We studied whether primary enzymatic antioxidant protection should influence cognitive decline (CD) in subjects aged 62-72 years volunteers in the Etude du Vieillissement Antériel (EVA) cohort. At baseline, we measured red blood cells activities of two enzymes: cytoplasmic form of superoxide dismutase (CuZn-SOD) and seleno dependent glutathione peroxidase (GSH-Px). During the 4 year-follow up (follow-up rate of 81%), a drop of at least 3 points in MMSE score was observed in 71 subjects (7.2%) defining individuals with CD+ among the 980 individuals. Initial GSH-Px activity appeared to be significantly lower in individual CD+ (41.2 +/- 10.3 U/g Hb vs. 44.4 +/- 9.4 in CD-, p = 0.008). Conversely, there was an increase of CuZn-SOD activity in CD+ subjects (1.13 +/- 0.10 U/mg Hb vs. 1.10 +/- 0.10, p = 0.05). Taking into account the ratio between these two levels suggest that the equilibrium between these two enzymes, an important determinant of oxidative stress level, is associated with CD. These results are independent of other potential risk factors for CD (education, Apolipoprotein E, hypertension) and suggest that this primary enzymatic system could be related to CD during aging.