Uric Acid and the Risk of Alzheimer’s Disease

Abstract

Alzheimer’s disease (AD) is a very common neurodegenerative disorder of the central nervous system, characterized by dementia, cognitive impairment, and memory loss, and the global prevalence is increasing. Many epidemiologic studies have considered the association between uric acid and AD, yet the relationship remains elusive. The objective of this study was to validate whether or not uric acid is indeed associated with AD. We compared different prospective studies and ultimately found that it is also a controversial issue. Further higher quality prospective evidence on the relationship between uric acid and AD in different age stage are needed to determine the causal association and its exact pathogenetic mechanisms.

Alzheimer’s disease (AD) is the most common neurodegenerative disorder of the central nervous system, characterized by dementia, cognitive impairment, and memory loss with senile plaques and neurofibrillary tangles. ¹ The global prevalence of AD is estimated to amount to 26.6 million and will increase to 106.2 million by the year 2050, and at that time, 1 in 85 persons worldwide will be living with the disease which places a considerable burden on the society. ² Many studies show that acetylcholine esterase inhibitors, the N-Methyl-d-aspartate-type glutamate receptor antagonist, are widely used for the treatment of AD, but these drugs cannot have a significant effect and could not stop the deterioration of AD. ³ Therefore, disease-modifying drugs or preventive therapy to improve the prognosis of patients with AD is needed.

To our knowledge, the pathogenesis of AD has not been completely elucidated, although a large number of hypotheses that have been put forward tend to excitotoxicity, inflammation, oxidative stress, and so on. But more and more evidence has provided strong support of the amyloid β-induced oxidative stress hypothesis of AD pathogenesis and indicated that oxidative stress plays an important role in the pathogenesis of AD. ^4,5 Due to high brain oxygen consumption, abundant polyunsaturated fatty acid content and the relative paucity of antioxidant enzymes of the central nervous system make it particularly vulnerable to damage by free radicals.

Uric acid (UA) is a kind of endogenous, water-soluble antioxidant and a by-product of purine metabolism as well as a major natural antioxidant in plasma that reduces oxidative stress and protects against free radicals. Many studies showed that UA is associated with an increased risk of myocardial infarction, stroke, and cardiovascular mortality. ^6,7 There is a well-recognized epidemiological link between higher levels of UA and the increased risk of AD. ^{8 -10} However, many studies have reported serum UA levels were significantly higher in patients with AD compared to controls, ^{11 -13} since UA may play an antioxidant role and may have a protective role against AD. But the evidence for this is limited. Although a number of clinical studies have assessed the association between UA and AD outcome, the association between UA and AD is debated.

Recently, a meta-analysis of 11 studies including 2708 participants conducted by Chen et al suggested that serum UA levels do not differ significantly in patients with AD, ¹⁴ which was the same as the conclusions of some large studies, ^15,16 but many studies also indicated that serum UA levels are significantly lower in patients with AD in comparison to control participants, supporting the purported potential neuroprotective role of UA. ^17,18 This recent controversial report challenges whether or not UA is indeed associated with AD. Therefore, it is imperative for us to explore the attendant concerns. (1) Uric acid has a substantially increased risk of AD symptoms and it can be observed in future research whether lowering of UA could slow the deterioration of AD. (2) Plasma of other possible factors, such as different diet, nutrition profile, systemic diseases, and drug-taking history, had an impact on deterioration of the AD. (3) Estrogen has an impact on UA in men and women, and whether the change in serum UA levels in patients with AD is affected by gender difference still needs to be confirmed by further studies.

In summary, future research should be well designed to investigate the association between UA and patients with AD. First of all, more experimental studies that assess UA in animal models of AD should preferably be conducted to validate their relationship by different laboratories and individuals. Second, many factors that could influence the experimental results should be analyzed and then extending the duration of follow-up. Furthermore, the assessment of different dose of UA during follow-up should be considered. Further higher quality prospective evidence on the relationship between UA and AD in different age stage are needed to determine the causal association and its exact pathogenetic mechanisms.