The -4,752 C/T Polymorphism in the Presenilin 1 Gene Increases the Risk of Alzheimer's Disease in Apolipoprotein E4 Carriers

Objective We sought to establish an association between sporadic Alzheimer's disease (AD) and presenilin 1 (PSEN1) gene polymorphisms in the Japanese population.Methods A 5 kb fragment containing the putative promoter of the PSENl gene for randomly selected control subjects was subcloned into plasmid and sequenced to screen novel polymorphisms in this region. Patients and controls were genotyped for five polymorphic markers in the PSEN1 region. We then constructed haplotypes using the computer program HAPLO and compared the frequencies between cases and controls.Subjects A total of 189 AD cases (NINCDS-ADRDA criteria) and 240 controls were studied.Results We discovered a novel polymorphism with high heterozygosity on -4, 752 of the PSEN1 promoter region. A significant association was observed between the -4, 752 C/T polymorphism and late-onset AD. The odds ratio for AD associated with the CC vs non-CC genotype was 1.59 (95% CI=1.01-2.51), while that of e 4 vs non-e 4 in APOE gene was 4.41 (95% CI=2.72-7.16). The C allele was associated with a further increase in the risk of AD in APOE e 4 carriers. We found 12 major haplotypes using five polymorphisms. The distribution pattern was significantly different between cases and controls.Conclusion The PSEN1 gene -4, 752 C/T polymorphism modifies the risk for AD.(Internal Medicine 41: 823-828, 2002)