{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T11:06:47Z","timestamp":1789211207672,"version":"build-2803163510"},"posted":{"date-parts":[[2026,9,9]]},"group-title":"Genetic and Genomic Medicine","reference-count":45,"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\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,9,9]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>\n                    Alzheimer\u2019s disease (AD) pathology often accumulates years before memory loss, creating a need to identify high-risk individuals presymptomatically. Polygenic risk scores (PRS) stratify AD risk, but individual-level predictions remain uncertain. Extreme PRS may identify high-risk individuals independent of\n                    <jats:italic>APOE<\/jats:italic>\n                    .\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>Using GenoPred, extreme tails of 1,752 PRS methods were evaluated across four genetic ancestries using 11,200 autopsy- or clinically-defined AD cases and 19,321 controls (age \u226565) from the AD Sequencing Project (ADSP) Release 5.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>\n                    Individuals in the extreme upper PRS tail were significantly enriched for AD in all ancestries: Admixed American (\n                    <jats:italic>\n                      P\n                      <jats:sub>adj<\/jats:sub>\n                    <\/jats:italic>\n                    =0.02727), African (\n                    <jats:italic>\n                      P\n                      <jats:sub>adj<\/jats:sub>\n                    <\/jats:italic>\n                    =0.004827), East Asian (\n                    <jats:italic>\n                      P\n                      <jats:sub>adj<\/jats:sub>\n                    <\/jats:italic>\n                    =0.02824), and European (\n                    <jats:italic>\n                      P\n                      <jats:sub>adj<\/jats:sub>\n                    <\/jats:italic>\n                    =2.3068\u00d710\n                    <jats:sup>\u221213<\/jats:sup>\n                    ). No controls were observed among the 42 European- and 12 African-ancestry individuals with extreme PRS. Extreme PRS spanned\n                    <jats:italic>APOE<\/jats:italic>\n                    diplotypes; 38% occurred in non-\n                    <jats:italic>APOE<\/jats:italic>\n                    \u03b54 carriers.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>\n                    Rare subsets of individuals at the most extreme PRS thresholds have markedly elevated AD enrichment across ancestries and\n                    <jats:italic>APOE<\/jats:italic>\n                    diplotypes.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Data Availability<\/jats:title>\n                  <jats:p>All data are available through the ADSP, which is managed by The National Institute on Aging Genetics of Alzheimer\u2019s Disease Data Storage Site (NIAGADS).<\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.09.08.26362504","type":"posted-content","created":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T00:30:26Z","timestamp":1789000226000},"source":"Crossref","is-referenced-by-count":0,"title":["Rare extreme polygenic risk scores strongly indicate Alzheimer\u2019s disease risk"],"prefix":"10.64898","author":[{"given":"Elizabeth L.","family":"Ward","sequence":"first","affiliation":[{"name":"Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY 40506, USA"},{"name":"Division of Biomedical Informatics, Department of Internal Medicine, University of Kentucky, Lexington, KY 40506, USA"},{"name":"Department of Pathology and Laboratory Medicine, University of Kentucky, Lexington, KY 40506, USA"},{"name":"Department of Neuroscience, University of Kentucky, Lexington, KY 40506, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter T.","family":"Nelson","sequence":"additional","affiliation":[{"name":"Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY 