{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,6,5]],"date-time":"2026-06-05T10:59:58Z","timestamp":1780657198300,"version":"3.54.1"},"posted":{"date-parts":[[2026,6,2]]},"group-title":"Genetic and Genomic Medicine","reference-count":47,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,6,2]],"date-time":"2026-06-02T00:00:00Z","timestamp":1780358400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.medrxiv.org\/about\/FAQ#license"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["P30 AG072973"],"award-info":[{"award-number":["P30 AG072973"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["T32 AG078114"],"award-info":[{"award-number":["T32 AG078114"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["P20 GM130423"],"award-info":[{"award-number":["P20 GM130423"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["5UL1TR002366"],"award-info":[{"award-number":["5UL1TR002366"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["P30 AG035982"],"award-info":[{"award-number":["P30 AG035982"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,6,2]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>A recent Lancet Commission estimated that up to 45% of Alzheimer\u2019s Disease and Related Dementias (ADRD) cases could be prevented by addressing modifiable lifestyle risk factors. Meanwhile, genome-wide association studies (GWAS) have shown that common genetic variants also account for substantial ADRD risk. Whether a favorable lifestyle can offset risk in genetically predisposed individuals remains unclear.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>\n                    We conducted a retrospective cohort study of 105,886 participants from the\n                    <jats:italic>All of Us<\/jats:italic>\n                    Research Program enrolled between 2018\u20132023. Participants were over age 49, assigned male or female at birth, of European ancestry, and without ADRD at baseline. ADRD diagnoses were identified via electronic health records (EHR). Fourteen potentially modifiable risk factors for ADRD were assessed using surveys, EHR records, and wearable data. Genetic risk was quantified as a polygenic risk score (PRS) based on 81 independent GWAS loci and\n                    <jats:italic>APOE<\/jats:italic>\n                    \u03b54 genotype.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Overall, 967 incident ADRD events occurred over a median follow-up of 3.7 years. Ten out of 13 modifiable risk factors were significantly associated with ADRD. When grouped into risk factor profiles, intermediate and unfavorable modifiable risk factor scores were associated with substantially higher ADRD risk (HR 3.07, 95% CI 2.47\u20133.83; HR 8.01, 95% CI 6.39\u2013 10.05, respectively) compared to a favorable lifestyle; APOE \u03b54 dosage and polygenic risk score were also independently associated with ADRD risk. Among individuals in the highest polygenic risk group, a favorable lifestyle reduced ADRD risk from HR 18.63 (95% CI 10.25\u201333.86) to 1.90 (95% CI 0.94\u20133.81), whereas APOE \u03b54 homozygotes remained at elevated risk even with a favorable lifestyle (HR 6.52, 95% CI 2.97\u201314.33).<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>\n                    Our data suggest ADRD risk is driven more by modifiable risk factors and\n                    <jats:italic>APOE<\/jats:italic>\n                    genotype than polygenic risk score. Future genomic-informed risk assessments for ADRD should calibrate their findings to accurately identify high-risk individuals.\n                  <\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.06.01.26354634","type":"posted-content","created":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T03:55:11Z","timestamp":1780458911000},"source":"Crossref","is-referenced-by-count":0,"title":["A Favorable Modifiable Risk Factor Profile Mitigates Polygenic Risk for Alzheimer\u2019s Disease and Related Dementia"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0135-7576","authenticated-orcid":false,"given":"Clayton O.","family":"Mansel","sequence":"first","affiliation":[{"name":"Department of Cell Biology and Physiology, University of Kansas Medical Center, Kansas City, KS, USA"},{"name":"Alzheimer\u2019s