Project Summary Metabolic resistance (METS) and type II diabetes (T2D) hold one of the strongest associations with AD development, however, we know little in terms of how, at a precise mechanistic level, this prodromal metabolic phenotype actually leads to neurodegenerative changes that ultimately result in AD. We know equally little about how sex contributes in accelerating or slowing this progression and how known sex-specific differences for METS/T2D and AD affect this relationship. Given that the incidences of both diseases are skyrocketing, understanding these aspects is critical to develop optimal early/preventative therapeutic interventions for individuals with METS/T2D, at high risk for AD. However, addressing these questions using single targeted hypothesis-based approaches is difficult given the multifactorial nature of potential interactions (multiple disease factors, time, and sex) and is further confounded by changing/incomplete experimental designs across animal studies. To address these challenges, we seek to study the relationship between METS/T2D progression and AD in a more global genome-wide manner, coupled with powerful statistics and biochemical measurements to gain a clearer picture of the METS/T2D-AD relationship. Specifically, we propose to determine alterations in transcriptome, AD and METS-related mitochondrial, metabolic, and pathology changes, in both sexes, over time. We will use bioinformatics and large-scale statistical analysis tools to identify associations across these variables, in addition to sex hormone levels, and time. We will couple these observations with modifications of mitochondrial and metabolic genes (affected early in both diseases) and novel ones discovered via RNA seq to interrogate these relationships mechanistically in vitro.