Researchers at the University of Florida found that glucosamine use was associated with a greater likelihood that mild cognitive impairment would progress to dementia. Mild cognitive impairment, often shortened to MCI, describes measurable problems with memory or thinking that are greater than expected with normal aging but do not necessarily interfere substantially with everyday life.

The findings come from a large retrospective analysis of patient health records, supported by experiments involving 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 the researchers say they add to growing evidence that disrupted metabolism may play an important role in neurodegeneration.

The study was published in Nature Metabolism.

A Popular Supplement Comes 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 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 is widely sold without a prescription and is especially popular among older adults who take it for joint discomfort and joint health. Because of how commonly it is used, the researchers wanted to know whether it might 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 deidentified UF Health records collected from 2012 to 2024.

The researchers focused on patients diagnosed with either 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 MCI.

Glucosamine Linked to Dementia Progression

After accounting for age, sex and demographics, the researchers found that glucosamine use was associated with a 25% higher likelihood that mild cognitive impairment would progress to dementia.

Among people who already had ADRD, glucosamine use was also associated with a 25% higher mortality risk, meaning a greater likelihood of death during a defined period of time.

The researchers did not observe that mortality association in the MCI group. That difference suggests glucosamine may have a stronger effect once dementia is already established.

Importantly, the health record findings do not show that glucosamine itself causes dementia to progress. Observational studies can 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 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."

A Metabolic Pathway May Help Explain the Link

The researchers also uncovered evidence of a biological mechanism that could help explain the association.

Their work points to a metabolic pathway involving the attachment of sugar structures to proteins. This process is a normal and important part of cell biology, but the researchers found signs that it becomes excessively active in Alzheimer's disease.

Sun said that abnormal activity in this pathway could eventually become a target for new 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.

Plaques and tangles are two of the best known features of Alzheimer's disease. Plaques are abnormal deposits of a protein called amyloid beta that accumulate between brain cells, while tangles are twisted forms of the tau protein that develop inside neurons. Much Alzheimer's research 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 spatial technology developed in Sun's laboratory helped researchers examine the 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 to uncover intricate pathways that otherwise would stay hidden," Sun said.

The team then focused specifically on glucosamine. Glucosamine is a naturally occurring, sugar-related molecule that can cross the blood-brain barrier, the protective boundary that tightly controls which substances can move from the bloodstream into brain tissue.

Once inside the brain, glucosamine can enter biochemical pathways that construct complex sugar structures and attach them to proteins. Commercial glucosamine supplements can be produced from materials including shellfish shells or corn.

According to the researchers, the effects of glucosamine may depend heavily on the biological environment in which it is acting. A healthy brain and a brain affected by Alzheimer's may therefore respond differently to the same molecule.

The Alzheimer's brain appeared to be particularly vulnerable to this metabolic pathway.

Mouse Experiments Point to a Possible Mechanism

To explore the mechanism more closely, the scientists studied genetically modified mice.

Glucosamine significantly increased the attachment of sugar residues to proteins inside cells. At the same time, glucosamine-treated mice developed worse deficits in "social memory" -- or memory of recognition -- compared with the other animals.

When the researchers used a chemical treatment to suppress the sugar attachment process, memory performance improved.

That experiment suggested that excessive sugar tagging could play a direct role in the memory problems seen in the animals rather than simply occurring alongside them.

Human Alzheimer's Brain Tissue Shows the Same Pattern

The researchers next examined human brain tissue with Stefan Prokop, M.D.

Brain specimens from people with Alzheimer's disease, provided by the UF Neuromedicine Brain and Tissue Bank, showed significantly more sugar attachment than tissue from normal controls.

Combined with the mouse experiments and health record analysis, 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 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 results raise a potentially important question about glucosamine use among people with cognitive impairment or dementia, but they do not yet establish that people should stop taking the supplement. A controlled human clinical trial will be needed to determine whether glucosamine directly accelerates Alzheimer's progression and, if so, which patients may be most vulnerable.