Abstract
ObjectiveWe previously reported that genetic variants in SORCS1 increase the risk of AD, that over-expression of SorCS1 reduces γ-secretase activity and Aβ levels, and that SorCS1 suppression increases γ-secretase processing of APP and Aβ levels. We now explored the effect of variation in SORCS1 on memory.MethodsWe explored associations between SORCS1-SNPs and memory retention in the NIA-LOAD case control dataset (162 cases,670 controls) and a cohort of Caribbean Hispanics (549 cases,544 controls) using single marker and haplotype analyses.ResultsThree SNPs in intron 1, were associated with memory retention in the NIA-LOAD dataset or the Caribbean Hispanic dataset (rs10884402(A allele:β = −0.15,p = 0.008), rs7078098(C allele:β = 0.18,p = 0.007) and rs950809(C allele:β = 0.17,p = 0.008)) and all three SNPs were significant in a meta-analysis of both datasets (0.002<p<0.03). The corresponding A-T-T haplotype for these SNPs was associated with lower scores in both datasets (p = 0.02,p = 0.0009), and the complementary G-C-C haplotype was associated with higher scores in NIA-LOAD (p = 0.02). These associations were restricted to cases.ConclusionsVariation in intron 1 in SORCS1 is associated with memory changes in AD.
Highlights
The putative culprit in Alzheimer’s disease (AD) is the amyloid b (Ab) protein
Recruitment for the NIALOAD Study was approved by the relevant institutional review boards of the participating centers.The study was conducted according to the principles expressed in the Declaration of Helsinki
In the NIA-LOAD dataset, 11 SNPs were significantly associated with the memory savings score after correction for multiple testing and in the Caribbean Hispanic dataset two SNPs were associated (rs10884402 (p = 0.007) and rs2149196 (p = 0.04)). rs10884402 (A allele associated with lower scores in the Caribbean Hispanics, table 2), and rs7078098 and rs950809 (C alleles associated with higher scores in the NIALOD dataset) constitute a block of three adjacent SNPs that are 2.4 kb apart and are in linkage disequilibrium (LD) in both datasets
Summary
The putative culprit in Alzheimer’s disease (AD) is the amyloid b (Ab) protein. It is produced by b-secretase (BACE) cleavage of the amyloid precursor protein (APP) at the N-terminus of the Ab peptide followed by c-secretase cleavage of the membrane-bound C-terminal APP fragment [1]. APP and the secretases are integral transmembrane proteins, and are dynamically sorted into the plasma membrane and the membranes of intracellular organelles [2,3]. We and several other groups have recently reported [4,5,6] that variants in the sortilin-related VPS10 domain containing receptor 1 (SORCS1), which maps to chromosome 10q23–25, are associated with AD. We demonstrated that over expression of SorCS1 reduces c-secretase activity and Ab levels, and that suppression of
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