SUMMARY: PROJECT 1- AMYLOID AND TAU PET Trajectories of aβ and tau deposition can now be related to each other and to other biomarkers of preclinical AD as well as to clinical endpoints. Recent therapeutic trial failures highlight the critical need for a better understanding of how changing levels of pathology relate to each other and to clinical outcomes. Unfortunately, these relationships are complex, and optimized measures permitting robust tracking of dynamics remain underdeveloped, posing a barrier to efficient, rapid progress toward successful therapeutics. Initial study of these trajectories in HABS indicated that earlier aβ increase was detectable but was not associated with cognitive decline until a later observation period, during which time the decline was mediated by concurrent measures of tau accumulation. In the proposed HABS Cycle 3, Project 1 will focus on the progression and interrelated dynamics of aβ and tau pathologies assessed with PET acquired in the Imaging Core to identify stages of pathologic progression. We will leverage the HABS sample, with 9 years of amyloid and 4 years of tau PET follow up along with longitudinal neuropsychological data to characterize stages of progression in terms of time (Aim 1) and space (Aim 2), as well as explore novel plasma measures for manifestations of these stages (exploratory Aim 3). Specifically, HABS participants will undergo serial imaging with 11C Pittsburgh Compound B and 18F Flortaucipir PET with Aim 1, to characterize the temporal trajectory of each pathology, relate these trajectories to each other, identify dynamic connections between each that progress in successive intervals, and relate these findings to age, sex, and APOE genotype; Aim 2, to identify the specific anatomy of aβ and tau progression based on serial measures; and Aim 3 (Exploratory), investigate the associations of aβ and tau level and change measured with PET to measures obtained with blood biomarkers, and to correlate findings with autopsy brains as they become available. Project 1 will contribute to the overall Program goals: together we will assess the impact of modulating factors (Project 2) as well as the functional links (Project 3) that relate pathologic change to clinical phenotype (Project 4). Together, this research will ultimately improve sampling for clinical trials and therapeutic targeting strategies.