Surprising Alzheimer’s breakthrough: Sugar in neurons might be the missing link

 

A new study has identified an unexpected contributor to Alzheimer’s disease: glycogen, a complex sugar stored inside brain cells. While traditionally associated with muscles and the liver, glycogen appears to accumulate abnormally in neurons affected by Alzheimer’s and other tau-related disorders.

Scientists found that this buildup may worsen neurodegeneration by disrupting how cells manage energy and oxidative stress. Their findings, published in Nature Metabolism, suggest that breaking down glycogen could help protect neurons and offer a promising new direction for treating or preventing dementia.

Alzheimer’s disease is a progressive neurological condition that impairs memory, thinking, and behavior. It is the most common cause of dementia, especially among older adults. The disease is marked by two key biological abnormalities in the brain: plaques made of amyloid-beta protein and tangles made of another protein called tau.

These protein accumulations disrupt normal cell function, leading to inflammation, cell death, and brain shrinkage over time.

Despite extensive research, effective treatments for Alzheimer’s remain elusive. Most drug development has focused on clearing amyloid or tau from the brain, with limited success. Many researchers now believe that other factors, such as energy metabolism, inflammation, and oxidative stress, may play a role in determining who develops the disease and how quickly it progresses.

“Alzheimer’s disease, first identified over a century ago, remains one of the most challenging neurodegenerative conditions. Despite decades of research and numerous clinical trials aimed at targeting these aggregates, success has been limited,” said study author Pankaj Kapahi, a professor at the Buck Institute for Research on Aging.

“Surprisingly, many people with these protein buildups show little or no cognitive decline, and not everyone with hereditary risk factors develops the disease. This has led scientists to suspect that other overlooked factors may contribute to the onset and progression of Alzheimer’s.”

“Recent research has started to shine a light on the role of environmental and lifestyle factors—particularly diet—in shaping brain health. That question sparked our curiosity: could a rich diet influence the development of Alzheimer’s?”

Glycogen is the storage form of glucose, a sugar that serves as a vital source of energy. The liver and muscles contain most of the body’s glycogen, which is broken down when energy demands increase. The brain, though highly energy-dependent, contains only small amounts of glycogen, mainly in support cells called astrocytes. Neurons—the primary information-processing cells of the brain—have long been thought to store very little glycogen and to rely mainly on a continuous glucose supply from the bloodstream.

However, recent studies have hinted that neurons might store more glycogen than previously thought, especially in disease states. The Buck Institute researchers were interested in whether abnormal glycogen metabolism might be a hidden driver of Alzheimer’s and related tauopathies, and whether correcting it could slow or prevent the disease.

The research team used both fruit fly models and human stem cell-derived neurons to study tauopathies—diseases characterized by tau protein accumulation. In the fly experiments, they used genetic tools to overexpress human tau protein, including a mutant version linked to frontotemporal dementia. These flies developed signs of neurodegeneration, such as shortened lifespan, brain cell death, and structural damage.

The researchers compared flies fed a normal, protein-rich diet to those fed a low-protein, calorie-restricted diet, known to extend lifespan in many species. They also tested the effects of drugs and genetic changes that promote glycogen breakdown.

In parallel, they studied neurons derived from human induced pluripotent stem cells (iPSCs), including cells with two different tau mutations associated with dementia. These human neurons were grown in the lab and analyzed using fluorescent markers to assess glycogen accumulation, oxidative stress, and related metabolic activity.

The researchers found that tau-expressing neurons—both in flies and in human-derived cells—accumulated large amounts of glycogen. This buildup appeared to be linked to the tau protein itself, which physically interacted with glycogen and prevented its breakdown. The result was a toxic cycle: tau caused glycogen to build up, and the glycogen buildup made the tau accumulation worse.

When the researchers restored activity of an enzyme called glycogen phosphorylase (GlyP), which initiates glycogen breakdown, the effects were striking. In both flies and human neurons, breaking down glycogen reduced oxidative stress, lowered tau burden, and prevented cell death. It also extended the lifespan of tau-expressing flies by nearly 70 percent.

