{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T16:04:13Z","timestamp":1790179453698,"version":"4.1.0"},"posted":{"date-parts":[[2026,9,20]]},"group-title":"Genetic and Genomic Medicine","reference-count":75,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,9,20]],"date-time":"2026-09-20T00:00:00Z","timestamp":1789862400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"award":["AG058654"],"award-info":[{"award-number":["AG058654"]}],"id":[{"id":"https:\/\/ror.org\/049v75w11","id-type":"ROR","asserted-by":"publisher"}]},{"award":["AG058066"],"award-info":[{"award-number":["AG058066"]}],"id":[{"id":"https:\/\/ror.org\/049v75w11","id-type":"ROR","asserted-by":"publisher"}]},{"award":["AG062943"],"award-info":[{"award-number":["AG062943"]}],"id":[{"id":"https:\/\/ror.org\/049v75w11","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,9,20]]},"abstract":"<jats:title>Structured Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>The genetic architecture of Alzheimer disease remains incompletely understood. Founder populations such as the Amish offer a unique opportunity to identify additional genetic variation influencing the disease.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Method<\/jats:title>\n                  <jats:p>Using extensive pedigree and genomic data from Midwestern Amish communities, we estimated both pedigree- and SNP- based heritability of AD. In addition, genome-wide association studies and gene-based rare variant tests were performed.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>\n                    Heritability estimates suggested that common variants explain much of genetic risk among\n                    <jats:italic>APOE-<\/jats:italic>\n                    \u03b54 carriers, while unexplained heritability remains in non-carriers in the Amish. GWAS confirmed\n                    <jats:italic>APOE-<\/jats:italic>\n                    \u03b54 as the strongest genetic determinant of AD in the Amish. Rare variant analyses identified\n                    <jats:italic>RIN3<\/jats:italic>\n                    and\n                    <jats:italic>PILRA<\/jats:italic>\n                    as significantly associated with risk of cognitive impairment; suggestive signals including\n                    <jats:italic>CYP24A1<\/jats:italic>\n                    were also identified.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Discussion<\/jats:title>\n                  <jats:p>\n                    These findings highlight the contributions of common and rare variants to Alzheimer disease and suggest factors beyond common variants may contribute to disease susceptibility particularly among the\n                    <jats:italic>APOE<\/jats:italic>\n                    -\u03b54 non-carriers.\n                  <\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.09.17.26363309","type":"posted-content","created":{"date-parts":[[2026,9,20]],"date-time":"2026-09-20T21:55:14Z","timestamp":1789941314000},"source":"Crossref","is-referenced-by-count":0,"title":["Heritability and rare variant contributions to Alzheimer disease in the Midwestern Amish"],"prefix":"10.64898","author":[{"given":"Yining","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Population and Quantitative Health Sciences, Case Western Reserve University School of Medicine, Cleveland, OH, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yeunjoo E.","family":"Song","sequence":"additional","affiliation":[{"name":"Department of Population and Quantitative Health Sciences, Case Western Reserve University School of Medicine, Cleveland, OH, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weihuan","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Population and Quantitative Health Sciences, Case Western Reserve University School of Medicine, Cleveland, OH, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Audrey","family":"Lynn","sequence":"additional","affiliation":[{"name":"Department of Population and Quantitative Health Sciences, Case Western Reserve University School of Medicine, Cleveland, OH, USA"},{"name":"Cleveland Institute for Computational Biology, Case Western Reserve University School of Medicine, Cleveland, OH, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristy","family":"Miskimen","sequence":"additional","affiliation":[{"name":"Department of Population and Quantitative Health Sciences, Case Western Reserve University School of Medicine, Cleveland, OH, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarada L.","family":"Fuzzell","sequence":"additional","affiliation":[{"name":"Department of Population and Quantitative Health Sciences, Case Western Reserve University School of Medicine, Cleveland, OH, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sherri D.","family":"Hochstetler","sequence":"additional","affiliation":[{"name":"Department of Population and Quantitative Health Sciences, Case Western Reserve University School of Medicine, Cleveland, OH, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Renee A.","family":"Laux","sequence":"additional","affiliation":[{"name":"Department of Population and Quantitative Health Sciences, Case Western Reserve University School of Medicine, Cleveland, OH, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dawn","family":"Miller","sequence":"additional","affiliation":[{"name":"Department of Population and Quantitative Health Sciences, Case Western Reserve University School of Medicine, Cleveland, OH, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Penelope","family":"Miron","sequence":"additional","affiliation":[{"name":"Department of Population and Quantitative Health Sciences, Case Western Reserve University School of Medicine, Cleveland, OH, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura J.","family":"Caywood","sequence":"additional","affiliation":[{"name":"John P. 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