Association of regular glucosamine use with incident dementia: evidence from a longitudinal cohort and Mendelian randomization study

Dementia is characterized by an inexorably progressive impairment of cognition and the capacity to carry out activities of daily life. It is a heterogeneous syndrome posing a substantial burden on patients, their proxies, and national health-care systems [1]. In the UK, over 850,000 individuals suffer with dementia [2]. Globally, roughly 50 million individuals have dementia, with this figure expected to rise to 152 million by 2050 [1]. In the absence of effective pharmacological treatments for dementia, the identification and detailed investigation of potentially modifiable protective factors have gained considerable attention in recent years.

Glucosamine is a widely used non-vitamin, non-mineral supplement for relieving both osteoarthritis and joint discomfort [3]. It is an approved osteoarthritis prescription medication in most European nations and is widely used as a nutritional supplement in countries like the USA and Australia, where roughly 20% of adults use it daily [4, 5]. Despite the controversy regarding the efficacy of glucosamine supplements on osteoarthritis and joint discomfort [6, 7], glucosamine has been proved to have anti-inflammatory properties [8] and may prevent a wide range of diseases [9, 10]. In this instance, a variety of epidemiological studies have revealed that glucosamine consumption may protect against colorectal cancer [11, 12], lung cancer, [13], cardiovascular disease [14, 15], diabetes [16], and all-cause death [17]. Importantly, a cross-sectional research recorded the association between glucosamine consumption and better cognitive function [18]. However, research regarding the association between glucosamine use and dementia risk remains scant.

The importance of glucosamine in brain function has been highly supported by previous studies [19, 20]. Glucosamine mimicked the effects of a low-carbohydrate diet in a prior animal research, resulting in increased lifespan [21], and studies consistently showed that a low-carbohydrate diet protects against dementia [22, 23]. An animal study suggested that glucosamine may promote cognitive function by impacting energy metabolism [20]; other animal models have indicated the neuroprotective and anti-neuroinflammatory effects of glucosamine [24]. In addition, glucosamine participates in the O-linked N-acetylglucosaminylation of various proteins, which was verified to be related to many neurological or neurodegenerative diseases [25, 26]. Therefore, we hypothesize that regular use of glucosamine may have a causal influence on incident dementia.

Traditional observational studies include drawbacks such as residual confounding and/or reverse causation, inadequate adjustment (e.g., healthy lifestyle or other factors), and a focus on correlation rather than causation. By employing genetic variants as proxy for glucosamine use, Mendelian randomization (MR) avoids some of these limitations and provides genetic support for causal associations [27]. Thus, in addition to observational analysis, we performed MR to give additional insights for the assessment of potential causal relationships.

The mean age of the 494,814 participants was 56.5 years (SD 8.1) and the proportion of female was 54.4%. At baseline, 94,259 (19.0%) of participants reported using glucosamine. There was a higher percentage of older, female, non-smoking, and physically active glucosamine users than nonusers. In addition, glucosamine users had a lower TDI, higher prevalence of comorbidities such as cancer, hypertension, arthritis, and depression, but less cardiovascular disease, emphysema or chronic bronchitis, diabetes, high cholesterol, chronic kidney disease, and chronic liver disease. The percentage of using statin, opioids, non-aspirin NSAIDs, chondroitin, vitamins, minerals, and other dietary supplements was higher in glucosamine users than non-users (Table 1).

We found that 19.0% of participants used glucosamine; this number is close to the 22.0% of the Australians over 45 who also take glucosamine [5]. Our findings are in line with a prior cross-sectional investigation that found glucosamine intake to be related to better cognitive function [18]. Glucosamine users had a higher reasoning score and faster reaction speed than non-users [18]. Furthermore, in a mouse model, glucosamine exerted a cognition-enhancing function [20], which implicated the beneficial impact of glucosamine use on dementia prevention.

Because glucosamine and chondroitin supplements are typically used simultaneously once daily [6], our observed relationships might be attributed to either of these supplements. To address this concern, a sensitivity analysis was conducted to test whether glucosamine alone (without chondroitin) could prevent dementia. No substantial change occurred in the sensitivity analyses. Thus, we speculate that glucosamine use might have a preventive role in the development of dementia, independent of chondroitin co-administration.

In our study, a stronger effect was found between glucosamine use and AD among participants aged below 60 years compared with those above 60 years. The weaker effect of glucosamine use in older participants may be related to the gradual atrophy of the hippocampus and the reduction of cortical density as the age increases, resulting in the reduction of brain cell membrane receptors and the decreased sensitivity to drugs [67]. This result underscores the age-modified connection between glucosamine use and dementia and emphasizes the importance of early prevention of dementia.

