PROJECT SUMMARY/ABSTRACT Memory impairment and cognitive deficits are the most prominent feature of Alzheimer’s disease (AD); hence, current AD research has focused predominantly on CNS regions related to learning and memory, such as the hippocampus. However, one of the most consistently reported phenotypes in AD patients is weight loss, which may precede memory loss and cognitive decline by as much as 17 years, raising the question of whether hypothalamic dysfunction is an early cause of AD or merely coincident with disease onset? We propose that hypothalamic dysfunction during the preclinical stage of AD is an early causative step in a cascade of events culminating in dementia, which arises from complex interactions between genetic and environmental (GxE) risk factors that include diet and obesity. Our overall objective is to discover genetic variants and networks that modulate body weight across the lifespan, a clinically relevant biomarker of hypothalamic dysfunction that is predicative of cognitive status later in life. To this end, in Aim 1 we will use a novel mouse panel that incorporates high-risk human FAD mutations on a segregated background of genetic diversity (BXD panel) to identify modifiers that contribute to variation in body weight that is associated with cognitive decline. In Aim 2, we will identify genetic variants that modulate susceptibility to HFD, and derive directed networks and molecular pathways mediating the impact of diet and obesity on AD symptoms via causal inference analysis. In Aim 3, we will evaluate a priori candidates Igf1r, Esr2, and Apbb2 and up to 10 candidates from Aims 1 and 2, establishing the feasibility and independence of Aims. Successful completion of these aims will yield critical new insight into the pathogenesis of AD, including how modifiable environmental factors influence susceptibility and risk. Our deliverables include potential new biomarkers for early detection and new therapeutic strategies targeting the very earliest preclinical stages of the disease to delay or even prevent AD.