Genetic association between intronic polymorphism in presenilin-1 gene and late-onset Alzheimerʹs disease

Background Mutations in the presenilin-1 (PS-1) gene are associated with early-onset Alzheimerʹs disease. 40-50% of the risk for late-onset disease has been attributed to alleles at the apolipoprotein E (ApoE) locus. We have looked for an association between PS-1 and late-onset disease. Methods We collected blood samples from 208 white cases of dementia of the Alzheimer type and from 185 age-matched controls (mean ages 76·9 and 76·2 years, respectively; 58% female in each series). Clinical diagnostic accuracy for Alzheimerʹs disease in our patients is 96%. We also studied 29 African-American patients with dementia of the Alzheimer type and 50 age-matched controls (cases vs controls, 77·2 vs 72·0 years; 72 vs 77% female). We used PCR to test for an association between Alzheimerʹs disease and a polymorphism within the intron 3ʹ to exon 8 of the PS-1 gene. The ApoE genotype of most of the cases and controls was known from previous investigations. Findings Homozygosity of the 1 allele in the PS-1 gene was associated with a doubling of the risk for late-onset Alzheimerʹs disease compared with the [12]/[22] genotype (odds ratio 1·97, 95% Cl 1·29-3·00). The proportion of Alzheimerʹs disease cases in the white population that could be attributed to homozygosity at this locus, as estimated by the attributable fraction, was 0·22. This compares with 0·35 for a single copy of ApoE4 and 0·15 for two copies. The smaller African-American series showed similar distribution of PS-1 genotype between cases and controls. Interpretation In our white series of cases, PS-1 accounted for about half as much of the risk for late-onset Alzheimerʹs disease as did ApoE4.