Project Summary/Abstract Aging is associated with dopamine system dysfunction and the aggregation of hyperphosphorylated tau. Previous studies of cognitive aging have demonstrated the independent effects of dopamine dysregulation (e.g. deficits in reward processing) and tau aggregation (e.g. memory deficits). We propose to study the joint effects of dopamine and tau on cognition in aging using multimodal MR/PET neuroimaging. The central hypothesis is that increased levels of dopamine protect against cognitive decline, and can stabilize memory performance in the face of tau burden. The proposed work will leverage a unique training opportunity and collaboration between interdisciplinary researchers at the MGH Martinos Center for Biomedical Imaging and Brandeis University. I will gain expertise in cognitive aging as well as integrating fMRI and PET methodologies. Older adult participants from the ongoing longitudinal Brandeis Aging Brain Study will be invited to undergo simultaneous MR/PET neuroimaging to measure dopamine levels and neural activity during a reward memory task. Additionally, participants will return for a tau-PET scanning session. Our specific aims will test the hypotheses 1) that increased endogenous dopamine release is associated with better reward memory, especially in individuals with lower levels of tau, 2) that increased dopamine release is associated with increased variability in hippocampal neural activity (leading to improved reward memory), and 3) that individual baseline levels of dopamine and tau will be predictive of memory improvements upon receiving a dopamine-enhancing pharmaceutical (methylphenidate). Based on preliminary data, we expect to find that increased levels of dopamine will lead to more variable brain activity in the hippocampus and better reward memory in older adults, but that these effects will be attenuated by tau aggregation. We also predict that older adults with lower levels dopamine will show the greatest potential for memory improvements following pharmaceutically-induced dopamine enhancement, despite baseline levels of tau. Previously, the influences of dopamine and tau on cognitive aging have mostly been studied independently. This work will begin to bridge these subfields by studying the joint influences tau and dopamine on memory together in the same individuals. These experiments will contribute to an improved understanding of how neurochemistry and protein pathology interact to affect memory in older adults, and may suggest a mechanism by which cognitive function is preserved in the pre-clinical stages of age-related disease.