{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,26]],"date-time":"2026-02-26T14:58:57Z","timestamp":1772117937462,"version":"3.50.1"},"reference-count":48,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2024,9,5]],"date-time":"2024-09-05T00:00:00Z","timestamp":1725494400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["5R37AG015473"],"award-info":[{"award-number":["5R37AG015473"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["RF1AG015473"],"award-info":[{"award-number":["RF1AG015473"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R56AG051876"],"award-info":[{"award-number":["R56AG051876"]}],"id":[{"id":"10.13039\/100000002","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":[[2024,11]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>BACKGROUND<\/jats:title>\n                    <jats:p>Few rare variants have been identified in genetic loci from genome\u2010wide association studies (GWAS) of Alzheimer's disease (AD), limiting understanding of mechanisms, risk assessment, and genetic counseling.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS<\/jats:title>\n                    <jats:p>Using genome sequencing data from 197 families in the National Institute on Aging Alzheimer's Disease Family Based Study and 214 Caribbean Hispanic families, we searched for rare coding variants within known GWAS loci from the largest published study.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS<\/jats:title>\n                    <jats:p>\n                      Eighty\u2010six rare missense or loss\u2010of\u2010function (LoF) variants completely segregated in 17.5% of families, but in 91 (22.1%) families Apolipoprotein E (\n                      <jats:italic>APOE)\u2010<\/jats:italic>\n                      \ud835\udf004 was the only variant segregating. However, in 60.3% of families,\n                      <jats:italic>APOE<\/jats:italic>\n                      \ud835\udf004, missense, and LoF variants were not found within the GWAS loci.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>DISCUSSION<\/jats:title>\n                    <jats:p>\n                      Although\n                      <jats:italic>APOE<\/jats:italic>\n                      \ud835\udf004and several rare variants were found to segregate in both family datasets, many families had no variant accounting for their disease. This suggests that familial AD may be the result of unidentified rare variants.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Highlights<\/jats:title>\n                    <jats:p>\n                      <jats:list list-type=\"bullet\">\n                        <jats:list-item>\n                          <jats:p>Rare coding variants from GWAS loci segregate in familial Alzheimer's disease.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Missense or loss of function variants were found segregating in nearly 7% of families.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>APOE\u2010\ud835\udf004 was the only segregating variant in 29.7% in familial Alzheimer's disease.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>In Hispanic and non\u2010Hispanic families, different variants were found in segregating genes.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>No coding variants were found segregating in many Hispanic and non\u2010Hispanic families.<\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/alz.14221","type":"journal-article","created":{"date-parts":[[2024,9,5]],"date-time":"2024-09-05T03:37:53Z","timestamp":1725507473000},"page":"7580-7594","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Missense and loss\u2010of\u2010function variants at GWAS loci in familial Alzheimer's disease"],"prefix":"10.1002","volume":"20","author":[{"given":"Tamil Iniyan","family":"Gunasekaran","sequence":"first","affiliation":[{"name":"Department of Neurology Taub Institute for Research on Alzheimer's Disease and the Aging Brain and the Gertrude H. Sergievsky Center Columbia University  New York New York USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dolly","family":"Reyes\u2010Dumeyer","sequence":"additional","affiliation":[{"name":"Department of Neurology Taub Institute for Research on Alzheimer's Disease and the Aging Brain and the Gertrude H. Sergievsky Center Columbia University  New York New York USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kelley M.","family":"Faber","sequence":"additional","affiliation":[{"name":"Department of Medical and Molecular Genetics National Centralized Repository for Alzheimer's Disease and Related Dementias (NCRAD), 410\u00a0W. 10th St., HS 4000. Indiana University School of Medicine  Indianapolis Indiana USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alison","family":"Goate","sequence":"additional","affiliation":[{"name":"Department of Genetics &amp; Genomic Sciences Ronald M. Loeb Center for Alzheimer's disease Icahn School of Medicine at Mount Sinai Icahn Bldg., One