2-Deoxyglucose and Its Analogs as Novel Therapeutics to Build Resilience to Alzheimer’s Disease

Available evidence shows that pathological features of Alzheimer’s disease (AD) begin years before cognitive decline is clinically apparent. The insidious nature of AD evolution has focused attention on lifestyle approaches to build brain resilience and to forestall disease progression, even after symptom onset. Among important lifestyle influences, dietary approaches that augment cognition and delay aging have received significant attention. In particular, a dietary regimen called intermittent fasting (IF) has been shown to provide neuroprotection and enhance learning and memory in animal models of AD. Indeed, human studies, while preliminary, also point to a benefit of IF in AD and cognitive aging. A challenge in deploying IF has been a gap in our understanding of how to define a “therapeutic dose” of fasting sufficient to induce gene changes supportive of learning and memory and adaptive stress. Equally relevant would be the development of a drug that could mimic IF and provide a dose and schedule applicable to a broad population.

In this proposal, we will validate the use of an analog of glucose, 2-deoxy-D-glucose (2-DG), which is already being tested in humans for cancer, as a novel treatment for Alzheimer’s disease. Our hypothesis is that 2-DG, given daily, mimics the beneficial effects of intermittent fasting but it does so without having to fast. We have shown 2-DG works by driving an evolutionarily conserved adaptive response to starvation that includes the upregulation of dozens of genes involved in learning and memory and protein health. The proposal will also evaluate other glucose-like drugs to rigorously optimize this exciting therapeutic approach and define a biomarker that will facilitate its translation to human studies.