Glucosamine, a popular joint-pain supplement, may worsen outcomes in people with mild cognitive impairment (MCI), and a newly identified metabolic pathway involving excessive protein glycosylation could help explain why, new research suggests.

In a large electronic health record analysis, glucosamine use was associated with a 25% higher likelihood of progression from MCI to dementia over 5 years. Experiments in human brain tissue and mouse models suggested that excessive protein glycosylation may contribute to Alzheimer’s disease (AD) progression and that glucosamine supplementation could exacerbate the process by fueling glycan production.

Although preliminary, researchers said the findings point to glycan metabolism as a possible therapeutic target and raise questions about the safety of glucosamine use among patients with established dementia.

“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,” senior investigator Ramon Sun, PhD, director of the Center for Advanced Spatial Biomolecule Research and associate director for innovation at the McKnight Brain Institute at the University of Florida, Gainesville, Florida, said in a statement.

The study was published online on June 9 in Nature Metabolism.

Brain Hit From Glucosamine?

Using electronic health records, researchers identified more than 24,000 patients with AD and related dementias (ADRD) and nearly 42,000 patients with MCI. About 8% of patients in both cohorts reported taking glucosamine.

After adjustment for age, sex, and demographic variables, glucosamine use was associated with a 25% higher likelihood of progression from MCI to dementia over 5 years (P < .0010). Among patients with ADRD, taking the supplement was associated with a 25% increased risk for mortality at 10 years (P = .0023).

Because the analysis was observational, it remains unclear whether glucosamine directly contributed to worse outcomes or was associated with other factors linked to disease progression, researchers noted.

Still, the electronic health record data are “very provocative,” co-author Matt Gentry, PhD, chair of the Department of Biochemistry and Molecular Biology, University of Florida, said in a statement.

“While it’s an association and not proof of causality, it does raise an important clinical question that now deserves much more attention,” he noted.

A New Metabolic Driver of AD?

Mechanistically, previous studies have reported glycosylation changes in AD, but whether those changes contribute directly to disease progression has remained unclear.

To test the hypothesis that hyperglycosylation may be an active contributor to disease progression, the investigators used a combination of spatial metabolomics, lipidomics, and glycomics technologies to analyze postmortem human AD brain tissue and established mouse models of AD.

In human AD brain tissue, they observed evidence of increased glycan biosynthesis and widespread hyperglycosylation in both gray and white matter. Glycan abundance increased progressively with increasing neuropathologic disease severity, as measured by Braak staging.

In AD mice, suppressing glycosylation enzymes ameliorated cognitive deficits, while oral glucosamine supplementation exacerbated behavioral impairments, findings that the authors said support a causal role for glycan dysregulation in disease severity.

“These findings suggest that hyperglycosylation is not simply a secondary feature of neurodegeneration but may function as a critical driver of AD pathology,” they wrote.

They called for a large, double-blind clinical trial to evaluate the potential impact of glucosamine on AD progression at the population level. “This study provides a foundation for future translational efforts aimed at modulating glycan metabolism as a therapeutic approach in AD,” the authors concluded.

A Signal That’s Hard to Dismiss

What makes the study novel is that it doesn’t just identify a biomarker, said Shaheen Lakhan, MD, PhD, a neurologist and researcher based in Miami, Florida, who was not part of the research.

“It suggests we may be looking at part of the engine rather than just the smoke coming out of the exhaust pipe,” Lakhan told Medscape Medical News.

“The hyperglycosylation hypothesis is biologically plausible. Glycosylation is essentially the cell’s molecular labeling and shipping system. Proteins need the right sugar tags to fold correctly, travel to the right destination, and perform their intended function,” Lakhan said. “What this study suggests is that in Alzheimer’s disease, that system may be running in overdrive.”

The convergence of evidence adds to the paper’s strength, he added.

“The investigators found excessive glycosylation in human Alzheimer’s brains, reproduced it in two very different mouse models, tracked increased glycan production in real time, and then showed that dialing glycosylation down improved cognition while pushing it higher worsened cognition,” Lakhan said. “When human tissue, animal models, metabolic tracing, and behavioral outcomes all point in the same direction, it’s hard to dismiss the signal.”

Still, he cautioned against declaring hyperglycosylation a primary cause of AD.

“Alzheimer’s is less like a single broken circuit and more like a citywide power failure involving amyloid, tau, inflammation, vascular dysfunction, and metabolic stress. Hyperglycosylation may be another failing power station in that network – important, but probably not acting alone,” Lakhan said.

Clearly, the glucosamine findings are what will grab the most attention because millions of older adults take it every day, Lakhan commented.

“What makes the finding noteworthy is that glucosamine has never consistently delivered dramatic clinical benefits for most of the conditions for which it’s marketed. If a supplement offers modest or uncertain benefit but now carries a plausible signal for harm in Alzheimer’s disease, clinicians should at least pay attention,” he said.

However, based on this study, Lakhan doesn’t think every patient with MCI or dementia should immediately stop glucosamine.

“The human data are observational and cannot prove cause and effect. But it does change the conversation,” he said. “Until now, glucosamine was largely viewed as a benign supplement. This study raises the possibility that, in the Alzheimer’s brain, it may be adding fuel to a fire we are trying to extinguish.”

The study had no commercial funding. Disclosures for study authors can be found in the original article. Lakhan had no relevant disclosures.