Association between serum urate and CSF markers of Alzheimer's disease pathology in a population‐based sample of 70‐year‐olds

Fatima, Tahzeeb; Jacobsson, Lennart; Kern, Silke; Zettergren, Anna; Blennow, Kaj; Zetterberg, Henrik; Johansson, Lena; Dehlin, Mats; Skoog, Ingmar

doi:10.1002/dad2.12241

Cited by 4 publications

(6 citation statements)

References 62 publications

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“…CNS, central nervous system a median follow-up of 5 years, hazard ratios of developing AD among patients with gout were 0.71(95% CI, 0.62-0.80), and 0.76 (95% CI, 0.66-0.87) in univariate and multivariate analyses, respectively. 15 Finally, the current study by Fatima et al 8 appears to be consistent with the prior literature. 18,19 However, the employed analysis ushers in a much-needed discussion about research design to characterize the implications of urate production in the brain compared to systemically circulating urate levels as well as the role of the blood-brain barrier in urate transport.…”

Section: F I G U R Esupporting

confidence: 90%

“…Finally, the current study by Fatima et al. 8 appears to be consistent with the prior literature. 18 , 19 However, the employed analysis ushers in a much‐needed discussion about research design to characterize the implications of urate production in the brain compared to systemically circulating urate levels as well as the role of the blood–brain barrier in urate transport.…”

supporting

confidence: 92%

“…The study by Fatima et al. 8 provides a mechanism‐based approach for the possible role of serum urate in neurodegenerative diseases, in particular, Alzheimer's Disease (AD). As the global aging population grows, the global burden of neurodegenerative diseases becomes a significant unmet public health need.…”

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confidence: 99%

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Pathway for ascertaining the role of uric acid in neurodegenerative diseases

Roman

2022

Alz & Dem Diag Ass & Dis Mo

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Uric acid is the end product of purine metabolism. Elevated serum urate level, a condition known as hyperuricemia, is a cardiovascular disease risk factor. [1][2][3] Low urate level, a condition known as hypouricemia, is a risk factor for developing neurodegenerative diseases. 4 The upper normal uric acid levels could range between 6 and 6.8 mg/dL in healthy adults with normal kidney function. Maintaining normal urate levels provides significant antioxidant and neuroprotective effects.High urate levels above saturation threshold (6.8 mg/dL) are considered a pro-inflammatory condition, leading to increased oxidative stress, increased renin-angiotensin levels, activated aldosterone system, increased systemic vascular resistance, and reduced renal blood flow, and consequently hypertension and worsening kidney function. 5 Low serum urate levels are a risk factor for developing neurodegenerative diseases (Figure 1). Although the exact mechanism that uric acid exerts as a neuroprotective biochemical is not elucidated, it is believed that uric acid levels are scavengers of free radicals, superoxide, and hydrogen peroxide. 6 Urate levels are responsible for 55% of free radicals' scavenging capacity in the human body. 6,7 Thus, low uric acid levels could augment the risk of oxidative stress, increasing the accumulation of reactive oxygen species, which may permeate the effect of tau protein on neuro entanglement, leading to a decline in cognitive function and preclinical neurodegenerative diseases.The study by Fatima et al. 8 provides a mechanism-based approach for the possible role of serum urate in neurodegenerative diseases, in particular, Alzheimer's Disease (AD). As the global aging population grows, the global burden of neurodegenerative diseases becomes a significant unmet public health need. The neuroprotective and antioxidant effects of serum urate are emerging. Therefore, elucidating the possible neuroprotective mechanism could guide a systematic evaluation of the impact of varying serum urate levels on AD. Nonetheless, this study raises more discussion and creates more questions about the double-edged sword effect of urate levels.The published study has some limitations regarding the possible role of other clinical confounders that could impact urate levels. Therefore, more discussion about these limitations could improve future study design. For example, uric acid is primarily eliminated by the kidney, and hence, adjusting for baseline kidney function (i.e., estimated glomerular filtration rate [eGFR]) could have allowed for a better signal-to-noise ratio, especially in a relatively older population. Beside kidney func-This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

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Section: F I G U R Esupporting

confidence: 90%

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confidence: 92%

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Pathway for ascertaining the role of uric acid in neurodegenerative diseases

