Cognitive decline in Alzheimer disease (AD) is increasingly attributed to the neuronal impact of soluble oligomers of the amyloid-β peptide (AβOs). Current knowledge on the molecular and cellular mechanisms underlying the toxicity of AβOs stems largely from rodent-derived cell/tissue culture experiments or from transgenic models of AD, which do not necessarily recapitulate the complexity of the human disease. Here, we used DNA microarray and RT-PCR to investigate changes in transcription in adult human cortical slices exposed to sublethal doses of AβOs. The results revealed a set of 27 genes that showed consistent differential expression upon exposure of slices from three different donors to AβOs. Functional classification of differentially expressed genes revealed that AβOs impact pathways important for neuronal physiology and known to be dysregulated in AD, including vesicle trafficking, cell adhesion, actin cytoskeleton dynamics, and insulin signaling. Most genes (70%) were down-regulated by AβO treatment, suggesting a predominantly inhibitory effect on the corresponding pathways. Significantly, AβOs induced down-regulation of synaptophysin, a presynaptic vesicle membrane protein, suggesting a mechanism by which oligomers cause synapse failure. The results provide insight into early mechanisms of pathogenesis of AD and suggest that the neuronal pathways affected by AβOs may be targets for the development of novel diagnostic or therapeutic approaches.