Disease Research Center, University of Kansas Medical Center, Kansas City, KS, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Soniya","family":"Mishra","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Medical Informatics, University of Kansas Medical Center"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"Craver","sequence":"additional","affiliation":[{"name":"Institute for Population and Precision Health, Biological Science Division, The University of Chicago, Chicago, Illinois"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sebastian F.","family":"Salathe","sequence":"additional","affiliation":[{"name":"Department of Cell Biology and Physiology, University of Kansas Medical Center, Kansas City, KS, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John P.","family":"Thyfault","sequence":"additional","affiliation":[{"name":"Department of Cell Biology and Physiology, University of Kansas Medical Center, Kansas City, KS, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia A.","family":"Bauer","sequence":"additional","affiliation":[{"name":"Division of Epidemiology and Biostatistics, University of Illinois Chicago School of Public Health, Chicago, IL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diego R.","family":"Mazzotti","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Medical Informatics, University of Kansas Medical Center"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olivia J.","family":"Veatch","sequence":"additional","affiliation":[{"name":"Department of Cell Biology and Physiology, University of Kansas Medical Center, Kansas City, KS, USA"},{"name":"Alzheimer\u2019s Disease Research Center, University of Kansas Medical Center, Kansas City, KS, USA"},{"name":"Department of Internal Medicine, Division of Medical Informatics, University of Kansas Medical Center"},{"name":"Department of Psychiatry and Behavioral Sciences & Division of Medical Informatics, University of Kansas Medical Center, Kansas City, KS, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026060503000877000_2026.06.01.26354634v1.1","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-024-02796-z"},{"key":"2026060503000877000_2026.06.01.26354634v1.2","doi-asserted-by":"publisher","DOI":"10.1016\/j.gim.2023.100006"},{"key":"2026060503000877000_2026.06.01.26354634v1.3","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2026.02.018"},{"key":"2026060503000877000_2026.06.01.26354634v1.4","doi-asserted-by":"publisher","DOI":"10.1016\/j.xhgg.2025.100554"},{"key":"2026060503000877000_2026.06.01.26354634v1.5","unstructured":"World Health Organization. Global status report on the public response to dementia. Published online 2021."},{"key":"2026060503000877000_2026.06.01.26354634v1.6","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2212948"},{"key":"2026060503000877000_2026.06.01.26354634v1.7","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2023.13239"},{"key":"2026060503000877000_2026.06.01.26354634v1.8","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2025.12923"},{"key":"2026060503000877000_2026.06.01.26354634v1.9","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(15)60461-5"},{"key":"2026060503000877000_2026.06.01.26354634v1.10","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMsr1809937"},{"key":"2026060503000877000_2026.06.01.26354634v1.11","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pmed.1001779"},{"key":"2026060503000877000_2026.06.01.26354634v1.12","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.k4168"},{"key":"2026060503000877000_2026.06.01.26354634v1.13","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2019.9879"},{"key":"2026060503000877000_2026.06.01.26354634v1.14","doi-asserted-by":"publisher","DOI":"10.1136\/jnnp-2021-327396"},{"key":"2026060503000877000_2026.06.01.26354634v1.15","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-019-0547-7"},{"key":"2026060503000877000_2026.06.01.26354634v1.16","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-023-06957-x"},{"key":"2026060503000877000_2026.06.01.26354634v1.17","doi-asserted-by":"publisher","DOI":"10.7326\/0003-4819-153-9-201011020-00010"},{"key":"2026060503000877000_2026.06.01.26354634v1.18","unstructured":"Carlson C. Group