The discovery that could explain why 'Ozempic' could help against Alzheimer's

A new study by scientists at the Buck Institute for Aging Research has revealed a surprising factor in the fight against Alzheimer's and other forms of dementia : the brain's sugar metabolism. Published in Nature Metabolism , the research reveals how the breakdown of glycogen (a stored form of glucose) in neurons can protect the brain from toxic protein buildup and degeneration.

Glycogen is a reserve energy source stored in the liver and muscles . Although small amounts also exist in the brain, particularly in supporting cells called astrocytes , its role in neurons has long been considered insignificant. "This new study challenges that perspective, and does so with surprising implications," says Professor Pankaj Kapahi, senior author of the study. "Stored glycogen is not limited to the brain; it is involved in pathology," he continues.

The research team, led by postdoctoral researcher Dr. Sudipta Bar , found that in both fly and human models of tauopathy (a group of neurodegenerative diseases that includes Alzheimer's disease), neurons accumulate excess glycogen. More importantly, this accumulation appears to contribute to disease progression . Bar says that tau, the infamous protein that clumps together in Alzheimer's patients, appears to physically bind to glycogen, trapping it and preventing its breakdown.

When glycogen can't be broken down , neurons lose an essential mechanism for managing oxidative stress, a key factor in aging and neurodegeneration . By restoring the activity of an enzyme called glycogen phosphorylase (GlyP), which initiates the process of glycogen breakdown, the researchers found they could reduce tau-related damage in fruit flies and human stem cell-derived neurons.

Instead of using glycogen as fuel for energy production, these neurons, fueled by enzymes, redirected sugar molecules toward the pentose phosphate pathway (PPP), a crucial route for generating NADPH (nicotinamide adenine dinucleotide phosphate) and glutathione, molecules that protect against oxidative stress. "By increasing GlyP activity, brain cells were better able to detoxify harmful reactive oxygen species, thereby reducing damage and even prolonging the lifespan of the tauopathy model flies," Bar explains.

Even more promising, the team showed that dietary restriction , a well-known life-extending intervention, 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 dietary restriction could be reproduced by pharmacologically activating this sugar-clearing system. “This work could explain why GLP-1 drugs, such as Ozempic, now widely used for weight loss, show promise against dementia, possibly by mimicking dietary restriction,” Kapahi explains.

The researchers also confirmed similar glycogen accumulation and the protective effects of GlyP in human neurons derived from patients with frontotemporal dementia (FTD), reinforcing the potential for translational therapies. Kapahi says the study highlights the power of the fly as a model system for uncovering how metabolic dysregulation affects neurodegeneration. "Working with this simple animal allowed us to analyze human neurons in a much more specific way," he concludes.

Kapahi also credits Buck's highly collaborative environment as a key factor in the work. His lab, with expertise in fly aging and neurodegeneration, leveraged the proteomics expertise of the Schilling and Seyfried labs (at Emory University), as well as the Ellerby lab , which specializes in human iPSCs and neurodegeneration.

Kapahi says this study not only highlights glycogen metabolism as a key factor in the brain, but also opens a new avenue in the search for treatments for Alzheimer's and related diseases. "By uncovering how neurons manage sugar, we may have discovered a novel therapeutic strategy: one that targets the cell's internal chemistry to combat age-related decline," he says. "As we age as a society, findings like these offer hope that a better understanding, and perhaps a rebalancing, of the hidden sugar code in our brains could unlock powerful tools to combat dementia."