Screening of two mutations at exon 3 of the apolipoprotein E gene (sites 28 and 42) in a sample of patients with sporadic late-onset Alzheimer?s disease.

The search for further variation at the APOE gene in a sample of patients with sporadic late-onset Alzheimer's disease (AD) and related controls revealed two different mutations in the exon 3 of the gene. One, the Leu28Pro, always found on an APOE e*4 allele, was present in 5 of the 94 patients and in 1 of the 157 controls. The other, Thr42Ala, found on an e*3 allele, was observed in only one AD patient, who also carried the Leu28Pro, but in none of the controls. In the AD patient group the allele e*4 -, corresponding to Leu28Pro, showed a frequency of 0.027, compared with only 0.003 in the controls. Compared to E3/3 and E3/2 genotypes, the risk of developing AD associated with the genotypes carrying the e*4 allele, the well-established risk allele for AD onset, was observed to be high (OR = 3.16; 95% CI = 1.62 - 6.20 ; p = 0.0009 ), but the risk associated with genotypes carrying the Leu28 à Pro mutation was higher still (OR = 10.95 ; 95% CI = 1.25 - 95.75 p = 0.015 ). The higher risk associated with this mutation was assessed by meta-analysis carried out using the data of three patient groups from a previously published study (Kamboh et al. 1999) and from our study. The results indicated that, compared with all the other APOE genotypes, those carrying the Leu28Pro mutation were at a substantially higher risk of developing AD (OR = 4.25, 95% CI = 1.21 - 14.97).