Project Summary: By 2050, the prevalence of Alzheimer?s disease (AD) in the United States is predicted to reach 13.8 million. Despite worldwide research efforts, a cure for AD has not been identified. Thus, it is critical to identify preventive strategies that can reduce the risk of or delay the onset of AD. Physical activity (PA) has potential in this regard. Meta-analytic reviews and our own experimental studies show that older adults who participate in PA experience larger gains in cognitive performance than do controls. Prospective studies also show that PA is associated with a lower risk of AD and that the relationship between baseline PA and subsequent cognitive performance is moderated by a susceptibility gene for AD (apolipoprotein, APOE). In a Phase I proof-of-concept trial, we showed that individuals with a family history of AD (FH+) achieve cognitive benefits in association with PA and that these benefits were even evident in those with a genetic risk for AD (i.e., APOE e4 carriers, APOE4+). However, no published randomized controlled trial has assessed the effects of PA on cognition in cognitively normal FH+ individuals relative to APOE4 status. In addition, in currently funded trials beginning to address this gap, the focus is on older adults (65+); thus limiting the ability to identify protective effects that may be more evident with earlier interventions. Lastly, current evidence does not elucidate mechanisms to explain how PA benefits cognitive performance. These gaps in the literature have motivated our Phase II trial, in which we extend our past work by proposing a randomized clinical trial to: (a) test the causal link between PA and cognitive performance in middle-aged adults (40-65 years) with a FH+, and (b) determine if the effect is moderated by APOE4 carrier status. We will collect neuroimaging measures of cerebral structure, white matter integrity, and resting state connectivity; assess putative biological markers; and (using moderated mediation analyses) increase understanding of underlying mechanisms and of the extent to which effects are moderated by APOE4 carrier status. To test our hypotheses, we will randomly assign 240 cognitively normal, middle-aged adults to a 1-year PA program or a usual care control. We will assess cognitive performance at pre-, mid-, and post-test, and obtain MRI scans and blood samples at pre- and post- test. We will examine the effects of PA on cognitive performance and on neurological and biological mechanisms and will explore the moderating role of APOE4. A strength of this study is that we incorporate cognitive measures and MRI sequences used in a Phase III clinical trial (1R01AG053952) testing the effects of PA on cognition in older adults (65-80 years), and we are collaborating with the PI of that trial (Erickson). This will allow us to leverage NIH?s resources by compiling data across a broad age range. Importantly, findings from this study may support PA as a means of improving cognitive performance by those with a heightened risk for AD. This could have public health implications, because delaying AD by 1 year could reduce its incidence by 11%.