The protective association between glucosamine use and dementia may be explained by a few different processes. As a popular supplement that can pass through the blood–brain barrier, glucosamine may get to the hippocampus, striatum, and cortex [68, 69]. Meanwhile, several glucosamine transporters were identified in the brain [70]. For instance, glucose transporter 2 (GLUT2) was found in neurons and exhibited the greatest affinity for glucosamine [71, 72]. Intriguing evidence indicates that specific neuronal populations rely on GLUT2 to regulate glucose levels, thereby affecting their vulnerability to pathogenic mechanisms underlying AD [73, 74]. These studies highly support the important role of glucosamine on dementia. C-reactive protein, an indicator of systemic inflammation, was significantly lower in those who regularly took glucosamine, according to data from the National Health and Nutrition Examination Survey (NHANES) [8]. Animal studies also showed that glucosamine might suppress neuroinflammation [75], which is proved to increase the risk of dementia [76]. Furthermore, a prior research discovered that glucosamine might simulate a low-carbohydrate diet in mice through lowering glycolysis and enhancing amino acid catabolism [77]: consequently, glucosamine has been considered a mimicking agent for energy restriction [21]. Recent works demonstrated that a low-carbohydrate diet protects against the development of dementia [78, 79]. In addition, glucosamine could reverse the imbalanced gut microbiota [80]. Through the gut–brain axis, the gut microbiota modulates the brain functioning of the host and plays a significant role in dementia pathogenesis [81, 82]. Thus, glucosamine might have a beneficial effect on dementia pathology by regulating the gut microbiota. Other pathways may possibly be relevant and warrants further studies to explore the functional roles of glucosamine in dementia.

Our research had a number of advantages, such as a large number of participants and abundant data on dietary, health-related behaviors, and various factors that enabled us to examine the robustness of the findings and explore the effects of exposure in several subgroups. Furthermore, the MR analysis offered a superior method of obtaining somewhat less confounded estimates of causal associations that were not impacted by reverse causation or confounding. We admit that our research has limitations. Firstly, the “regular glucosamine use” was defined as self-reported at the baseline only, which might have changed in the follow-up period. Details on glucosamine use, such as dose and use duration, were not collected in the UK Biobank, which may weaken the study findings. Hence, further research that incorporates the glucosamine intake pattern and cross-validates the data on glucosamine for accuracy is required to delve into these connections. Secondly, UK Biobank did not record the adverse side effects participants suffered after using glucosamine. Nonetheless, glucosamine has been proved to be a safe supplementation for individuals with osteoarthritis due to its low risk of side effects including rare allergic reactions and gastrointestinal reactions [3]. Although people at high risk of diabetes showed reduced glucose tolerance after taking glucosamine [83, 84], studies have proved that in healthy people and diabetic patients, any oral dose of glucosamine will not affect the glucose metabolism and lipid status [85, 86]. Thirdly, in general, 20–100 imputed datasets are recommended, while in this study 5 datasets were imputed. Due to rather low proportions of missing data, we consider five imputed datasets to operate well. Fourthly, despite the SNPs we used were significantly correlated with the exposure, the genetic variants reflected only a modest portion of the overall variance in glucosamine intake, limiting them from being precise proxies of exposure. Given that we do not yet know how the genetic instruments work biologically, we cannot totally eliminate out breaches of the independence and exclusion restriction assumptions, especially with regard to pleiotropy [63]. Nevertheless, to infer reliable causal estimates, we used a variety of techniques, including Cochran's Q statistic, MR-PRESSO, weighted median, and MR-Egger. Fifthly, the interpretation of genetic liability of supplement use should be cautious as genetic predictors of glucosamine may capture participants with worse joint health [87]. We further adjusted osteoarthritis in the multivariable MR analysis to reduce bias. Sixthly, MR is a useful option for validating results; nevertheless, genetic variants reflect lifetime exposures rather than brief treatment modalities, which may create a bigger impact than a time-limited intervention [88]. Therefore, our findings should be taken cautiously, since they are hypothesis generating and warrant more clinical data to further investigate the connection between glucosamine intake and dementia. Seventhly, although the current definition for dementia was widely used in previous studies and the true positive rate for all-cause dementia collected in the UK Biobank was as high as 82.5% [89]; the true positive rates of Alzheimer’s disease and vascular dementia were lower than 75%. Thus, the results on the subtypes of dementia should be taken cautiously.

Regular glucosamine use was associated with a lower risk of all-cause dementia, AD, and vascular dementia, based on data from the UK Biobank cohort and a mendelian randomization study. The potential implications of our findings for dementia prevention need additional confirmation in well-powered randomized controlled trials. We also recommend additional basic scientific research to investigate the underlying mechanisms.