A team of researchers at the Buck Institute for Research on Aging, led by Professor Pankaj Kapahi, has uncovered a surprising link between a specific sugar in brain cells and the progression of Alzheimer’s disease. Their findings, published in Nature Metabolism, suggest that glycogen – a complex, stored form of glucose – may be more than an innocent bystander in neurodegeneration. It could be both a marker of the disease and a potential therapeutic target.
The Unexpected Role of Glycogen in the Brain
Glycogen is typically stored in the liver and muscles, serving as a quick-access energy reserve. The brain, though energy-hungry, has only small amounts, usually in support cells called astrocytes. Neurons themselves were believed to store very little glycogen. But the Buck Institute’s work shows that in Alzheimer’s and related tauopathies, neurons accumulate large amounts of glycogen—enough to interfere with normal cell function.
The researchers found that tau, a protein known for forming harmful tangles in Alzheimer’s, physically binds to glycogen in neurons. This binding prevents glycogen from breaking down, setting off a toxic cycle: tau causes glycogen buildup, and excess glycogen makes tau accumulation worse.
How Glycogen Harms Neurons
Under normal circumstances, glycogen breakdown releases glucose, which can be diverted into the pentose phosphate pathway. This pathway produces antioxidant molecules like NADPH and glutathione, which protect neurons from oxidative stress. But in Alzheimer’s-affected neurons, this protective process stalls because tau traps glycogen. Without proper breakdown, oxidative damage increases, further harming brain cells.
When the researchers restored the function of glycogen phosphorylase (GlyP)—the enzyme that breaks down glycogen—the results were striking. In fruit fly models and human stem cell-derived neurons, glycogen breakdown reduced oxidative stress, lowered tau buildup, prevented neuron death, and extended the lifespan of tau-expressing flies by nearly 70 percent.
Dietary and Drug Clues
The study also revealed that dietary restriction boosts glycogen breakdown by activating specific signaling pathways. Flies on a calorie-restricted diet showed reduced neurodegeneration, and drugs that mimic these effects produced similar benefits. This may help explain why certain diabetes and weight-loss drugs, like GLP-1 agonists, have shown early promise in Alzheimer’s research.
“Sugar metabolism in neurons is different from what was previously believed,” Kapahi explained. “We found that stored sugars in brain cells can help reduce harmful oxidative molecules. But when these sugars build up too much, they bind to toxic proteins and make the disease worse.”
Implications for Alzheimer’s Treatment
The findings suggest that targeting glycogen metabolism could offer a new approach to slowing or preventing Alzheimer’s progression. Potential strategies might include drugs that enhance glycogen breakdown, dietary interventions, or a combination of both. Importantly, the study’s authors stress that more work is needed to determine whether glycogen accumulation is a cause or effect of neurodegeneration, and whether it appears early enough to serve as a useful treatment target.
“This unexpected connection between diet, sugar metabolism, and protein aggregation opens exciting new avenues for Alzheimer’s research,” Kapahi said. “Our long-term goal is to develop therapeutic strategies based on these findings.”
A Promising but Early-Stage Discovery
While the results are promising, the research was conducted mainly in fruit flies and lab-grown neurons, meaning human trials will be essential to confirm the effect. The team plans to explore how glycogen interacts with tau in more detail, and whether specific diets or medications can safely alter this process in living patients.
If confirmed in humans, this discovery could shift Alzheimer’s treatment strategies away from focusing solely on amyloid and tau clearance, and toward managing the brain’s sugar metabolism—a change that might finally offer real hope for slowing the disease.
