Background: Associations between the APOE genotype and various medical conditions have been documented at a very young age. The association between the APOE genotype and cognitive performance varies at different ages. APOE related changes in brain activation have been recently reported for middle aged and elderly subjects. Objective: To explore APOE related alterations during cognitive activation in a population of young adults. Methods: Using H215O positron emission tomography (PET), imaging was carried out in 20 healthy young adults (age 19 to 28 years; four ε4 carriers and 16 non-ε4 carriers) during a non-verbal memory task. Voxel-wise multiple regression analyses were undertaken, with the activation difference PET counts as the dependent variable and the APOE genotype as the independent variable. Results: Brain regions were identified where ε4 carriers showed significantly lower or higher activation than non-carriers. Conclusions: The results suggest that APOE dependent modulation of cerebral flow may be present even at a young age. This may reflect an APOE related physiological heterogeneity which may or may not predispose to brain disease in the ensuing decades or, less likely, the effect of very early Alzheimer’s disease related pathological changes.