OBJECTIVES: To determine the relationship between apolipoprotein E (APOE) ɛ4 and Alzheimer's disease (AD) in the Mexican Mestizo population, as well as its effects on the cognitive profile of AD and elderly Mestizos without dementia. DESIGN: Cross‐sectional analysis of a cohort study. SETTING: Evaluations were conducted at the geriatrics clinic of an academic medical hospital in Mexico City. PARTICIPANTS: Forty‐nine elderly subjects with AD and 141 controls selected from a representative sample of Mexican Mestizos aged 65 to 96 who participated in the Prevalence Survey of Dementia in the Mexico City Elderly Population cohort. MEASUREMENTS: All subjects underwent APOE genotypification and a comprehensive clinical and neuropsychological evaluation. RESULTS: There were no significant differences in ɛ3 and ɛ4 frequencies between the subjects with and without AD and a tendency toward higher ɛ4 and lower ɛ3 allele frequencies in subjects aged 75 and older. No association was found between APOE ɛ4 and the presence of AD. The age‐, sex‐, and education‐adjusted risk for AD associated with at least one ɛ4 allele was 1.01 (95% confidence interval=0.45–2.23). Performance on a long‐term visual memory test was significantly worse in APOE ɛ4 carriers than in APOE ɛ3 carriers only in the group with AD. CONCLUSION: APOE ɛ4 did not increase the risk for AD in this Mexican Mestizo elderly urban population sample, although the presence of this allele seems to modify its clinical expression.