PROJECT SUMMARY In both aging and Alzheimer's disease (AD), hyperphosphorylated forms of the tau protein preferentially develop within the CA1 subfield of the hippocampus. The hippocampus is critical to normal memory function, and thus tau deposition within CA1 may lead to age- and disease-related memory decline. However, the contribution of hippocampal tau to CA1 dysfunction and behavioral expression of memory impairment has not previously been investigated. The current study aims to determine the effects of hippocampal tau pathology on CA1 activation and behavioral performance during memory using a multimodal neuroimaging approach in cognitively normal older adults. Tau pathology will be measured with positron emission tomography (PET) and the novel second-generation tau-PET tracer [18F] MK-6240, which enables reliable quantification of hippocampal tau-PET signal for the first time. We will use functional magnetic resonance imaging (fMRI) to assess CA1 activation during memory processing. Recent studies have proposed that CA1 specifically supports statistical learning, a type of memory in which regularities between experiences are learned. Older adults will thus perform a statistical learning task during fMRI acquisition to derive measures of CA1 activation and statistical learning behavioral performance. We will also measure amyloid-β with [18F] Florbetapir PET and CA1 volume with structural MRI to explore the additional contribution of these factors. In Aim 1, we will determine the relationship between statistical learning behavioral performance and CA1 activation in aging by comparing activation between high- and low-performing older adults, and modeling activation changes across the task. In Aim 2, we will identify how tau pathology within the hippocampus is related to both CA1 activation and statistical learning behavioral performance. Finally, in Aim 3, we will measure functional connectivity between hippocampal subfields and the entorhinal cortex during the statistical learning task, and determine the effects of tau pathology on this connectivity. Findings from this study will help elucidate the role of hippocampal tau pathology on age- and disease-related memory decline. Additionally, behavioral performance on statistical learning tasks may emerge as a sensitive biomarker for early hippocampal tau pathology. Completion of the proposed research will directly support the applicant's training goals, including (1) fMRI experimental design and advanced analysis, (2) additional PET training with new tracers and high-resolution quantification, (3) conceptual development in cognitive neuroscience of memory, and (4) growth of skills to support an academic career. The University of California, Irvine provides a network of innovative cognitive neuroscience and Alzheimer's researchers with world-class facilities for neuroimaging. Dr. Michael Yassa, the sponsor, is a leader in studying age-related memory decline with multimodal neuroimaging. The com...