BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder with an as yet poorly understood etiology. Both environmental and genetic factors have been implicated as predisposing factors. The apolipoprotein E (APOE) ɛ4 allele is an established genetic susceptibility factor for AD for several populations including the Tunisian population. Polymorphism rs769446 (-427 T/C) at the promoter region of the APOE gene is postulated to affect the expression of the gene through differential binding of transcription factors. AIMS: This study aims at examining the APOE promoter polymorphism rs769446 for possible association with AD in a Tunisian population. METHODS: Using a case-control study design, a sample of 85 patients and 90 controls were investigated for association with the rs769446 polymorphism. RESULTS: No evidence of association was found in this population upon comparison between patients and healthy controls or upon stratification by APOE ɛ4. CONCLUSIONS: Investigations of potential gene-gene and gene-environmental interactions for this polymorphism need to be further conducted.