A widely used joint-health supplement is under scrutiny after researchers linked glucosamine to worsened memory in Alzheimer’s mice and poorer real-world outcomes in people with dementia.
Study: Hyperglycosylation is a metabolic driver of Alzheimer’s disease. Image Credit: Atthapon Raksthaput / Shutterstock
Glucosamine supplementation worsened memory deficits in an Alzheimer’s mouse model and was associated with poorer clinical outcomes in dementia patients, according to a new study published in the journal Nature Metabolism.
Glycosylation in Alzheimer’s Disease
Alzheimer’s disease (AD) is an age-related neurodegenerative disease characterized by neuronal loss, synaptic dysfunction, cognitive decline, and induction of neuroinflammation.
Recent evidence suggests that metabolic dysfunction, including altered glucose and lipid metabolism and mitochondrial function, plays a significant role in AD pathophysiology and progression. Furthermore, restoration of glucose metabolism has been linked to reduced AD progression in animals.
Despite growing evidence highlighting metabolic shifts in AD pathophysiology, dynamic changes in interconnected metabolic pathways and their byproducts (metabolites) as hallmarks and drivers of AD have not been comprehensively explored.
Glycosylation is a vital biochemical process in which glycans (complex carbohydrate molecules) are covalently attached to target proteins, ensuring their structural stability and functionality. Glycan metabolism is tightly linked to glucose and glucosamine availability, and aberrant glycan processing has been linked to protein instability, impaired cell signaling, and induction of neurodegenerative mechanisms.
In the brain, glycosylation plays a pivotal role in neuronal communication by shaping synaptic plasticity, neurotransmitter-receptor function, and neuroimmune signaling. Aberrant glycosylation has been linked to altered microglial function, neuroinflammation, tau protein aggregation and propagation, and amyloid-beta plaque formation.
Given the potential association of glycosylation with major hallmarks of AD pathology, University of Florida researchers conducted a large-scale analysis of patient health records, along with spatial multiomics and isotope-tracing studies of human brain tissue and mouse models of AD, hypothesizing that hyperglycosylation is a pathological hallmark of AD.
Hyperglycosylation Worsens Cognitive Deficits
The researchers applied advanced imaging techniques to AD mouse models and human post-mortem brain tissue and observed increased N-glycan abundance across white and grey matter regions in AD brain samples. These observations suggest a metabolic shift towards hyperglycosylation.
In human samples, grey matter hyperglycosylation increased progressively across Braak stages, whereas white matter increases appeared earlier and did not persist through later stages. This finding suggests that hyperglycosylation may vary across brain regions and disease stages.
Given the significant involvement of glycans in maintaining brain function, the researchers next investigated the functional impact of hyperglycosylation in AD pathophysiology. They conducted both genetic and dietary perturbations in AD mice to modulate glycan biosynthesis.
By conducting genetic knockdown of key glycosylation enzymes, they observed cognitive improvements in AD mice. In contrast, they observed increased glycosylation and behavioral impairments in 5xFAD mice after oral glucosamine administration. These observations support a causal role for glycan dysregulation in disease severity in mouse models and suggest a functional impact of hyperglycosylation in AD pathology.
However, these short-term interventions did not measurably alter amyloid plaque burden, tauopathy, or reactive astrocyte abundance, suggesting that glycosylation may affect cognitive deficits through mechanisms beyond classic AD pathology markers.
Glucosamine Use in Dementia Patients
Given that glucosamine is a popular over-the-counter supplement frequently used by older adults for joint health, the researchers extended these animal study findings to human populations.
They used a natural language processing approach to screen health records of patients diagnosed with Alzheimer’s Disease and Related Dementias (ADRD) or mild cognitive impairment and found that about 8% of patients from each disease group had documented glucosamine use.
The correlation analysis, controlling for patients’ age, sex, and demographic characteristics, showed that glucosamine use was associated with a 25% increase in mortality risk over a 10-year survival analysis among patients with ADRD, but not among patients with mild cognitive impairment. These observations suggest that patients with established dementia may be more susceptible to glucosamine-related negative outcomes.
The analysis further showed that glucosamine use was associated with a 25% higher proportion of patients transitioning from mild cognitive impairment to ADRD.
Alzheimer’s Metabolic Therapy Implications
The study reveals that hyperglycosylation driven by increased glycan biosynthesis in the brain may significantly contribute to AD pathophysiology. Given these findings, the researchers believe that this complex metabolic pathway could serve as a novel therapeutic target for AD.
Glycosylation is a complex biological process of attaching complex carbohydrate glycans to target proteins to improve stability. Using glycoproteomic analysis, the study confirmed that most of the glycosylated proteins identified in AD are neuronal membrane proteins critical for action potential propagation and synaptic transmission.
Given that glucosamine is a widely used dietary supplement and is directly involved in glycan biosynthesis, the researchers supplemented genetically modified mice with glucosamine and found significantly increased protein glycosylation and worsening of cognitive deficits.
They further supported these findings by analyzing health records of patients with ADRD or mild cognitive impairment. The findings of both animal and human studies indicate that glucosamine may worsen neurodegenerative vulnerability in established dementia, although the human data remain observational.
Notably, the researchers found that approximately 8% of study patients had documented glucosamine use, and the authors estimate that extrapolating this percentage to the broader US AD and dementia population could mean that more than one million patients may be exposed to a supplement that requires further clinical safety evaluation.
However, the human analysis was retrospective and based on documented supplement use in health records, which means it cannot establish causality. Over-the-counter supplement use may be under-recorded, and residual confounding remains possible.
Given the clinical consequences of these findings, 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.
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