Age-related changes in the hippocampus increase vulnerability to impaired learning and memory. Our goal is to understand how a genetic vulnerability to cognitive impairment can be modified by aging and sex. Mice with a mutation in the cAMP response element binding (CREB) protein gene (CREB(alphadelta-) deficient mice) have a mild cognitive impairment and show test condition-dependent learning and memory deficits. We tested three ages of CREB(alphadelta-) deficient and wild-type (WT) mice in two Morris water maze (MWM) protocols: four trials per day with a 3-5 min inter-trial interval (ITI) (MWM4) and two trials per day with a 1 min ITI (MWM2). All CREB(alphadelta-) deficient mice performed well in the easier MWM4, except for the aged females that performed poorly. In the harder MWM2, young male and female and middle-aged male CREB(alphadelta-) deficient mice performed well, but aged male and all middle-aged and aged female CREB(alphadelta-) deficient mice were impaired. These results show that mice with a genetic vulnerability to impaired learning and memory exhibit increased vulnerability with age that is most apparent among females. Thus, a genetic predisposition to cognitive impairment may render females more vulnerable than males to such deficits with age.