Gout or Hyperuricemia and Dementia Risk: A Meta-Analysis of Observational Studies

Abstract

Background:

As a natural antioxidant, uric acid has neuroprotective effects. The association between uric acid levels and dementia risk was reported by previous studies. However, recently published studies showed that the relationship between uric acid and dementia risk might be heterogeneous in dementia subtypes.

Objective:

This study aimed to clarify the relationship between hyperuricemia (or gout) and dementia.

Methods:

The PubMed and Web of Science databases were systematically searched up to April 2024 to identify relevant studies. A meta-analysis was conducted using hazard ratios (HR) or odds ratios (OR) and 95% confidence interval (CI) as pooled indicators. Heterogeneity between the studies was examined using Cochran’s Q statistic and I² statistic. Subgroup analyses were conducted for gender and age. Stratification analysis, sensitivity analyses and meta-regression were conducted to explore possible explanations for heterogeneity. Publication bias was assessed by funnel plot and Egger’s test.

Results:

A total of 11 studies met the inclusion criteria including 2,928,152 participants were abstracted. Hyperuricemia (or gout) did not reduce the overall risk of dementia (OR/HR = 0.92, 95% CI: 0.81–1.05) and vascular dementia (OR/HR = 0.74, 95% CI: 0.53–1.05), but may have a protective effect against Alzheimer’s disease (OR/HR = 0.82, 95% CI: 0.70–0.96). Subgroup analysis showed that a lower risk of dementia was observed in men (OR/HR = 0.83, 95% CI: 0.77–0.90) and patients whose age under 65 (OR/HR = 0.83, 95% CI: 0.72–0.95).

Conclusions:

Patients with gout or hyperuricemia have a low risk of Alzheimer’s disease.

Keywords

Alzheimer’s disease dementia gout hyperuricemia meta-analysis uric acid

INTRODUCTION

The global prevalence of dementia is estimated to be as high as 24 million and is predicted to double every 20 years by 2040, 1 imposing a significant global socioeconomic impact. 2 Dementia syndrome includes different etiologies, the most common cause of dementia is Alzheimer’s disease (AD), followed by dementia with Lewy bodies (DLB), vascular dementia (VaD), and frontotemporal dementia (FTD). 3 DLB and Parkinson’s disease dementia (PDD) are currently considered subtypes of Lewy body diseases (LBD). 4 Oxidative stress and neuroinflammation are believed to play an important role in the pathogenesis of dementia. Relevant research reported a positive correlation between oxidative stress and impaired cognitive function5,6, 5,6 and reported cellular oxidation is the main molecular cause of neurodegenerative diseases.

Uric acid (UA) has been shown as a strong antioxidant,7,8, 7,8 accounting for up to 60% of the free radical scavenging capacity in plasma, 9 capable of scavenging reactive oxygen species, 10 increasing antioxidant enzyme activity, 11 and reducing oxidative stress. 12 Besides, since uric acid exerts a neuroprotective effect by stabilizing calcium homeostasis and protecting mitochondrial function, 13 many scholars believe that UA may provide neuroprotection in AD 14 and reduce the risk of dementia.

Scheepers et al. 15 and Euser et al. 16 included people with normal uric acid levels in their studies, and both studies supported a lower risk of AD in individuals with higher serum uric acid levels (HR = 0.78, 95% CI = 0.66–0.91, HR = 0.89, 95% CI = 0.80–0.99). However, after including people with normal uric acid levels, high circulating levels of UA are positively associated with dementia risk. 17 Previous studies have assessed blood uric acid levels only at baseline and may not be representative of the patient’s long-term blood uric acid levels during the follow-up period. This review aimed to re-evaluate the risk of dementia in participants with and without gout and to explore the possible effects of uric acid on dementia, given that hyperuricemia is the most important risk factor for gout attacks.14,18, 14,18

MATERIALS AND METHODS

Search strategy

A systematic search of relevant publications up to April 2024 was conducted using PubMed and Web of Science databases with no restriction on the year of study. The search strings contain terms given below:(“dementia*” OR “Alzheimer’s Disease” OR “Alzheimer*” OR “AD” OR “frontotemporal dementia” OR “Dementia with Lewy bodies” OR “Lewy body dementia” OR “Parkinson’s disease dementia” OR “Vascular Dementia”) AND (“hyperuricemia” OR “gout” OR “uric acid” OR “urate” OR “UA”). Details can be found in supplementary materials (Supplementary Table 1). The search extended to all fields of text, searches were limited to the English language only. Ethical approval from an institutional review board was not necessary in this study. PROSPERO ID: CRD42023423359.

