PROJECT SUMMARY 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 systems-wide changes 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. Taken together, these data suggest a key underlying risk factor for AD that might be targeted for therapeutics is metabolic dysfunction. However, causal links between age-onset changes in energetics and AD are unclear. AMP- activated protein kinase (AMPK) is a highly conserved master regulator of energy homeostasis that we and others have shown links energetics to the rate of aging in multiple species. AMPK is a central homeostatic regulator of multiple cellular systems including transcriptional and post-translational signaling networks, protein homeostasis, and organelle dynamics. Which of these links the effects of AMPK and metabolic dysfunction to AD is unclear. Since negative feedback loops tend to exist to return a cell to homeostasis, targeting multiple effectors of AMPK in tandem rather than AMPK alone may prove more effective in AD. We recently reported that AMPK increases lifespan in C. elegans via remodeling of systemic mitochondrial metabolism, which correlates with mitochondrial network fragmentation in peripheral tissues. In addition, we have shown a role for RNA splicing homeostasis in the effects of AMPK on longevity and the UPRER modulator XBP-1. Here we use C. elegans to expedite discovery of cellular mechanisms that modulate the effect of AMPK on AD pathophysiology, and target multiple networks simultaneously to reduce age and Aβ induced decline in neuronal function.