\n                  .\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>Author summary<\/jats:title>\n                  <jats:p>\n                    Human\n                    <jats:italic>APOE<\/jats:italic>\n                    gene variants govern the risk of Alzheimer\u2019s disease (AD) and other disorders. Three alleles are widespread: ancestral\n                    <jats:italic>E4<\/jats:italic>\n                    and human-specific\n                    <jats:italic>E3<\/jats:italic>\n                    and\n                    <jats:italic>E2<\/jats:italic>\n                    . AD risk declines in the order\n                    <jats:italic>E4<\/jats:italic>\n                    &gt;\n                    <jats:italic>E3<\/jats:italic>\n                    &gt;\n                    <jats:italic>E2<\/jats:italic>\n                    . It has been assumed that the\n                    <jats:italic>APOE<\/jats:italic>\n                    allotype we inherit is laid down at birth, but we report that\n                    <jats:italic>APOE<\/jats:italic>\n                    mRNA is enzymatically edited to convert\n                    <jats:italic>E4<\/jats:italic>\n                    to\n                    <jats:italic>E3<\/jats:italic>\n                    \/\n                    <jats:italic>E2<\/jats:italic>\n                    , and\/or\n                    <jats:italic>E2<\/jats:italic>\n                    to\n                    <jats:italic>E3<\/jats:italic>\n                    \/\n                    <jats:italic>E4<\/jats:italic>\n                    . Up to \u223c10% conversion was seen in brain, and up to 100%\n                    <jats:italic>in vitro<\/jats:italic>\n                    driven by the RNA-editing enzyme APOBEC1. Proteomic analysis of human plasma argues that edited\n                    <jats:italic>APOE<\/jats:italic>\n                    transcripts are functional\n                    <jats:italic>in vivo<\/jats:italic>\n                    .\n                  <\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.09.03.749263","type":"posted-content","created":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T13:05:12Z","timestamp":1788959112000},"source":"Crossref","is-referenced-by-count":0,"title":["mRNA editing of the Alzheimer\u2019s risk gene\n                  <i>APOE<\/i>"],"prefix":"10.64898","author":[{"given":"Val\u00e9rie","family":"Blanc","sequence":"first","affiliation":[{"name":"Division of Gastroenterology, Washington University School of Medicine, St. Louis, MO 63110, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samantha J.","family":"Griffiths","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology, Washington University School of Medicine, St. Louis, MO 63110, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J\u00fcrgen","family":"Haas","sequence":"additional","affiliation":[{"name":"Division of Infection Medicine, University of Edinburgh Medical School, Little France, Edinburgh, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas O.","family":"Davidson","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology, Washington University School of Medicine, St. Louis, MO 63110, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard","family":"Lathe","sequence":"additional","affiliation":[{"name":"Division of Infection Medicine, University of Edinburgh Medical School, Little France, Edinburgh, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026091116350889000_2026.09.03.749263v1.1","doi-asserted-by":"publisher","DOI":"10.1126\/science.8346443"},{"key":"2026091116350889000_2026.09.03.749263v1.2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.ne.19.030196.000413"},{"key":"2026091116350889000_2026.09.03.749263v1.3","doi-asserted-by":"crossref","first-page":"102954","DOI":"10.1016\/j.ebiom.2020.102954","article-title":"Apolipoprotein E (APOE) genotype-associated disease risks: a phenome-wide, registry-based, case-control study utilising the UK Biobank","volume":"59","year":"2020","journal-title":"EBioMedicine"},{"key":"2026091116350889000_2026.09.03.749263v1.4","doi-asserted-by":"publisher","DOI":"10.1093\/gerona\/gly174"},{"key":"2026091116350889000_2026.09.03.749263v1.5","doi-asserted-by":"crossref","first-page":"2677","DOI":"10.1002\/alz.13020","article-title":"APOE and immunity: research highlights","volume":"19","year":"2023","journal-title":"Alzheimers Dement"},{"key":"2026091116350889000_2026.09.03.749263v1.6","doi-asserted-by":"crossref","first-page":"1740","DOI":"10.1016\/S0022-2275(20)32160-X","article-title":"Apolipoprotein E-deficient mice have impaired innate immune responses to Listeria monocytogenes in vivo","volume":"39","year":"1998","journal-title":"J. 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