Determinants of Individual Differences in the Efficacy of Aerobic Exercise to Improve Brain Health and Reduce Alzheimer Disease Risk in Older African Americans

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PROJECT SUMMARY/ABSTRACT Older African Americans—especially those with lower income and those living in urban neighborhoods— have a greater risk of Alzheimer’s disease (AD) compared to the general population. This health disparity is attributable, in part, to modifiable factors including insufficient levels of aerobic exercise. However, not everyone gains the same degree of neuroprotection from exercise. For the proposed project, we plan to investigate genetic risk as a novel source of response heterogeneity to exercise interventions in African Americans. Previously, we demonstrated that five months of twice-weekly cardio-dance exercise can increase the dynamic rearrangement (or “neural flexibility”) of resting-state networks within the medial temporal lobe (MTL), one of the earliest brain regions impacted by AD. Moreover, this improved neural flexibility mediates intervention-related improvements in generalization, the ability to apply past learning to novel task demands. Given our earlier findings that generalization is impaired in preclinical AD, these results suggest a novel circuit-level mechanism, MTL neural flexibility, through which exercise may reduce risk for dementia. Moreover, we discovered that the cognitive benefits of exercise in older African Americans are diminished in those with a risk variant of the ABCA7 (rs3764650) gene. Two key limitations to our previous exercise studies were: (1) interventions limited to two 60-minute classes/week, below the recommended 150 minutes/week, and (2) too few participants to evaluate the effect of ABCA7 on exercise-induced changes on neural flexibility. We propose to recruit 280 sedentary older African Americans, ages 60 and above, to be randomized to one of two equally engaging six-month interventions, a Cardio Dance Fitness (CDF) intervention, and a Strength, Flexibility, & Balance active control. All participants will undergo—at enrollment and post-intervention—health assessments, cognitive tests, and structural and functional magnetic resonance imaging (fMRI), and a blood-draw to assess amyloid (A𝛽 42/40) and tau (p-tau231, p-tau181). This will enable us to test: 1) the effect of the CDF intervention on a cognitive marker of AD risk, generalization; 2) the effect of the CDF intervention on a fMRI biomarker of AD, neural flexibility, and determine whether improvements in neural flexibility mediate improvements in generalization; and 3) whether ABCA7 genotypic variations moderate the efficacy of the CDF intervention for reducing AD risk. Impact: This work lays the foundation for future larger clinical trials to develop personalized exercise prescriptions for older African Americans with varying genetic, health, and social-determinant risk profiles, so as to optimize the impact of this low-cost non-pharmaceutical intervention for improving their brain health.