{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T09:38:10Z","timestamp":1791279490399,"version":"4.1.0"},"reference-count":32,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2015,2,3]],"date-time":"2015-02-03T00:00:00Z","timestamp":1422921600000},"content-version":"vor","delay-in-days":2,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"publisher","award":["P50AG08702, R37AG15473, RO1AG037212"],"award-info":[{"award-number":["P50AG08702, R37AG15473, RO1AG037212"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Annals of Neurology"],"published-print":{"date-parts":[[2015,2]]},"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>Common single nucleotide polymorphisms in the <jats:italic>SORL1<\/jats:italic> gene have been associated with late onset Alzheimer disease (LOAD), but causal variants have not been fully characterized nor has the mechanism been established. The study was undertaken to identify functional <jats:italic>SORL1<\/jats:italic> mutations in patients with LOAD.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>This was a family\u2010 and cohort\u2010based genetic association study. Caribbean Hispanics with familial and sporadic LOAD and similarly aged controls were recruited from the United States and the Dominican Republic, and patients with sporadic disease of Northern European origin were recruited from Canada. Prioritized coding variants in <jats:italic>SORL1<\/jats:italic> were detected by targeted resequencing and validated by genotyping in additional family members and unrelated healthy controls. Variants transfected into human embryonic kidney 293 cell lines were tested for A\u03b240 and A\u03b242 secretion, and the amount of the amyloid precursor protein (APP) secreted at the cell surface was determined.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Seventeen coding exonic variants were significantly associated with disease. Two rare variants (rs117260922\u2010E270K and rs143571823\u2010T947M) with minor allele frequency (MAF)\u2009&lt;\u20091% and 1 common variant (rs2298813\u2010A528T) with MAF\u2009=\u200914.9% segregated within families and were deemed deleterious to the coding protein. Transfected cell lines showed increased A\u03b240 and A\u03b242 secretion for the rare variants (E270K and T947M) and increased A\u03b242 secretion for the common variant (A528T). All mutants increased the amount of APP at the cell surface, although in slightly different ways, thereby failing to direct full\u2010length APP into the retromer\u2010recycling endosome pathway.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>Common and rare variants in <jats:italic>SORL1<\/jats:italic> elevate the risk of LOAD by directly affecting APP processing, which in turn can result in increased A\u03b240 and A\u03b242 secretion. Ann Neurol 2015;77:215\u2013227<\/jats:p><\/jats:sec>","DOI":"10.1002\/ana.24305","type":"journal-article","created":{"date-parts":[[2014,11,7]],"date-time":"2014-11-07T16:28:04Z","timestamp":1415377684000},"page":"215-227","source":"Crossref","is-referenced-by-count":174,"title":["Coding mutations in <scp><i>SORL<\/i><\/scp><i>1<\/i> and <scp>A<\/scp>lzheimer disease"],"prefix":"10.1002","volume":"77","author":[{"given":"Badri N.","family":"Vardarajan","sequence":"first","affiliation":[{"name":"Taub Institute for Research on Alzheimer's Disease and the Aging Brain"},{"name":"Gertrude H. Sergievsky Center Columbia University New York NY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yalun","family":"Zhang","sequence":"additional","affiliation":[{"name":"Tanz Centre for Research in Neurodegenerative Diseases and Department of Medicine University of Toronto Toronto Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph H.","family":"Lee","sequence":"additional","affiliation":[{"name":"Taub Institute for Research on Alzheimer's Disease and the Aging Brain"},{"name":"Gertrude H. Sergievsky Center Columbia University New York NY"},{"name":"Cambridge Institute for Medical Research Department of Clinical Neurosciences University of Cambridge Cambridge United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rong","family":"Cheng","sequence":"additional","affiliation":[{"name":"Taub Institute for Research on Alzheimer's Disease and the Aging Brain"},{"name":"Gertrude H. Sergievsky Center Columbia University New York NY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher","family":"Bohm","sequence":"additional","affiliation":[{"name":"Tanz Centre for Research in Neurodegenerative Diseases and Department of Medicine University of Toronto Toronto Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mahdi","family":"Ghani","sequence":"additional","affiliation":[{"name":"Tanz Centre for Research in Neurodegenerative Diseases and Department of Medicine University of Toronto Toronto Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christiane","family":"Reitz","sequence":"additional","affiliation":[{"name":"Taub Institute for Research on Alzheimer's Disease and the Aging Brain"},{"name":"Gertrude H. Sergievsky Center Columbia University New York NY"},{"name":"Departments of Neurology College of