Hippocampal activation is associated with longitudinal amyloid accumulation and cognitive decline.

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