The apolipoprotein E (APOE) is a well-established risk factor for late-onset Alzheimer's disease (AD). Several studies have attempted to confirm the association between the polymorphism located at position -491 in the transcriptional regulatory region of the APOE gene and AD. We examined in 85 AD patients and 90 control subjects of a Tunisian population the potential involvement of this polymorphism as a risk factor for AD, either through an independent effect or through interaction with the existing APOE ε4 allele risk. The T allele frequency was significantly higher in the AD patients group (45.3 %) than in the controls group (32.78 %) and may possibly constitute a significant risk factor for AD. The APOE ε4 allele did not influence the distribution of the -491 polymorphism after stratification.