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Participants in Long\u2010Life Family Study (LLFS) exhibit delayed onset of dementia, offering a unique opportunity to investigate LOAD genetics.<\/jats:p><\/jats:sec><jats:sec><jats:title>METHODS<\/jats:title><jats:p>We conducted a whole genome sequence analysis of 3475 LLFS members. Genetic associations were examined in six independent studies (<jats:italic>N<\/jats:italic>\u00a0=\u00a014,260) with a wide range of LOAD risk. Association analysis in a sub\u2010sample of the LLFS cohort (<jats:italic>N<\/jats:italic>\u00a0=\u00a01739) evaluated the association of LOAD variants with beta amyloid (A\u03b2) levels.<\/jats:p><\/jats:sec><jats:sec><jats:title>RESULTS<\/jats:title><jats:p>We identified several single nucleotide polymorphisms (SNPs) in tight linkage disequilibrium within the <jats:italic>MTUS2<\/jats:italic> gene associated with LOAD (rs73154407, <jats:italic>p<\/jats:italic>\u00a0=\u00a07.6\u00a0\u00d7\u00a010<jats:sup>\u22129<\/jats:sup>). Association of <jats:italic>MTUS2<\/jats:italic> variants with LOAD was observed in the five independent studies and was significantly stronger within high levels of A\u03b242\/40 ratio compared to lower amyloid.<\/jats:p><\/jats:sec><jats:sec><jats:title>DISCUSSION<\/jats:title><jats:p><jats:italic>MTUS2<\/jats:italic> encodes a microtubule associated protein implicated in the development and function of the nervous system, making it a plausible candidate to investigate LOAD biology.<\/jats:p><\/jats:sec><jats:sec><jats:title>Highlights<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p>Long\u2010Life Family Study (LLFS) families may harbor late onset Alzheimer's dementia (LOAD) variants.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>LLFS whole genome sequence analysis identified <jats:italic>MTUS2<\/jats:italic> gene variants associated with LOAD.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>The observed LLFS variants generalized to cohorts with wide range of LOAD risk.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>The association of <jats:italic>MTUS2<\/jats:italic> with LOAD was stronger within high levels of beta amyloid.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Our results provide evidence for <jats:italic>MTUS2<\/jats:italic> gene as a novel LOAD candidate locus.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec>","DOI":"10.1002\/alz.13718","type":"journal-article","created":{"date-parts":[[2024,2,21]],"date-time":"2024-02-21T08:16:28Z","timestamp":1708503388000},"page":"2670-2679","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Whole genome\u2010wide sequence analysis of long\u2010lived families (Long\u2010Life Family Study) identifies <i>MTUS2<\/i> gene associated with late\u2010onset Alzheimer's disease"],"prefix":"10.1002","volume":"20","author":[{"given":"Laura","family":"Xicota","sequence":"first","affiliation":[{"name":"Department of Neurology Columbia University Irving Medical Center  New York City New York USA"},{"name":"The Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Irving Medical Center  New York City New York USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephanie","family":"Cosentino","sequence":"additional","affiliation":[{"name":"Department of Neurology Columbia University Irving Medical Center  New York City New York USA"},{"name":"The Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Irving Medical Center  New York City New York USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Badri","family":"Vardarajan","sequence":"additional","affiliation":[{"name":"Department of Neurology Columbia University Irving Medical Center  New York City New York USA"},{"name":"The Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Irving Medical Center  New York City New York USA"},{"name":"Gertrude H. 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