The hippocampal formation and entorhinal cortex have been found to be pathologically affected in early phases of Alzheimer's disease (AD). Using fMRI, we examined whether early pre-clinical functional changes could be observed in these regions during encoding of novel associations in pre-symptomatic individuals who carry a mutation in the Presenilin-1 (PS-1) gene. These subjects will develop AD around the age of 45 (Lopera et al., 1997). 7 PS-1 pre-symptomatic carriers (M age = 32.42 years SD= 6.39) and 6 matched controls (M age = 31.66 years, SD= 6.59) were selected from a Colombian population with familial AD. Subjects performed a face-name associative encoding task adapted from Sperling et al. (2001). The fMRI paradigm used a mixed-design with three conditions, novel face-name pairs, repeated face-name pairs and fixation. Subjects also performed a recognition test following encoding. Subjects were scanned using a Phillips Achieva 1.5T scanner, and analysis was carried out using SPM5. Carriers showed significantly less activation in medial temporal lobe (MTL) regions in response to novel face-name pairs and greater activation in dorsolateral prefrontal regions in response to repeated face-name pairs, compared with controls. For the novel vs. repeated contrast, the activation peaks were localized to the anterior regions of the MTL, including anterior hippocampus and entorhinal cortex. These findings are consistent with Sperling et al. (2003) who reported significantly less activation in the hippocampal formation in patients with mild AD compared to elderly controls. PS-1 pre-symptomatic carriers demonstrated differential encoding activation in the MTL compared to matched controls. PS-1 mutation, leading to AD pathology, may impact the efficiency with which critical brain regions, including MTL regions, are recruited during memory encoding. These results suggest that fMRI has the capacity to detect changes in brain function prior to the onset of symptoms of AD, and with future study, may be a useful early diagnostic marker for Alzheimer's disease.