Inclusion and exclusion criteria

Two reviewers screened all candidate records based on the following criteria. The inclusion criteria are as follows: 1) Subjects: patients diagnosed with gout; 2) Outcome measures: odds ratio (OR) or hazard ratio (HR) and 95% confidence interval (CI) of the incidence of all-cause dementia (ACD), AD, VaD, FTD, DLB, and PDD; 3) Observational studies, such as cohort studies or case-control studies. The exclusion criteria are as follows: 1) Full text or complete data of odds ratio (OR) or hazard ratio (HR) and 95% confidence interval (CI) cannot be obtained; 2) case reports, non-clinical studies, review articles, editorials, reviews, and hypothesis papers and meta-analysis; 3) studies without clear diagnostic definition of hyperuricemia, gout, or dementia; 4) duplication of literature. Any discordance was resolved by discussion or determined by a third investigator.

Data extraction and quality

Two authors assessed the eligibility of all retrieved studies and extracted relevant data independently. Any differences were resolved through discussion with the third researcher. Extraction included first author, year, country(region), study design, sample size, follow-up information, mean age, gender distribution, diagnostic criteria for gout, hyperuricemia, and dementia, hazard ratio (HRs) or odds ratios (ORs) and their 95% confidence intervals, exclusion of prevalent dementia, statistical analysis models, information related to methodological quality assessment. Newcastle-Ottawa Scale (NOS) was used to evaluate the quality of the included studies. NOS consisted of three parts: selection comparability, and outcome evaluation. NOS scores range from 0 to 9 points, with scores ≥6 points defined as high quality.

Statistical analysis

The hazard ratio (HR) and odds ratio (OR) were used as statistical indicators to combine the data and estimate the risk of dementia in simple gout cases and mixed cases (gout or hyperuricemia). Results are reported as forest plots with effect sizes of 95% CIs. Cochran’s Q test and I² test were performed to appraise the heterogeneity of HR and OR between the included studies. p < 0.10 or I² > 50% was assumed significant heterogeneity. A random-effects model was adopted when significant heterogeneity was present. Otherwise, a fixed-effects model was used. Subgroup analysis and meta-regression analysis were used to investigate the sources of heterogeneity, and sensitivity analysis was used to evaluate the stability of the results. Funnel plot and Egger’s test were used to assess potential publication bias. In all analyses, a two-sided p < 0.05 was considered statistically significant. All statistical analyses were conducted using Stata 15.

RESULTS

Basic features and quality evaluation

A total of 2,747 relevant literature were retrieved through systematic searches of PubMed and Web of Science databases, 1,839 duplicate literatures were removed, 826 were excluded by reading the title, 41 were excluded by reading the abstract, and 30 were excluded through full-text review (Fig. 1). Finally, 11 observational studies (cohort studies, case-control studies) published between 2013 and 2023 were included, involving a total of 2,928,152 participants, including 2 case-control studies, 2 nested case-control studies and 7 cohort studies (Table 1). A meeting abstract 19 was not given a NOS score due to incomplete research methods. The other included studies were all medium-high quality: 1 study scored 7, 1 study scored 8, and 8 studies scored 9 (Table 1).

Fig. 1

Selection process of article.

