Several clinical, epidemiological, and pathological observations suggest that vascular risk factors are associated with cognitive performances. The renin-angiotensin system components, major determinants of the cardiovascular system, are expressed in the brain. To estimate their potential impact on cognitive performances, we studied the association between cognitive functioning and an insertion/deletion (I/D) polymorphism of the angiotensin I-converting enzyme (ACE) gene. In a sample of 1168 highly performing subjects (59-71 years), DD homozygotes had the lowest cognitive scores as evaluated by the Mini-Mental State Examination. Cognitive decline at 4-year follow-up (defined as the loss of at least 3 points in Mini-Mental State Examination score) was more prevalent in these subjects, the odds ratio being equal to 1.53 (95% CI: 1.04-2.24) with subjects ID as reference class. Moreover, the combined effect of the presence of at least one APOE epsilon4 allele and ACE DD homozygosity was a risk factor for cognitive decline. This report reinforces the hypothesis of an influence of cardiovascular risk factors on cognitive performances.