Successful prevention of Alzheimer’s disease (AD) dementia may rely on intervention at the earliest possible point in the AD pathological cascade, hypothesized to be the accumulation of amyloid-beta (Aβ). The standard PET approach for Aβ detection is based on widespread cortical Aβ burden and often fails to capture early Aβ. The proposed K01 project will develop optimized spatial extent measures that allow for robust identification of individuals in an earlier stage of amyloidosis than previously studied. This approach should provide a more dynamic biomarker of A localization for investigating early A‘s role in the AD pathological cascade and has the potential to serve as a more sensitive outcome in future prevention trials. Aim 1 will use longitudinal data from clinically normal (CN) individuals from the Harvard Aging Brain Study (HABS) to 1) develop an optimized spatial extent metric based on a scientifically rigorous investigation of how different possible methods for computing spatial extent respond to simulated noise, 2) validate the sensitivity and specificity of the optimal spatial extent approach (EXT) to predict future A accumulation over 3-11 years, and 3) implement EXT in an independent sample of standard PET- screen fails from the AHEAD 3-45 Study to assess the alignment between plasma Aβ+ and EXT+ for detecting the earliest Aβ deposits. Aim 2 will use EXT to evaluate the earliest changes in tau using plasma biomarkers (ptau217) and flortaucipir-PET and assess whether EXT may provide a better predictive marker of those at risk for tau proliferation than standard cortical Aβ-PET approaches. Aim 3 will evaluate whether the improved quantification of the earliest A deposits with EXT allows for more sensitive detection of long-term and immediate cognitive changes associated with emerging A. These findings will help provide a framework for future prevention trials to intervene earlier in the disease process than has previously been attempted. Furthermore, the EXT approach will open a wide range of potential future directions to study how emerging Aβ relates to other important factors in AD pathogenesis (i.e. inflammation, synaptic function) to establish an independent research program. To help Dr. Michelle Farrell achieve these aims, a multidisciplinary mentorship team has been assembled from the Harvard Medical School community to complement didactic coursework in PET physics and pharmacokinetics, plasma biomarkers, advanced statistical analysis, and clinical trials. Dr. Reisa Sperling will serve as the primary mentor overseeing research and career progress and providing training in clinical trial design and conduct to maximize the translational potential of the planned research. Dr. Keith Johnson and Dr. Julie Price will serve as co-mentors to provide comprehensive training in PET research. The mentorship team will be rounded out by two research advisors (Dr. Rob Rissman: plasma biomarkers, Dr. Brian Healy: statistics) and two contr...