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Lookup NU author(s): Dr Christopher Morris
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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-4 (APOE-4) carrier status. Haplotype tagging single-nucleotide polymorphisms (SNPs) with a set of seven allelic variants of LRP6 identified a putative riskhaplotype, which includes a highly conserved coding sequence SNP: Ile-1062 3 Val. Functional analyses revealed that the associated allele Val-1062, an allele previously linked to low bone mass, has decreased -catenin signaling in HEK293T cells. Our study unveils a genetic relationship between LRP6 and APOE and supports the hypothesis that altered Wnt/-catenin signaling may be involved in this neurodegenerative disease.
Author(s): De Ferrari GV, Papassotiropoulos A, Biechele T, De-Vrieze FW, Avila ME, Major MB, Myers A, Saez K, Henriquez JP, Zhao A, Wollmer MA, Nitsch RM, Hock C, Morris CM, Hardy J, Moon RT
Publication type: Article
Publication status: Published
Journal: Proceedings of the National Academy of Sciences of the USA
Year: 2007
Volume: 104
Issue: 22
Pages: 9434–9439
ISSN (print): 0027-8424
ISSN (electronic): 1091-6490
Publisher: National Academy of Sciences
URL: http://www.pnas.org/cgi/reprint/0603523104v1
