Using data collected in the context of a population-based study, we evaluated whether having higher circulating levels of UA is associated with a higher probability of being affected by dementia syndrome in older persons. Our cross-sectional analysis suggests a positive association between high circulating levels of UA and the presence of a dementia syndrome. Persons with circulating UA levels in the highest tertile showed a threefold higher probability of being affected by a dementia syndrome. The probability of having dementia remained significantly higher independent of several confounders such as age, sex, education, BMI, smoking habit, total energy and alcohol consumption, vitamin E and cholesterol plasma levels, hypertension, renal function, cardiovascular and cerebrovascular diseases. Persons with UA levels within the middle UA tertile showed a clear tendency to be affected by a dementia syndrome with about twofold higher probability.
To the best of our knowledge, this is the first population-based study conducted to investigate the relationship between circulating levels of UA and dementia considering the confounding effects of behavioral and health-related conditions. Earlier studies reported a positive correlation between UA levels and cognitive performance estimated in adult persons using the IQ. However, these studies suffered from several methodological limitations such as the small sample size, the lack of information about confounders, and the limited neuropsychological evaluation [32
In a selected small sample of older subjects admitted to outpatient clinic, Rinaldi et al. [34
] found lower plasma levels of UA and other antioxidants both in patients with mild cognitive impairment and Alzheimer's disease as compared to controls. Similarly, Nieto et al. [35
] reported lower levels of UA and albumin in patients with Alzheimer's disease admitted to an acute-care ward compared to a control group, independent of age, BMI and sex. The authors interpreted the lower levels of UA as an attempt to counteract the increased oxidative stress associated with dementia [34
]. However, no information was available in these studies concerning potential confounders, in particular the major medical illnesses causing hospital admission, the presence of drug therapy or lifestyle factors affecting circulating UA levels.
More recently, Schretlen et al. [18
] demonstrated that healthy older men and women with serum UA at the high end of the normal range perform worse in neuropsychological tests investigating several cognitive domains, i.e. processing speed, working memory and verbal memory, compared with those with low-intermediate UA concentrations.
To date, the biological mechanisms linking UA to cognitive functions are unknown. Some authors suggest that UA is a surrogate marker of metabolic and cardiovascular diseases leading to brain damage [35
]. Moreover, it is speculated that the high levels of UA associated with these conditions may potentially counteract the oxidative stress associated with cardiovascular diseases, Parkinson's and Alzheimer's diseases [36
]. The biochemical data demonstrating antioxidant properties of UA against free radicals support this hypothesis [6
In our study, high levels of UA are associated with dementia independent of underlying metabolic risk factors and cardiovascular diseases. However, the association was partially attenuated after adjustment for kidney disease and cardiovascular and cerebrovascular diseases.
The pathogenetic pathway linking UA to either dementia or conditions leading to dementia may be identified in its ability to increase inflammation, a condition well known to be involved in the pathogenesis of cognitive impairment. It has been demonstrated that soluble UA may exert a proinflammatory activity by mimicking an internal ‘danger signal’ that stimulates the maturation and the immunoactivity of dendritic cells [38
]. Previous epidemiological data from our group showed that UA is positively associated with several proinflammatory markers, such as IL-6, TNF-α, CRP and white blood cells, and predicts the development of pathological levels over a 3-year period of follow-up [9
Our hypothesis that UA may have an independent detrimental effect on cognitive functions is also consistent with previous studies showing that high circulating UA levels may be causally involved in the development and progression of endothelial dysfunction [10
], arteriolosclerosis, hypertension [11
], atherothrombosis [40
], metabolic diseases [12
], and cardiovascular and cerebrovascular diseases [41
The present study has some limitations. First, because of the cross-sectional nature of our data, a causal pathway from UA to dementia is suggested but could not be definitively proven. Indeed, a possible mechanism of reverse causality should be considered. We cannot exclude the possibility that serum UA increases in response to dementia because of accelerated cellular turnover due to the underlying pathological mechanisms. Then, we could only measure circulating UA levels whose relationship with brain tissue levels is currently unknown. However, on the other side, the available evidence suggests that serum UA levels are relatively stable over time in the same individual unless relevant changes occur in her or his health status or lifestyle [42
]. Moreover, since we did not perform a detailed neuropsychological evaluation of participants with an MMSE score >26, it is possible that the group considered as having normal cognitive functions also included participants with mild cognitive impairment.
In conclusion, our study points to a positive association between high circulating levels of UA and dementia syndome which, at least in part, is independent of most cardiovascular, cerebrovascular and metabolic risk factors. If these findings are confirmed in future studies, it would be worthwhile to perform clinical trials aimed at determining whether the pharmacological reduction in UA levels prevents the onset or delays the progression of dementia.