The amyloid hypothesis suggests that beta-amyloid (A?) deposition leads to alterations in neural function and ultimately to cognitive decline in Alzheimer?s disease. However, factors that underlie A? deposition are incompletely understood. One proposed model suggests that synaptic activity leads to increased A? deposition. More specifically, hyperactivity in the hippocampus may be detrimental and could be one factor that drives A? deposition. To test this model, we examined the relationship between hippocampal activity during a memory task using fMRI and subsequent longitudinal change in A? using PIB-PET imaging in cognitively normal older adults. We found that greater hippocampal activation at baseline was associated with increased A? accumulation. Furthermore, increasing A? accumulation mediated the influence of hippocampal activation on declining memory performance, demonstrating a crucial role of A? in linking hippocampal activation and memory. These findings support a model linking increased hippocampal activation to subsequent A? deposition and cognitive decline.