- Glucosamine use was associated with faster progression from mild cognitive impairment to dementia in a large retrospective study.
- Among Alzheimer’s patients, glucosamine use correlated with higher mortality risk over 10 years.
- Researchers suggested that glucosamine may be harmful after neurodegeneration begins, but not before.
Glucosamine — a popular supplement used for joint pain — was associated with faster progression to Alzheimer’s disease and worse survival among Alzheimer’s patients, a retrospective study of electronic health records suggested.
Glucosamine use was linked with a 25% higher likelihood of progression from mild cognitive impairment to dementia (P<0.001) over 5 years, reported Ramon Sun, PhD, of the University of Florida McKnight Brain Institute in Gainesville, and co-authors.
In a 10-year survival analysis, use of the supplement was tied to a 25% increase in mortality risk among patients with Alzheimer’s disease or related dementias (P=0.0023), the researchers noted in Nature Metabolism.
Ten-year survival analyses in people with mild cognitive impairment showed no significant difference between glucosamine users and non-users (P=0.252), suggesting some effects of glucosamine may be specific to people with established neurodegeneration rather than the general population, Sun and colleagues noted.
“Glucosamine is one of the most widely used supplements in the U.S., with roughly 40 million users overall. Around 8% of patients in our dementia cohort took it. That works out to roughly half a million people in this clinical population alone,” Sun said.
“The harm appears specific to a brain already in neurodegeneration,” he pointed out. “Earlier Mendelian randomization work linked glucosamine to lower dementia risk in cognitively healthy adults. Our healthy-mouse data are consistent with that. The supplement looks safe or possibly protective before disease onset, and harmful after.”
The findings were based on the health charts from roughly 24,000 patients in the University of Florida health system who were diagnosed with Alzheimer’s disease or related dementias from 2012 to 2024. The analysis also included about 41,000 patients with mild cognitive impairment.
The researchers tracked patients who had documented glucosamine usage for at least 1 year after being diagnosed with dementia or mild cognitive impairment. Overall, about 8% received glucosamine. The median follow-up was about 5 years.
The retrospective analysis was part of a larger project that investigated possible metabolic drivers of Alzheimer’s disease.
Glucosamine is a natural amino sugar produced by the body and found in healthy cartilage. Arthritis patients often take glucosamine supplements, though the American College of Rheumatology does not recommend them.
Glucosamine can cross the blood-brain barrier and influence pathways that build complex sugar structures on proteins, a process known as glycosylation. N-linked glycosylation could integrate with pathological features of Alzheimer’s disease, possibly influencing its progression, Sun and colleagues suggested.
In transgenic Alzheimer’s mouse models, for example, glucosamine increased the attachment of sugar residues to proteins, leading to worse cognitive outcomes. When Sun’s team suppressed this attachment in mice, memory improved.
The researchers also found that sugar attachment was significantly increased in human Alzheimer’s brain specimens compared with specimens from controls.
“The harm signal is not just an epidemiological association,” Sun noted. “N-glycan accumulation in postmortem Alzheimer’s disease brains scales with Braak stage. Isotope tracing shows the brain produces more N-glycans, not that clearance fails.”
The findings suggest that N-glycosylation is a targetable pathway for combating Alzheimer’s disease, observed Yasuhiko Kizuka, PhD, of Gifu University in Japan, in an accompanying commentary.
“The results of the epidemiological analysis of individuals who use glucosamine, together with the results of glucosamine supplementation in the Alzheimer’s disease mouse models, warrant a future clinical trial to determine whether glucosamine uptake in individuals with mild cognitive impairment and Alzheimer’s disease worsens clinical symptoms,” Kizuka wrote. “Clarifying these issues could pave the way for understanding and overcoming Alzheimer’s disease in the future.”
Glucosamine is a supplement that a meaningful fraction of dementia and cognitively impaired patients take with no current guidance to consider stopping after diagnosis, Sun noted. “Our data argue that conversation should happen,” he said.
The study results are preliminary and require validation, the researchers acknowledged. “We are evaluating which N-glycan pathway inhibitors are candidates for central nervous system penetration. Several such inhibitors exist in cancer research, but none has been developed for the brain or tested in Alzheimer’s disease,” Sun pointed out.
“In parallel, we want to test discontinuation in patients. A standard placebo-controlled randomized trial would not be ethical now that we have a harm signal in this same population,” he said.
“The cleanest design is to identify Alzheimer’s or mildly cognitively impaired patients already taking glucosamine, ask them to stop, and follow cognition longitudinally,” he added. “This would directly test whether removing the supplement slows decline.”
