{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,2,2]],"date-time":"2026-02-02T05:54:09Z","timestamp":1770011649833,"version":"3.49.0"},"posted":{"date-parts":[[2026,1,29]]},"group-title":"Epidemiology","reference-count":53,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,1,29]],"date-time":"2026-01-29T00:00:00Z","timestamp":1769644800000},"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":[[2026,1,29]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Untargeted mass spectrometry remains underutilised for blood-based biomarker discovery in dementia research from large cohorts, where affinity-based approaches dominate. To address this, we examined mass-spectrometry\u2013derived proteomic correlates of cognitive function, genetic predisposition to cognitive health,\n                  <jats:italic>APOE<\/jats:italic>\n                  \u03b54 status, and incident dementia. Using multivariate Bayesian regression, we assessed associations between 439 independent mass spectrometry signals and five cognitive outcomes\u2014four cognitive tests and a cognitive function polygenic score\u2014in Generation Scotland (n = 14,258). We observed associations between three cognitive tests (digit symbol, vocabulary and verbal fluency) and a mass spectrometry signal that mapped to selenoprotein P (absolute \u03b2\n                  <jats:sub>range<\/jats:sub>\n                  = 0.02 \u2013 0.03, posterior inclusion probability \u2265 0.95). Carrying one or two copies of the\n                  <jats:italic>APOE<\/jats:italic>\n                  \u03b54 allele was associated with a lower mass spectrometry signal that mapped to afamin (\u03b2 = -0.08 and -0.2, respectively, p &lt; 3.1 x 10\n                  <jats:sup>-4<\/jats:sup>\n                  , n = 14,745). A higher mass spectrometry signal that maps to both complement c2 and complement factor B proteins was associated with lower hazard for incident dementia (hazard ratio = 0.75, p &lt; 3.1 x 10\n                  <jats:sup>-4<\/jats:sup>\n                  , n\n                  <jats:sub>cases<\/jats:sub>\n                  = 212 and n\n                  <jats:sub>controls<\/jats:sub>\n                  = 6,765) diagnosed up to 17 years after blood sampling. We identified specific independent mass spectrometry signals which may be candidate biomarkers of cognitive function,\n                  <jats:italic>APOE<\/jats:italic>\n                  \u03b54 status, and could aid in the early detection of dementia; however, further replication studies in other populations are required.\n                <\/jats:p>","DOI":"10.64898\/2026.01.27.26344912","type":"posted-content","created":{"date-parts":[[2026,1,30]],"date-time":"2026-01-30T00:15:20Z","timestamp":1769732120000},"source":"Crossref","is-referenced-by-count":0,"title":["Proteomic biomarkers of cognitive function,\n                  <i>APOE<\/i>\n                  \u03b54 status, and dementia in Generation Scotland"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2972-821X","authenticated-orcid":false,"given":"Hannah M.","family":"Smith","sequence":"first","affiliation":[{"name":"Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0404-6295","authenticated-orcid":false,"given":"Joanna E.","family":"Moodie","sequence":"additional","affiliation":[{"name":"Lothian Birth Cohorts, Department of Psychology, University of Edinburgh, Edinburgh, UK"},{"name":"Lothian Birth Cohorts, Edinburgh Futures Institute, University of Edinburgh, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gail","family":"Davies","sequence":"additional","affiliation":[{"name":"Lothian Birth Cohorts, Department of Psychology, University of Edinburgh, Edinburgh, UK"},{"name":"Lothian Birth Cohorts, Edinburgh Futures Institute, University of Edinburgh, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anne","family":"Richmond","sequence":"additional","affiliation":[{"name":"Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Josephine A.","family":"Robertson","sequence":"additional","affiliation":[{"name":"Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aleksandra D.","family":"Chybowska","sequence":"additional","affiliation":[{"name":"Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Camilla","family":"Drake","sequence":"additional","affiliation":[{"name":"MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Poppy","family":"Adkin","sequence":"additional","affiliation":[{"name":"Eliptica Limited, The London Cancer Hub, Cotswold Road, Sutton, London, UK"},{"name":"MRC Clinical Trials Unit, University College London, London, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Spyros I.","family":"Vernardis","sequence":"additional","affiliation":[{"name":"Eliptica Limited, The London Cancer Hub, Cotswold Road, Sutton, London, UK"},{"name":"The Francis Crick Institute, Molecular Biology of Metabolism Laboratory, London, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Arturas","family":"Grauslys","sequence":"additional","affiliation":[{"name":"Eliptica Limited, The London Cancer Hub, Cotswold Road, Sutton, London, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matthew E. H.","family":"White","sequence":"additional","affiliation":[{"name":"The Francis Crick Institute, Molecular Biology of Metabolism Laboratory, London, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sergej","family":"Andrejev","sequence":"additional","affiliation":[{"name":"Eliptica Limited, The London Cancer Hub, Cotswold Road, Sutton, London, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Charles","family":"Brigden","sequence":"additional","affiliation":[{"name":"Eliptica Limited, The London Cancer Hub, Cotswold Road, Sutton, London, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christoph B.","family":"Messner","sequence":"additional","affiliation":[{"name":"The Francis Crick Institute, Molecular Biology of Metabolism Laboratory, London, UK"},{"name":"Precision Proteomics Centre, Swiss Institute of Allergy and Asthma Research, University of Zurich, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Caroline","family":"Hayward","sequence":"additional","affiliation":[{"name":"MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aleksej","family":"Zelezniak","sequence":"additional","affiliation":[{"name":"Eliptica Limited, The London Cancer Hub, Cotswold Road, Sutton, London, UK"},{"name":"The Francis Crick Institute, Molecular Biology of Metabolism Laboratory, London, UK"},{"name":"Department of Biology and Biological Engineering, Chalmers University of Technology, Gothenburg, Sweden"},{"name":"Randall Centre for Cell & Molecular Biophysics, King\u2019s College London, New Hunt\u2019s House, Guy\u2019s Campus, SE1 1UL London, UK"},{"name":"Institute of Biotechnology, Life Sciences Centre, Vilnius University, Sauletekio al. 7, LT10257, Vilnius, Lithuania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Markus","family":"Ralser","sequence":"additional","affiliation":[{"name":"Eliptica Limited, The London Cancer Hub, Cotswold Road, Sutton, London, UK"},{"name":"The Francis Crick Institute, Molecular Biology of Metabolism Laboratory, London, UK"},{"name":"Institute of Biotechnology, Life Sciences Centre, Vilnius University, Sauletekio al. 7, LT10257, Vilnius, Lithuania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ilse","family":"Kr\u00e4tschmer","sequence":"additional","affiliation":[{"name":"Institute of Science and Technology Austria, Am Campus 1, 3400 Klosterneuburg, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matthew R.","family":"Robinson","sequence":"additional","affiliation":[{"name":"Institute of Science and Technology Austria, Am Campus 1, 3400 Klosterneuburg, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Simon 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