We examined the association of apolipoprotein E (apo E) genotype with cognitive performance in Alzheimer's disease (AD) and Mild Cognitive Impairment (MCI) patients and in normal subjects. One hundred fifty-seven AD patients, 35 MCI patients who developed AD during longitudinal follow-up, and 341 normal control subjects from the Mayo Clinic Alzheimer's Disease Patient Registry were studied. All participants were typed for apo E using polymerase chain reaction-based assay, epsilon 4+ and epsilon 4- groups were compared on cognitive factor scores of Verbal Comprehension, Perceptual Organization, Attention/Concentration, Learning, and Retention. Raw delayed verbal recall and visual confrontation naming scores supplemented these scores. Multivariate ANOVA was completed for cognitive scores. As expected, a main effect for diagnostic group was present across all scores. Multivariate main effects for age group and apo E genotype were also statistically significant. Subsequent within-group comparisons revealed no genotype differences for control subjects across all cognitive scores except raw delayed recall where an interaction indicated that older epsilon 4+ control subjects actually scored better than younger epsilon 4+ patients. Genotype differences were present for the Retention factor in the MCI sample and for Verbal Comprehension and Learning in the AD sample. In a combined cognitive impairment sample (AD + MCI), genotype differences were present for Verbal Comprehension, Learning, and Retention. Possession of an apo E epsilon 4 allele did not appear to be associated with poorer cognitive performance among normal control subjects. In the AD and MCI samples, epsilon 4+ status was associated with greater memory impairment in analyses including duration of illness as a covariate. In combined AD + MCI analyses, epsilon 4 homozygosity was associated with poorer retention, learning, and verbal comprehension at a given disease duration. Possession of the epsilon 4 genotype may influence cognition in a dose-response relationship.