PROJECT SUMMARY/ABSTRACT This project is aimed at understanding the processes that drive decline in cognitive function with aging. Over the past decade it has become increasingly clear that many normal individuals often harbor the pathology that is associated with Alzheimer’s disease (AD): β-amyloid (Aβ) plaques and pathological accumulation of the microtubule associated protein tau. With the ability to detect and track these pathologies during life using multiple techniques including positron emission tomography (PET), we have learned that Aβ and tau pathology are associated with, and can predict decline in cognition, particularly episodic memory (EM), in otherwise cognitively normal people. Nevertheless, there is considerable variability associated with how individuals respond to AD pathology. Some show resilience: that is, they do not display impairment in EM despite evidence of pathology, while others may demonstrate resistance: they do not show evidence of pathology when existing group level data predicts its occurrence. The next phase of this project is oriented towards understanding how some people show successful aging outcomes despite the presence of AD pathology or show lower levels of pathology then expected. We will begin by defining two groups of successful agers from the Berkeley Aging Cohort Study (BACS) who have 3 or more longitudinal visits. The first definition makes use of a widely applied approach to select individuals performing at high levels in cross sectional cognitive measures. We refer to these as exceptional agers (EA) and will use a novel method deploying machine learning to predict “cognitive age” from a battery of neuropsychological tests. Those who fall in the “youngest” 20 percent of the cognitive age gap (CAG – difference between actual and predicted age) are defined as EA. Second, we will use a novel approach to define successful agers as those who show maintenance of EM performance over time, that is a slope of 0 or above on an EM composite measured at 3 or more timepoints. All of these individuals will receive longitudinal neuropsychological testing and PET scanning for AD pathology: Aβ PET with [11C]PIB and tau PET with [18F]Flortaucipir. At the first visit in this grant phase, participants will have an added PET scan to measure synaptic density with the ligand [18F]SynVesT1 that binds to the synaptic vesicle 2A protein. Based on extensive preliminary data, we predict that several different mechanisms underlie successful aging outcomes despite AD pathology: (1) Thicker mid-cingulate cortex will confer resilience to the effects of tau on EM decline (2) Successful agers will show less tau pathology and slower rates of Aβ and tau deposition because they are in earlier stages of Aβ deposition and (3) synaptic density in successful agers will be greater in specific brain regions including prefrontal cortex and mid-cingulate cortex and this will also confer resilience to AD pathology.