PROJECT SUMMARY Alzheimer’s disease (AD) is a progressive, incurable neurodegenerative disease that is the cause of a majority of dementia in the United States. The pathologic hallmarks of AD are extracellular neuritic plaques composed of amyloid beta (Aβ) and intraneuronal neurofibrillary tangles composed of aggregated microtubule associated protein tau (MAPT/Tau). However, the inciting and driving events of AD are incompletely understood. Recent work in the field has focused on experimental testing of hypotheses generated from genome-wide association and RNA-Sequencing studies. In my proposed project, I will integrate Drosophila experimental data with AD- associated human gene coexpression networks, then test a handful of promising candidate driver genes for their ability to control the transcriptional processes associated with AD. My proposed project leverages preliminary data from two separate projects addressing two separate facets of Tau-associated AD biology. I designed a screen of Drosophila homologs of 366 human genes prioritized from large human AD gene coexpression networks, which was carried out in the lab of Dr. Juan Botas (see Letter of Support) and resulted in a promising list of 14 genes which strongly modify the trajectory of Tau-induced neurotoxicity. I separately analyzed transcriptomic data collected in our lab from Tau transgenic Drosophila at multiple ages and identified a set of 4,992 genes with expression behavior significantly different from that observed in parallel control flies. By combining these two preliminary data sets identifying genes which change their expression behavior in response to Tau and genes which causally modify Tau-associated neurodegeneration with AD-associated human coexpression networks, my project aims to identify candidate genes which control the transcriptional programs responsible for causing AD. I will then directly test each candidate driver for structural and functional modification of Tau-associated neurodegeneration and for ability to control network-level gene expression changes associated with AD in humans. I hypothesize that conserved human AD network driver genes will possess Drosophila gene homologs that (i) demonstrate altered expression in response to Tau, and (ii) causally interact to modify Tau-induced neurodegeneration. Overall, my cross-species approach will allow dissection of a causal chain linking candidate driver genes, altered brain transcriptional network expression, and the development of AD. The highlighted driver genes will identify outstanding potential therapeutic targets.