Measuring neurodevelopmental effects of genetic risk for Alzheimer's disease via cross-sectional study of brain, cognitive, and physical fitness variables in periadolescent children

Project Summary/Abstract As our population ages, Alzheimer’s Disease (AD) and related pathologies will continue to increase in prevalence, making the investigation of modifiable and non-modifiable risk factors related to AD critical. Non- modifiable risk factors, such as genetic risk that individuals are born with, and modifiable risk factors, such as physical activity (PA) and cardiorespiratory fitness (CRF) levels, significantly influence brain development and disease pathology. Utilizing a lifespan perspective to investigate the ways in which these risk factors effect brain development during childhood, a critical period of neurodevelopment, may lead to novel insights on mechanisms and prevention of AD in the brain. This proposal aims to study the relationships between cognition, physical activity (PA), cardiorespiratory fitness (CRF), genetics, and the development AD-vulnerable brain networks in a cohort of periadolescents (aged 8-13 years old). Evidence suggests that PA and CRF can enhance the brain’s functional connections in networks most vulnerable to AD pathology, including the Default Mode Network (DMN), and the Frontoparietal Network (FPN). Investigating these networks in relation to PA and CRF during this critical neurodevelopmental period will aid in the understanding of how modifiable risk factors influence AD-vulnerable brain networks. While it is well known that APOE-ε4 status influences AD risk, more recent evidence suggests PA and CRF may help mitigate risk associated with genetic profile, however this relationship has not been investigated in developing cohorts. In order to fill the gap in this research area, cognitive, brain imaging, and genetic data will be collected as part of larger (N = 270) cohort of periadolescents enrolled in the parent study (R01 AG064247), in addition to PA monitoring and CRF testing completed as part of an additional sub-study designed by the applicant. We hypothesize that greater PA and CRF will be associated with enhanced memory and executive function ability, as well as greater within-network functional connectivity profiles that support cognition. Interactions of these findings will also be investigated in relation to APOE allele status, as we also hypothesize that PA and CRF levels may moderate the relationship between cognitive development and genetic risk. The applicant, an MD/PhD student at the University of Nebraska Medical Center, will be able to develop skills related to hypothesis generation and testing, human-subjects research methods, data analysis, and development of scholarly products. Throughout the proposed research and clinical training, advanced courses, clinical preceptorships, workshops, and hands-on experiences will be completed in order to develop the scientific skills necessary to fulfill the aims and become a rigorous and well- rounded physician scientist.