GENETIC ASSOCIATION BETWEEN INTRONIC POLYMORPHISM IN PRESENILIN-1 GENE AND LATE-ONSET ALZHEIMERS-DISEASE

Background Mutations in the presenilin-1 (PS-1) gene are associated wi th early-onset Alzheimer's 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 d isease. Methods We collected blood samples from 208 white cases of dem entia of the Alzheimer type and from 185 age matched controls (mean ag es 76.9 and 76.2 years, respectively; 58% female in each series). Clin ical diagnostic accuracy for Alzheimer's disease in our patients is 96 %. We also studied 29 African-American patients with dementia of the A lzheimer 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 Alzheimer's disease and a polymorphism within the intron 3' to exon 8 of the PS-1 gene. The ApoE genotype of most of the cases and c ontrols 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 Alzheimer's disease compared with the [12]/[22] g enotype (odds ratio 1.97, 95% CI 1.29-3.00). The proportion of Alzheim er's 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 0.1 5 for two copies. The smaller African-American series showed similar d istribution of PS-1 genotype between cases and controls. Interpretatio n In our white series of cases, PS-1 accounted for about half as much of the risk for late-onset Alzheimer's disease as did ApoE4.