Table 1

Characteristics of the included studies

No.	Study	Years	Region	Study design	Baseline	Sample size	Follow-up (y) (Exposure/Control)	Age (y)	Sex (male)	Diagnosis code of gout/hyperuricemia	Diagnosis of gout/hyperuricemia (whether use urate-lowering therapy)	Diagnosis of dementia
1	Lai SW 20	2013	Taiwan	case-control	2000–2010	4945	NA	≥65	46%	1	NO	1
2	Hong JY 22	2015	Taiwan	cohort	2002–2008	143511	4.3±2.1∖4.4±2.0	≥50	63%	1	NO	1
3	Lu N 23	2016	UK	cohort	1995–2013	298029	5.1∖5.3	≥40	71%	3	YES	3
4	Engel B 11	2018	Germany	case-control	2004	137640	at least 3	≥60	37%	2	NO	2
5	Crowley L 19	2018	UK	cohort	1998–2016	366905	median 5±6.2	62±15.2	73%	NA	NO	NA
6	Singh JA 21	2018	U.S.A.	cohort	2006–2012	1712821	6	≥65	43%	1	NO	1
7	Chuang TJ 24	2020	Taiwan	nested case-control	2000–2008	3242	7.8±2.4	≥50	60%	1	YES	1
8	Mikhailichenko N 26	2021	Taiwan	nested case-control	2000–2008	4584	7.8±2.4∖7.8±2.3	≥50	51%	1	YES	1
9	Min KH 25	2021	Korea	cohort	2002–2013	135768	11	>60	63%	2	NO	2
10	Kim JH 27	2022	Korea	cohort	2002	30312	4.38∖4.94	all	92%	2	YES	2
11	Lee EJ 10	2023	Korea	cohort	2002	90395	12	>40	80%	2	NO	2

Gout/hyperuricemia definition: 1: ICD-9, 2: ICD-10, 3: Read classification 2.0, 4: gout treatment. Dementia definition: 1: ICD-9, 2: ICD-10, 3: Read classification.

Table 1

Characteristics of the included studies (cont.)

No.	Study	Exclusion of dementia at baseline	Matching method (code)	Logistic regression model	Cox regression model	Adjustments	Outcome	Subtype of dementia	NOS
1	Lai SW 20	NA	1,2,3,8	YES	NO	men: 1,8,9,12	AD	AD	5
						women: 1,7,8,9,12
2	Hong JY 22	YES	1,2,3,8	NO	YES	1,2,8	all dementia	AD&VaD	9
3	Lu N 23	YES	1,3,7,9	NO	YES	1,2,6,7,8,9,13,15	AD	AD	9
4	Engel B 11	YES	1,2,3,4,8	YES	NO	1,2,8,9	all dementia	\	7
5	Crowley L 19	NA	1,2,4,9	NO	YES	1,2,6,7,8	all dementia	AD&VaD	9
6	Singh JA 21	NA	NA	NO	YES	8,9,10	all dementia	\	8
7	Chuang TJ 24	YES	1,2,3,10	YES	NO	8,10	all dementia	\	9
8	Mikhailichenko N 26	YES	1,2,3,10	YES	NO	8,10	all dementia	AD&VaD&other	9
9	Min KH 25	YES	1,2,8	YES	YES	1,2,5,8	all dementia	\	9
10	Kim JH 27	YES	1,2,3,9	NO	YES	1,2,5,8	all dementia	AD&VaD&mixed	9
11	Lee EJ 10	YES	1,2,5,6,8	NO	YES	1,2,3,5,6,7,8,11	AD	AD	9

Matching method: 1 = age, 2 = sex/gender, 3 = index date, 4 = follow-up time, 5 = monthly income, 6 = residential area (urban or rural), 7 = BMI, 8 = 1 : 4, 9 = 1 : 5, 10 = 1 : 1. Adjustments: 1 = Age, 2 = sex/gender, 3 = Race/Region, 4 = Educational level, 5 = Socioeconomic status/income, 6 = Smoking/Alcohol use, 7 = BMI/obesity, 8 = Comorbidity/Charlson Comorbidity index, 9 = Medication use, 10 = urate-lowering drugs, 11 = physiological and biochemical indexes, 12 = head injury, 13 = GPs (general practitioner) visits, 14 = APOE ɛ4, 15 = entry-time.

For included populations, Lai et al. 20 and Singh et al. 21 included elderly people (≥65 years old) only, and 8 studies10,11,22–27 , 10,11,22–27 included non-elderly people. Two studies11,20, 11,20 included patients with gout and hyperuricemia, and 9 studies10,19,21–27 , 10,19,21–27 included gout patients only. In terms of exposure definition, except one meeting abstract 19 does not have complete inclusion criteria and one study used read classification diagnostic code, 23 the other studies10,11,20–22,24–27 , 10,11,20–22,24–27 used ICD diagnostic code. Besides the diagnostic code, four studies23,24,26,27 , 23,24,26,27 also considered ‘receiving anti-gout/urate-lowering therapy’ as the diagnostic criterion, which might become selection bias. Eight studies10,11,22–27 , 10,11,22–27 excluded baseline dementia diagnosis, and the remaining 3 studies did not mention it.19 –21

In terms of comparability, 1 study 21 did not report a matching method, while the other 10 studies mainly used age, gender, and index date as matching criteria, with matching ratios of 1 : 1,24,26, 24,26 1 : 4,10,11,20,22,25 , 10,11,20,22,25 or 1 : 5.19,23,27 , 19,23,27 Studies mainly adjusted for age, metabolic diseases comorbidities, and medication use (Table 1).