Physicians and Surgeons, Columbia University New York NY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dolly","family":"Reyes\u2010Dumeyer","sequence":"additional","affiliation":[{"name":"Taub Institute for Research on Alzheimer's Disease and the Aging Brain"},{"name":"Gertrude H. Sergievsky Center Columbia University New York NY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yufeng","family":"Shen","sequence":"additional","affiliation":[{"name":"Departments of Systems Biology College of Physicians and Surgeons, Columbia University New York NY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ekaterina","family":"Rogaeva","sequence":"additional","affiliation":[{"name":"Tanz Centre for Research in Neurodegenerative Diseases and Department of Medicine University of Toronto Toronto Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"St George\u2010Hyslop","sequence":"additional","affiliation":[{"name":"Tanz Centre for Research in Neurodegenerative Diseases and Department of Medicine University of Toronto Toronto Ontario Canada"},{"name":"Cambridge Institute for Medical Research Department of Clinical Neurosciences University of Cambridge Cambridge United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard","family":"Mayeux","sequence":"additional","affiliation":[{"name":"Taub Institute for Research on Alzheimer's Disease and the Aging Brain"},{"name":"Gertrude H. Sergievsky Center Columbia University New York NY"},{"name":"Departments of Neurology College of Physicians and Surgeons, Columbia University New York NY"},{"name":"Departments of Psychiatry College of Physicians and Surgeons, Columbia University New York NY"},{"name":"Department of Epidemiology School of Public Health, Columbia University New York NY"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2015,2,3]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M601660200"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1515\/BC.2002.193"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng1943"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2802"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11910-008-0060-8"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1212\/01.wnl.0000280581.39755.89"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1001\/archneur.64.4.501"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1097\/WNR.0b013e3282f13e7a"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0058618"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1001\/archneurol.2010.346"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurobiolaging.2007.10.013"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btp324"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1101\/gr.107524.110"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btp352"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btq214"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkq603"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1002\/0471142905.hg0720s76"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.1101\/gr.097857.109"},{"key":"e_1_2_7_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2011.05.029"},{"key":"e_1_2_7_21_1","doi-asserted-by":"publisher","DOI":"10.1159\/000329467"},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.1086\/338688"},{"key":"e_1_2_7_23_1","doi-asserted-by":"publisher","DOI":"10.1038\/35024009"},{"key":"e_1_2_7_24_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M406289200"},{"key":"e_1_2_7_25_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature04667"},{"key":"e_1_2_7_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jalz.2010.03.013"},{"key":"e_1_2_7_27_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2013.2973"},{"key":"e_1_2_7_28_1","doi-asserted-by":"publisher","DOI":"10.1038\/mp.2012.15"},{"key":"e_1_2_7_29_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature13127"},{"key":"e_1_2_7_30_1","article-title":"Inbreeding among Caribbean Hispanics from the Dominican Republic and its effects on risk of Alzheimer disease","author":"Vardarajan BN","journal-title":"Genet Med"},{"key":"e_1_2_7_31_1","doi-asserted-by":"publisher","DOI":"10.1097\/GIM.0b013e3181d38f2f"},{"key":"e_1_2_7_32_1","doi-asserted-by":"publisher","DOI":"10.1002\/mds.23965"},{"key":"e_1_2_7_33_1","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.3007747"}],"container-title":["Annals of Neurology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fana.24305","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ana.24305","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,6]],"date-time":"2023-10-06T10:08:50Z","timestamp":1696586930000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/ana.24305"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,2]]},"references-count":32,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2015,2]]}},"alternative-id":["10.1002\/ana.24305"],"URL":"https:\/\/doi.org\/10.1002\/ana.24305","archive":["Portico"],"relation":{},"ISSN":["0364-5134","1531-8249"],"issn-type":[{"value":"0364-5134","type":"print"},{"value":"1531-8249","type":"electronic"}],"subject":[],"published":{"date-parts":[[2015,2]]}}}