40506, USA"},{"name":"Department of Pathology and Laboratory Medicine, University of Kentucky, Lexington, KY 40506, USA"},{"name":"Department of Neuroscience, University of Kentucky, Lexington, KY 40506, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0188-8094","authenticated-orcid":false,"given":"Yuriko","family":"Katsumata","sequence":"additional","affiliation":[{"name":"Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY 40506, USA"},{"name":"Department of Biostatistics, University of Kentucky, Lexington, KY 40506, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7207-4696","authenticated-orcid":false,"given":"David W.","family":"Fardo","sequence":"additional","affiliation":[{"name":"Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY 40506, USA"},{"name":"Department of Biostatistics, University of Kentucky, Lexington, KY 40506, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7980-2166","authenticated-orcid":false,"given":"Gregory A.","family":"Jicha","sequence":"additional","affiliation":[{"name":"Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY 40506, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"the Alzheimer\u2019s Disease Neuroimaging Initiative","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5309-1570","authenticated-orcid":false,"given":"Justin B.","family":"Miller","sequence":"additional","affiliation":[{"name":"Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY 40506, USA"},{"name":"Division of Biomedical Informatics, Department of Internal Medicine, University of Kentucky, Lexington, KY 40506, USA"},{"name":"Department of Neuroscience, University of Kentucky, Lexington, KY 40506, USA"},{"name":"Department of Microbiology, Immunology, and Molecular Genetics, University of Kentucky, Lexington, KY 40506, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026091203300538000_2026.09.08.26362504v1.1","first-page":"22","article-title":"Alzheimer\u2019s disease facts and figures","volume":"2026","year":"2026","journal-title":"Alzheimers Dement"},{"key":"2026091203300538000_2026.09.08.26362504v1.2","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(12)70228-4"},{"key":"2026091203300538000_2026.09.08.26362504v1.3","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(12)70227-2"},{"key":"2026091203300538000_2026.09.08.26362504v1.4","doi-asserted-by":"publisher","DOI":"10.1001\/archpsyc.63.2.168"},{"key":"2026091203300538000_2026.09.08.26362504v1.5","doi-asserted-by":"publisher","DOI":"10.1001\/jama.1997.03550160069041"},{"key":"2026091203300538000_2026.09.08.26362504v1.6","doi-asserted-by":"crossref","first-page":"1284","DOI":"10.1001\/jamaneurol.2023.3599","article-title":"APOE Genotype and Alzheimer Disease Risk Across Age, Sex, and Population Ancestry","volume":"80","year":"2023","journal-title":"JAMA Neurol"},{"key":"2026091203300538000_2026.09.08.26362504v1.7","doi-asserted-by":"publisher","DOI":"10.1038\/S41588-018-0311-9"},{"key":"2026091203300538000_2026.09.08.26362504v1.8","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-022-01024-z"},{"key":"2026091203300538000_2026.09.08.26362504v1.9","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-019-0358-2"},{"key":"2026091203300538000_2026.09.08.26362504v1.10","doi-asserted-by":"crossref","unstructured":"Baker E , Escott-Price V . Polygenic Risk Scores in Alzheimer\u2019s Disease: Current Applications and Future Directions. Frontiers in Digital Health. 