Project Abstract Alzheimer’s disease and related dementias (ADRD) are chronic diseases without cure and affect disproportionately more Hispanics and African Americans than White Americans. The risk factors and mechanisms causing ADRD and disparity are, however, poorly understood. To combat ADRD and eliminate the disparity, we need to better understand the risk factors and mechanisms causing dementia and disparity. We address this urgent need in Drosophila, in which mutant flies for most genes are already available, and functions of all genes can be readily manipulated in specific cells or neural circuits via state-of-the-art transgenic approaches. It is indeed highly feasible in Drosophila to study the contributions of practically all genes and their interactions with each other and with non-genetic risk factors to dementia. To this end, the overarching objective of this study is to discover the risk factors and mechanisms for ADRD and their disparity using innovative strategies. ADRD are multifactorial, involving genetic and non-genetic risk factors. Social stress, in particular, is known to enhance ADRD risk and progression while the underlying mechanism is unknown. Notably, multiple lines of evidence point to social stigma such as perceived discrimination and acculturation stress as key factors contributing to cancer and brain health disparities in ethnic/racial minorities including Hispanics. We found that heterozygous mutations in Scully (Scu) coding for the ortholog of human HSD17B10 (Ab binding protein) cause the aging-dependent and social-stress sensitive impairment in inhibitory control and memory loss. Scu is a multifunctional protein with many interacting molecules (Scu network). In this project, we will investigate the interaction of the Scu network genes and social stress as a model for ADRD disparity in Hispanics. The objective of the BBRC award is to advance our knowledge of health disparities that profoundly impact the Hispanic community through basic, behavioral, and clinical research. The proposed work is thus in line with the objective of the BBRC award. As the UTEP and El Paso community are largely Hispanics, this study will promote research relevant to our students and community and also increase the representation of Hispanics in neuroscience research that is disproportionately low at present.