Brain’s sugar processing may fuel Alzheimer's pathology, study finds

It has long been known that the brain’s ability to metabolize a simple form of sugar called glucose gradually decreases as we age, and there is increasing evidence that this is more pronounced in the brains of patients with Alzheimer’s disease.

Now, a new University of Florida study of postmortem human brains suggests that slower glucose and glycogen metabolism in the brain actually contributes to the development of Alzheimer’s, rather than just being a secondary effect of the disease.

“Sugar metabolism in the brain seems to be not just a bystander but something that actually drives Alzheimer’s pathology,” said Stefan Prokop, M.D., who conducted the research at the UF Neuromedicine Human Brain and Tissue Bank he directs.

Published today in Cell Reports Medicine, the findings bolster evidence for preventive factors such as physical exercise and modulating carbohydrate consumption, as these and other factors influence the amount of glucose stored in cells, including brain cells.

“We know that lifestyle factors such as exercise and diet have an influence and are protective against Alzheimer’s,” Prokop said, “and this could be a link that explains why.”

Together with first author Jonathan Villareal, a UF MD-Ph.D. scholar, Prokop led a research team that analyzed 230 postmortem human brains and found substantial increases in microscopic sugar bodies (called corpora amylacea and spherical glycogen patches) in Alzheimer’s brains compared with nondiseased brains.

Then, in collaboration with Ramon Sun, Ph.D., and Matthew Gentry, Ph.D., the team used a high-tech method (called matrix-assisted laser desorption ionization mass spectrometry imaging) to spatially map overall glycogen metabolism in the samples. They found that these metabolic changes were present even in brain regions that hadn’t yet developed Alzheimer’s pathology, suggesting they precede and contribute to the disease.

“We saw that people with Alzheimer’s disease have many more sugar bodies than people without Alzheimer’s disease. And then we started looking into metabolism and saw it’s not just these sugar bodies, but it’s glucose storage and metabolism that changes,” said Prokop, a researcher with the McKnight Brain Institute, the Norman Fixel Institute for Neurological Diseases at UF Health and UF’s Center for Translational Research in Neurodegenerative Disease.

The research team then tested Alzheimer’s disease mouse models to confirm their findings.

The next step, Prokop said, is to test how directly manipulating glycogen metabolism affects Alzheimer’s pathology, a strategy that could also apply to other neurodegenerative diseases.

The findings build on a paper recently published in Nature Metabolism by this research group, which found an association between taking glucosamine, a popular over-the-counter supplement used for joint pain, and a higher likelihood of progressing from mild cognitive impairment to Alzheimer’s disease.