{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T15:31:25Z","timestamp":1784215885949,"version":"3.55.0"},"reference-count":47,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2014,7,29]],"date-time":"2014-07-29T00:00:00Z","timestamp":1406592000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["U01-AG032984"],"award-info":[{"award-number":["U01-AG032984"]}],"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":["R01-AG025259"],"award-info":[{"award-number":["R01-AG025259"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Annals of Neurology"],"published-print":{"date-parts":[[2014,9]]},"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>Much of the genetic basis for Alzheimer disease (AD) is unexplained. We sought to identify novel AD loci using a unique family\u2010based approach that can detect robust associations with infrequent variants (minor allele frequency\u2009&lt;\u20090.10).<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We conducted a genome\u2010wide association study in the Framingham Heart Study (discovery) and NIA\u2010LOAD (National Institute on Aging\u2013Late\u2010Onset Alzheimer Disease) Study (replication) family\u2010based cohorts using an approach that accounts for family structure and calculates a risk score for AD as the outcome. Links between the most promising gene candidate and AD pathogenesis were explored <jats:italic>in silico<\/jats:italic> as well as experimentally in cell\u2010based models and in human brain.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Genome\u2010wide significant association was identified with a <jats:italic>PLXNA4<\/jats:italic> single nucleotide polymorphism (rs277470) located in a region encoding the semaphorin\u20103A (SEMA3A) binding domain (meta\u2010analysis <jats:italic>p<\/jats:italic> value [meta\u2010P]\u2009=\u20094.1 \u00d7 10<jats:sup>\u22128<\/jats:sup>). A test for association with the entire region was also significant (meta\u2010P\u2009=\u20093.2 \u00d7 10<jats:sup>\u22124<\/jats:sup>). Transfection of SH\u2010SY5Y cells or primary rat neurons with full\u2010length PLXNA4 (TS1) increased tau phosphorylation with stimulated by SEMA3A. The opposite effect was observed when cells were transfected with shorter isoforms (TS2 and TS3). However, transfection of any isoform into HEK293 cells stably expressing amyloid \u03b2 (A\u03b2) precursor protein (APP) did not result in differential effects on APP processing or A\u03b2 production. Late stage AD cases (n\u2009=\u20099) compared to controls (n\u2009=\u20095) had 1.9\u2010fold increased expression of TS1 in cortical brain tissue (<jats:italic>p<\/jats:italic>\u2009=\u20091.6 \u00d7 10<jats:sup>\u22124<\/jats:sup>). Expression of TS1 was significantly correlated with the Clinical Dementia Rating score (\u03c1\u2009=\u20090.75, <jats:italic>p<\/jats:italic>\u2009=\u20092.2 \u00d7 10<jats:sup>\u22124<\/jats:sup>), plaque density (\u03c1\u2009=\u20090.56, <jats:italic>p<\/jats:italic>\u2009=\u20090.01), and Braak stage (\u03c1\u2009=\u20090.54, <jats:italic>p<\/jats:italic>\u2009=\u20090.02).<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>Our results indicate that PLXNA4 has a role in AD pathogenesis through isoform\u2010specific effects on tau phosphorylation. Ann Neurol 2014;76:379\u2013392<\/jats:p><\/jats:sec>","DOI":"10.1002\/ana.24219","type":"journal-article","created":{"date-parts":[[2014,7,8]],"date-time":"2014-07-08T06:57:30Z","timestamp":1404802650000},"page":"379-392","source":"Crossref","is-referenced-by-count":66,"title":["<scp><i>PLXNA<\/i><\/scp><i>4<\/i> is associated with <scp>A<\/scp>lzheimer disease and modulates tau phosphorylation"],"prefix":"10.1002","volume":"76","author":[{"given":"Gyungah","family":"Jun","sequence":"first","affiliation":[{"name":"Departments of Medicine Boston University School of Medicine Boston MA"},{"name":"Ophthalmology Boston University School of Medicine Boston MA"},{"name":"Department of Biostatistics Boston University School of Public Health Boston MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hirohide","family":"Asai","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Experimental Therapeutics Boston University School of Medicine Boston MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ella","family":"Zeldich","sequence":"additional","affiliation":[{"name":"Department of Biochemistry Boston University School of Medicine Boston MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elodie","family":"Drapeau","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Friedman Brain Institute Icahn School of Medicine at Mount Sinai New York NY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"CiDi","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Biochemistry Boston University School of Medicine Boston MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jaeyoon","family":"Chung","sequence":"additional","affiliation":[{"name":"Departments of Medicine Boston University School of Medicine Boston MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jong\u2010Ho","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Health Sciences and Technology Graduate School Samsung Advanced Institute for Health Science and Technology  Seoul Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sehwa","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Health Sciences and Technology Graduate School Samsung Advanced Institute for Health Science and Technology  Seoul Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vahram","family":"Haroutunian","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Friedman Brain Institute Icahn School of Medicine at Mount Sinai New York NY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tatiana","family":"Foroud","sequence":"additional","affiliation":[{"name":"Department of Medical and Molecular Genetics Indiana University School of Medicine Indianapolis IN"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryozo","family":"Kuwano","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics Brain Research Institute Niigata University  Niigata Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan L.","family":"Haines","sequence":"additional","affiliation":[{"name":"Department of Epidemiology and Biostatistics Case Western Reserve University Cleveland OH"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margaret A.","family":"Pericak\u2010Vance","sequence":"additional","affiliation":[{"name":"John P. 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