Brain sugar metabolism may be the key to Alzheimer’s disease

Scientists have found that neurons differ from previously imagined burning, revealing a potential new avenue to combat Alzheimer’s disease and other forms of dementia.

This study published in natural metabolism shows that breaking down stored brain sugars, called glycogen, can protect neurons from the accumulation of toxic proteins characterized by these devastating diseases.

This discovery challenges long-standing assumptions about brain energy metabolism and provides new insights into the effects of certain diabetes drugs. It also provides a potential explanation for how dietary restrictions protect the aging brain.

“This new study challenges this view and does it with amazing meanings,” explains Professor Pankaj Kapahi. “Stored glycogen is not only sitting in the brain; it is involved in pathology.”

Sugar Connection

The researchers found that in human models of fruit flies and tau-related diseases, including Alzheimer’s, neurons accumulate excess glycogen, a stored form of glucose that is often associated with liver and muscle energy reserves. This accumulation appears to directly lead to disease progression.

The team found that tau proteins that form characteristic tangles in the brains of Alzheimer’s patients will physically bind to glycogen and prevent it from collagen breaking normally. This creates a vicious cycle: the inability to deal with trapped glycogen, resulting in cellular stress and further tau accumulation.

When the researchers restored the activity of glycogen phosphorylase (the enzyme that breaks down glycogen), they observed significant improvements in laboratory models and human brain cells from patients with dementia.

Redirecting brain energy

The most surprising findings involve how to use glycogen after neurons rupture. Neurons do not burn them through normal metabolic pathways to redirect sugar molecules to a specialized pathway called the pentose pentose phosphate pathway (PPP).

This alternative route produces powerful antioxidants, including glutathione, that protects neurons from oxidative stress, a key factor in brain aging and neurodegeneration. Research shows specific benefits:

• Reduced accumulation of toxic proteins in neurons
• Lower reactive oxygen species destruction
• Extended life span of disease models
• Improved mitochondrial function in human neurons

Dietary contact

Studies have shown that dietary restrictions (known to prolong life and delay neurodegeneration) enhance glycogen rupture through camp-mediated pathways. The researchers successfully mimicked these protective effects using molecules called 8-BR-cAMP, suggesting potential drug targets.

“This work could explain why the GLP-1 drug, which is now widely used to lose weight, may show hope for dementia by mimicking dietary restrictions,” Capahi noted.

This connection provides a mechanical explanation of why certain metabolic interventions and drugs can protect cognitive function, thus opening up new avenues for therapeutic development.

From flies to humans

The team validated their findings across multiple systems, from fruit flies to human neurons, which are from patients with frontotemporal dementia. Key details not highlighted in the press release: The team confirmed similar patterns of glycogen accumulation in neurons from patients with two different TAU ​​mutations (R406W and V337M), thereby enhancing the clinical relevance they found.

When the researchers overexpressed a human version of glycogen phosphorylation in diseased neurons, they successfully reduced the accumulation of glycogen and restored normal mitochondrial function, the bond cell power Hoth that swung in neurodegeneration.

Possibility of treatment

The results show that enhanced glycogen rupture can represent novel therapeutic strategies for Alzheimer’s disease and related diseases. Instead of directly targeting tau protein, this approach has largely failed in clinical trials, the study notes that metabolic interventions can enhance the brain’s natural defense capabilities.

“By discovering how neurons manage sugar, we may have unearthed a novel therapeutic strategy: a strategy to target intracellular chemical reactions to resist age-related decline,” explains Capahi. The approach has the potential to be used with existing treatments to provide a more comprehensive neuroprotection effect.

As the global population continues to age, such discoveries offer hope that understanding and rebalancing the hidden metabolic processes of the brain can unlock powerful new tools to combat dementia and preserve cognitive health.

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