The oldest old are the fastest-growing segment of our population and have the highest prevalence of dementia. Little is known about the genetics of cognitive health in the very old. The aim of this study was to determine whether the genetic risk factors for Alzheimer disease (AD)-namely, apolipoprotein E (APOE) ε4 allele and a family history of dementia-continue to be important factors in the cognitive health of the very old. Case- control studies suggest that the effect of genetic factors diminishes at age >75 years. The present prospective study provided evidence to the contrary. We studied 114 Caucasian subjects who were physically healthy and cognitively intact at age 75 years and who were followed, for an average of 4 years, with neurological, psychometric, and neuroimaging examinations. Excellent health at entry did not protect against cognitive decline. Incidence of cognitive decline rose sharply with age. ε4 and a family history of dementia (independent of ε4) were associated with an earlier age at onset of dementia. Subjects who had ε4 or a family history of dementia had a ninefold-higher age-specific risk for dementia than did those who had neither ε4 nor a family history of dementia. These observations suggest that the rate of cognitive decline increases with age and that APOE and other familial/genetic factors influence the onset age throughout life.