For outcome, the main outcome of 8 studies was ACD,11,19,21,22,24–27 , 11,19,21,22,24–27 7 studies assessed AD,10,19,20,22,23,26,27 , 10,19,20,22,23,26,27 and 4 studies assessed VaD.19,22,26,27 , 19,22,26,27 Our search keywords include FTD, DLB, and PDD, but no study independently analyzing the relationship between gout (or hyperuricemia) and the risk of FTD, DLB, or PDD was found. Some included studies11,25, 11,25 classified LBD or PDD as all-cause dementia.

Gout (or hyperuricemia) and dementia risk

11 studies were included, and analysis of the main outcomes found that gout (or hyperuricemia) had no meaningful effects on the risk of overall dementia (OR/HR = 0.92, 95% CI: 0.81–1.05, I² = 97.1%, p < 0.001) (Fig. 2). Considering the high heterogeneity between studies (I² = 97.1%, p < 0.001), potential sources of heterogeneity needed to be explored.

Fig. 2

Forest plot for the association between gout (or hyperuricemia) and overall dementia risk.

Sources of heterogeneity and sensitivity analysis

The stratified analysis explores the heterogeneous sources of overall dementia risk. By gender ratio stratification, when the male proportion ≥50%, the overall risk of dementia was reduced (OR/HR = 0.87, 95% CI: 0.78–0.98), while when the male proportion <50%, the overall risk of dementia was increased (OR/HR = 1.05, 95% CI: 0.89–1.23). By age stratification, the overall risk of dementia increased in the population aged ≥65 (OR/HR = 1.15, 95% CI: 1.08–1.23), but a decrease in the studies which including those under 65 (OR/HR = 0.88, 95% CI: 0.79–0.98). Stratification based on treatment, it was found that receiving uric acid lowering drug treatment did not reverse the research results (all patients used drugs versus not all patients used drugs: OR/HR = 0.91, 95% CI: 0.75–1.09 versus OR/HR = 0.92, 95% CI: 0.82–1.03) (Supplementary Table 2).

Meta regression analysis was conducted on factors such as publication year, research type, and use of uric acid lowering drugs, and the results were not statistically significant (Supplementary Table 3). Based on stratified analysis, we believe that age and gender ratio are the potential sources of heterogeneity. To further verify the robustness of the results, sensitivity analysis was conducted by excluding references one by one, indicating that the results are robust (Supplementary Figure 1).

Subgroup analysis

The included studies mainly reported subgroup results of AD and VaD but did not report other common types of dementia results (DLB, PDD, etc.). Considering that gender ratio and age are potential sources of heterogeneity, further extracted data for subgroup analysis.

Subgroup analysis based on dementia subtypes showed that gout (or hyperuricemia) was not associated with VaD risk (OR/HR = 0.74, 95% CI: 0.53–1.05) (Fig. 3), but a lower risk of AD (OR/HR = 0.82, 95% CI: 0.70–0.96) (Fig. 4).

Fig. 3

Forest plot for the association between gout (or hyperuricemia) and VaD risk.

Fig. 4

Forest plot for the association between gout (or hyperuricemia) and AD risk.

Compared to females, male patients have a lower overall risk of dementia (OR/HR = 0.89, 95% CI: 0.79–1.01 versus OR/HR = 0.83, 95% CI: 0.77–0.90). Additionally, analyses stratified by age indicated that gout (or hyperuricemia) was not associated with dementia risk in people aged ≥65 years (OR/HR = 0.84, 95% CI:0.68–1.04), but in studies including people younger than 65 years old a reduced risk of dementia was observed (OR/HR = 0.83, 95% CI: 0.72–0.95) (Table 2).

