The Brain’s Hidden Sugar Code: A Breakthrough in Dementia Research

A groundbreaking study from the Buck Institute for Research on Aging, published in Nature Metabolism, is reshaping our understanding of brain health. It reveals that sugar metabolism—specifically the breakdown of glycogen within neurons—may play a critical protective role in neurodegenerative diseases like Alzheimer’s and frontotemporal dementia.

Rethinking Glycogen in the Brain

Glycogen, the stored form of glucose, is typically associated with muscles and the liver. In the brain, small amounts are found in astrocytes, the support cells. For years, scientists assumed neurons had little use for glycogen. But this new research flips that assumption. In both fruit fly models and human-derived neurons mimicking Alzheimer’s-like disease, neurons began to accumulate glycogen abnormally. More importantly, the toxic tau protein—a hallmark of Alzheimer’s—binds to this trapped sugar, interfering with its normal breakdown.

A Sugar-Based Defense Mechanism

This glycogen buildup turns out to be harmful because it deprives neurons of a key metabolic route: the pentose phosphate pathway. This pathway doesn't generate energy directly, but it produces powerful detoxifying molecules like NADPH and glutathione, which help protect brain cells from oxidative stress. By reactivating the enzyme GlyP (glycogen phosphorylase) to restore glycogen breakdown, researchers saw striking improvements—less tau damage, better oxidative balance, and even longer lifespan in tauopathy model flies. The same benefits were observed in human neurons derived from patients with frontotemporal dementia, making this mechanism highly relevant for multiple forms of neurodegeneration.

Dietary Restriction, Drugs, and Dementia

One of the most compelling aspects of the study is that dietary restriction (DR)—known to extend lifespan and delay age-related diseases—increased GlyP activity and reduced neuronal damage. Even more promising, the researchers replicated these effects pharmacologically using a molecule called 8-Br-cAMP, suggesting that drug-based therapies could mimic the benefits of DR without the need to restrict food intake.

This discovery may also help explain the growing interest in GLP-1 receptor agonists, currently used for type 2 diabetes and weight loss, as potential treatments for Alzheimer’s. These drugs may support the same sugar-clearing pathways in the brain, helping to reduce oxidative stress and slow degeneration.

Why It Matters

This research uncovers a hidden role of neuronal glycogen metabolism as a built-in defense system against brain aging and disease. By clearing excess sugar and activating protective detox pathways, neurons can better resist damage caused by tau and oxidative stress. Instead of focusing solely on removing toxic proteins, future therapies may work by rebalancing the brain’s inner sugar chemistry—offering a fresh and hopeful path in the fight against dementia.

The full study, “Neuronal glycogen breakdown mitigates tauopathy via pentose-phosphate-pathway-mediated oxidative stress reduction,” is available in Nature Metabolism , June 30, 2025. DOI: 10.1038/s42255-025-01314-w.