Gustave L. Levy Place  New York New York USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Brad","family":"Boeve","sequence":"additional","affiliation":[{"name":"Department of Neurology, Mayo Clinic  Rochester Minnesota USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carlos","family":"Cruchaga","sequence":"additional","affiliation":[{"name":"Department of Psychiatry Washington University in St. Louis, Rand Johnson Building, 600 S Euclid Ave., Wohl Hospital Building  St. Louis Missouri USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Margaret","family":"Pericak\u2010Vance","sequence":"additional","affiliation":[{"name":"John P Hussman Institute for Human Genomics Dr. John T Macdonald Foundation Department of Human Genetics University of Miami Miller School of Medicine  Miami Florida USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jonathan L.","family":"Haines","sequence":"additional","affiliation":[{"name":"Department of Population &amp; Quantitative Health Sciences and Cleveland Institute for Computational Biology. Case Western Reserve University  Cleveland Ohio USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Roger","family":"Rosenberg","sequence":"additional","affiliation":[{"name":"Department of Neurology University of Texas Southwestern Medical Center  Dallas Texas USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Debby","family":"Tsuang","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Behavioral Sciences University of Washington, GRECC VA Puget Sound, 1660 South Columbian Way  Seattle Washington USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Diones Rivera","family":"Mejia","sequence":"additional","affiliation":[{"name":"Los Centros de Diagn\u00f3stico y Medicina Avanzada y de Conferencias M\u00e9dicas y Telemedicina CEDIMAT, Arturo Logro\u00f1o Plaza de la Salud, Dr. Juan Manuel Taveras Rodr\u00edguez, C. Pepillo Salcedo esq  Santo Domingo Dominican Republic"},{"name":"Universidad Pedro Henr\u00edquez Urena, Av.\u00a0John F.\u00a0Kennedy Km.\u00a07\u20101\/2\u00a0Santo Domingo\u00a01423  Santo Domingo Dominican Republic"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Martin","family":"Medrano","sequence":"additional","affiliation":[{"name":"Pont\u00edficia Universidad Cat\u00f3lica Madre y Maestra (PUCMM), Autopista Duarte Km 1 1\/2  Santiago de los Caballeros Dominican Republic"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rafael A.","family":"Lantigua","sequence":"additional","affiliation":[{"name":"Department of Neurology Taub Institute for Research on Alzheimer's Disease and the Aging Brain and the Gertrude H. Sergievsky Center Columbia University  New York New York USA"},{"name":"Department of Medicine Vagelos College of Physicians and Surgeons Columbia University, and the New York Presbyterian Hospital  New York New York USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert A.","family":"Sweet","sequence":"additional","affiliation":[{"name":"Departments of Psychiatry and Neurology University of Pittsburgh  Pittsburgh Pennsylvania USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David A.","family":"Bennett","sequence":"additional","affiliation":[{"name":"Rush Alzheimer's Disease Center Rush University Medical Center, 1750, West Harrison St  Chicago Illinois USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert S.","family":"Wilson","sequence":"additional","affiliation":[{"name":"Rush Alzheimer's Disease Center Rush University Medical Center, 1750, West Harrison St  Chicago Illinois USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Camille","family":"Alba","sequence":"additional","affiliation":[{"name":"Department of Anatomy Physiology and Genetics Uniformed Services University of the Health Sciences  Bethesda Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Clifton","family":"Dalgard","sequence":"additional","affiliation":[{"name":"Department of Anatomy Physiology and Genetics Uniformed Services University of the Health Sciences  Bethesda Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tatiana","family":"Foroud","sequence":"additional","affiliation":[{"name":"Department of Medical and Molecular Genetics National Centralized Repository for Alzheimer's Disease and Related Dementias (NCRAD), 410\u00a0W. 10th St., HS 4000. Indiana University School of Medicine  Indianapolis Indiana USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Badri N.","family":"Vardarajan","sequence":"additional","affiliation":[{"name":"Department of Neurology Taub Institute for Research on Alzheimer's Disease and the Aging Brain and the Gertrude H. Sergievsky Center Columbia University  New York New York USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Richard","family":"Mayeux","sequence":"additional","affiliation":[{"name":"Department of Neurology Taub Institute for Research on Alzheimer's Disease and the Aging Brain and the Gertrude H. 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