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Rare coding variants segregated in families were tested for association in an independent cohort of 506 patients with sporadic AD and 498 cognitively normal controls. East Asians data from the Exome Aggregation Consortium (ExAC) were used as a reference control.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>A novel rare variant, P410S of <jats:italic>PLD3<\/jats:italic> was found in an early\u2010onset AD family. <jats:italic>LRRK2<\/jats:italic> I2012T, a causative mutation of Parkinson\u2019s disease, was identified in another early\u2010onset AD family. Missense variants in <jats:italic>ABCA7<\/jats:italic> (P143S and A1507T) and <jats:italic>CR1<\/jats:italic>(T239M) were significantly associated with familial AD (<jats:italic>P<\/jats:italic>\u00a0=\u00a00.005437, 0.001383, 0.000549), a missense variant in <jats:italic>TREM2<\/jats:italic>(S183C) was significantly associated with AD (<jats:italic>P<\/jats:italic>\u00a0=\u00a00.000396) when compared with the East Asian controls in ExAC database. A non\u2010frameshift variant in FUS (G223del) was frequent in AD cases and significantly associated with familial AD (<jats:italic>P<\/jats:italic>\u00a0=\u00a00.008).<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>Multiple rare coding variants of causal and risk neurodegenerative genes were presented in clinically diagnosed AD families that may confer risk of AD. Our data supported that the clinical, pathological, and genetic architectures of AD, PD, and FTD\/ALS may overlapping. We propose that targeted sequencing on neurodegenerative\u2010related genes is necessary for genetically unclear AD families.<\/jats:p><\/jats:sec>","DOI":"10.1002\/acn3.51197","type":"journal-article","created":{"date-parts":[[2020,9,17]],"date-time":"2020-09-17T19:03:08Z","timestamp":1600369388000},"page":"1985-1995","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["Association of rare variants in neurodegenerative genes with familial Alzheimer\u2019s disease"],"prefix":"10.1002","volume":"7","author":[{"given":"Weiwei","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Neurology Xiangya Hospital Central South University Changsha China"},{"name":"Molecular Imaging Center Xiangya Hospital Central South University Changsha China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bin","family":"Jiao","sequence":"additional","affiliation":[{"name":"Department of Neurology Xiangya Hospital Central South University Changsha China"},{"name":"National Clinical Research Center for Geriatric Disorders Central South University Changsha China"},{"name":"Key laboratory of Hunan Province in Neurodegenerative Disorders Central South University Changsha China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tingting","family":"Xiao","sequence":"additional","affiliation":[{"name":"Department of Neurology Xiangya Hospital Central South University Changsha China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xixi","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Neurology Xiangya Hospital Central South University Changsha China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinxin","family":"Liao","sequence":"additional","affiliation":[{"name":"Department of Geriatric Xiangya Hospital Central South University Changsha China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuewen","family":"Xiao","sequence":"additional","affiliation":[{"name":"Department of Neurology Xiangya Hospital Central South University Changsha China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lina","family":"Guo","sequence":"additional","affiliation":[{"name":"Department of Neurology Xiangya Hospital Central South University Changsha China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenhua","family":"Yuan","sequence":"additional","affiliation":[{"name":"Department of Neurology Xiangya Hospital Central South University Changsha China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinxiang","family":"Yan","sequence":"additional","affiliation":[{"name":"Department of Neurology Xiangya Hospital Central South University Changsha China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beisha","family":"Tang","sequence":"additional","affiliation":[{"name":"Department of Neurology Xiangya Hospital Central South University Changsha China"},{"name":"National Clinical Research Center for Geriatric Disorders Central South University Changsha China"},{"name":"Key laboratory of Hunan Province in Neurodegenerative Disorders Central South University Changsha China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5237-6155","authenticated-orcid":false,"given":"Lu","family":"Shen","sequence":"additional","affiliation":[{"name":"Department of Neurology Xiangya Hospital Central South University Changsha China"},{"name":"National Clinical Research Center for Geriatric Disorders Central South University Changsha China"},{"name":"Key laboratory of Hunan Province in Neurodegenerative Disorders Central South University Changsha China"},{"name":"Key Laboratory of Organ Injury Aging and Regenerative Medicine of Hunan Province Changsha China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2020,9,17]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jalz.2012.11.007"},{"key":"e_1_2_7_3_1","first-page":"S4","article-title":"Prevalence of dementia and major subtypes in Europe: a collaborative study of population\u2010based cohorts. 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