{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T03:22:41Z","timestamp":1790220161291,"version":"4.1.0"},"reference-count":28,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2022,5,1]],"date-time":"2022-05-01T00:00:00Z","timestamp":1651363200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["alz-journals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Alzheimer's &amp;amp; Dementia"],"published-print":{"date-parts":[[2023,2]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Studies of cognitive impairment (CI) in Amish communities have identified sibships containing CI and cognitively unimpaired (CU) individuals. We hypothesize that CU individuals may carry protective alleles delaying age at onset (AAO) of CI.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>A total of 1522 individuals screened for CI were genotyped. The outcome studied was AAO for CI individuals or age at last normal exam for CU individuals. Cox mixed\u2010effects models examined association between age and single nucleotide variants (SNVs).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Three SNVs were significantly associated (\n                      <jats:italic>P<\/jats:italic>\n                      &lt; 5 \u00d7 10\n                      <jats:sup>\u20138<\/jats:sup>\n                      ) with AAO on chromosomes 6 (rs14538074; hazard ratio [HR] = 3.35), 9 (rs534551495; HR = 2.82), and 17 (rs146729640; HR = 6.38). The chromosome 17 association was replicated in the independent National Institute on Aging Genetics Initiative for Late\u2010Onset Alzheimer's Disease dataset.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>\n                      The replicated genome\u2010wide significant association with AAO on chromosome 17 is located in the\n                      <jats:italic>SHISA6<\/jats:italic>\n                      gene, which is involved in post\u2010synaptic transmission in the hippocampus and is a biologically plausible candidate gene for Alzheimer's disease.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/alz.12686","type":"journal-article","created":{"date-parts":[[2022,5,1]],"date-time":"2022-05-01T11:09:07Z","timestamp":1651403347000},"page":"611-620","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Genetic variants in the\n                    <i>SHISA6<\/i>\n                    gene are associated with delayed cognitive impairment in two family datasets"],"prefix":"10.1002","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1293-3839","authenticated-orcid":false,"given":"Jairo","family":"Ramos","sequence":"first","affiliation":[{"name":"John P. Hussman Institute for Human Genomics University of Miami Miller School of Medicine  Miami Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura J.","family":"Caywood","sequence":"additional","affiliation":[{"name":"John P. Hussman Institute for Human Genomics University of Miami Miller School of Medicine  Miami Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael B.","family":"Prough","sequence":"additional","affiliation":[{"name":"John P. Hussman Institute for Human Genomics University of Miami Miller School of Medicine  Miami Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jason E.","family":"Clouse","sequence":"additional","affiliation":[{"name":"John P. Hussman Institute for Human Genomics University of Miami Miller School of Medicine  Miami Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sharlene D.","family":"Herington","sequence":"additional","affiliation":[{"name":"John P. Hussman Institute for Human Genomics University of Miami Miller School of Medicine  Miami Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan H.","family":"Slifer","sequence":"additional","affiliation":[{"name":"John P. Hussman Institute for Human Genomics University of Miami Miller School of Medicine  Miami Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. Denise","family":"Fuzzell","sequence":"additional","affiliation":[{"name":"Case Western Reserve University School of Medicine  Cleveland Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarada L.","family":"Fuzzell","sequence":"additional","affiliation":[{"name":"Case Western Reserve University School of Medicine  Cleveland Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sherri D.","family":"Hochstetler","sequence":"additional","affiliation":[{"name":"Case Western Reserve University School of Medicine  Cleveland Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristy L.","family":"Miskimen","sequence":"additional","affiliation":[{"name":"Case Western Reserve University School of Medicine  Cleveland Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leighanne R.","family":"Main","sequence":"additional","affiliation":[{"name":"Case Western Reserve University School of Medicine  Cleveland Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael D.","family":"Osterman","sequence":"additional","affiliation":[{"name":"Case Western Reserve University School of Medicine  Cleveland Ohio USA"},{"name":"Cleveland Institute for Computational Biology Case Western Reserve University  Cleveland Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew F.","family":"Zaman","sequence":"additional","affiliation":[{"name":"John P. Hussman Institute for Human Genomics University of Miami Miller School of Medicine  Miami Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrice L.","family":"Whitehead","sequence":"additional","affiliation":[{"name":"John P. Hussman Institute for Human Genomics University of Miami Miller School of Medicine  Miami Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Larry D.","family":"Adams","sequence":"additional","affiliation":[{"name":"John P. Hussman Institute for Human Genomics University of Miami Miller School of Medicine  Miami Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Renee A.","family":"Laux","sequence":"additional","affiliation":[{"name":"Case Western Reserve University School of Medicine  Cleveland Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yeunjoo E.","family":"Song","sequence":"additional","affiliation":[{"name":"Case Western Reserve University School of Medicine  Cleveland Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tatiana M.","family":"Foroud","sequence":"additional","affiliation":[{"name":"Indiana Alzheimer's Disease Center Indiana University School of Medicine  Indianapolis Indiana USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard P.","family":"Mayeux","sequence":"additional","affiliation":[{"name":"Taub Institute on Alzheimer's Disease and the Aging Brain Department of Neurology Columbia University  New York New York USA"},{"name":"Gertrude H. Sergievsky Center Columbia University  New York New York USA"},{"name":"Department of Neurology Columbia University  New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"St. George\u2010Hyslop","sequence":"additional","affiliation":[{"name":"University of Toronto  Toronto Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paula K.","family":"Ogrocki","sequence":"additional","affiliation":[{"name":"University Hospitals Cleveland Medical Center  Cleveland Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alan J.","family":"Lerner","sequence":"additional","affiliation":[{"name":"University Hospitals Cleveland Medical Center  Cleveland Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffery M.","family":"Vance","sequence":"additional","affiliation":[{"name":"John P. 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