Common genetic variation within the Low-Density Lipoprotein Receptor-Related Protein 6 and late-onset Alzheimer's disease

doi:10.1073/pnas.0603523104

Common genetic variation within the Low-Density Lipoprotein Receptor-Related Protein 6 and late-onset Alzheimer's disease

*Howard Hughes Medical Institute and
^†Department of Pharmacology and Institute for Stem Cell and Regenerative Medicine, University of Washington School of Medicine, Seattle, WA 98195;
^‡Departamentos de Bioquímica y Biología Molecular,
^††Estadística, y de
^‡‡Biología Celular, Universidad de Concepción, P.O. Box 160-C Concepción 4089100, Chile;
^¶Division of Molecular Psychology and Life Sciences Training Facility, Biozentrum, University of Basel, 4055 Basel, Switzerland;
^‖Division of Psychiatry Research, University of Zurich, Lenggstrasse 31, 8029 Zurich, Switzerland;
**Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892; and
^§§Institute for Aging and Health, MRC Building, Newcastle General Hospital, Newcastle-upon-Tyne NE4 6BE, United Kingdom

Edited by Elaine Fuchs, The Rockefeller University, New York, NY, and approved April 20, 2007 (received for review May 1, 2006)

Abstract

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 (LRP6) gene, a coreceptor for Wnt signaling. Here, we report the association between common LRP6 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–National Institute on Aging Genetics Initiative. As shown in the genome-wide linkage studies, our association depends mainly on apolipoprotein E-ε4 (APOE-ε4) carrier status. Haplotype tagging single-nucleotide polymorphisms (SNPs) with a set of seven allelic variants of LRP6 identified a putative risk haplotype, which includes a highly conserved coding sequence SNP: Ile-1062 → Val. Functional analyses revealed that the associated allele Val-1062, an allele previously linked to low bone mass, has decreased β-catenin signaling in HEK293T cells. Our study unveils a genetic relationship between LRP6 and APOE and supports the hypothesis that altered Wnt/β-catenin signaling may be involved in this neurodegenerative disease.

Footnotes

^§To whom correspondence may be addressed. E-mail: rtmoon{at}u.washington.edu or gdeferrari{at}udec.cl
Author contributions: G.V.D.F., A.P. and T.B. contributed equally to this work; G.V.D.F., A.P., T.B., F.W.D.-V., A.M., J.H., and R.T.M. designed research; G.V.D.F., A.P., T.B., M.E.A., M.B.M., A.M., J.P.H., A.Z., M.A.W., R.M.N., and C.H. performed research; C.M.M. contributed new reagents/analytic tools; G.V.D.F., A.P., T.B., F.W.D.-V., A.M., K.S., J.H., and R.T.M. analyzed data; and G.V.D.F. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/cgi/content/full/0603523104/DC1.
Abbreviations:

AD,

Alzheimer's disease;

SNP,

single-nucleotide polymorphism;

htSNP,

haplotype-tagging SNP;

LDLR,

Low-Density Lipoprotein Receptor;

LRP6,

LDLR-Related Protein 6;

APOE,

apolipoprotein E.