{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,4,20]],"date-time":"2026-04-20T15:44:03Z","timestamp":1776699843919,"version":"3.51.2"},"posted":{"date-parts":[[2026,4,17]]},"group-title":"Epidemiology","reference-count":63,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,4,17]],"date-time":"2026-04-17T00:00:00Z","timestamp":1776384000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,4,17]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>\n                    The apolipoprotein E (\n                    <jats:italic>APOE<\/jats:italic>\n                    ) locus is the strongest genetic risk factor for late-onset Alzheimer\u2019s disease (AD). Variation in\n                    <jats:italic>APOE<\/jats:italic>\n                    isoforms is known to have diverse pleiotropic effects on circulating lipids and other metabolites, but effects on the circulating proteome across the life course are not well characterised. We investigated the specific effects of\n                    <jats:italic>APOE<\/jats:italic>\n                    \u03b54 and\n                    <jats:italic>APOE<\/jats:italic>\n                    \u03b52 carriage on the circulating proteome in middle-age and later life.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>\n                    In primary modelling, we analysed associations of\n                    <jats:italic>APOE<\/jats:italic>\n                    \u03b54 and \u03b52 carriage (reference \u03b53\/\u03b53) with circulating proteins in UK Biobank participants (\n                    <jats:italic>N<\/jats:italic>\n                    = 42,642; age = 39.1 to 70.9 years). Using multivariable linear regression, we conducted ancestry-specific analyses of 2,922 assayed plasma proteins across individuals of European (EUR), African (AFR), and South Asian (SAS) ancestry. To identify age-dependent effects, stratified analyses were performed with the sample split into age groups. We then performed replication analyses of\n                    <jats:italic>APOE<\/jats:italic>\n                    -associated proteins in age-matched groups, using data from two independent UK-based cohorts.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>\n                    We identified 351 proteins associated with \u03b52 carriage and 480 with \u03b54 carriage among individuals of European ancestry (\n                    <jats:italic>n<\/jats:italic>\n                    = 40,092); 130 of these were associated with both \u03b52 and \u03b54 carriage (with either consistent or inverse association directions). These included established biomarkers of neurodegeneration (GFAP and NEFL) and other proteins implicated by AD genetic risk loci (e.g., TREM2, CTSB, IDUA, SORT1, GRN). Many of these proteins are linked to other neurodegenerative diseases besides AD. In multiple age groups, \u03b54 carriage was strongly associated with consistent differences in circulating APOE, MENT, and PLA2G7 levels across ancestries and cohorts.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>\n                    <jats:italic>APOE<\/jats:italic>\n                    \u03b54 and \u03b52 exert broad, often age-dependent effects on the plasma proteome, detectable decades before typical ages of AD diagnoses, highlighting a potential early window for monitoring and intervention.\n                  <\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.04.16.26351010","type":"posted-content","created":{"date-parts":[[2026,4,17]],"date-time":"2026-04-17T23:15:19Z","timestamp":1776467719000},"source":"Crossref","is-referenced-by-count":0,"title":["Plasma proteomics of\n                  <i>APOE<\/i>\n                  genotype: age-specific analyses in UK population-based cohorts"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3783-1943","authenticated-orcid":false,"given":"Amy","family":"Packer","sequence":"first","affiliation":[{"name":"Unit for Lifelong Health & Ageing, University College London, London, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tahsina","family":"Khatun","sequence":"additional","affiliation":[{"name":"Unit for Lifelong Health & Ageing, University College London, London, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"James W","family":"Groves","sequence":"additional","affiliation":[{"name":"Dementia Research Centre, UCL Queen Square Institute of Neurology, University College London, London, United Kingdom"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5893-0831","authenticated-orcid":false,"given":"Tony","family":"Wyss-Coray","sequence":"additional","affiliation":[{"name":"Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA, USA"},{"name":"The Phil and Penny Knight Initiative for Brain Resilience, Stanford University, Stanford, CA, USA"},{"name":"Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jonathan M","family":"Schott","sequence":"additional","affiliation":[{"name":"Dementia Research Centre, UCL Queen Square Institute of Neurology, University College London, London, United Kingdom"},{"name":"UK Dementia Research Institute at UCL, University College London, London, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Petroula","family":"Proitsi","sequence":"additional","affiliation":[{"name":"Centre for Preventive Neurology, Wolfson Institute of Population Health, Queen Mary University of London, London, UK"},{"name":"Department of Basic and Clinical Neuroscience, King\u2019s College London, London, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emma L","family":"Anderson","sequence":"additional","affiliation":[{"name":"Division of Psychiatry, University College London, London, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dylan M","family":"Williams","sequence":"additional","affiliation":[{"name":"Unit for Lifelong Health & Ageing, University College London, London, UK"},{"name":"Division of Psychiatry, University College London, London, 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