In the present study, the interaction of age and apolipoprotein E (apoE)-genetic background on cognitive abilities was investigated in young (5-6 months) and aged (14-16 months) female apolipoprotein E-knockout (apoE0/0) and wild-type mice. Cognitive abilities are known to be affected by the steroid hormones corticosterone and estrogen. Therefore, we measured the activity and reactivity of the hypothalamic-pituitary-adrenal (HPA) axis expressed by circadian corticosterone concentrations and responses to novelty and controlled the regularity of the estrous cycle. Young female apoE0/0 mice acquired the water maze task and showed a similar latency and search strategy to locate the platform as young female wild-type mice. Similar corticosterone responses to novelty were observed in both genotypes. Regularity of the estrous cycle was disturbed in a small percentage of the young apoE0/0 female mice. However, in aged female apoE0/0 mice water maze performance was impaired with search strategies less persistent than in aged wild-type mice. In parallel, increased corticosterone concentrations were measured in apoE0/0 mice in response to novelty and during the circadian cycle. The percentage of mice with an irregular estrous cycle increased with age, but was comparable for apoE0/0 and wild-type mice. Thus, although disruption of the apoE gene affects the regularity of the estrous cycle in young mice, it is the enhanced corticosterone secretion, which parallels the cognitive decline in the aging female apoE0/0 mice.