Alzheimer disease (AD) risk is significantly influenced by the APOE2 and APOE4 alleles. In turn, the -491AT and TH1/E47cs polymorphisms alter APOE gene expression levels. To determine whether these two alleles exert any significant effect on AD development we have analysed the genotypes of the APOE promoter -491AT and Th1/E47cs polymorphisms in 163 AD patients and 155 controls divided into three age at onset/age dependent subgroups. Our study has detected a Th1/E47cs-T allele accumulation in healthy individuals over 75 years of age, which suggests it plays a protective role against AD. The Th1/E47cs-T allele may provide greater protection against AD than APOE2, although this awaits proof of Th1/E47cs-T allele overrepresentation in healthy individuals of other populations.