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 Leu28→Pro, always found on an APOE e*4 allele, was present in five of the 94 patients and in 1 of the 157 controls. The other, Thr42→Ala, found on an e*3 allele, was observed in only one AD patient, who also carried the Leu28→Pro, but in none of the controls. In the AD patient group the allele e*4−, corresponding to Leu28→Pro, 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→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. [4] and from our study. The results indicated that, compared with all the other APOE genotypes, those carrying the Leu28→Pro mutation were at a substantially higher risk of developing AD (OR=4.25; 95% CI=1.21–14.97).