Alzheimer's disease (AD) is associated with significant, progressive cognitive decline, unimpeded by FDA-approved drugs. Key defects in mitochondrial fuel metabolism could contribute to cognitive decline in AD. The primary mitochondrial fuel of choice for the brain in the fasted (and fed) state is glucose. Conversely, fasted mitochondrial fuel of choice for the rest of the body is fatty-acids. Hence fuel oxidation is partitioned between glucose for the brain, and fatty-acids for the rest of the body. Aging is a major risk factor for AD. Mitochondrial fatty-acid oxidation (MFO) is impaired in aging, and brain glucose uptake is decreased in patients with AD, but underlying mechanisms are not well understood. Aging and mitochondrial dysfunction are also associated with insulin resistance (a hallmark of AD), which limits brain glucose-uptake. AD is also strongly linked to neuroinflammation. Could mitochondrial dysfunction, insulin resistance and neuroinflammation be mechanistically linked in patients with AD, and more importantly, could they be reversed to improve cognition? Ongoing work from my lab has uncovered that Oxidative Stress (OxS) could be the unifying link. OxS is strongly linked to AD. Glutathione (GSH, the most abundant intracellular antioxidant protein) combats OxS. GSH deficiency predisposes to OxS, and is linked to AD. We reported that elevated OxS in older humans is caused by GSH deficiency due to diminished synthesis because of decreased availability of its precursor amino-acids glycine and cysteine. Supplementing glycine and cysteine (as N-acetylcysteine, a cysteine donor) orally as GlyNAC for 2w corrected deficiencies of glycine, cysteine and GSH, and lowered OxS in older humans to levels in younger humans, reversed impaired MFO, and lowered insulin resistance by 40%. Since aging is a major risk factor for AD, we studied cognition in 8 older humans before and after receiving GlyNAC for 24w and after stopping GlyNAC for 12w, and outcomes compared to 8 unsupplemented young, healthy controls: older humans had impaired cognition, elevated OxS, lower MFO, higher mitochondrial glucose oxidation (MGO), higher insulin resistance and inflammation. GlyNAC supplementation for 24w significantly improved cognition and whole-body mitochondrial fuel oxidation, and lowered OxS, insulin resistance, and inflammation. After stopping GlyNAC, all benefits began to recede. We studied 98-week old C57BL/6J mice and found that compared to young 20-week old mice, they had cognitive decline, and severely impaired ability of mitochondrial complexes I and II to oxidize glucose substrates pyruvate, glutamate and succinate, and elevated inflammation (TSPO expression) GlyNAC supplementation for 8-weeks corrected these defects and improved cognition. Collectively, these data suggest that abnormalities in brain MGO, inflammation, OxS, and insulin resistance combine to cause cognitive decline, and GlyNAC (via GSH) can correct these defects to improve cognition. How...