Popular Joint Supplement Glucosamine Linked to Faster Alzheimer's Progression in Large Retrospective Study
Key Insights
A University of Florida study found glucosamine use was associated with a 25% higher likelihood of progression from mild cognitive impairment (search) to dementia in a large patient record analysis.
Among patients already diagnosed with Alzheimer's disease (search) and related dementias, glucosamine use was linked to a 25% increase in mortality risk.
Advanced imaging of human brain tissue and mouse models revealed an overactive sugar-tagging metabolic pathway that may explain glucosamine's potential harmful effects in the Alzheimer's brain.
A new study from University of Florida neuroscientists has found that glucosamine, a widely used over-the-counter supplement for joint pain, is associated with a significantly higher likelihood of progressing from mild cognitive impairment (search) (MCI) to Alzheimer's disease (search). The findings, published June 9 in Nature Metabolism, draw on a large retrospective analysis of patient health records combined with advanced imaging studies of human brain tissue and mouse models.
The research raises urgent clinical questions about the safety of a supplement taken by millions of older adults. "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
To investigate whether glucosamine could influence Alzheimer's disease (search) and related dementias (ADRD (search)), the research team collaborated with Yi Guo, Ph.D., and Jiang Bian, Ph.D., using artificial intelligence to analyze deidentified UF Health records collected between 2012 and 2024. They focused on patients diagnosed with either ADRD or MCI.
The analysis revealed that glucosamine use was relatively common in both groups. A total of 1,896 patients with ADRD (search) and 2,750 patients with MCI reported taking the supplement, representing approximately 8% of each group. After controlling for age, sex, and demographics, the data 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 (search). Notably, no similar increase was seen among patients with MCI, suggesting that the supplement's effects may differ depending on the stage of disease.
An Overactive Metabolic Pathway
The study identified a specific biological process that may help explain the association: a protein and sugar-tagging pathway that appears excessively active in Alzheimer's disease (search). According to the researchers, this pathway could represent a new target for future interventions.
"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 enabled 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 explained.
How Glucosamine Affects the Brain
Glucosamine 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, defined as 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 (search) 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."
The researchers emphasize that the results do not prove that glucosamine causes dementia and will need to be confirmed in clinical trials. However, the work adds to growing evidence that metabolic dysfunction plays an important role in neurodegenerative diseases and underscores the need for caution regarding over-the-counter supplement use in populations at risk for dementia.