Gout/hyperuricemia reduces the risk of Alzheimer's disease: A meta‐analysis based on latest evidence

Abstract Objective Previous studies have found the potential role of gout or hyperuricemia in subsequent development of Alzheimer's disease (AD) but reported inconsistent results. We conducted the current meta‐analysis to evaluate whether an association exists between gout/ hyperuricemia and AD. Methods We systematically searched PubMed and EMBASE for the published cohort studies that measured the risk of AD in subject with gout/ hyperuricemia up to May 20, 2023. Data extraction was employed by two authors independently. Rev Man 5.3 and Stata 15.0 software were used to calculate the relative ratio (RR) or hazard ratio (HR) for including studies. Subgroup analysis was performed to assess the sources of heterogeneity. A random‐effects model was adopted when heterogeneity was present. The funnel plot, Begg's test, and and Egger's test were used to assess publication bias. Results After rigorous screening, seven eligible studies were included in the final analyses. Pooled results indicated that gout or hyperuricemia decreases the risk of AD (RR: 0.69, 95% CI: 0.64∼0.72), with a high heterogeneity of 93%. Subgroup analyses showed that regional distribution was the source of heterogeneity. Egger's and Begg's tests as well as visual inspection of funnel plot suggested no publication bias in the studies. Conclusion The findings suggested that gout or hyperuricemia might have a protective effect against AD. This negative correlation should be verified by more cohort studies due to the existence of substantial heterogeneity.

Gout is a systemic inflammatory disorder characterized by the formation of hyperuricemia and the deposition of monosodium urate (MSU) crystals in the synovial fluid of articular and peri-articular tissues, resulting in gouty arthropathy, tophi formation and organ damage (Lee, 2019).Gout is now considered a typical inflammatory disease driven by activation of the body's innate immune system, also known as an "autoinflammatory disease" (Zhao et al., 2022).In addition, immune system dysfunction plays a key role in the pathogenesis of neurodegenerative diseases (DeMaio et al., 2022).Previous studies have shown that elevated levels of uric acid linked to a reduced risk of neurodegenerative diseases such as multiple sclerosis (Rentzos et al., 2006), Parkinson's disease (Seifar et al., 2022) and AD (Du et al., 2016).Some cohort studies have suggested that hyperuricemia is associated with better cognitive function (Chen et al., 2021;Tan et al., 2023).Yet, by contrary, several epidemiological studies have shown that elevated serum uric acid was associated with cognitive impairment (Alam et al., 2020;Huang et al., 2022), especially AD (Johnson et al., 2023).Therefore, it is unclear whether gout or hyperuricemia is prone to AD or prevent against AD.
Because of the inconsistencies among studies, we conducted an upto-date cohort based meta-analysis to quantify the correlation of gout or hyperuricemia with AD.

METHODS
These systematic review and meta-analysis were conducted in accordance with the preferred reporting items for systematic reviews and meta-analysis (PRISMA) guidelines (Moher et al., 2009).

Search strategy
Two investigators (LW and Zheng Tan) independently searched the PubMed and EMBASE for papers published from their inceptions to May 20, 2023.Medical Subject Headings (MESH) terms set in the search were ("gout" OR "arthrolithiasis" OR "podagra" OR "dominus merborum" OR "hyperuricaemia") AND ("Dementia" OR "Alzheimer's disease" OR "Mixed Dementia" OR "Cognitive decline" OR "Cognitive impairment") NOT ("case report" OR "review" OR "meta-analysis").

Study selection
Articles were included if they fulfilled the following inclusion crite-

Data extraction and quality assessment
The following data were extracted independently by two authors (ZT and F-YW): first author, publication year, geographic location (country), study design, sample size, male ratio, mean or range of age among patients, diagnostic criteria of gout/ hyperuricemia and dementia, duration of follow-up, outcome, adjustment, and study quality .The Newcastle-Ottawa Scale (NOS) (Stang, 2010) was applied to assess the quality of the studies.Differences in the extracted data were rechecked after consultation with a third author (W-PW) until consensus was achieved.The scale score ranged from 0 to 9 for case-control or cohort studies.Studies with scores of <3, 4-6, and ≥7 points were considered to have a low, medium, and high quality, respectively.