Table 2

Subgroup analysis

Subgroup	No	HR (95% CI)	p	I²	p
Outcome
AD	7	0.82 (0.70–0.96)	0.012	91.00%	0
VaD	4	0.76 (0.53–1.05)	0.092	96.30%	0
Age
≥65	4	0.85 (0.68–1.04)	0.119	82.50%	0
covers younger age	6	0.83 (0.72–0.95)	0.008	92.90%	0
Sex
male	5	0.83 (0.77–0.90)	0	35.70%	0.105
female	5	0.89 (0.79–1.01)	0.076	58.20%	0.008

Publication bias

On visual inspection, the funnel plot seemed to be asymmetrical (Supplementary Figure 2). Further corrected the result by trim-and-fill method, after adding 2 virtual literature, the combined effect indicators obtained did not reverse (OR/HR = 0.90, 95% CI: 0.79–1.19) (Supplementary Figure 3). Egger’s test (p = 0.599 > 0.05) also did not reveal potential publication bias, indicating the robustness of the results.

DISCUSSION

This meta-analysis, based on 11 observational studies involving 2,928,152 participants, comprehensively assesses the risk association of gout or hyperuricemia with overall dementia and dementia subtypes. The results showed that gout and hyperuricemia do not increase the risk of overall dementia, but may have a protective effect on AD, which is consistent with the results of studies by Pan et al., Khan et al., and Zhou et al.28 –30

A possible explanation for the contradictory research results is that uric acid plays dual roles of antioxidant and pro-oxidation in the human body 31 and has different molecular behaviors under different pathological conditions: 14 uric acid only exhibits antioxidant effects in the hydrophilic environment. 32 After chemical microenvironment changes, uric acid may have a pro-oxidative effect.8,33, 8,33 Moreover, uric acid reacts with oxidants to exert antioxidant effects, producing free radicals 34 that act as pro-inflammatory factors that further lead to oxidative stress. 32

As the main types of dementia, the main pathological mechanisms of AD and VaD are related to oxidative stress and neuroinflammation. However, Aβ aggregation in AD long-term stimulates glial cells to release cytokines, accelerating the pathological cascade of AD; 35 the main cause of VaD is chronic cerebral hypoperfusion, 36 obstruction or reduction of cerebral blood flow leads to neuronal nutrient deficiency and death, 37 and the pathological mechanism is related to neuronal apoptosis. 36 Uric acid may promote the progression of AD and VaD by activating inflammation-related mechanisms 17 and increasing oxidative stress. At the same time, uric acid can also enhance the adverse effects of Aβ on neuronal cells, 38 lead to endothelial dysfunction, 39 and play a role in the progression of AD 40 and VaD respectively.

Hyperuricemia is closely related to inflammation and can induce inflammation or activate auto-inflammation, 14 increase the reactivity of monocytes to pro-inflammatory stimuli, 41 and is the main risk factor for gout attacks.14,18, 14,18 In the case of hyperuricemia, urate can initiate the development of gout and maintain chronic inflammation.14,42, 14,42. During neurological diseases, the blood-brain barrier structure is loose, and peripheral immune cells can be recruited into the brain parenchyma to promote neuroinflammation and induce neurodegeneration. 7 Therefore, taking into account the physiological characteristics of uric acid, the specific impact of uric acid on the pathological processes of AD and VaD, and the possible negative impact of long-term hyperuricemia on chronic neuroinflammation, one possible explanation is that the antioxidant effect of uric acid offsets the chronic inflammatory harm of uric acid in patients, and the result is that it does not increase the overall risk of dementia and VaD.

In subgroup analysis, male patients with gout (or hyperuricemia) have a lower risk of overall dementia (OR/HR = 0.83, 95% CI: 0.77–0.90 versus OR/HR = 0.89, 95% CI: 0.79–1.01). There are 3 possible reasons: 1) Estrogen promotes uric acid excretion and reduces blood uric acid concentration.43,44, 43,44 The overall estrogen level of women is relatively high, and the protective effect of uric acid on dementia may not be significant due to its fast metabolism; 2) AD is the most common subtype of dementia (accounting for 60–80% of all cases), 45 and due to factors such as gender differences and socio-cultural influences, the incidence of AD in women is higher than that in men; 46 3) Under the same APOE genotype, female AD has a higher incidence rate, more obvious symptoms, faster deterioration, higher diagnosis rate of AD, and the protective effect of uric acid not significant. The combination of multiple factors promotes the more significant protective effect of uric acid on dementia in males. However, as age increases, the risk of gout (or hyperuricemia) increases, and postmenopausal estrogen levels decrease, which may lead to a similar risk of gout in elderly men and women, 47 indicating that the influence of age is stronger than that of gender.

