{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T14:50:44Z","timestamp":1793285444122,"version":"4.5.0"},"reference-count":69,"publisher":"National Academy of Sciences","issue":"22","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2007,5,29]]},"abstract":"<jats:p>\n                    Genome-wide linkage studies have defined a broad susceptibility region for late-onset Alzheimer's disease on chromosome 12, which contains the Low-Density Lipoprotein Receptor-Related Protein 6 (\n                    <jats:italic>LRP6<\/jats:italic>\n                    ) gene, a coreceptor for Wnt signaling. Here, we report the association between common\n                    <jats:italic>LRP6<\/jats:italic>\n                    variants and late-onset Alzheimer's disease in a multicenter case-control series as well as in a large family-based series ascertained by the National Institute of Mental Health\u2013National Institute on Aging Genetics Initiative. As shown in the genome-wide linkage studies, our association depends mainly on apolipoprotein E-\u03b54 (\n                    <jats:italic>APOE<\/jats:italic>\n                    -\u03b5\n                    <jats:italic>4<\/jats:italic>\n                    ) carrier status. Haplotype tagging single-nucleotide polymorphisms (SNPs) with a set of seven allelic variants of\n                    <jats:italic>LRP6<\/jats:italic>\n                    identified a putative risk haplotype, which includes a highly conserved coding sequence SNP: Ile-1062 \u2192 Val. Functional analyses revealed that the associated allele\n                    <jats:italic>Val-1062<\/jats:italic>\n                    , an allele previously linked to low bone mass, has decreased \u03b2-catenin signaling in HEK293T cells. Our study unveils a genetic relationship between\n                    <jats:italic>LRP6<\/jats:italic>\n                    and\n                    <jats:italic>APOE<\/jats:italic>\n                    and supports the hypothesis that altered Wnt\/\u03b2-catenin signaling may be involved in this neurodegenerative disease.\n                  <\/jats:p>","DOI":"10.1073\/pnas.0603523104","type":"journal-article","created":{"date-parts":[[2007,5,22]],"date-time":"2007-05-22T18:08:20Z","timestamp":1179857300000},"page":"9434-9439","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":230,"title":["Common genetic variation within the Low-Density Lipoprotein Receptor-Related Protein 6 and late-onset Alzheimer's disease"],"prefix":"10.1073","volume":"104","author":[{"given":"Giancarlo V.","family":"De Ferrari","sequence":"first","affiliation":[{"name":"*Howard Hughes Medical Institute and"},{"name":"Department of Pharmacology and Institute for Stem Cell and Regenerative Medicine, University of Washington School of Medicine, Seattle, WA 98195;"},{"name":"Departamentos de Bioqu\u00edmica y Biolog\u00eda Molecular,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Papassotiropoulos","sequence":"additional","affiliation":[{"name":"Division of Molecular Psychology and Life Sciences Training Facility, Biozentrum, University of Basel, 4055 Basel, Switzerland;"},{"name":"Division of Psychiatry Research, University of Zurich, Lenggstrasse 31, 8029 Zurich, Switzerland;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Travis","family":"Biechele","sequence":"additional","affiliation":[{"name":"*Howard Hughes Medical Institute and"},{"name":"Department of Pharmacology and Institute for Stem Cell and Regenerative Medicine, University of Washington School of Medicine, Seattle, WA 98195;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabienne","family":"Wavrant De-Vrieze","sequence":"additional","affiliation":[{"name":"**Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miguel E.","family":"Avila","sequence":"additional","affiliation":[{"name":"Departamentos de Bioqu\u00edmica y Biolog\u00eda Molecular,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael B.","family":"Major","sequence":"additional","affiliation":[{"name":"*Howard Hughes Medical Institute and"},{"name":"Department of Pharmacology and Institute for Stem Cell and Regenerative Medicine, University of Washington School of Medicine, Seattle, WA 98195;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amanda","family":"Myers","sequence":"additional","affiliation":[{"name":"**Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katia","family":"S\u00e1ez","sequence":"additional","affiliation":[{"name":"Estad\u00edstica, y de"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan P.","family":"Henr\u00edquez","sequence":"additional","affiliation":[{"name":"Biolog\u00eda Celular, Universidad de Concepci\u00f3n, P.O. Box 160-C Concepci\u00f3n 4089100, Chile;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alice","family":"Zhao","sequence":"additional","affiliation":[{"name":"**Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. Axel","family":"Wollmer","sequence":"additional","affiliation":[{"name":"Division of Psychiatry Research, University of Zurich, Lenggstrasse 31, 8029 Zurich, Switzerland;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roger M.","family":"Nitsch","sequence":"additional","affiliation":[{"name":"Division of Psychiatry Research, University of Zurich, Lenggstrasse 31, 8029 Zurich, Switzerland;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christoph","family":"Hock","sequence":"additional","affiliation":[{"name":"Division of Psychiatry Research, University of Zurich, Lenggstrasse 31, 8029 Zurich, Switzerland;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chris M.","family":"Morris","sequence":"additional","affiliation":[{"name":"Institute for Aging and Health, MRC Building, Newcastle General Hospital, Newcastle-upon-Tyne NE4 6BE, United 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