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

Giancarlo V. De Ferrari, Andreas Papassotiropoulos, Travis Biechele, Fabienne Wavrant De-Vrieze, Miguel E. Avila, Michael B. Major, Amanda Myers, Katia Sáez, Juan P. Henríquez, Alice Zhao, M. Axel Wollmer, Roger M. Nitsch, Christoph Hock, Chris M. Morris, John Hardy, Randall T. Moon

Research output: Contribution to journalArticle

182 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)9434-9439
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume104
Issue number22
DOIs
StatePublished - May 29 2007

Keywords

  • APOE
  • LRP-6
  • Neurodegenerative
  • Single-nucleotide polymorphism
  • Wnt

ASJC Scopus subject areas

  • Genetics
  • General

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    De Ferrari, G. V., Papassotiropoulos, A., Biechele, T., De-Vrieze, F. W., Avila, M. E., Major, M. B., Myers, A., Sáez, K., Henríquez, J. P., Zhao, A., Axel Wollmer, M., Nitsch, R. M., Hock, C., Morris, C. M., Hardy, J., & Moon, R. T. (2007). Common genetic variation within the Low-Density Lipoprotein Receptor-Related Protein 6 and late-onset Alzheimer's disease. Proceedings of the National Academy of Sciences of the United States of America, 104(22), 9434-9439. https://doi.org/10.1073/pnas.0603523104