Contributions of modifiable physical attributes to cognitive and brain aging

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ABSTRACT With the rapid acceleration of the aging population and repeated failures to find a pharmacological cure for Alzheimer’s disease (AD), it is of paramount importance to identify modifiable physical attributes that are most likely to attenuate cognitive and neural decline in older adults. Individual studies have demonstrated that mobility, cardiorespiratory fitness, and muscle strength/power are associated with cognition among older adults. However, because these physical attributes have been studied in isolation, it remains unknown which of these attributes are most critical for successful cognitive aging and brain maintenance (keeping the brain young). Our long-term goal is to develop a precision medicine model of cognitive aging; that is, to identify which physical attributes are associated with specific cognitive functions and implement individually tailored exercise programs to optimize those cognitive abilities among older adults. Our overall objective in the current proposal is to directly examine differential contributions of mobility, cardiorespiratory fitness, and muscle strength/power metrics to current cognitive abilities, brain health, and longitudinal cognitive decline. Our central hypothesis is that these physical attributes account for unique variance in cognition, but that their relative predictive abilities will differ within specific cognitive domains and neural networks. Using gold-standard assessments of mobility, cardiorespiratory fitness, muscle strength/power, cognition, and brain structure and function (magnetic resonance imaging; MRI) in young, middle-aged, and older adults, we will pursue the following aims: 1) Determine the contribution of physical attributes to cognition, with a specific emphasis on episodic memory and executive function, among older adults. 2) Determine the contribution of physical attributes to cortical thickness (T1-weighted MRI), white matter microstructure (diffusion-weighted MRI) and brain function (functional MRI) among older adults. 3) Identify which physical attributes predict cognitive decline over a 2.5-year period in older adults and whether polygenic risk scores for AD moderate the association between physical attributes and cognitive decline. We will examine which modifiable physical attributes, including functional aspects of the motor system, predict cognitive decline among older adults. Outcome data from this proposal will impact the development of lifestyle interventions for optimization of cognitive performance among older adults, as the study will provide critical knowledge to optimize future exercise intervention studies aimed at mitigating age- and Alzheimer’s disease-related cognitive and neural decline. Moreover, we will examine whether physical attribute-brain-cognition associations are age dependent. The current proposal is well-suited for the mission of the National Institutes of Aging, as we propose to examine modifiable physical attributes that will maximize high quality-of-life years and independent functioning (via maintenance of cognitive and brain health) prior to mortality.