Jennifer L. Etnier, Ph.D. - US grants

19. Genetics, Behavior and Aging. The epsilon 4 allele of apolipoprotein E (ApoE-e4) has been identified as a genetic risk factor for cognitive impairment, cognitive decline, and the experience of Alzheimer's Disease (AD). However, the presence of ApoE-e4 does not guarantee these cognitive outcomes. Therefore, one important direction for future research is to identify variables that may interact with ApoE genotype to determine cognitive outcomes. Physical activity is a behavioral variable that may play a role in the expression of the ApoE genotype relative to cognition. Physical activity has been shown to be associated with better cognitive abilities and with lessened cognitive decline with age. Further, the effects of physical activity on cognition have been shown in men to be moderated by ApoE genotype. Thus, the primary purpose of the proposed study is to add to the extant literature by testing the interactive effects of physical activity and ApoE genotype on the cognitive performance of a sample of older women. The literature will also be extended by assessing aerobic fitness which will provide insight into the causal mechanisms which may underlie the relationships being tested. Community-dwelling older women (50-80 years) who have a family history of AD will be recruited. Participants will perform a battery of cognitive tests, will have their blood drawn to determine their ApoE genotype, will complete a physical activity questionnaire, and will perform a maximal aerobic fitness test. It is hypothesized that the beneficial effects of physical activity and aerobic fitness on cognitive performance will be moderated by the presence of the ApoE-4 allele. Regression analyses will be used to test these effects. This study will advance our knowledge about the behavioral variables that modify genetic risk for cognitive impairment in older women. ApoE-4 is well established as a risk factor for cognitive decline and for the experience of AD. However, behavioral variables such as physical activity may impact the expression of this genetic risk factor and this study will extend our knowledge regarding this relationship. Additionally, the findings of this study will have important implications for identifying participants for whom physical activity may be especially beneficial with regards to cognition.

DESCRIPTION (provided by applicant): By 2030, the global prevalence of Alzheimer's disease (AD) is predicted to reach 65.7 million. Despite worldwide research efforts, a cure for AD has not been identified. Thus, it is important to identify preventive strategies that can reduce the risk of or delay the onset of AD [1]. Physical activity (PA) has potential as a preventative strategy. Our research [2, 3] and that of others [4, 5] shows 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 [6-9] and that the relationship between baseline PA and subsequent cognitive performance is moderated by a susceptibility gene for AD (apolipoprotein, APOE) [10-13]. However, the potential moderating role of APOE genotype on the effects of PA on cognitive performance has not been tested experimentally in humans; thus we do not know who receives the greatest cognitive benefits from PA. Additionally, we do not understand the mechanisms which explain how PA benefits cognitive performance. These gaps in the literature are the motivation behind our long range plan of research designed to further our understanding of the potential role of PA in the mitigation of cognitive decline and in the delay of AD. These gaps are also the impetus for this specific study in which we: 1) establish the feasibility of an 8-month PA intervention with persons with a family history of AD and use statistical modeling to inform the design of a future randomized control trial (RCT); 2) assess change in cognitive performance across the PA intervention and determine whether this change differs as a function of APOE genotype; 3) determine whether change in peripheral brain-derived neurotrophic factor, pBDNF (which is a plausible mechanism of the effects and has been linked to AD) predicts change in cognitive performance across the PA intervention; and 4) examine the differential effects of APOE genotype on the effects of PA on various cognitive domains. We will ascertain APOE genotype in 100 older cognitively normal individuals to identify APOE e4 carriers (n=30) and gender-matched non-carriers (n=30) to participate in an 8-month PA program. We will assess cognitive performance at baseline and will assess cognitive performance and pBDNF at the pre-test, mid-test, and post-test. This initial study will provide foundational evidence and will guide the development of a RCT further testing the moderating role of APOE genotype and the mediating role of pBDNF on the effects of PA on cognitive performance. The identification of effective interventions for the maintenance of cognitive performance in older adults at risk for AD has important public health implications because few preventive strategies for AD have been identified and because a therapy that delays the development of AD by 5 years could reduce the risk of AD by 50%. PA has promise in this regard and is particularly attractive because it is cost-effective and has relatively few negative side-effects. Further, if PA is beneficial for persons with a genetic risk for AD, this cold be particularly important because these individuals show signs of preclinical AD in middle-age [14, 15]. PUBLIC HEALTH RELEVANCE: Delaying the onset of AD by 6 months can reduce the prevalence of AD by 100,000 persons after 10 years [16]; thus, understanding the potential of PA as a preventative treatment to delay AD has important public health implications. If our research indicates that PA is specifically beneficial for persons with a genetic risk for AD, this would be particularly important because evidence suggests that these individuals show signs of preclinical AD in middle-age [14, 15]. Further, if our research demonstrates that peripheral BDNF is an underlying mechanism of the effect, this would contribute to our ability to effectively prescribe the optimal dose of PA for cognitive benefits. This line of research may ultimately establish PA as a behavioral preventive treatment for individuals with an APOE genotype that puts them at increased genetic risk for AD.

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%.