The-48 C/T polymorphism in the presenilin 1 promoter is associated with anincreased risk of developing Alzheimer's disease and an increased A beta load in brain

Mutations in the presenilin 1 gene (PS1) account for the majority of early onset, familial, autosomal dominant forms of Alzheimer's disease (AD), wher eas its role in other late onset forms of AD remains unclear. A -48 CIT pol ymorphism in the PS1 promoter has been associated with an increased genetic risk in early onset complex AD and moreover has been shown to influence th e expression of the PS1 gene. This raises the possibility that previous con flicting findings from association studies with homozygosity for the PS1 in tron 8 polymorphism might be the result of linkage disequilibrium with the -48 CC genotype. Here we provide further evidence of increased risk of AD a ssociated with homozygosity for the -48 CC genotype (odds ratio=1.6). We al so report a phenotypic correlation with A beta (40), A beta (42(43)), and t otal A beta load in AD brains. The -48 CC genotype was associated with 47% greater total A beta load (p <0.003) compared to CT + TT genotype bearers. These results suggest that the -48 C/T polymorphism in the PS1promoter may increase the risk of AD, perhaps by altering PS1 gene expression and thereb y influencing A beta load.