New Research Links Brain Glycogen to Alzheimer's Disease Progression

Recent findings from the Buck Institute for Research on Aging reveal that glucose stores in the brain, specifically in the form of glycogen, play a critical role in the degeneration of neurons associated with Alzheimer's disease. This research, published in the journal Nature Metabolism on July 6, 2025, highlights a previously underestimated interaction between tau proteins, known for their harmful accumulation in Alzheimer’s patients, and glycogen, presenting new avenues for potential treatments.

Alzheimer's disease, classified as a tauopathy, is characterized by the pathological aggregation of tau proteins within neurons. While previous studies have explored the consequences of tau accumulation, the role of glycogen, traditionally viewed merely as an energy reserve for the muscles and liver, has not been adequately understood. Dr. Pankaj Kapahi, a molecular biologist at the Buck Institute and co-author of the study, states, "Stored glycogen doesn't just sit there in the brain; it is involved in pathology."

The research team investigated tau-glycogen interactions using models created in the fruit fly Drosophila melanogaster. Their findings showed elevated glycogen levels not only in these models but also in the brain cells of humans diagnosed with Alzheimer's. The study detailed a crucial mechanism: the presence of tau disrupts the normal metabolism of glycogen, resulting in the accumulation of both tau and glycogen. This accumulation is associated with a decline in neuron defense mechanisms, further exacerbating neuronal damage.

Key to this interaction is the enzyme glycogen phosphorylase (GlyP), responsible for converting glycogen into usable energy. By enhancing GlyP activity in fruit fly models, the researchers noted an improvement in the breakdown of glycogen, leading to reduced cellular damage and extended lifespan in the test subjects. Sudipta Bar, a biologist at the Buck Institute, noted, "By increasing GlyP activity, the brain cells could better detoxify harmful reactive oxygen species, thereby reducing damage."

Additionally, the team explored the effects of dietary restrictions, which have been previously linked to improved brain health. Fruit flies on a low-protein diet exhibited increased longevity and decreased brain damage, suggesting that dietary modifications may enhance GlyP activity and thus alter the disease trajectory.

The implications of this research extend to the development of pharmacological interventions. The team created a drug based on the 8-Br-cAMP molecule to replicate the benefits of dietary restrictions, which demonstrated similar protective effects in their experiments with fruit flies. Interestingly, this work aligns with studies on GLP-1 receptor agonists, such as Ozempic, which are known for managing diabetes and promoting weight loss, yet are also emerging as potential protectors against dementia. The researchers theorize that these drugs may influence glycogen metabolism pathways, offering a dual benefit.

Dr. Kapahi emphasizes the significance of these findings: "By discovering how neurons manage sugar, we may have unearthed a novel therapeutic strategy that targets the cell's inner chemistry to fight age-related decline." This research underscores the importance of understanding the complex biochemical processes in the brain, particularly as aging populations face increasing rates of neurodegenerative diseases. The potential to rebalance the brain's sugar management system could unlock new therapeutic tools in the battle against dementia, offering hope for future treatments as society ages.

The study not only sheds light on the mechanisms of Alzheimer's disease but also opens new avenues for research into metabolic interventions that could mitigate its impact, thereby improving the quality of life for millions affected by this devastating condition.