A widely used supplement for joint pain has been linked to a potentially worrying outcome in people with early cognitive problems.
Researchers at the University of Florida found that glucosamine use was associated with a higher likelihood of mild cognitive impairment progressing to dementia. Mild cognitive impairment, often abbreviated to mild cognitive impairment, describes measurable problems with memory or thinking that are greater than expected with normal aging but do not necessarily substantially interfere with daily life.
The findings come from a large retrospective analysis of patients’ medical records, supported by experiments with human brain tissue and mouse models of Alzheimer’s disease. The results remain preliminary and will need to be tested in a human clinical trial, but researchers say they add to growing evidence that altered metabolism may play an important role in neurodegeneration.
The study was published in Nature metabolism.
A popular supplement is under scrutiny
“In the United States, there are about 7 million people living with Alzheimer’s and millions more with related dementias, such as Lewy bodies or frontotemporal dementia,” said senior author Ramon Sun, Ph.D., director of the Center for Advanced Research in Space Biomolecules and associate director of innovation at UF’s McKnight Brain Institute. “Many of these people are actively taking an over-the-counter supplement that could worsen the progression of their disease.”
Glucosamine is widely sold over the counter and is especially popular among older adults who take it for joint discomfort and health. Because of how frequently it is used, researchers wanted to know if it could influence Alzheimer’s disease and related dementias, known as ADRD.
Working with Yi Guo, Ph.D., and Jiang Bian, Ph.D., the team used artificial intelligence to analyze de-identified UF health records collected between 2012 and 2024.
The researchers focused on patients diagnosed with ADRD or mild cognitive impairment, or MCI. In both groups, 8% of patients reported using glucosamine. That included 1,896 people with ADRD and 2,750 people with mild cognitive impairment.
Glucosamine linked to dementia progression
After taking into account age, sex and demographics, the researchers found that glucosamine use was associated with a 25% greater chance of MCI progressing to dementia.
Among people who already had ADRD, glucosamine use was also associated with a 25% higher risk of mortality, meaning a higher chance of death over a defined period of time.
The researchers did not observe this association with mortality in the group with mild cognitive impairment. That difference suggests that glucosamine might have a stronger effect once dementia is established.
Importantly, findings from medical records do not show that glucosamine itself causes dementia to progress. Observational studies may reveal associations, but other differences between people who take a supplement and those who do not may contribute to the results.
“The electronic health record data is very provocative,” said Matt Gentry, Ph.D., chair of the UF Department of Biochemistry and Molecular Biology and co-author of the study. “While this is an association and not proof of causality, it raises an important clinical question that now deserves much more attention.”
A metabolic pathway may help explain the link
The researchers also discovered evidence of a biological mechanism that could help explain the association.
Their work points to a metabolic pathway that involves the attachment of sugar structures to proteins. This process is a normal and important part of cell biology, but researchers found signs that it becomes excessively active in Alzheimer’s disease.
Sun said abnormal activity in this pathway could eventually become a target for new treatments.
“Our results suggest that altered metabolism contributes significantly to the progression of Alzheimer’s, and addressing the metabolic defect could be an important complement to approaches focused on Alzheimer’s plaques and tangles,” Sun said.
Plaques and tangles are two of the most well-known features of Alzheimer’s disease. Plaques are abnormal deposits of a protein called beta amyloid that build up between brain cells, while tangles are twisted forms of the protein tau that develop inside neurons. Much of the research on Alzheimer’s has traditionally focused on these abnormalities, but scientists are increasingly studying additional processes that may contribute to the disease.
Mapping thousands of molecules in the brain
A space technology developed in Sun’s lab helped researchers examine metabolic changes in much greater detail.
“This technology allows us to examine thousands and thousands of molecules created when the body breaks down food or drugs and discover intricate pathways that would otherwise remain hidden,” Sun said.
The team then focused specifically on glucosamine. Glucosamine is a natural sugar-related molecule that can cross the blood-brain barrier, the protective boundary that strictly controls what substances can pass from the bloodstream into brain tissue.
Once inside the brain, glucosamine can enter biochemical pathways that build complex sugar structures and bind them to proteins. Commercial glucosamine supplements can be produced from materials including shellfish or corn husks.
According to researchers, the effects of glucosamine may depend largely on the biological environment in which it acts. Therefore, a healthy brain and a brain affected by Alzheimer’s disease may respond differently to the same molecule.
The brain of the person with Alzheimer’s appeared to be particularly vulnerable to this metabolic pathway.
Experiments with mice point to a possible mechanism
To more closely explore the mechanism, the scientists studied genetically modified mice.
Glucosamine significantly increased the binding of sugar residues to proteins within cells. At the same time, the glucosamine-treated mice developed worse deficits in “social memory” (or recognition memory) compared to the other animals.
When researchers used a chemical treatment to suppress the sugar-binding process, memory performance improved.
That experiment suggested that excessive sugar marking could play a direct role in the memory problems seen in the animals rather than simply occurring along with them.
Human Alzheimer’s brain tissue shows the same pattern
Next, the researchers examined the human brain tissue with Stefan Prokop, MD.
Brain samples from people with Alzheimer’s disease, provided by the UF Neuromedicine Brain and Tissue Bank, showed significantly more sugar adherence than tissue from normal controls.
Combined with experiments on mice and analysis of medical records, the findings suggest that abnormal metabolism may be more than a secondary consequence of Alzheimer’s disease. The researchers reported that it could instead contribute to the disease process itself.
“Proteins are the molecular machines of cells, and many of them need sugar tags added in the right way to fold correctly, travel to the right place and do their job,” Gentry said. “What we found in Alzheimer’s is that this sugar labeling system appears to be overactive. The brain of the person with Alzheimer’s adds too many of these sugar structures, and this appears to contribute to the disease rather than protect against it.”
The results raise a potentially important question about glucosamine use among people with cognitive impairment or dementia, but do not yet establish that people should stop taking the supplement. A controlled clinical trial in humans will be necessary to determine whether glucosamine directly accelerates the progression of Alzheimer’s and, if so, which patients may be most vulnerable.