Data synthesis and analysis
Data analysis was conducted using RevMan 5.3 and Stata 15.0 Software.We extracted the HR or RR with 95% confidence intervals (CI) from each study to evaluate the relationship between LOE and risk of dementia.Heterogeneity of HR or RR across articles was assessed using the Cochrane's Q and I 2 statistic; I 2 <50%, 50%∼75%, and > 75% indicated low, medium, and high homogeneity, respectively (Higgins et al., 2003).Subgroup was conducted to evaluate the possible sources of the heterogeneity.Egger's and Begg's tests were performed to assess publication bias.A two-tailed p value < .05indicated statistically significant.

Identification of studies
As shown in Figure 1, we retrieved a total of 576 articles from our database search.Out of those, after removing duplicates, 474 articles Forest plot presenting effect estimates for the risk of AD in patients with gout or hyperuricemia.
remained and then for further filtering by their titles and abstracts.

Study characteristics
The details of the included studies were shown in Table 1.Of these studies, four were conducted in Europe, while the other three in Asia.
Three studies had sample sizes over 100,000, and the other four had sample size less than 50,000.Furthermore, follow-up lasted longer than 10 years in four studies, whereas less than 10 years in other three.
All studies were of high quality (NOS score ≥7).

The effect of gout or hyperuricemia on AD
Pooled results showed that individuals presenting with gout or hyperuricemia had a high probability of reducing AD (RR = 0.69, 95%CI: 0.66∼0.72; Figure 2).There was a moderate risk of heterogeneity among the studies (I 2 = 93%, p < .001).

Subgroup analysis
In the subgroup analysis for the RR of AD with gout or hyperuricemia patients, including study design, sample size, location, and adjustment for confounding factors indicated consistent results (p for subgroup differences all > .05).Neither subgroup analysis by study design nor sample size could explain the origin of the higher heterogeneity.However, when using regional distribution as subgroup, the Asia studies showed lower heterogeneity (I 2 = 28%, Table 2).This indicated that regional distribution was the source of heterogeneity.

Publication bias
On visual inspection, the funnel plot seemed to be asymmetrical (Figure 3).However, both the Begg's test (t = −1.50,p = .133)and

DISCUSSION
In the current meta-analysis, we comprehensively evaluated the association between gout/hyperuricemia and AD based on evidence from high-quality cohort studies.Interestingly, the results showed a 31% AD risk reduction for gout or hyperuricemia.This indicated that gout or hyperuricemia might be a protective factor approach to prevent AD formation.Additionally, these relationships remained consistent across subgroup and sensitivity analyses.
Although a previous meta-analysis investigated the association between gout/hyperuricemia and dementia, the results suggested no statistically significant risk of all-cause dementia in patients with gout or hyperuricemia (Pan et al., 2021).In other words, it did not imply that gout or hyperuricemia was free of risk for all types of dementia.The recognized evidence is that gout or hyperuricemia is a risk factor for stroke and closely related to the occurrence of vascular dementia (Cipolletta et al., 2022;Serdarevic et al., 2020).The lack of subgroup analysis due to the limited inclusion of studies may be a reasonable explanation for the negative conclusion in that metaanalysis.In addition, a recent meta-analysis by Li et al. (2023) included four primary studies, exploring the relationship between gout and the risk of AD, but omitted three other important studies that may have reduced the statistical power.By contrast, in the current analysis, we included more recent studies and analyzed data on the basis of subgroups, thus providing potential evidence for the association between gout/hyperuricemia and AD.
The role of gout or hyperuricemia in the pathogenesis of AD has often been described as controversial (Singh, 2018).As mentioned above, our study showed a negative correlation between gout/hyperuricemia and AD.However, there were some previous studies with totally different conclusion: reporting that gout or hyperuricemia had no correlation with AD or even a positive association (describing gout or hyperuricemia as a risk factor) (Lai et al., 2013;Lee, 2019;Singh & Cleveland, 2018).Evidence that links chronic inflammation to neurodegenerative processes in AD is accumulating.Persistent systemic inflammation in patients with hyperuricemia or gout can also TA B L E 1 The characteristics of the included studies.affect the inflammatory response of brain immune cells (Wang et al., 2021;Zhao et al., 2022).On the one hand, activated astrocytes play a vital neuroprotective role by inhibiting senile plaques (SPs) aggregation and Aβ-amyloid deposition (Singh, 2022); on the other hand, they also promote the release of reactive oxygen species (ROS) and inflammatory cytokines in turn (Bai et al., 2022).In addition, superoxide enzymes produced in uric acid formation also increase the oxidative stress response (Liu et al., 2021).Thus, oxidative stress may act as a bridge connecting the pathogenesis of hyperuricemia and AD, at least partially explaining the increased risk of AD in elderly gout or hyperuricemia patients.

