Age-related cognitive decline and pathological brain changes are a widespread and growing public health issue. Several environmental factors, including engagement in physical activity and personality, have been shown to have potential protective effects in slowing cognitive decline and preserving healthy brain aging. However, the underlying mechanisms providing exercise- or personality-induced resilience to aging and disease remains largely unknown. Importantly, there has been an emergence of several novel biomarkers to study healthy brain aging and age-related neurodegenerative diseases including in vivo assessments of tau burden and brain metabolism via positron emission tomography (PET) imaging and neurofilament light chain (NfL), a marker of neurodegeneration, via Age-related cognitive decline and pathological brain changes are a widespread and growing public health issue. Several environmental factors, including engagement in physical activity and personality, have been shown to have potential protective effects in slowing cognitive decline and preserving healthy brain aging. However, the underlying mechanisms providing exercise- or personality-induced resilience to aging and disease remains largely unknown. Importantly, there has been an emergence of several novel biomarkers to study healthy brain aging and age-related neurodegenerative diseases including in vivo assessments of tau burden and brain metabolism via positron emission tomography (PET) imaging and neurofilament light chain (NfL), a marker of neurodegeneration, via blood-based biomarkers. During the first part of my thesis research, I examined these emerging biomarkers within healthy aging and AD cohorts at Washington University, in the Australian Imaging, Biomarkers, and Lifestyle (AIBL) cohort, and in the Dominantly Inherited Alzheimer Network (DIAN) observational study (Chapters 2 - 5). For the second part of my thesis research, I first used my new knowledge and experience with these biomarkers to characterize and determine the influence of physical activity on cerebral glucose metabolism (Chapter 6). Next, to better translate these findings to an exercise intervention in the future, I further completed a pilot study to determine feasibility and validity of performing a submaximal exercise protocol in a diverse US population (Chapter 7). For the third part of my thesis research, I discovered a cross-sectional association between personality traits and neurofibrillary tangle pathology. Taken together, the results from my thesis suggest utility in all three emerging biomarkers examined (tau-PET, blood-based NfL, and multi-tracer brain metabolism PET) for monitoring and understanding complex changes associated with brain aging and disease. Additionally, this thesis research adds to the current understanding of the potential role of increased physical activity in preservation of glycolytic metabolism in the aging brain and increased risk of AD-related tau pathophysiology in neurotic personality traits. Further research extending these findings to longitudinal studies are needed to help determine directionality of the observed effects.