Rather than fueling energy production through glycolysis, the glycogen-derived glucose was diverted into the pentose phosphate pathway. This pathway produces antioxidant molecules like NADPH and glutathione, which protect cells from damage caused by reactive oxygen species. The researchers confirmed that oxidative stress levels dropped sharply in cells with active glycogen breakdown. Blocking this pathway erased the protective effects.

The team also found that dietary restriction increased glycogen phosphorylase activity through a well-known signaling mechanism involving cyclic AMP and protein kinase A. Treating flies with a drug that mimics this pathway had similar effects to calorie restriction, reducing cell death and extending lifespan. This may help explain why drugs used to treat diabetes and promote weight loss—such as GLP-1 agonists—show early signs of benefit in Alzheimer’s trials.

“Sugar metabolism in neurons is different from what was previously believed,” Kapahi told PsyPost. “We found that stored sugars in brain cells can help reduce reactive oxygen species—harmful byproducts of normal metabolism.

However, when these sugars accumulate too much, they can bind to toxic protein buildups and make the condition worse. We identified a pathway that breaks down this sugar buildup in neurons.”

Proteomic and metabolomic analyses supported these findings. The researchers identified dozens of metabolic and mitochondrial genes affected by diet, tau, and glycogen metabolism. Importantly, they found similar changes in brain tissue from Alzheimer’s patients, including upregulation of enzymes involved in glycogen metabolism.

“Using a fruit fly model, our team uncovered a powerful link between a rich diet and the progression of Alzheimer’s-like symptoms,” Kapahi explained. “Under the leadership of postdoctoral researcher Dr. Sudipta Bar, we made a fascinating discovery: neurons in Alzheimer’s patients accumulate an unusual amount of glycogen—a complex sugar molecule not typically found in large quantities in healthy brain cells. Because of its complex structure, glycogen can attach to toxic proteins and may accelerate their aggregation.”

“Even more intriguing, Dr. Bar found that neurons metabolize glycogen differently than other organs, hinting at a unique metabolic vulnerability in the brain. He also identified key upstream proteins and signaling pathways that may be harnessed to prevent or reverse this harmful process. This unexpected connection between diet, sugar metabolism, and protein aggregation opens exciting new avenues for Alzheimer’s research and potential therapies.”

Although the results are promising, the study has several limitations. Most of the experiments were conducted in fruit flies or lab-grown neurons, which do not fully replicate the complexity of the human brain. While human data were used for comparison, more work is needed to confirm whether glycogen metabolism plays the same role in living patients.

It is also unclear whether glycogen accumulation is a cause or a consequence of neurodegeneration, or whether it occurs early enough in the disease process to serve as a useful therapeutic target. Long-term studies in animal models and clinical trials will be needed to explore whether enhancing glycogen breakdown can slow cognitive decline or improve brain health.

The researchers plan to continue exploring how glycogen interacts with tau and other proteins, and whether certain diets or medications can modify this process. “Our long-term goal is to develop therapeutic strategies based on our findings,” Kapahi said.

“In addition, we aim to explore the many questions this study has raised, such as: How does glycogen breakdown help rescue disease pathology? Which metabolic pathways are altered by glycogen breakdown? And how does glycogen bind to toxic proteins?”

“We would like to acknowledge the valuable contributions of Prof. Lisa Ellerby, Prof. Birgit Schilling, and Prof. Tara Tracy from the Buck Institute, as well as Prof. Nicholas Seyfried from Emory University, along with their lab members, for their support and collaboration in this study.”

-Eric W. Dolan

The study, “Neuronal glycogen breakdown mitigates tauopathy via pentose-phosphate-pathway-mediated oxidative stress reduction,” was authored by Sudipta Bar, Kenneth A. Wilson, Tyler A. U. Hilsabeck, Sydney Alderfer, Eric B. Dammer, Jordan B. Burton, Samah Shah, Anja Holtz, Enrique M. Carrera, Jennifer N. Beck, Jackson H. Chen, Grant Kauwe, Fatemeh Seifar, Ananth Shantaraman, Tara E. Tracy, Nicholas T. Seyfried, Birgit Schilling, Lisa M. Ellerby, and Pankaj Kapahi.

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