Country
However, if we accept that gout or hyperuricemia leads to risk reduction, what is the reason or mechanism behind this reverse association?A vital mechanism may be the dual effects of uric acid on prooxidation and antioxidation (Kang & Ha, 2014;Ndrepepa, 2018), but there are few studies comparing the strength of their interactions for circulating uric acid metabolism.As antioxidants and free radical scavenger, uric acid also plays a neuroprotective role by alleviating oxidative stress damage induced by aging or inflammation (Tana et al., 2018).In addition, mitochondrial dysfunction has been confirmed as one of the pathogenesis of AD (Perez Ortiz & Swerdlow, 2019), while uric acid preserves mitochondrial function by inhibiting the cytotoxic effect of lactoperoxidase and repairing DNA damaged by oxygen radical (Johnson et al., 2023;Yu et al., 1998).
Recent clinical studies have found that younger older adults (65-79 years) may be more helpful in exposing the cognitive effects of high uric acid (Euser et al., 2009).This is consistent with our meta-analysis results, as the initial average age at which gout or hyperuricemia was diagnosed in the most of included studies ranged from 60 to 80 years old.It has been speculated that elevated uric acid in midlife may promote cognitive reserve but subsequent long-term chronic elevation could induce its prooxidant property (Alam et al., 2020).
For the subgroup analysis, the source of heterogeneity may be related to regional distribution.Therefore, more studies from different regions are needed to clarify the connection of gout or hyperuricemia with risk of AD.Some limitations should be addressed.First, as mentioned above, there are the limited studies that examine the effect of gout or hyperuricemia on AD, thereby reducing the accuracy of the pooled estimates.
Additionally, it is not possible to distinguish the different effects of gout on various types of dementia.Second, inconsistencies in the clinical diagnostic criteria for gout, hyperuricemia and AD across studies may affect the stability of outcomes.Third, previous studies have shown that the use of antigout preparations, with particular reference to benzbromarone, was negatively correlated with dementia (Taipale et al., 2018).Since statistical adjustments in numerous studies did not include drugs use, it is possible that the risk of dementia in gout or hyperuricemia patients was underestimated.Finally, although most of included studies employed maximum adjusted risk estimates for potential factors, residual confounding of unmeasured factors would persist, which is an inherent limitation of clinical research.
In summary, our meta-analysis suggested negative relationship of gout or hyperuricemia with risk of AD.This finding supports the F I G U R E 3 Funnel plot for AD in patients with gout or hyperuricemia.
protective effect of gout or hyperuricemia on cognitive function.More basic and clinical evidence from future studies needs to be clarified the cause-and-effect association between gout and AD.

G U R E 1
Flow diagram of the literature selection process.
ria: (1) prospective or retrospective cohort studies; (2) the exposed group consisted of gout or hyperuricemia patients, while controlled group consisted of AD patients; (3) report of risk estimates [hazard ratios (HR) or rate ratios (RR)] with 95% confidence intervals (CIs) as the outcome; (4) studies without restrictions by language of publication.Additionally, reviews, case-control or crosssectional studies, and publications without adequate data were excluded.FI BMI, body mass index; CAD, coronary heart disease; DSM-IV, Diagnostic and Statistical Manual of Mental Disorders, Version IV; ICD-9, International Classification of Diseases, Ninth Revision; ICD-10, International Classification of Diseases, Tenth Revision; NINCDS-ADRDA, National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association.
TA B L E 2 Subgroup analysis for the risk ratio of AD in patients with gout/hyperuricemia.