Introduction: A polygenic risk score for coronary artery disease (PRS CAD ) integrates information from many sites of DNA variation into a single metric of inherited susceptibility. Heightened metabolic activity of the amygdala (AmygA), a stress-associated brain center, associates with increases in leukopoietic activity, atherosclerosis and CVD risk. We hypothesized that genes included in the PRS CAD link to MI in part by encoding for heightened stress-associated neurobiological activity. Accordingly, we tested whether CVPRS associates with heightened AmygA as a contributing factor linking high CVPRS and CVD events. Methods: Individuals (N=16821, median age (IQR): 63 (52, 74) years, 46% male) were identified from the Partners Biobank where genome-wide PRS CAD and principle components of ancestry (PCI) were calculated. Using validated 18 FDG-PET/CT imaging methods, AmygA was measured in individuals with prior clinical imaging (N=854). MI incidence was derived using International Classification of Diseases (ICD) diagnoses. Traditional CVD risk factors and psychiatric history were obtained using ICD codes and questionnaires and were used for covariable adjustments. Linear and logistic regression were employed. Results: A total of 2046 (12.1%) participants experienced an MI. PRS CAD associated with increased AmygA after adjusting for age and sex (β [95% confidence interval (CI)]: 0.099 [0.015, 0.183], p=0.021) as well as increased MI incidence (odds ratio (OR) [95% CI]: 1.208 [1.120, 1.302], p<0.001) ( Table 1, Figure 1 ). Concurrently, AmygA associated with increased MI incidence in adjusted analyses (OR [95% CI]: 1.451 [1.061, 1.983], p=0.003). Conclusion: High PRS CAD associates with higher AmygA and AmygA in-turn associates with MI. These findings suggest increased stress-related neurobiological activity may contribute to the link between PRS CAD and MI.