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.
