Despite a long-term focus on the role of Amyloid Beta (Aβ) peptide plaques in Alzheimer’s Disease (AD) pathology, downstream processes connecting cause to effect remain unclear, limiting the synthesis of targeted therapeutic compounds. Furthermore, controversy surrounds which species of Aβ are cytotoxic, and clinical trials designed to target Aβ directly have been less successful than anticipated. This adds critical importance to the need to step back and define alternative factors that exacerbate AD pathology and might instead be modulated to lower disease risk. Loss of metabolic homeostasis is one of the hallmarks of the aging process that might contribute to AD pathophysiology and neurodegeneration. In support of this hypothesis, recent data show that, beyond type II diabetes, obese patients with metabolic dysfunction have increased risk of AD, while dietary restriction (DR) maintains metabolic homeostasis and is neuroprotective. We are investigating whether a key underlying risk factor for AD that might be targeted for therapeutics is metabolic dysfunction.