Energy expenditure, cognitive function, and biomarker features of Alzheimer's disease

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PROJECT SUMMARY / ABSTRACT This is an application for a Mentored Patient-Oriented Research Career Development Award (K01). The goal of the proposed project is to provide the candidate with advanced skills necessary to develop an independent research program focused on the association between physical activity and cognitive decline and dementia, particularly as it pertains to Alzheimer disease-related dementias (ADRDs). To facilitate this long-term career goal the candidate will: focus on two physical activity-related measures of energy expenditure (“energetics”) (1) cardiorespiratory fitness and (2) the energetic cost of walking, as objective markers of the physiological consequences of habitual physical activity. Recent published work by the candidate suggests that measures of energetics may optimally capture the physiological mechanisms underlying the beneficial effects of physical activity on risk for cognitive decline. This research indicates that lower levels of cardiorespiratory fitness –the integrated ability to deliver oxygen to the musculoskeletal system during sustained activity– is associated with cognitive decline, increased rate of brain atrophy, and decreased resting cerebral blood flow and that a higher energetic cost of walking –the oxygen needed for customary paced walking– is associated with increased odds of amyloid positivity and accelerated hippocampal and brain atrophy. This application proposes a longitudinal study to i) investigate the extent to which changes in energetics track with changes in cognition and AD biomarkers, ii) assess which modifiable energetic measure may hold the greatest predictive value with respect to the forgoing outcomes; and iii) investigate mitochondrial function as a potential underlying biological mechanism of energetics-brain associations. With a transdisciplinary mentorship team, the applicants career development plan builds on his previous research training to gain proficiency in: 1) advanced neuroimaging techniques, using PET and MRS, 2) physical activity-related measures of energy expenditure and post-exercise MRS assessment of oxidative capacity (a correlate of mitochondrial function), 3) cognitive changes associated with aging and ADRD, 4) longitudinal statistical analysis, 5) professional development, and 6) responsible conduct of research. The research objectives and training goals of this K01 award will provide a learning environment to advance the applicants knowledge in cognitive aging and ADRD and facilitate his transition to an independent investigator examining the impact of modifiable lifestyle activities on cognitive decline in older persons.