PROJECT SUMMARY/ABSTRACT Alzheimer’s disease (AD) is the most common cause of dementia in the elderly with currently no cure or effective disease-modifying therapy. The pathogenesis of AD is unclear; however, a leading hypothesis is that accumulation of amyloid-beta (Aβ) peptides derived from the amyloid precursor protein is one of the earliest pathological events resulting in neuronal dysfunction, at least in part by dysregulating intracellular Ca2+ homeostasis, and disruption of neural networks culminating in dementia. While cognitive impairment is the major manifestation of AD, non-cognitive manifestations such as unintentional body weight loss often occurs prior to the cognitive decline. Furthermore, weight loss in AD correlates with worsening disease progression and increased mortality, while weight gain is protective. Collectively, this suggests that brain regions such as the hypothalamus that regulate body weight and systemic metabolism may be selectively vulnerable to Aβ early in the pathogenesis of AD during the presymptomatic or preclinical stages. However, the cellular and molecular mechanisms underlying the early systemic metabolic dysfunction in AD have remain largely unexplored. Therefore, the goal of this application is to test the hypothesis that hypothalamic networks regulating systemic metabolism are selectively vulnerable to Aβ pathology and contribute to the early pathogenesis of AD. We will use a “bench-to-bedside” strategy using state-of-the-art molecular, neurophysiological, imaging, and genomic approaches in genetic mouse models, and verify key findings in clinically relevant human studies. We will test the following working hypotheses: (a) disruption of intracellular Ca2+ homeostasis by Aβ is an early pathological event leading to dysfunction of leptin-responsive hypothalamic NPY/AgRP neurons; (b) Aβ causes disruption of hypothalamic networks regulating systemic metabolism; and (c) central leptin signaling dysfunction is an early manifestation of human subjects with Alzheimer’s disease. The findings from this project will shed light on the mechanisms underlying early selective vulnerability in the hypothalamic network regulating systemic metabolism and identify the cell types affected, thereby filling a knowledge gap in our understanding of one of the earliest clinical manifestations of AD.