Medial temporal lobe regions, including the hippocampus and entorhinal cortex, are pathologically affected during the early phases of Alzheimer's disease (AD). Our goal was to examine whether functional MRI could be used to detect early pre-clinical functional changes in medial temporal lobe regions in pre-symptomatic individuals carrying the E280A Presenilin 1 (PSEN1) mutation. Our participants were recruited from the world's largest known autosomal dominant early-onset AD (EOAD) kindred, located in Antioquia, Colombia. 16 presenilin 1 (PSEN1) presymptomatic mutation carriers (M age = 34.14 years SD = 5.36) and 18 noncarriers (M age = 34.27 years, SD = 5.37) were studied using functional MRI. Subjects were matched for age, sex, education, and neuropsychological performance. During fMRI scanning, subjects performed a novel picture encoding task adapted from Stern et al. (1996) which reliably activates MTL regions and has been used previously in subjects with mild cognitive impairment (Dickerson et al. 2004). Subjects performed a force-choice recognition test following encoding. Subjects were scanned using a Phillips Achieva 1.5T scanner, and analysis was carried out using SPM8. Both groups performed similarly on the post-scan recognition memory task. All subjects showed activation in the posterior hippocampus and parahippocampal gyrus during the encoding of novel scenes. Carriers showed a greater extent of activation within the left hippocampus than noncarriers. Carriers also showed lesser extent of activation within posterior parietal regions compared to noncarriers. PSEN1 presymptomatic carriers demonstrated greater extent of activation within the hippocampal formation during picture encoding compared to noncarriers. Our findings are consistent with previous studies that have reported changes in fMRI activation during presymptomatic stages of AD and suggest that functional changes within MTL regions occur well before the onset of cognitive symptoms.