Increasing evidence indicates that variants in promoter of the beta-amyloid precursor protein (APP) gene could up-regulate the APP gene expression and aggravate the amyloid beta protein (A beta) accumulation, thus contributing to the development of Alzheimer's disease (AD). In Chinese Han populations we found three polymorphisms in APP promoter: -877T/C(rs466433), -955A/G(rs364048) and -9G/C. The -877T and -955A alleles were over-represented in 209 sporadic AD (SAD) patients when compared to those in 437 healthy individuals. Furthermore, -877T/C and -955A/G were in strong linkage disequilibrium and they constructed a relatively risky -877T/-955A and a relatively protective -877C/-955G. Luciferase reporter assay indicated -877T/-955A had four times higher transcriptional activity than -877C/-955G. A more marked increase in -877T/-955A transcriptional activity was seen when under A beta(25-35) treatment. As for the -9G/C polymorphism, significant differences between the two alleles were not observed either in genetic evaluation or in functional assay. The present study provides strong evidence that APP promoter polymorphisms that significantly increase APP expression levels are associated with development of SAD.
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