Common joint supplement may accelerate Alzheimer's disease progression

New research has found an association between taking glucosamine, a popular over-the-counter supplement used for joint pain, and a higher likelihood of progressing from mild cognitive impairment to Alzheimer's disease.

The finding by University of Florida neuroscientists is based on a large retrospective analysis of patients' records as well as supporting data from advanced imaging technology used to scan human brain specimens and Alzheimer's disease mouse models.

While the results are preliminary and require validation in a human clinical trial, they provide yet another piece of a much bigger mechanistic picture involving metabolic dysregulation and neurodegeneration, according to the study published today in Nature Metabolism.

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. A lot of these people actively take an over-the-counter supplement that could be making their disease progression worse."

Ramon Sun, Ph.D., senior author, director of the Center for Advanced Spatial Biomolecule Research and associate director for innovation of UF's McKnight Brain Institute

As glucosamine is widely available and commonly used by seniors for joint health, researchers set out to investigate whether it could have any effect in Alzheimer's disease and related dementias, known as ADRD.

With collaborators Yi Guo, Ph.D., and Jiang Bian, Ph.D., the team used artificial intelligence to comb deidentified UF Health records from 2012 to 2024 for patients diagnosed with either ADRD or mild cognitive impairment, or MCI. They found that a significant proportion - 8% - of both types of patients reported taking glucosamine: 1,896 with ADRD and 2,750 with MCI.

After controlling for age, sex and demographics, the analysis showed that glucosamine use was associated with a 25% higher likelihood of progression from mild cognitive impairment to dementia.

In addition, researchers found that taking glucosamine was associated with a 25% increase in mortality risk, or the likelihood of death within a specified time frame, among ADRD patients. For the MCI group, there was no such impact, suggesting the impact of glucosamine may be greater in patients with established dementia.

Notably, said Sun, researchers revealed that a metabolic process in which a protein and sugar-tagging pathway is overactive in Alzheimer's could be a new target for intervention.

"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.

These new insights were made possible by powerful new spatial technology developed by Sun's lab.

"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.

To peer more deeply into these pathways, the research team focused on glucosamine, a naturally occurring sugar-related molecule that can cross the blood-brain barrier and feed into pathways that build complex sugar structures on proteins. In supplements, it can be made from substances such as shellfish shells or corn.

The findings suggest that glucosamine's impact may depend on biological context, with the Alzheimer's brain appearing more vulnerable to this metabolic pathway than the nondiseased brain, said Matt Gentry, Ph.D., chair of UF's Department of Biochemistry and Molecular Biology and a study co-author.

"The electronic health record data are very provocative," Gentry said. "While it's an association and not proof of causality, it does raise an important clinical question that now deserves much more attention."

In genetically modified mice, the research team showed that glucosamine significantly increased the attachment of sugar residues to proteins in cells. Deficits in "social memory" - or memory of recognition - worsened in glucosamine-treated mice. Conversely, when researchers chemically suppressed this attachment process, memory improved.

Then, in collaboration with Stefan Prokop, M.D., the team found significantly increased sugar attachment in Alzheimer's brain specimens from the UF Neuromedicine Brain and Tissue Bank compared with normal controls. Taken together, these results suggest that such metabolic dysfunction is not simply a secondary aspect of Alzheimer's pathology but a contributing driver, they reported.

"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."