Mutations in the presenilin 1 gene (PS1) account for the majority of early onset, familial, autosomal dominant forms of Alzheimer's disease (AD), whereas its role in other late onset forms of AD remains unclear. A −48 C/T polymorphism in the PS1 promoter has been associated with an increased genetic risk in early onset complex AD and moreover has been shown to influence the expression of the PS1 gene. This raises the possibility that previous conflicting findings from association studies with homozygosity for the PS1 intron 8 polymorphism might be the result of linkage disequilibrium with the –48 CC genotype. Here we provide further evidence of increased risk of AD associated with homozygosity for the −48 CC genotype (odds ratio=1.6). We also report a phenotypic correlation with Aβ40, Aβ42(43), and total Aβ load in AD brains. The −48 CC genotype was associated with 47% greater total Aβ load (p<0.003) compared to CT + TT genotype bearers. These results suggest that the –48 C/T polymorphism in thePS1 promoter may increase the risk of AD, perhaps by altering PS1 gene expression and thereby influencing Aβ load.
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