A new study published in Nature Metabolism reports that glucosamine supplementation may worsen memory deficits in Alzheimer’s disease mouse models and is associated with poorer clinical outcomes in people with dementia, according to findings released on June 14.
Researchers from the University of Florida conducted a large-scale analysis involving patient health records, spatial multiomics, and isotope-tracing studies of human brain tissue and mouse models. They hypothesized that hyperglycosylation—a metabolic process where complex carbohydrate molecules are attached to proteins—may be a pathological hallmark of Alzheimer’s disease.
The study found increased N-glycan abundance across white and grey matter regions in both AD mouse models and human post-mortem brain tissue. In mice, genetic knockdown of key glycosylation enzymes led to cognitive improvements. Conversely, oral administration of glucosamine resulted in increased glycosylation and behavioral impairments. The researchers said these observations support a causal role for glycan dysregulation in disease severity but noted that short-term interventions did not alter classic pathology markers such as amyloid plaque burden or tauopathy.
Extending their research to humans, the team used natural language processing on health records from patients diagnosed with Alzheimer’s Disease and Related Dementias (ADRD) or mild cognitive impairment. About 8% of each group had documented glucosamine use. Correlation analysis controlling for age, sex, and demographics showed that glucosamine use was associated with a 25% increase in mortality risk over ten years among ADRD patients but not among those with mild cognitive impairment. Additionally, there was a 25% higher proportion of patients transitioning from mild cognitive impairment to ADRD among glucosamine users.
The researchers emphasized that while animal data suggest causality between hyperglycosylation driven by increased glycan biosynthesis and worsening AD pathology, the human findings remain observational due to limitations such as retrospective design and possible under-recording of supplement use. The authors estimate that more than one million U.S. dementia patients could be exposed to potential risks related to glucosamine supplementation based on extrapolated usage rates.
Given these findings, the researchers highlight an urgent need for well-designed clinical trials: “the researchers highlight the urgent need for well-designed, double-blind clinical trials to systematically evaluate the impact of glucosamine on cognitive decline in patients with dementia.”