Health Cooperative. Dementia. PheKB. https:\/\/phekb.org\/phenotype\/10"},{"key":"2026060503000877000_2026.06.01.26354634v1.19","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(24)01296-0"},{"key":"2026060503000877000_2026.06.01.26354634v1.20","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-021-00783-5"},{"key":"2026060503000877000_2026.06.01.26354634v1.21","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-024-01937-x"},{"key":"2026060503000877000_2026.06.01.26354634v1.22","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-022-01024-z"},{"key":"2026060503000877000_2026.06.01.26354634v1.23","doi-asserted-by":"publisher","DOI":"10.1186\/s12864-025-11693-9"},{"key":"2026060503000877000_2026.06.01.26354634v1.24","doi-asserted-by":"publisher","DOI":"10.1038\/s41380-023-02089-w"},{"key":"2026060503000877000_2026.06.01.26354634v1.25","doi-asserted-by":"publisher","DOI":"10.1001\/jamaneurol.2020.3536"},{"key":"2026060503000877000_2026.06.01.26354634v1.26","doi-asserted-by":"publisher","DOI":"10.1001\/jamanetworkopen.2024.40411"},{"key":"2026060503000877000_2026.06.01.26354634v1.27","doi-asserted-by":"publisher","DOI":"10.1007\/s11606-023-08102-w"},{"key":"2026060503000877000_2026.06.01.26354634v1.28","doi-asserted-by":"publisher","DOI":"10.1002\/ana.78060"},{"key":"2026060503000877000_2026.06.01.26354634v1.29","doi-asserted-by":"publisher","DOI":"10.1016\/j.jalz.2017.09.016"},{"key":"2026060503000877000_2026.06.01.26354634v1.30","doi-asserted-by":"publisher","DOI":"10.3233\/JAD-2011-110917"},{"key":"2026060503000877000_2026.06.01.26354634v1.31","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000201419"},{"key":"2026060503000877000_2026.06.01.26354634v1.32","doi-asserted-by":"publisher","DOI":"10.1016\/j.jad.2024.11.005"},{"key":"2026060503000877000_2026.06.01.26354634v1.33","doi-asserted-by":"publisher","DOI":"10.1192\/bjo.2019.100"},{"key":"2026060503000877000_2026.06.01.26354634v1.34","doi-asserted-by":"publisher","DOI":"10.1038\/s41562-023-01579-9"},{"key":"2026060503000877000_2026.06.01.26354634v1.35","doi-asserted-by":"publisher","DOI":"10.1097\/EDE.0000000000001316"},{"key":"2026060503000877000_2026.06.01.26354634v1.36","doi-asserted-by":"publisher","DOI":"10.1093\/aje\/kwx246"},{"key":"2026060503000877000_2026.06.01.26354634v1.37","doi-asserted-by":"publisher","DOI":"10.1093\/jamia\/ocad260"},{"key":"2026060503000877000_2026.06.01.26354634v1.38","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.m131"},{"key":"2026060503000877000_2026.06.01.26354634v1.39","doi-asserted-by":"publisher","DOI":"10.1038\/s41562-023-01579-9"},{"key":"2026060503000877000_2026.06.01.26354634v1.40","doi-asserted-by":"publisher","DOI":"10.1016\/j.ypmed.2017.12.027"},{"key":"2026060503000877000_2026.06.01.26354634v1.41","doi-asserted-by":"publisher","DOI":"10.1097\/WAD.0000000000000693"},{"key":"2026060503000877000_2026.06.01.26354634v1.42","doi-asserted-by":"publisher","DOI":"10.1159\/000321984"},{"key":"2026060503000877000_2026.06.01.26354634v1.43","doi-asserted-by":"publisher","DOI":"10.1002\/alz.12165"},{"issue":"4","key":"2026060503000877000_2026.06.01.26354634v1.44","first-page":"575","article-title":"High frequency of the apolipoprotein E *4 allele in African pygmies and most of the African populations in sub-Saharan Africa","volume":"69","year":"1997","journal-title":"Hum Biol"},{"key":"2026060503000877000_2026.06.01.26354634v1.45","doi-asserted-by":"publisher","DOI":"10.1016\/j.lanepe.2022.100576"},{"key":"2026060503000877000_2026.06.01.26354634v1.46","doi-asserted-by":"publisher","DOI":"10.1093\/braincomms\/fcab308"},{"key":"2026060503000877000_2026.06.01.26354634v1.47","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-025-03891-5"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.64898\/2026.06.01.26354634","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,5]],"date-time":"2026-06-05T10:00:17Z","timestamp":1780653617000},"score":1,"resource":{"primary":{"URL":"http:\/\/medrxiv.org\/lookup\/doi\/10.64898\/2026.06.01.26354634"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,2]]},"references-count":47,"URL":"https:\/\/doi.org\/10.64898\/2026.06.01.26354634","relation":{},"subject":[],"published":{"date-parts":[[2026,6,2]]},"subtype":"preprint"}}