Testing sex as a moderator of health impacts of upward mobility on indicators for AD risk in young adulthood

Abstract Early poverty and lower education attainment are associated with increased rates of Alzheimer's Disease (AD), and lower cognitive functioning in later adulthood. Upwardly mobile youth who “strive” to rise above poverty typically have better cognitive outcomes in early adulthood. However, our preliminary data suggest that striving during adolescence can be stressful, particularly for females. Such stress may result in altered brain-gut axis signaling and systemic inflammation, which could set the stage for AD pathophysiology to begin unfolding before its onset in older adulthood. Women are at greater risk for striving-related stress, stress-related health problems, and critically, when they possess other AD risk factors such as apolipoprotein-ε4 (ApoE-ε4) gene status, they are more likely to develop AD. We hypothesize that due to sex-specific vulnerabilities (such as stress) females, but not males, with greater mobility opportunity will exhibit more physical health risks (namely obesity and inflammation as well as altered gut microbiome profiles) in early adulthood, which will in turn be negatively associated with cognitive outcomes and brain structure/function. We will test this hypothesis in a cohort of young adults (now age 23) who have participated in the Reducing Inequities through Social and Educational Change Follow-up (RISE-Up) Study since 2003. RISE-Up is a natural experiment using the admissions lottery of several high-performing public charter high schools to identify comparable groups of adolescents “randomized” into high- (mobility opportunity) and lower-performing (static) schools. The RISE-Up study provides a unique chance to better understand how adolescent mobility opportunities differentially influence adult cognitive health and AD risk in females and males. To this end, we will pursue three aims: (1) Identify the impact of mobility opportunity on young adult general cognitive ability (which we propose will link with later life resilience to AD), and test sex as a moderator; (2) Establish links between mobility opportunity, inflammatory markers, and microbiome functional potential, and determine whether those links are moderated by sex. Additionally, we will test whether sex and ApoE-ε4 status interact to predict inflammatory markers and microbiome functional potential; (3) Delineate associations between health (inflammatory markers, microbiome functional potential) and brain structure/function in early adulthood, probe their associations with general cognitive ability, and examine sex is a moderator.