Scientists Discover Sugar “Switch” That Protects Brain Health from Alzheimer’s Disease

A groundbreaking study from the Buck Institute for Research on Aging has uncovered a surprising defense mechanism against Alzheimer’s disease and other forms of neurodegeneration: the way neurons manage glycogen, the brain’s stored form of sugar. Published in Nature Metabolism, the research shows that breaking down glycogen inside neurons shields the brain from harmful tau tangles, oxidative stress, and metabolic dysfunction.

While glycogen is typically recognized as an energy source for the liver and muscles, the brain also stores small amounts—mainly in astrocytes. Until now, glycogen’s role in neurons was considered negligible. But as Professor Pankaj Kapahi, PhD, the study’s senior author, explained, “Our findings show that glycogen in neurons is not inert; it can actively contribute to Alzheimer’s and other neurodegenerative diseases.”

Led by Dr. Sudipta Bar, the team found that neurons in both fruit fly and human models of tauopathy—a group of disorders defined by tau protein buildup—accumulated excessive glycogen. This accumulation, they discovered, fueled neurodegeneration by trapping glycogen in tau tangles, preventing its breakdown, and increasing vulnerability to oxidative stress.

Restoring the activity of glycogen phosphorylase (GlyP)—the key enzyme for glycogen breakdown—helped neurons detoxify harmful free radicals. When neurons were able to activate GlyP, they redirected sugar breakdown products into the pentose phosphate pathway (PPP), boosting molecules like NADPH and glutathione that fight oxidative stress. This not only reduced cellular damage but also extended the lifespan of flies with tauopathy, highlighting a powerful new avenue for brain health interventions.

Interestingly, dietary restriction, a known method for extending lifespan, naturally increased GlyP activity in fly models, suggesting a link between metabolism and protection from Alzheimer’s disease. By using the compound 8-Br-cAMP, researchers pharmacologically mimicked these dietary benefits, opening possibilities for neuro supplements or drugs that replicate these protective effects. Professor Kapahi noted that GLP-1 drugs, often used for weight loss, may benefit dementia patients by mimicking aspects of dietary restriction.

Importantly, similar patterns of glycogen accumulation and protective benefits of GlyP activation were observed in human neurons derived from patients with frontotemporal dementia (FTD), supporting the relevance of these findings beyond fly models.

“This study reveals metabolic dysfunction as a key driver of neurodegeneration and identifies glycogen metabolism as an overlooked but promising target for therapies,” Kapahi said. He also highlighted how brain stimulation strategies could work alongside metabolic treatments to further protect against diseases like Alzheimer’s.
Kapahi credited the success of this research to the collaborative environment at the Buck Institute, where experts in fly genetics, proteomics, and human stem-cell biology combined efforts. “Understanding how neurons handle sugar opens new doors for tackling neurodegeneration, and could lead to innovative treatments to maintain brain health and fight Alzheimer’s disease,” he added.