Roman

2022

Alz & Dem Diag Ass & Dis Mo

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“…Several studies have examined the association of uric acid with AD from the neuropathological perspective, with contradictory findings. For example, a positive association between serum uric acid levels and CSF amyloid beta (Aβ) 42 was found in cognitively healthy men (β = 0.55, P = .04) [ 7 ]. Li and colleagues reported that serum uric acid levels were negatively correlated with CSF Aβ 42 levels among cognitively healthy older adults [e.i., individuals with highest uric acid (> 75% percentile) had lower CSF Aβ 42 levels relative to those with lowest uric acid (β = –5.1×10 −4 , p = 0.019)] [ 8 ].…”

Section: Introductionmentioning

confidence: 99%

Sex-dependent association of serum uric acid levels with amyloid accumulation among amyloid-positive older adults

Zhao,

Guan

2024

PLoS ONE

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We aimed to examine the potential effect of sex on the longitudinal association of baseline serum uric acid levels with brain amyloid accumulation over time among older adults with and without abnormal amyloid. At baseline, the study sample comprised 499 older adults, including 276 men and 223 women. Linear mixed-effects regression models were fitted to estimate the individual slopes of change in brain amyloid accumulation [as measured by AV45 standardized uptake value ratio (SUVR)] over time. At baseline, we did not observe a relationship between serum uric acid levels and brain amyloid deposition in women or men regardless of amyloid status. Among amyloid negative subjects, women and men did not differ in the relationship between baseline serum uric acid and the annual change in amyloid accumulation in subjects with normal amyloid levels. In amyloid positive women, serum uric acid levels were not associated with the annual change in amyloid accumulation (unstandardized β = 0.0005, SE = 0.0006, p value = 0.4179). However, in amyloid positive men, serum uric acid levels were negatively associated with the annual change in amyloid accumulation (unstandardized β = -0.0015, SE = 0.0005, p value = 0.0048). These findings support a potential sex-specific effect on the relationship between serum uric acid levels and amyloid accumulation among amyloid positive older adults.

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“…Some observational studies suggest that high UA levels may have deleterious effects on brain health, including the development of cerebral small vessel disease and cognitive decline [10,11]. However, studies have also indicated that serum UA plays a neuroprotective role in the diseases of Alzheimer's and Parkinson's and that low blood UA levels are not only associated with faster disease progression, but are also indicative of malnutrition [12][13][14][15]. Appropriate increases in UA levels within the normal range can instead delay the onset and progression of cognitive impairment [16].…”

Section: Introductionmentioning

confidence: 99%

Uric acid levels and risk of cognitive impairment: Dose-response meta-analysis of prospective cohort studies

Liu,

Peng,

Yang

et al. 2023

PLoS ONE

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Purpose Studying the effects of uric acid levels on cognitive function and quantifying the dose-response relationship. Methods Based on PubMed and Embase search terms, we identified prospective cohort studies that included blood uric acid as a risk factor and cognitive impairment as a result up to September 2022. We extracted pooled relative risks (RRs) and corresponding 95% confidence intervals (CIs). Results Nine reports (including 488,915 participants and 5516 cognitive impairment cases) with median follow-up of 8.8–22 years were eligible for analyses. Compared with lowest category of blood uric acid concentration, the combined RR of cognitive impairment events in the highest classification was 0.81 (95% CI: 0.70–0.92, P < 0.001). Dose-response analysis of eight reports (including 484,297 participants and 5059 cognitive impairment cases) showed that there was no evidence of a curvilinear relationship between blood uric acid levels and cognitive impairment (P = 0.51 for nonlinear relationship). The summary RR of cognitive impairment for an increase of 1 mg/dL blood uric acid level was 0.98 (95% CI: 0.95–1.00; linear trend P = 0.07, I2 = 67.1%, heterogeneity P < 0.05). There was also a linear negative association between blood uric acid levels and cognitive impairment risk in the male subgroup analysis (RR = 0.97, 95% CI: 0.95–0.99, P < 0.05). Conclusion Levels of blood uric acid are not related to risk of cognitive impairment. A subgroup analysis shows that the rise in blood uric acid levels in the male population is related to a decreased risk of cognitive impairment. These results need to be confirmed by further studies.

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Association between serum urate and CSF markers of Alzheimer's disease pathology in a population‐based sample of 70‐year‐olds

Cited by 4 publications

References 62 publications

Pathway for ascertaining the role of uric acid in neurodegenerative diseases

Pathway for ascertaining the role of uric acid in neurodegenerative diseases

Sex-dependent association of serum uric acid levels with amyloid accumulation among amyloid-positive older adults

Uric acid levels and risk of cognitive impairment: Dose-response meta-analysis of prospective cohort studies

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