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 language | English (US) |
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Pages (from-to) | 9434-9439 |
Number of pages | 6 |
Journal | Proceedings of the National Academy of Sciences of the United States of America |
Volume | 104 |
Issue number | 22 |
DOIs | |
State | Published - May 29 2007 |
Externally published | Yes |
Keywords
- APOE
- LRP-6
- Neurodegenerative
- Single-nucleotide polymorphism
- Wnt
ASJC Scopus subject areas
- Genetics
- General