PROJECT SUMMARY/ABSTRACT: Research Project (D) Alzheimer?s disease (AD) is a devastating, progressive neurological disorder that selectively degrades the cognition of many older adults ? 5.4 million are living with AD in the US today and the estimated prevalence by 2050 is 13.8 million. Patients diagnosed with AD often live 8-10 years with the disease, but declines in memory and other cognitive abilities mean that patients face loss of independence and high costs for healthcare ($160 billion in 2016). Management of AD risk with targeted interventions is a needed part of our public health response, and attention to genetic factors affecting AD risk will be essential to those efforts because they are present throughout the lifespan. Critically, it is possible that genetic AD risk factors may bias brain development to increase vulnerability to AD later in life. A putative neurodevelopmental influence of genes on AD vulnerability would be consistent with 1) the predictive power of early cognitive ability for later AD risk, and 2) wide variability in how AD pathology (e.g., A? deposition) relates to AD symptomology (e.g., memory loss). Here, we hypothesize that AD risk genes alter neurodevelopment of the brain systems most affected by AD in ways that increase AD vulnerability. If true, then properties of AD-affected brain structures and brain networks such as the hippocampus and functionally-coupled memory networks will vary with genetic AD risk even during youth. Measuring how genetic factors affect brain development will elucidate lifelong trends for AD risk while highlighting new opportunities for early intervention. The project lead is a new, early-stage investigator with a background in the cognitive neuroscience of memory and expertise in methods including neuroimaging and neuropsychology. In this proposal his team will apply these methods to the study of early genetic effects on neurodevelopment that may affect the risk of late-onset neurodegenerative diseases including AD. Key preliminary data from large developmental datasets have provided important early support for this hypothesis, and the current proposal describes a new, tightly focused project designed to fill critical gaps in our existing knowledge. The specific aims are: 1) Measure effects of AD- related genes on developmental structural differences in AD-vulnerable brain regions; 2) Quantify how genes affect development of functional brain networks that are later vulnerable to AD; 3) Test developmental differences in AD-vulnerable cognitive abilities that are attributable to AD-related genes. For these Aims, Dr. Warren will develop a new dataset from a large sample (N=184) of healthy youths aged 9, 12, or 15 years-old that combines neuroimaging (brain structure/function), neuropsychological tests (cognition), and genomic assays (AD-related genes) in a cross-sectional design. Dr. Warren?s team will analyze these data to better understand the pressing clinical problem of AD from a developmental risk perspective. While addressing AD by studying children appears counterintuitive, this approach may be a crucial step toward addressing a looming public health catastrophe: some of today?s children are primed to become tomorrow?s dementia patients.