The study found that people with mild cognitive impairment who reported taking glucosamine were more likely to progress to dementia than those who did not use the supplement. Researchers also uncovered evidence suggesting that glucosamine may interact with biological processes in the brain that are already disrupted in Alzheimer's disease.

The findings, published June 9 in Nature Metabolism, are based on a large analysis of patient health records combined with advanced imaging studies of human brain tissue and mouse models of Alzheimer's disease.

Although the results do not prove that glucosamine causes dementia and will need to be confirmed in clinical trials, researchers say the work adds to growing evidence that metabolic dysfunction plays an important role in neurodegenerative diseases.

"In the United States, there are about 7 million people living with Alzheimer's and millions more with related dementias such as Lewy body or frontotemporal dementia," said senior author Ramon Sun, Ph.D., director of the Center for Advanced Spatial Biomolecule Research and associate director for innovation of UF's McKnight Brain Institute. "A lot of these people actively take an over-the-counter supplement that could be making their disease progression worse."

Glucosamine Use and Dementia Risk

Because glucosamine is widely available and frequently used by older adults to support joint health, the researchers wanted to determine whether it could influence Alzheimer's disease and related dementias (ADRD).

Working with collaborators Yi Guo, Ph.D., and Jiang Bian, Ph.D., the team used artificial intelligence to analyze deidentified UF Health records collected between 2012 and 2024. They focused on patients diagnosed with either ADRD or mild cognitive impairment (MCI).

Among those patients, researchers found that glucosamine use was relatively common. A total of 1,896 patients with ADRD and 2,750 patients with MCI reported taking the supplement, representing about 8% of each group.

After accounting for factors such as age, sex, and demographics, the analysis showed that glucosamine use was associated with a 25% greater likelihood that patients with MCI would later develop dementia.

Researchers also observed that glucosamine use was linked to a 25% increase in mortality risk among people already diagnosed with ADRD. No similar increase was seen among patients with MCI, suggesting that the supplement's effects may differ depending on the stage of disease.

A Potentially Important Metabolic Pathway

The study also pointed to a specific biological process that may help explain the association.

Researchers identified evidence that a protein and sugar-tagging pathway is excessively active in Alzheimer's disease. According to the team, this pathway could represent a new target for future treatments.

"Our results suggest that altered metabolism is a significant contributor to Alzheimer's progression and, in addition, addressing the metabolic defect could be an important complement to approaches focused on Alzheimer's plaques and tangles," Sun said.

The discovery was made possible by advanced spatial analysis technology developed in Sun's laboratory.

"This technology allows us to examine thousands and thousands of molecules created when the body breaks down food or drugs and to uncover intricate pathways that otherwise would stay hidden," Sun said.

How Glucosamine Affects the Brain

To investigate further, researchers focused on glucosamine because it is a naturally occurring sugar-related molecule that can cross the blood-brain barrier. Once in the brain, it can contribute to biochemical pathways involved in building complex sugar structures on proteins. Commercial glucosamine supplements are often produced from materials such as shellfish shells or corn.

The findings suggest that glucosamine's effects may depend heavily on the biological environment in which it is acting.

"The electronic health record data are very provocative," said Matt Gentry, Ph.D., chair of UF's Department of Biochemistry and Molecular Biology and a study co-author. "While it's an association and not proof of causality, it does raise an important clinical question that now deserves much more attention."

According to Gentry, the Alzheimer's brain may be especially susceptible to disruptions in this pathway compared with healthy brain tissue.

Mouse Studies and Human Brain Tissue Findings

Experiments in genetically modified mice provided additional support for the hypothesis.

Researchers found that glucosamine significantly increased the attachment of sugar molecules to proteins within cells. Mice receiving glucosamine also showed worsening deficits in social memory, which is the ability to recognize and remember other individuals.

When scientists chemically reduced this sugar-tagging activity, memory performance improved.

The team then examined human brain tissue from the UF Neuromedicine Brain and Tissue Bank in collaboration with Stefan Prokop, M.D. Compared with healthy control samples, Alzheimer's brain specimens showed substantially higher levels of sugar attachment to proteins.

Taken together, the researchers say these findings suggest that this metabolic abnormality may actively contribute to Alzheimer's disease rather than simply occur as a consequence of it.

"Proteins are the cell's molecular machines, and many of them need sugar tags added in just the right way to fold correctly, travel to the right place and do their jobs," Gentry said. "What we found in Alzheimer's is that this sugar-tagging system appears to be overactive. The Alzheimer's brain is adding too many of these sugar structures, and this seems to contribute to the disease rather than protect against it."