PROJECT SUMMARY Individuals with a family history of alcoholism (FH+) are 4 to 8 times more likely to develop an alcohol use disorder (AUD) compared to individuals with no such family histories. We developed the Family Health Patterns project to characterize risk-related phenotypic characteristics of FH+ young adults. During our recent funding period, we have identified robust links between increased early life adversity (ELA) in FH+ and their (a) blunted stress reactivity, (b) increased antisocial tendencies, (c) poor affect regulation, and (d) impaired cognitive performance. In our neuroimaging studies, we identified diffusivity changes in frontal white matter tracts in both FH+ young adults and children, suggesting decreased myelination and axon damage in underlying neural circuitry. We interpret these collective findings to suggest that increased ELA in FH+ individuals induces lasting neurobiological changes and consequent behavioral effects that increase AUD risk. To guide the present proposal, we developed a heuristic model of how ELA contributes to risk-related phenotypic characteristics in FH+ persons. We propose that convergent epigenetic and transcriptomic dysregulation of immune genes increase inflammation and immunoreactivity, thereby impairing myelination and/or damaging axons in developing frontal white matter tracts. The resulting impaired communication to and from the prefrontal cortex contributes to phenotypic characteristics of increased antisocial tendencies and poorer affect regulation and cognitive performance, increasing AUD risk. Here we propose to test this model by examining inflammatory gene expression, functional changes in immunoreactivity, and cerebral white matter myelin levels and axon damage markers in FH+ and FH– young adults. We will then examine relationships of these variables with ELA exposure and risk-related phenotypic characteristics. This proposal rigorously builds on our extensive findings on FH+ behavioral and biological phenotypes by testing a novel, overarching model of AUD risk. While extensive preclinical evidence exists illustrating ELA induces long-lasting dysregulation of the immune system and resulting neural and behavioral sequela, our proposal breaks new ground by comprehensively examining these relationships in humans using advanced immunology and multimodal neuroimaging together with in-depth behavioral and clinical assessments.