Abstract Body

Current theories of Alzheimer’s disease (AD) pathogenesis postulate that β-amyloid facilitates spread of pathological tau from the entorhinal cortex (ERC) to neocortically connected targets. Much remains unclear about this model, including the role of neural activity. We studied normal older participants from the Berkeley Aging Cohort Study using PET measures of β-amyloid and tau, and functional MRI. We investigated relationships between functional connectivity, neural activity during performance of a memory task, and patterns and rates of tau deposition. First, we show that functional connectivity between the hippocampus and medial parietal cortex (MPC) is related to tau deposition in MPC, thus providing evidence that the pathway from ERC to neocortex transits via the hippocampus. We also show that neural activity in the medial temporal lobe (MTL) at baseline is related to the rate of subsequent tau deposition. Higher activation in ERC and parahippocampal cortex during a memory task in ERC is related to faster tau accumulation in these regions. In order to investigate these effects on MTL function, we examined the phenomenon of repetition suppression, whereby neural activity is normally suppressed for the repeated presentation of a previous stimulus. We found that tau was associated with increased neural activity during the memory task, and was also associated with reduced repetition suppression. Together these findings support a model whereby tau spreads to neocortex via the hippocampus, with higher neural activity related to both higher rates of tau deposition and dysfunction of the MTL memory system.