{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T01:01:00Z","timestamp":1791594060955,"version":"4.3.4"},"reference-count":65,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2024,4,30]],"date-time":"2024-04-30T00:00:00Z","timestamp":1714435200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"publisher","award":["U54AG054345"],"award-info":[{"award-number":["U54AG054345"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["alz-journals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Alzheimer's &amp;amp; Dementia"],"published-print":{"date-parts":[[2024,7]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>INTRODUCTION<\/jats:title><jats:p>Genome\u2010wide association studies have identified over 70 genetic loci associated with late\u2010onset Alzheimer's disease (LOAD), but few candidate polymorphisms have been functionally assessed for disease relevance and mechanism of action.<\/jats:p><\/jats:sec><jats:sec><jats:title>METHODS<\/jats:title><jats:p>Candidate genetic risk variants were informatically prioritized and individually engineered into a LOAD\u2010sensitized mouse model that carries the AD risk variants <jats:italic>APOE<\/jats:italic> \u03b54\/\u03b54 and Trem2*R47H. The potential disease relevance of each model was assessed by comparing brain transcriptomes measured with the Nanostring Mouse AD Panel at 4 and 12 months of age with human study cohorts.<\/jats:p><\/jats:sec><jats:sec><jats:title>RESULTS<\/jats:title><jats:p>We created new models for 11 coding and loss\u2010of\u2010function risk variants. Transcriptomic effects from multiple genetic variants recapitulated a variety of human gene expression patterns observed in LOAD study cohorts. Specific models matched to emerging molecular LOAD subtypes.<\/jats:p><\/jats:sec><jats:sec><jats:title>DISCUSSION<\/jats:title><jats:p>These results provide an initial functionalization of 11 candidate risk variants and identify potential preclinical models for testing targeted therapeutics.<\/jats:p><\/jats:sec><jats:sec><jats:title>Highlights<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p>A novel approach to validate genetic risk factors for late\u2010onset AD (LOAD) is presented.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>LOAD risk variants were knocked in to conserved mouse loci.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Variant effects were assayed by transcriptional analysis.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Risk variants in <jats:italic>Abca7<\/jats:italic>, <jats:italic>Mthfr<\/jats:italic>, <jats:italic>Plcg2, and Sorl1<\/jats:italic> loci modeled molecular signatures of clinical disease.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>This approach should generate more translationally relevant animal models.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec>","DOI":"10.1002\/alz.13840","type":"journal-article","created":{"date-parts":[[2024,4,30]],"date-time":"2024-04-30T10:18:22Z","timestamp":1714472302000},"page":"4970-4984","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["In vivo validation of late\u2010onset Alzheimer's disease genetic risk factors"],"prefix":"10.1002","volume":"20","author":[{"given":"Michael","family":"Sasner","sequence":"first","affiliation":[{"name":"The Jackson Laboratory  Bar Harbor Maine USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christoph","family":"Preuss","sequence":"additional","affiliation":[{"name":"The Jackson Laboratory  Bar Harbor Maine USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ravi 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L.","family":"Oblak","sequence":"additional","affiliation":[{"name":"Stark Neurosciences Research Institute, School of Medicine, Indiana University  Indianapolis Indiana USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter Bor\u2010Chian","family":"Lin","sequence":"additional","affiliation":[{"name":"Stark Neurosciences Research Institute, School of Medicine, Indiana University  Indianapolis Indiana USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bridget","family":"Perkins","sequence":"additional","affiliation":[{"name":"Stark Neurosciences Research Institute, School of Medicine, Indiana University  Indianapolis Indiana USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Disha","family":"Soni","sequence":"additional","affiliation":[{"name":"Stark Neurosciences Research Institute, School of Medicine, Indiana University  Indianapolis Indiana 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