Understanding the developmental impact of environmental risk factors on brain and cognitive systems vulnerable to Alzheimers disease in children

Alzheimer's disease (AD) is a pressing issue in the United States, affecting over 6 million Americans and ranking as the fifth-leading cause of death in 2020 for persons 65 and over. Approximately 90% of AD cases are sporadic, reflecting an established contribution to AD risk of environmental and lifestyle risk factors (ERF).

ERF impact AD risk throughout the lifespan, but ERF during critical developmental periods may influence late- life disease risk beyond what is currently appreciated. This may be demonstrated by abnormal brain maturation (structural or functional) due to ERF exposure. While late onset AD is not often diagnosed until one’s mid 60s,

utilizing a lifespan approach acknowledges early life ERF that may influence risk to disease. Utilizing an AD lens can help investigate these early life influences, with the goal of identifying early interventions for reducing neurodegenerative risk. The F99 phase of my proposal will investigate prenatal and childhood ERF and their

association with memory. The central hypothesis is that AD associated ERF (AD-ERF) during childhood are linked to the neurodevelopment of AD associated brain systems (hippocampus, hippocampal dependent memory), and these links affect AD vulnerability in late life. There is a notable gap in understanding how early-

life AD-ERF bias cognitive development towards neurodegenerative risk. To investigate this, I will measure how a person’s environmental exposures (stress, socioeconomic status, neighborhood deprivation index) in the prenatal, personal, and parental environments (as identified through a factor analysis using the Adolescent

Brain and Cognitive Development study: Aim1A) controlling for familial AD risk (via grandparent/great grandparent blood biomarker assay: collected from parent study) influence hippocampal dependent RM in children. The F99 phase will include training in reproducible neuroimaging, advanced statistics, and scientific

communication. Completion of the F99 phase lays a strong intellectual, technical, and professional foundation for the postdoctoral (K00) phase of this award. During the K00 phase, training in epigenetics and AD- associated biological aging will develop knowledge, expertise, and skills essential to becoming an independent

investigator. It is my long-term goal to establish a multi-disciplinary research laboratory focused on studying modifiable AD risk factors in order to develop and implement treatments or preventative programs that might reduce AD risk in populations with high vulnerability due to their environment. This research will shed light on

the relationship between environments and development, offering insights into the predictive power of the environment in shaping AD risk. Ultimately, this work could lead to early interventions for AD, addressing the looming public health crisis posed by an aging, AD-vulnerable US population.