A new paper reveals that glycogen stored in the brain plays a central role in tauopathies, a group of neurodegenerative disorders including Alzheimer’s and frontotemporal dementia.
The team shows that boosting glycogen breakdown in neurons helps reduce toxic protein aggregates and oxidative stress, opening a new therapeutic path in conditions that currently lack effective treatments.
Who ran the study?
The work was led by Pankaj Kapahi and colleagues at the Buck Institute for Research on Aging, with collaborators across U.S. universities. The group specializes in how nutrient-sensing pathways and metabolic processes influence aging and neurodegeneration.
The authors include Sudipta Bar, Kenneth Wilson and Birgit Schilling, combining expertise in proteomics, stem cell biology and fruit fly genetics. Their interdisciplinary approach allowed them to connect molecular pathways with both human samples and model organisms.
What the researchers found
Glycogen has been regarded mainly as an energy reserve in the liver and muscles. The new results show that in the brain, glycogen accumulation contributes directly to tau pathology. In fruit fly models and in neurons derived from patients, excessive glycogen was linked to disrupted metabolism and cellular stress.
At the core of the interaction is tau protein itself, which appears to bind glycogen and block its normal use. This creates a vicious cycle: tau promotes glycogen buildup, which in turn worsens tau accumulation, leading to escalating damage inside neurons.
Why glycogen breakdown matters
The key enzyme glycogen phosphorylase (GlyP) turns glycogen into usable glucose. When researchers increased GlyP activity in flies, glycogen stores were consumed and harmful reactive oxygen species were reduced. Brain cells became more resilient, and lifespan was extended in the tauopathy models.
The study further shows that dietary restriction, long known to promote brain health, works in part by stimulating glycogen breakdown. Flies on a low-protein diet lived longer and had less neuronal damage, underscoring the metabolic link.
From diet to drugs
Inspired by dietary restriction, the team tested a compound called 8-Br-cAMP to mimic its effects. Treated flies showed similar protection, pointing to a pharmacological route to boost GlyP activity.
The authors also note potential ties with GLP-1 receptor agonists such as Ozempic, drugs designed for diabetes and obesity that are now being explored as anti-dementia therapies. These drugs may interact with the same glycogen pathways uncovered in the study.
Why it matters
By uncovering how neurons handle sugar, the research identifies impaired glycogen metabolism as a hallmark of tauopathies. It suggests that restoring glycogen balance could slow or even reverse disease processes in Alzheimer’s and related disorders.
As Kapahi concludes, “Understanding and rebalancing the brain’s hidden sugar code may unlock powerful tools against age-related decline.” With dementia cases rising worldwide, such metabolic strategies offer a promising new line of defense.
A Study published in Nature Metabolism.