PROJECT SUMMARY /ABSTRACT There is considerable individual variability in how much and how quickly cognitive abilities change with age. The better we understand the biological mechanisms that influences if and how aging affects brain structure and function, the more able we will be to intervene effectively in a person-specific manner. The overarching goal of this renewal application is to better understand the inflammatory, vascular, neurodegenerative, and lifestyle/behavioral contributions to this clinically important diversity in brain aging trajectories. We propose to continue following our deeply phenotyped cohort of 250 functionally intact older normals with our detailed cognitive, neuroimaging, and biometric characterizing over two additional time points. Our first aim is to define the separate and interactive pathways by which biologic and lifestyle variables influence age-related decline in brain structure and function Our second aim will determine of predictive value of innovative plasma markers of proteins associated with Alzheimer’s and neurodegeneration. Our third aim will incorporate innovative, objective, real-time measures of sleep and physical activity. Accomplishing these aims will have a highly significant impact on the field. Validating plasma biomarkers of pathology and clarifying the complex interplay of factors that influence brain aging trajectories will lead to better prediction and prevention of adverse brain aging and inform person-specific interventions.