2020;Volume 2 - 2020.","DOI":"10.3389\/fdgth.2020.00014"},{"key":"2026091203300538000_2026.09.08.26362504v1.11","doi-asserted-by":"crossref","first-page":"4506","DOI":"10.1038\/s41467-021-24082-z","article-title":"Identifying individuals with high risk of Alzheimer\u2019s disease using polygenic risk scores","volume":"12","year":"2021","journal-title":"Nature Communications"},{"key":"2026091203300538000_2026.09.08.26362504v1.12","first-page":"e12226","article-title":"Polygenic score modifies risk for Alzheimer\u2019s disease in APOE \u03b54 homozygotes at phenotypic extremes","volume":"13","year":"2021","journal-title":"Alzheimer\u2019s & Dementia: Diagnosis, Assessment & Disease Monitoring"},{"key":"2026091203300538000_2026.09.08.26362504v1.13","doi-asserted-by":"crossref","first-page":"8484","DOI":"10.1002\/alz.14284","article-title":"Enrichment for clinical trials of early AD: Combining genetic risk factors and plasma p-tau as screening instruments","volume":"20","year":"2024","journal-title":"Alzheimer\u2019s & Dementia"},{"key":"2026091203300538000_2026.09.08.26362504v1.14","doi-asserted-by":"crossref","first-page":"78","DOI":"10.14283\/jpad.2020.64","article-title":"Polygenic Risk Scoring is an Effective Approach to Predict Those Individuals Most Likely to Decline Cognitively Due to Alzheimer\u2019s Disease","volume":"8","year":"2021","journal-title":"The Journal of Prevention of Alzheimer\u2019s Disease"},{"key":"2026091203300538000_2026.09.08.26362504v1.15","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-018&ndash;0183-z"},{"key":"2026091203300538000_2026.09.08.26362504v1.16","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1002\/alz.12207","article-title":"Gene- and age-informed screening for preclinical Alzheimer\u2019s disease trials","volume":"17","year":"2021","journal-title":"Alzheimers Dement"},{"key":"2026091203300538000_2026.09.08.26362504v1.17","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2407934"},{"key":"2026091203300538000_2026.09.08.26362504v1.18","doi-asserted-by":"crossref","first-page":"101662","DOI":"10.1016\/j.gim.2025.101662","article-title":"Challenges in clinical translation of polygenic risk score analyses: A systematic review","volume":"28","year":"2026","journal-title":"Genetics in Medicine"},{"key":"2026091203300538000_2026.09.08.26362504v1.19","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1007\/s12687-023-00645-z","article-title":"Clinical utility of polygenic risk scores: a critical 2023 appraisal","volume":"14","year":"2023","journal-title":"J Community Genet"},{"key":"2026091203300538000_2026.09.08.26362504v1.20","doi-asserted-by":"crossref","unstructured":"Euesden J , Gowrisankar S , Qu AX , Jean PS , Hughes AR , Pulford DJ . Cognitive Decline in Alzheimer\u2019s Disease: Limited Clinical Utility for GWAS or Polygenic Risk Scores in a Clinical Trial Setting. Genes (Basel). 2020;11.","DOI":"10.3390\/genes11050501"},{"key":"2026091203300538000_2026.09.08.26362504v1.21","doi-asserted-by":"crossref","first-page":"1697","DOI":"10.1007\/s00439-022-02452-x","article-title":"The clinical utility of polygenic risk scores in genomic medicine practices: a systematic review","volume":"141","year":"2022","journal-title":"Hum Genet"},{"key":"2026091203300538000_2026.09.08.26362504v1.22","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-019-0379-x"},{"key":"2026091203300538000_2026.09.08.26362504v1.23","doi-asserted-by":"crossref","unstructured":"Kullo IJ . Clinical use of polygenic risk scores: current status, barriers and future directions. Nature Reviews Genetics. 2025.","DOI":"10.1038\/s41576-025-00900-8"},{"key":"2026091203300538000_2026.09.08.26362504v1.24","doi-asserted-by":"publisher","DOI":"10.1038\/s41380-018-0112-7"},{"key":"2026091203300538000_2026.09.08.26362504v1.25","doi-asserted-by":"publisher","DOI":"10.1212\/NXG.0000000000000194"},{"key":"2026091203300538000_2026.09.08.26362504v1.26","doi-asserted-by":"crossref","unstructured":"Ward EL , Nelson PT , Katsumata Y , Fardo DW , Jicha GA, ADNI , et al. Alzheimer\u2019s Polygenic Risk Scores Are Not Interchangeable: Evidence from 1,752 Models. medRxiv. 2026:2026.09.02.26362060.","DOI":"10.64898\/2026.09.02.26362060"},{"key":"2026091203300538000_2026.09.08.26362504v1.27","doi-asserted-by":"crossref","unstructured":"Pain O , Al-Chalabi A , Lewis CM . The GenoPred pipeline: a comprehensive and scalable pipeline for polygenic scoring. Bioinformatics. 