{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T00:44:27Z","timestamp":1793321067858,"version":"4.5.0"},"reference-count":22,"publisher":"SAGE Publications","issue":"3","license":[{"start":{"date-parts":[[2025,3,14]],"date-time":"2025-03-14T00:00:00Z","timestamp":1741910400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"funder":[{"name":"NIA","award":["U01AG058589"],"award-info":[{"award-number":["U01AG058589"]}]}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Journal of Alzheimer\u2019s Disease"],"published-print":{"date-parts":[[2025,4]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Prior studies examined variants within presenilin-2 (\n                      <jats:italic>PSEN2<\/jats:italic>\n                      ), presenilin-1 (\n                      <jats:italic>PSEN1<\/jats:italic>\n                      ), and amyloid precursor protein (\n                      <jats:italic>APP<\/jats:italic>\n                      ) genes. However, previously-reported clinically-relevant variants and other predicted damaging missense (DM) variants have not been characterized in a newer release of the Alzheimer's Disease Sequencing Project (ADSP).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>\n                      To characterize previously-reported clinically-relevant variants and DM variants in\n                      <jats:italic>PSEN2, PSEN1, APP<\/jats:italic>\n                      within the participants from the ADSP.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We identified rare variants (MAF\u2009&lt;\u20091%) in\n                      <jats:italic>PSEN2<\/jats:italic>\n                      ,\n                      <jats:italic>PSEN1,<\/jats:italic>\n                      and\n                      <jats:italic>APP<\/jats:italic>\n                      in 14,641 individuals with whole genome sequencing and 16,849 individuals with whole exome sequencing available (N\n                      <jats:sub>total\u2009<\/jats:sub>\n                      =\u200931,490). We additionally curated variants from ClinVar, OMIM, and Alzforum and report carriers of variants in clinical databases as well as predicted DM variants in these genes.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      We detected 31 previously-reported clinically-relevant variants with alternate alleles observed within the ADSP: 4 variants in\n                      <jats:italic>PSEN2<\/jats:italic>\n                      , 25 in\n                      <jats:italic>PSEN1<\/jats:italic>\n                      , and 2 in\n                      <jats:italic>APP<\/jats:italic>\n                      . The overall variant carrier rate for the 31 clinically-relevant variants in the ADSP was 0.3%. We observed that 79.5% of the variant carriers were cases compared to 3.9% were controls. In those with AD, the mean age of onset of AD among carriers of these clinically-relevant variants was 19.6\u2009\u00b1\u20091.4 years earlier compared with noncarriers (p\u2009=\u20097.8\u2009\u00d7\u200910\n                      <jats:sup>\u221257<\/jats:sup>\n                      ). Additionally, we identified 197 rare variants (MAF\u2009&lt;\u20091%) within ADSP participants not reported in known clinical databases.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>A small proportion of individuals in the ADSP are carriers of a previously-reported clinically-relevant variant allele for AD and these participants have significantly earlier age of AD onset compared to noncarriers.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1177\/13872877251320375","type":"journal-article","created":{"date-parts":[[2025,3,14]],"date-time":"2025-03-14T07:24:44Z","timestamp":1741937084000},"page":"841-851","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":3,"title":["Frequency of variants in Mendelian Alzheimer's disease genes within the Alzheimer's Disease Sequencing Project"],"prefix":"10.1177","volume":"104","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1317-2739","authenticated-orcid":false,"given":"Dongyu","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2336-685X","authenticated-orcid":false,"given":"Alexandra","family":"Scalici","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8621-7360","authenticated-orcid":false,"given":"Yanbing","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3043-3942","authenticated-orcid":false,"given":"Honghuang","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2658-1566","authenticated-orcid":false,"given":"Achilleas","family":"Pitsillides","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9730-0306","authenticated-orcid":false,"given":"Nancy","family":"Heard-Costa","sequence":"additional","affiliation":[{"name":"Department of Medicine, Boston University School of Medicine, Boston, MA, USA"},{"name":"NHLBI Framingham Heart Study, Framingham, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0276-2899","authenticated-orcid":false,"given":"Carlos","family":"Cruchaga","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Washington University School of Medicine, St Louis, MO, USA"},{"name":"Hope Center for Neurological Disorders, Washington University School of Medicine, St Louis, MO, USA"},{"name":"NeuroGenomics and Informatics, Washington University School of Medicine, St Louis, MO, USA"},{"name":"Department of Neurology, Washington University School of Medicine, St Louis, MO, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-3934-6110","authenticated-orcid":false,"given":"Ellen","family":"Ziegemeier","sequence":"additional","affiliation":[{"name":"Department of Neurology, Washington University School of Medicine, St Louis, MO, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3409-1110","authenticated-orcid":false,"given":"Joshua C","family":"Bis","sequence":"additional","affiliation":[{"name":"Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Myriam","family":"Fornage","sequence":"additional","affiliation":[{"name":"Brown Foundation Institute of Molecular Medicine, McGovern Medical School and Human Genetics Center, School of Public Health, University of Texas Health Science Center at Houston, Houston, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8813-0544","authenticated-orcid":false,"given":"Eric","family":"Boerwinkle","sequence":"additional","affiliation":[{"name":"Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA"},{"name":"Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philip L","family":"De Jager","sequence":"additional","affiliation":[{"name":"Center for Translational &amp; Computational Neuroimmunology, Department of Neurology, Columbia University Medical Center, New York, NY, USA"},{"name":"Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Irving Medical Center, New York, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ellen","family":"Wijsman","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, University of Washington, Seattle, WA, USA"},{"name":"Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2871-3603","authenticated-orcid":false,"given":"Jos\u00e9e","family":"Dupuis","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alan E","family":"Renton","sequence":"additional","affiliation":[{"name":"Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, NY, USA"},{"name":"Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6135-2622","authenticated-orcid":false,"given":"Sudha","family":"Seshadri","sequence":"additional","affiliation":[{"name":"NHLBI Framingham Heart Study, Framingham, MA, USA"},{"name":"Department of Neurology, Boston University School of Medicine, Boston, MA, USA"},{"name":"Glenn Biggs Institute for Alzheimer's Disease and Neurodegenerative Diseases, University of Texas Health San Antonio, San Antonio, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0576-2472","authenticated-orcid":false,"given":"Alison M","family":"Goate","sequence":"additional","affiliation":[{"name":"Ronald M. 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