Brain Sugar Metabolism May Hold Key to Alzheimer’s

Scientists have discovered that neurons burn sugar differently than previously thought, revealing a potential new pathway to combat Alzheimer’s disease and other forms of dementia.

The research, published in Nature Metabolism, shows that breaking down stored brain sugar—called glycogen—can protect neurons from the toxic protein buildup that characterizes these devastating diseases.

The finding challenges long-held assumptions about brain energy metabolism and offers fresh insight into why certain diabetes medications show promise against dementia. It also provides a potential explanation for how dietary restriction might protect the aging brain.

“This new study challenges that view, and it does so with striking implications,” explains Professor Pankaj Kapahi from the Buck Institute for Research on Aging. “Stored glycogen doesn’t just sit there in the brain; it is involved in pathology.”

The Sugar Connection

Researchers found that in both fruit fly and human models of tau-related diseases (including Alzheimer’s), neurons accumulate excessive amounts of glycogen—a stored form of glucose typically associated with liver and muscle energy reserves. This buildup appears to contribute directly to disease progression.

The team discovered that tau protein, which forms the characteristic tangles in Alzheimer’s patients’ brains, physically binds to glycogen and prevents its normal breakdown. This creates a vicious cycle: trapped glycogen can’t be processed, leading to cellular stress and further tau accumulation.

When researchers restored activity of glycogen phosphorylase—the enzyme that breaks down glycogen—they observed remarkable improvements in both laboratory models and human brain cells derived from dementia patients.

Redirecting Brain Energy

The most surprising discovery involved how neurons use glycogen once it’s broken down. Rather than burning it for energy through normal metabolic pathways, neurons redirect the sugar molecules into a specialized pathway called the pentose phosphate pathway (PPP).

This alternate route generates powerful antioxidants, including glutathione, that protect neurons from oxidative stress—a key factor in brain aging and neurodegeneration. The research showed specific benefits:

• Reduced toxic protein accumulation in neurons
• Lower levels of damaging reactive oxygen species
• Extended lifespan in disease models
• Improved mitochondrial function in human neurons

Dietary Connections

The study revealed that dietary restriction—known to extend lifespan and delay neurodegeneration—naturally enhances glycogen breakdown through a cAMP-mediated pathway. The researchers successfully mimicked these protective effects using a molecule called 8-Br-cAMP, suggesting potential drug targets.

“This work could explain why GLP-1 drugs, now widely used for weight loss, show promise against dementia, potentially by mimicking dietary restriction,” Kapahi noted.

This connection provides a mechanistic explanation for why certain metabolic interventions and medications might protect cognitive function, opening new avenues for therapeutic development.

From Flies to Humans

The research team validated their findings across multiple systems, from fruit flies to human neurons derived from patients with frontotemporal dementia. A crucial detail not emphasized in the press release: the team confirmed similar glycogen accumulation patterns in neurons from patients with two different tau mutations (R406W and V337M), strengthening the clinical relevance of their discoveries.

When researchers overexpressed the human version of glycogen phosphorylase in diseased neurons, they successfully reduced glycogen buildup and restored normal mitochondrial function—key cellular powerhouses that falter in neurodegeneration.

Therapeutic Possibilities

The findings suggest that enhancing glycogen breakdown could represent a novel therapeutic strategy for Alzheimer’s and related diseases. Rather than targeting tau protein directly—an approach that has largely failed in clinical trials—this research points toward metabolic interventions that could bolster the brain’s natural defenses.

“By discovering how neurons manage sugar, we may have unearthed a novel therapeutic strategy: one that targets the cell’s inner chemistry to fight age-related decline,” Kapahi explains. The approach could potentially work alongside existing treatments to provide more comprehensive neuroprotection.

As populations worldwide continue aging, discoveries like these offer hope that understanding and rebalancing the brain’s hidden metabolic processes could unlock powerful new tools for combating dementia and preserving cognitive health.