Age is an important factor affecting the incidence of dementia, 1 and the incidence of AD increases from about 0.5% per year for people aged 65–70 years to about 6–8% per year for people over 85 years old. 48 There is no association with the risk of dementia in people aged ≥65 years but in studies including people aged <65 years, the risk of dementia is significantly reduced. The possible reason is that young people have a lower risk of AD compared to elderly people, and the protective factor of age is mistakenly attributed to the protective effect of uric acid. In studies of people aged ≥65, the confounding effect of age decreases, while the impact of comorbidity increases, directly or indirectly leading to an increased risk of dementia.

There is a certain difference between the results of stratified analysis of the main outcome and age subgroup analysis: in stratified analysis, gout (or hyperuricemia) increases the overall dementia risk in people aged ≥65 (OR/HR = 1.15, 95% CI: 1.08–1.23), while in subgroup analysis, gout is no association with dementia risk in people aged ≥65 (OR/HR = 0.85, 95% CI: 0.68–1.04). Differences may come from gender ratios: reviewing the characteristics of the included studies, 2 articles were included in the age-stratified analysis of main outcomes with the male ratio <50% (46% 20 and 43%, 21 respectively), while the age subgroup included two more studies with the male ratio of 71% 23 and 92%, 27 respectively. Based on the previous discussion on the results of gender subgroup analysis, we believe that gender has an impact on the results when included in the same age group. When the proportion of males in the population is low, gout (or hyperuricemia) tends to show an increased risk of dementia. As the proportion of males increases tends to show no association between gout (or hyperuricemia) and dementia.

In addition, 8 studies reported the risk of AD,10,19,20,22,23,26,27 , 10,19,20,22,23,26,27 5 included younger populations (<65 years),10,22,23,26,27 , 10,22,23,26,27 6 accounted for more than half of the male population,10,19,22,23,26,27 , 10,19,22,23,26,27 and 4 received urate-lowering therapy.20,22,23,26 , 20,22,23,26 Therefore, the protective effect of gout (or hyperuricemia) in AD should be accepted carefully.

Reviewing the 11 studies included, only 1 reported negative results, 20 indicating a small possibility of publication bias. By using funnel plots, trim-and-fill method, and Egger tests, it has been proven that there is no publication bias, reflecting the credibility of the results of this study.

Limitations

There were some limitations in this study: firstly, through subgroup analysis and meta-regression, it is speculated that gender and age are possible sources of high heterogeneity (I² = 97.1%, p = 0.000). Secondly, we introduced a language bias because our study was limited to studies published in English.

Conclusion

Patients with gout or hyperuricemia have a low risk of AD.

AUTHOR CONTRIBUTIONS

Yirou Yao (Conceptualization; Data curation; Formal analysis; Investigation; Methodology; Writing – original draft); Shun Zhu (Conceptualization; Data curation; Investigation; Writing – original draft); Jingnian Ni (Project administration; Writing – original draft); Mingqing Wei (Funding acquisition; Project administration; Supervision; Writing – review & editing); Ting Li (Project administration; Supervision; Writing – review & editing); Siwei Long (Methodology; Writing – original draft); Jing Shi (Funding acquisition; Project administration; Supervision; Writing – review & editing); Jinzhou Tian (Funding acquisition; Project administration; Supervision; Writing – review & editing).

Footnotes

ACKNOWLEDGMENTS

The authors have no acknowledgments to report.

FUNDING

This work was supported by the National key research and development program (2023YFC3504304) and the Beijing University of Chinese Medicine “decoding Chinese Medicine” collaborative research project (BZY-JMZY-2022-002).

CONFLICT OF INTEREST

The authors have no conflict of interest to report.

DATA AVAILABILITY

The data supporting the findings of this study are available within the article.

The supplementary material is available in the electronic version of this article: .

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