The University of Florida study combined patient health records with experiments in human brain tissue and mice to investigate whether changes in how sugars attach to proteins could contribute to Alzheimer’s disease.
While industry commentators described the biological findings as worthy of further investigation, they cautioned against interpreting the human data as evidence that glucosamine contributes to dementia progression.
Study raises questions about glucosamine
Published in Nature Metabolism, the study investigated glycosylation, a normal process in which sugars attach to proteins and influence how they function. The researchers examined whether excessive glycosylation could play a role in Alzheimer’s disease.
Using human brain tissue and mouse models of Alzheimer’s disease, they found increased production of these sugar structures in diseased brains. Reducing the activity of enzymes involved in the process improved cognitive outcomes in mice.
Giving glucosamine to mice with Alzheimer’s disease had the opposite effect, increasing glycosylation in the brain and worsening measures of social memory. Researchers did not observe the same effects in healthy mice, suggesting that the effect could depend on changes already occurring in a brain affected by disease.
The team also analyzed electronic health records collected through the University of Florida Health System between 2012 and 2024. The analysis included 24,481 patients with Alzheimer’s disease and related dementias and 41,884 patients with mild cognitive impairment (MCI).
After adjusting for age, sex and demographics, glucosamine use was associated with a 25% higher mortality risk among patients with Alzheimer’s disease and related dementias. The researchers did not find a significant association with mortality among patients with MCI.
Glucosamine use was also associated with a 25% higher likelihood of progressing from MCI to Alzheimer’s disease and related dementias.
The Council for Responsible Nutrition (CRN), however, cautioned against interpreting those associations as evidence of cause and effect.
“The new study from the University of Florida raises an interesting mechanistic hypothesis involving glycan metabolism, but the human data are observational and should not be misinterpreted or misreported as proof that glucosamine causes Alzheimer’s disease progression,” CRN said in a statement to NutraIngredients.
The organization added that the findings did not change the safety profile of glucosamine when used as directed for joint support in generally healthy adults.
Could arthritis explain the association?
A central concern raised by industry commentators was whether glucosamine use could be a marker for health conditions that independently influence dementia risk.
Consumers commonly use glucosamine for joint pain and osteoarthritis. CRN noted that these conditions may accompany reduced mobility, lower physical activity and frailty, factors that are themselves associated with dementia outcomes.
These factors “do not appear to have been fully accounted for, making this a key limitation of the study,” according to CRN.
Jacob Teitelbaum, MD, was more critical of the epidemiological analysis, arguing that chronic pain and arthritis could account for at least some of the association.
“This does not mean that glucosamine caused the increased risk of dementia...rather, it simply shows what has been demonstrated in numerous other studies,” he told NI, noting that chronic pain is associated with a 43% higher risk of dementia.
Dr. Teitelbaum argued that comparing glucosamine users with non-users becomes difficult if the groups differ in their underlying levels of arthritis and chronic pain.
“The glucosamine study did not control for this at all,” he emphasized.
“It basically took people with arthritis severe enough to have been put on glucosamine and compared them to all people, largely with no pain,” he added.
The study’s electronic health record analysis adjusted its survival models for age, sex and demographic factors but did not list osteoarthritis or chronic pain among those adjustments.
Mechanistic findings complicate the picture
Unlike an observational study alone, the research also explored a possible biological explanation for the association using human brain tissue and mouse models.
Mark Miller, PhD, principal at Kaiviti Consulting, said the mechanistic work made the findings worth further investigation but did not establish supplemental glucosamine as a primary cause of dementia progression.
“My interpretation at this stage is that glucosamine supplementation is not a key driver for dementia although it may amplify a pathology in motion in some cases,” said Dr. Miller .
“Rather, inflammation, systemic and local, is much more likely to be key,” he noted.
Dr. Miller said the distinction between a disease “driver” and an “amplifier” was important, and that glucosamine could potentially worsen a biological process already underway in some people without being responsible for starting the disease.
The mouse findings leave room for that interpretation. Glucosamine worsened memory measures in mice modeling Alzheimer’s disease but did not produce the same effects in healthy mice.
Dr. Miller also raised questions about dose and metabolism, including whether the amount of glucosamine typically consumed as a supplement and the way the body processes it could produce the same effects in the human brain.
“The role of glycosylation in dementia is interesting, and this warrants study,” he said.
The University of Florida researchers interpreted their findings as evidence that altered metabolism in Alzheimer’s disease could make the brain more vulnerable to increased glycan production.
For Dr. Miller, however, the findings pointed toward a question requiring further investigation rather than a settled mechanism linking supplementation to dementia.
Previous research points in different directions
CRN and Dr. Teitelbaum also pointed to prior population-based research that reported neutral or inverse associations between glucosamine use and dementia.
CRN said analyses involving nearly 500,000 participants with follow-up periods of between nine and 12 years had either found no significant association with incident Alzheimer’s disease or reported a lower dementia risk among glucosamine users.
“Taken together, the evidence is mixed and hypothesis-generating, not definitive,” the organization said.
Dr. Teitelbaum cited three previous prospective studies, including a 2023 study published in BMC Medicine that linked regular glucosamine use to a lower risk of dementia.
A separate 2023 study published in Alzheimer’s Research & Therapy also examined habitual glucosamine use and dementia risk, while a 2024 analysis in The Journals of Gerontology: Series A reported no association between glucosamine supplementation and dementia or Parkinson’s disease.
The conflicting results highlight one of the difficulties of observational research: People who take a supplement may differ from non-users in underlying health, lifestyle or other characteristics that can also influence their health outcomes.
In the case of glucosamine, the industry commentators argued that the reason for taking the supplement could be particularly important.
“When you have different study results, it is important to look at why,” Dr. Teitelbaum said.
“You cannot look at a group of people with arthritis and compare that to a group without arthritis and then attribute differences to some other variable,” he added.
Clinical trial needed to test link
The University of Florida researchers argued that the combination of patient data, human brain findings and mouse experiments strengthened the case for further investigation.
They called for a large, double-blind clinical trial to determine whether glucosamine itself affects cognitive decline, writing that “we strongly advocate for a large-scale, double-blind clinical trial to definitively determine its impact on AD progression at the population level.”
Such a trial could help distinguish whether glucosamine contributes directly to disease progression or whether supplement use primarily identifies patients with other risk factors, such as osteoarthritis, chronic pain or reduced physical activity.
CRN advised consumers with MCI, Alzheimer’s disease or complex medical conditions to review their supplement use with a qualified healthcare provider rather than making abrupt changes based on a single study.
For Dr. Miller, the study raised an important question about the role of metabolism in dementia without providing a final answer on glucosamine.
“This study is intriguing and points us down the road of metabolism as a potential site that drives cognitive decline...however, we have been misled before and there are many remaining questions,” he said.
Source: Nature Metabolism. 8, 1410–1425 (2026). https://doi.org/10.1038/s42255-026-01538-4. “Hyperglycosylation is a metabolic driver of Alzheimer’s disease”. Authors: T.R. Hawkinson, et al.
