Scientists found that brain cells can tap a hidden sugar stash to clean up the toxic proteins behind Alzheimer’s.
By kick-starting an enzyme called GlyP, they reroute stored sugar into a protective pathway, easing damage in flies and human neurons. Fasting and a drug mimic spark the same effect, hinting that weight-loss meds and diet tweaks might one day guard our memories.
Brain Sugar Breakthrough
A groundbreaking new study from the Buck Institute for Research on Aging has uncovered a surprising new player in the fight against Alzheimer’s and other forms of dementia: brain sugar metabolism. Published in Nature Metabolism, the research shows that breaking down glycogen—a form of stored sugar—in brain cells may help protect against toxic protein buildup and brain degeneration.
Glycogen is usually known as a backup energy source found in the liver and muscles. While small amounts also exist in the brain, mainly in support cells called astrocytes, its role inside neurons—the brain’s main signaling cells—has long been considered unimportant. But this study flips that idea on its head.
“This new study challenges that view, and it does so with striking implications,” says Professor Pankaj Kapahi, PhD, senior scientist on the study. “Stored glycogen doesn’t just sit there in the brain; it is involved in pathology.”
GlyP Enzyme Shields Neurons
Led by postdoctoral researcher Dr. Sudipta Bar, the team discovered that neurons in both fly and human models of Alzheimer’s-like disease begin to hoard glycogen. Even more surprising, the sticky tau protein—infamous for forming damaging tangles in Alzheimer’s patients—seems to bind directly to this sugar, trapping it and preventing it from being broken down.
That sugar trap turns out to be a big problem. Without the ability to break down glycogen, neurons lose a critical way to manage oxidative stress, a major driver of aging and brain decline. But when researchers reactivated an enzyme called glycogen phosphorylase (GlyP), which jumpstarts sugar breakdown, they saw a dramatic improvement. Damage from tau proteins decreased in both fruit flies and human-derived brain cells.
Instead of burning the sugar for energy, these neurons redirected it into a special protective pathway called the pentose phosphate pathway. This route produces molecules like NADPH and Glutathione, which help cells detoxify harmful byproducts. “By increasing GlyP activity, the brain cells could better detoxify harmful reactive oxygen species, thereby reducing damage and even extending the lifespan of tauopathy model flies,” said Bar.
Diet & Drugs Boost Protection
Even more promising, the team demonstrated that dietary restriction (DR)—a well-known intervention to extend lifespan—naturally enhanced GlyP activity and improved tau-related outcomes in flies. They further mimicked these effects pharmacologically using a molecule called 8-Br-cAMP, showing that the benefits of DR might be reproduced through drug-based activation of this sugar-clearing system. “This work could explain why GLP-1 drugs, now widely used for weight loss, show promise against dementia, potentially by mimicking dietary restriction,” said Kapahi.
Researchers also confirmed similar glycogen accumulation and protective effects of GlyP in human neurons derived from patients with frontotemporal dementia (FTD), strengthening the potential for translational therapies. Kapahi says the study emphasizes the power of the fly as a model system in uncovering how metabolic dysregulation impacts neurodegeneration. “Work in this simple animal allowed us to move into human neurons in a much more targeted way,” he said.
Kapahi also acknowledges the Buck’s highly collaborative atmosphere as a major factor in the work. His lab, with expertise in fly aging and neurodegeneration, took advantage of proteomics expertise in the Schilling lab and the Seyfried lab (at Emory University) as well as the Ellerby lab which has expertise in human iPSCs and neurodegeneration.
Kapahi says this study not only highlights glycogen metabolism as an unexpected hero in the brain but also opens up a new direction in the search for treatments against Alzheimer’s and related diseases. “By discovering how neurons manage sugar, we may have unearthed a novel therapeutic strategy: one that targets the cell’s inner chemistry to fight age-related decline,” he says. “As we continue to age as a society, findings like these offer hope that better understanding—and perhaps rebalancing—our brain’s hidden sugar code could unlock powerful tools for combating dementia.”
Reference: “Neuronal glycogen breakdown mitigates tauopathy via pentose-phosphate-pathway-mediated oxidative stress reduction” 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, 30 June 2025, Nature Metabolism.
DOI: 10.1038/s42255-025-01314-w
The work was supported by NIH grants R01AG038688, R21AG054121, AG045835, R01AG071995, R01AG070193, T32AG000266-23, R01AG061879, P01AG066591 and 1S10 OD016281. Other support came from the Hevolution Foundation, American Federation of Aging Research, the Larry L. Hillblom Foundation and the CatalystX award from Alex and Bob Griswold
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