A supplement widely used to treat joint pain has been linked to potentially concerning results in people with early-onset cognitive problems.
Researchers at the University of Florida found that glucosamine consumption was associated with a greater likelihood that mild cognitive impairment would progress to dementia. Mild cognitive impairment, often abbreviated to MCI, describes measurable problems with memory or thinking that are greater than expected with normal aging, but do not necessarily interfere substantially with daily life.
The findings come from a large retrospective analysis of patients’ health records, supported by experiments involving human brain tissue and mouse models of Alzheimer’s disease. The findings remain preliminary and will need to be tested in a human clinical trial, but the researchers say they add to growing evidence that disrupted metabolism may play an important role in neurodegeneration.
The study was published in Natural metabolism.
Popular Supplement Comes Under Scrutiny
“In the United States, approximately 7 million people live with Alzheimer’s disease and millions more have associated dementias such as Lewy body dementia or frontotemporal dementia,” said lead author Ramon Sun, Ph.D., director of the Center for Advanced Spatial Biomolecule Research and associate director for innovation at UF’s McKnight Brain Institute. “Many of these people are actively taking over-the-counter supplements that could worsen the progression of their disease.”
Glucosamine is widely sold without a prescription and is especially popular among older adults who take it to relieve discomfort and improve joint health. Because of its common use, 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 from 2012 to 2024.
The researchers focused on patients diagnosed with ADRD or mild cognitive impairment, or MCI. In both groups, 8% of patients reported using glucosamine. This included 1,896 people with ADRD and 2,750 people with MCI.
Glucosamine linked to progression of dementia
After accounting for age, gender and demographics, researchers found that glucosamine consumption was associated with a 25% higher likelihood of mild cognitive impairment progressing to dementia.
Among people already with MDA, glucosamine consumption was also associated with a 25% higher mortality risk, meaning a greater likelihood of death over a defined period of time.
Researchers did not observe this mortality association in the MCI group. This difference suggests that glucosamine may have a stronger effect once dementia is already established.
It is important to note that health record results do not show that glucosamine itself causes the progression of dementia. Observational studies may reveal associations, but other differences between people who take a supplement and those who don’t may contribute to the results.
“Electronic health record data is very provocative,” said Matt Gentry, Ph.D., chair of UF’s Department of Biochemistry and Molecular Biology and co-author of the study. “Although this is an association and not proof of causation, 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 this association.
Their work suggests a metabolic pathway involving the attachment of sugar structures to proteins. This process is a normal and important part of cell biology, but researchers have 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 impaired metabolism significantly contributes to the progression of Alzheimer’s disease and, furthermore, resolving the metabolic defect could be an important complement to approaches focusing on plaques and tangles in Alzheimer’s disease,” 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 Alzheimer’s research has traditionally focused on these abnormalities, but scientists are increasingly studying other processes that may contribute to the disease.
Mapping thousands of molecules in the brain
Space technology developed in Sun’s lab has helped researchers examine metabolic changes in much more detail.
“This technology allows us to look at thousands and thousands of molecules created when the body breaks down foods or drugs and discover complex 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 tightly controls which substances can pass from the bloodstream to brain tissue.
Once inside the brain, glucosamine can enter the biochemical pathways that build complex sugar structures and attach them to proteins. Commercial glucosamine supplements may be produced from materials such as shellfish shells or corn.
According to the researchers, the effects of glucosamine could strongly depend on the biological environment in which it acts. A healthy brain and a brain affected by Alzheimer’s disease can therefore react differently to the same molecule.
The brains of people with Alzheimer’s appear to be particularly vulnerable to this metabolic pathway.
Mouse experiments point to possible mechanism
To explore the mechanism more closely, scientists studied genetically modified mice.
Glucosamine significantly increased the attachment of sugar residues to proteins inside cells. At the same time, the glucosamine-treated mice developed greater 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.
This experiment suggested that excessive sugar labeling might play a direct role in the memory problems seen in the animals rather than simply occurring alongside them.
Human brain tissue with Alzheimer’s disease shows the same pattern
The researchers then examined 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 greater sugar uptake than tissue from normal controls.
Combined with the mouse experiments and analysis of health records, the results suggest that abnormal metabolism may be more than a secondary consequence of Alzheimer’s disease. The researchers reported that it may instead contribute to the disease process itself.
“Proteins are the molecular machines of cells, and many of them need to add sugar tags in the right way to fold properly, move to the right place and do their job,” Gentry said. “What we found in Alzheimer’s disease is that this sugar-marking system seems to be overactive. The Alzheimer’s brain adds too many of these sugar structures, and that seems to contribute to the disease rather than protect against it.”
The findings raise a potentially important question about glucosamine use in people with cognitive impairment or dementia, but they don’t yet establish that people should stop taking the supplement. A controlled human clinical trial will be needed to determine whether glucosamine directly accelerates the progression of Alzheimer’s disease and, if so, which patients might be most vulnerable.
Gn Health
