{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,1,25]],"date-time":"2026-01-25T23:29:01Z","timestamp":1769383741456,"version":"3.49.0"},"posted":{"date-parts":[[2025,5,23]]},"group-title":"Neurology","reference-count":49,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,5,23]],"date-time":"2025-05-23T00:00:00Z","timestamp":1747958400000},"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":[[2025,5,23]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>\n                    Recent genome-wide association studies (GWAS) for Alzheimer\u2019s Disease and related dementias (ADRD) have increased statistical power via larger analysis datasets from biobanks by 1) including non-age-matched controls and prevalent cases, and\/or 2) including individuals who report a family history of ADRD as proxy cases. However, these methods have the potential to increase noise and distort genetic associations which are important for genomic-informed prevention and treatment of ADRD. Here, we sought to understand how the effect sizes of genetic associations in ADRD could be sensitive to these methodological choices, using\n                    <jats:italic>APOE<\/jats:italic>\n                    genotypes as an example.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>\n                    Participants in the\n                    <jats:italic>All of Us<\/jats:italic>\n                    Research Program over the age of 49 at enrollment (n=258,693) were assigned one of four categories: incident ADRD (developed after enrollment in\n                    <jats:italic>All of Us<\/jats:italic>\n                    ), prevalent ADRD (present on enrollment), proxy ADRD (participant noted a family history of ADRD), and control (no history or diagnosis of ADRD). Dementia diagnoses were determined using available Electronic Health Records (EHR) and\n                    <jats:italic>APOE<\/jats:italic>\n                    genotype was determined using whole-genome sequencing. Effect sizes for the associations between\n                    <jats:italic>APOE<\/jats:italic>\n                    risk alleles and ADRD diagnoses were compared using polychotomous logistic regression.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>\n                    The mean age of the cohort was 67\u00b110 years, and it was 58% female; 63% clustered predominantly with European genetic reference populations. Among the participants, 3,107 (1.2%) had prevalent ADRD, 301 (0.1%) had incident ADRD, and 19,910 (7.7%) reported a family history of ADRD (proxy ADRD). Both prevalent and proxy ADRD had attenuated associations with\n                    <jats:italic>APOE<\/jats:italic>\n                    genotype compared to incident ADRD. The adjusted generalized ratio (95% CI) (AGR) for incident ADRD for\n                    <jats:italic>APOE<\/jats:italic>\n                    \u03b54 heterozygotes was 2.95 (2.31-3.74) compared to 2.10 (1.96-2.24) and 1.42 (1.32-1.55) for proxy and prevalent ADRD, respectively. For\n                    <jats:italic>APOE<\/jats:italic>\n                    \u03b54 homozygotes, the effect sizes were even more different. Furthermore,\n                    <jats:italic>APOE<\/jats:italic>\n                    association effect sizes increased when restricting the control (no ADRD) group to older age brackets.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>\n                    Our study highlights how genetic associations with ADRD can be sensitive to how cases are defined in biobanks like\n                    <jats:italic>All of Us<\/jats:italic>\n                    , with effect sizes downwardly biased when using prevalent or by-proxy cases compared to incident cases.\n                  <\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2025.05.22.25328175","type":"posted-content","created":{"date-parts":[[2025,5,23]],"date-time":"2025-05-23T19:10:14Z","timestamp":1748027414000},"source":"Crossref","is-referenced-by-count":0,"title":["Downward bias in the association between APOE and Alzheimer\u2019s Disease using prevalent and by-proxy disease sampling in the All of Us Research Program"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0135-7576","authenticated-orcid":false,"given":"Clayton O.","family":"Mansel","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Valentina","family":"Ghisays","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jonathan D.","family":"Mahnken","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Russell H.","family":"Swerdlow","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eric M.","family":"Reiman","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jason H.","family":"Karnes","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joshua C.","family":"Denny","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Olivia J.","family":"Veatch","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2025052523151176000_2025.05.22.25328175v1.1","unstructured":"Alzheimer\u2019s Association. 2024 Alzheimer\u2019s Association Facts and Figures. 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