Researchers found that glucosamine use was associated with a higher likelihood that mild cognitive impairment, or MCI, would progress to dementia. MCI involves measurable problems with memory or thinking that are more severe than expected with normal aging but do not necessarily interfere substantially with daily life.

The findings come from a large retrospective analysis of patient health records, supported by experiments involving human brain tissue and a mouse model of Alzheimer’s disease. The results are preliminary and do not prove that glucosamine causes dementia progression. Human clinical trials will be needed to determine whether the supplement directly affects the disease.

Still, the researchers say the findings add to growing evidence that metabolic disruption may play an important role in neurodegeneration and Alzheimer’s disease progression.

Why researchers are examining glucosamine and dementia risk

Glucosamine is widely available without a prescription and is especially popular among older adults who take it for joint discomfort and joint health. Because the supplement is so commonly used, researchers wanted to investigate whether it could affect Alzheimer’s disease and related dementias, collectively known as ADRD.

“About 7 million people in the United States have Alzheimer’s disease, and millions more have related dementias such as Lewy body dementia and frontotemporal dementia,” said senior author Dr. Ramon Sun, director of the Center for Advanced Spatial Biomolecular Research and associate director of innovation at the University of California’s McKnight Brain Institute.

“Many of these people are actively taking over-the-counter supplements that can worsen the progression of the disease,” Sun said.

Working with Dr. Yi Guo and Dr. Jiang Bian, the research team used artificial intelligence to analyze de-identified UF Health records collected from 2012 through 2024.

The researchers focused on patients diagnosed with ADRD or MCI. In both groups, 8% of patients reported using glucosamine. The analysis included 1,896 patients with ADRD and 2,750 patients with MCI.

Glucosamine was associated with a 25% higher risk of dementia progression

After accounting for age, gender and demographic factors, the researchers found that glucosamine use was associated with a 25% higher likelihood of MCI progressing to dementia.

Among people who already had ADRD, glucosamine use was also associated with a 25% higher risk of death, meaning users were more likely to die within the study period.

The researchers found no association between glucosamine use and mortality among people with MCI. This difference may suggest that the supplement’s effects are stronger after dementia has already been established, although further research is needed.

Importantly, the health record analysis does not show that glucosamine itself causes dementia progression. Observational studies can identify associations, but other differences between people who take glucosamine and those who do not may help explain the results.

“Electronic medical record data is very provocative,” said study co-author Dr. Matt Gentry, chair of the university’s Department of Chemistry and Molecular Biology. “While this is an association and not proof of causation, it does raise important clinical questions and now deserves more attention.”

How metabolism may be connected to Alzheimer’s disease

The researchers also identified evidence of a biological mechanism that could help explain the association between glucosamine and dementia progression.

The study focused on metabolic pathways involved in attaching sugar structures to proteins. This process is a normal and important part of cell biology. However, researchers have found signs that it becomes overactive in Alzheimer’s disease.

Proteins perform many of the cell’s essential functions, and they often need to be tagged with sugar structures in the correct way to fold properly and move to the right location. According to the researchers, excessive sugar tagging may interfere with these processes.

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

“Our findings suggest that metabolic changes significantly contribute to the progression of Alzheimer’s disease, and furthermore, addressing metabolic defects may be an important complement to approaches focused on Alzheimer’s disease plaques and Alzheimer’s disease,” Sun said.

Plaques and tangles are two of the best-known hallmarks of Alzheimer’s disease. Plaques are abnormal deposits of amyloid beta that accumulate between brain cells, while tangles are twisted forms of the tau protein found inside neurons. Although Alzheimer’s research has traditionally focused heavily on these abnormalities, scientists are increasingly studying other biological processes that may contribute to the disease.

Brain-mapping technology helped identify metabolic changes

Spatial techniques developed in Sun’s laboratory allowed the researchers to examine metabolic changes in greater detail.

“This technology allows us to examine the thousands of molecules produced when the body breaks down food and drugs, revealing complex pathways that would otherwise be 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, which tightly controls the substances that move from the bloodstream into brain tissue.

Once in the brain, glucosamine enters biochemical pathways that build complex sugar structures and attach them to proteins. Commercial glucosamine supplements can be made from materials such as seashells and corn.

According to the researchers, glucosamine’s effects may depend largely on the biological environment in which it acts. A healthy brain and a brain affected by Alzheimer’s disease may respond differently to the same molecule.

The researchers said Alzheimer’s brains appear to be particularly vulnerable to this metabolic pathway.

Mouse study suggests a possible explanation for memory problems

To investigate the potential mechanism further, scientists studied genetically modified mice.

Glucosamine significantly increased the attachment of sugar residues to proteins inside the animals’ cells. At the same time, mice given glucosamine developed more severe deficits in social memory, or the ability to recognize other animals, compared with other mice.

When researchers used chemical treatments to inhibit the sugar-attachment process, the mice’s memory improved.

The experiment suggested that excessive sugar tagging may play a direct role in the memory deficits observed in the animals rather than simply occurring alongside them.

Human Alzheimer’s brain tissue showed the same pattern

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

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 may contribute to the disease process itself.

“Proteins are the molecular machinery of the cell, and many of them need to be sugar-tagged in the right way in order to fold correctly and move to the right place to do their job,” Gentry said. “What we found in Alzheimer’s disease is that this sugar-tagging system appears to be overactive. The Alzheimer’s brain is adding too many of these sugar structures, and this appears to be contributing to the disease rather than preventing it.”

Should people stop taking glucosamine?

The findings raise important questions about glucosamine use among people with MCI or dementia, but they do not establish that people should stop taking the supplement.

Because the study was observational, it cannot determine whether glucosamine directly accelerates Alzheimer’s disease or dementia progression. Human clinical trials will be needed to test that possibility and determine which patients, if any, may be most vulnerable.