2024;40.","DOI":"10.1093\/bioinformatics\/btae551"},{"key":"2026091203300538000_2026.09.08.26362504v1.28","doi-asserted-by":"publisher","DOI":"10.1001\/archneur.58.3.397"},{"key":"2026091203300538000_2026.09.08.26362504v1.29","doi-asserted-by":"crossref","first-page":"851","DOI":"10.3233\/ADR-230189","article-title":"A Two-Year Observational Study to Evaluate Conversion Rates from High- and Low-Risk Patients with Amnestic Mild Cognitive Impairment to Probable Alzheimer\u2019s Disease in a Real- World Setting","volume":"8","year":"2024","journal-title":"J Alzheimers Dis Rep"},{"key":"2026091203300538000_2026.09.08.26362504v1.30","doi-asserted-by":"publisher","DOI":"10.1038\/nature15393"},{"key":"2026091203300538000_2026.09.08.26362504v1.31","doi-asserted-by":"publisher","DOI":"10.1038\/nature09298"},{"key":"2026091203300538000_2026.09.08.26362504v1.32","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btq559"},{"key":"2026091203300538000_2026.09.08.26362504v1.33","doi-asserted-by":"crossref","unstructured":"Chang CC , Chow CC , Tellier LC , Vattikuti S , Purcell SM , Lee JJ . Second-generation PLINK: rising to the challenge of larger and richer datasets. GigaScience. 2015;4.","DOI":"10.1186\/s13742-015-0047-8"},{"key":"2026091203300538000_2026.09.08.26362504v1.34","doi-asserted-by":"crossref","first-page":"1776","DOI":"10.1038\/s41467-019-09718-5","article-title":"Polygenic prediction via Bayesian regression and continuous shrinkage priors","volume":"10","year":"2019","journal-title":"Nature Communications"},{"key":"2026091203300538000_2026.09.08.26362504v1.35","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-022-01054-7"},{"key":"2026091203300538000_2026.09.08.26362504v1.36","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2020.03.013"},{"key":"2026091203300538000_2026.09.08.26362504v1.37","doi-asserted-by":"publisher","DOI":"10.1002\/gepi.22050"},{"key":"2026091203300538000_2026.09.08.26362504v1.38","first-page":"5424","article-title":"LDpred2: better, faster, stronger","volume":"36","year":"2020","journal-title":"Bioinformatics"},{"key":"2026091203300538000_2026.09.08.26362504v1.39","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopsych.2021.04.018"},{"key":"2026091203300538000_2026.09.08.26362504v1.40","doi-asserted-by":"publisher","DOI":"10.1086\/519795"},{"key":"2026091203300538000_2026.09.08.26362504v1.41","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-024-01704-y"},{"key":"2026091203300538000_2026.09.08.26362504v1.42","doi-asserted-by":"crossref","unstructured":"Cohen WW . Fast Effective Rule Induction. In: Prieditis A , Russell S , editors. Machine Learning Proceedings 1995. San Francisco (CA): Morgan Kaufmann; 1995. p. 115\u201323.","DOI":"10.1016\/B978-1-55860-377-6.50023-2"},{"key":"2026091203300538000_2026.09.08.26362504v1.43","doi-asserted-by":"publisher","DOI":"10.1145\/1656274.1656278"},{"key":"2026091203300538000_2026.09.08.26362504v1.44","doi-asserted-by":"crossref","first-page":"e1002270","DOI":"10.1371\/journal.pmed.1002270","article-title":"APP, PSEN1, and PSEN2 mutations in early-onset Alzheimer disease: A genetic screening study of familial and sporadic cases","volume":"14","year":"2017","journal-title":"PLOS Medicine"},{"key":"2026091203300538000_2026.09.08.26362504v1.45","doi-asserted-by":"crossref","unstructured":"Andrews SJ , Renton AE , Fulton-Howard B , Podlesny-Drabiniok A , Marcora E , Goate AM . The complex genetic architecture of Alzheimer\u2019s disease: novel insights and future directions. eBioMedicine. 2023;90.","DOI":"10.1016\/j.ebiom.2023.104511"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.64898\/2026.09.08.26362504","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T10:30:19Z","timestamp":1789209019000},"score":1,"resource":{"primary":{"URL":"http:\/\/medrxiv.org\/lookup\/doi\/10.64898\/2026.09.08.26362504"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,9]]},"references-count":45,"URL":"https:\/\/doi.org\/10.64898\/2026.09.08.26362504","relation":{},"subject":[],"published":{"date-parts":[[2026,9,9]]},"subtype":"preprint"}}