Skip to main content

Advertisement

SpringerLink
Log in

Inverse Association Between Serum Uric Acid Levels and Alzheimer’s Disease Risk

  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

Abstract

The association between Alzheimer’s disease and uric acid levels had gained great interest in recent years, but there was still lack of definite evidence. A systematic review and meta-analysis of relevant studies was performed to comprehensively estimate the association. Relevant studies published before October 26, 2014, were searched in PubMed, Embase, and China Biology Medicine (CBM) databases. Study-specific data were combined using random-effects or fixed-effects models of meta-analysis according to between-study heterogeneity. Twenty-four studies (21 case-control and 3 cohort studies) were finally included into the meta-analysis. Those 21 case-control studies included a total of 1128 cases of Alzheimer’s disease and 2498 controls without Alzheimer’s disease. Those 3 cohort studies included a total of 7327 participants. Meta-analysis showed that patients with Alzheimer’s disease had lower levels of uric acid than healthy controls (weighted mean difference (WMD) = −0.77 mg/dl, 95 % CI −2.28 to −0.36, P = 0.0002). High serum uric acid levels were significantly associated with decreased risk of Alzheimer’s disease (risk ratio (RR) = 0.66, 95 % CI 0.52–0.85, P = 0.001). There was low risk of publication bias in the meta-analysis. There is an inverse association between serum uric acid levels and Alzheimer’s disease. High serum uric acid level is a protective factor of Alzheimer’s disease.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Barnes DE, Yaffe K (2011) The projected effect of risk factor reduction on Alzheimer’s disease prevalence. Lancet Neurol 10(9):819–828

    Article  PubMed  PubMed Central  Google Scholar 

  2. Johansson JU, Woodling NS, Wang Q, Panchal M, Liang X, Trueba-Saiz A, Brown HD, Mhatre SD et al (2014) Prostaglandin signaling suppresses beneficial microglial function in Alzheimer’s disease models. J Clin Invest

  3. Benz N, Hatz F, Bousleiman H, Ehrensperger MM, Gschwandtner U, Hardmeier M, Ruegg S, Schindler C et al (2014) Slowing of EEG background activity in Parkinson’s and Alzheimer’s disease with early cognitive dysfunction. Front Aging Neurosci 6314

  4. McCord MC, Aizenman E (2014) The role of intracellular zinc release in aging, oxidative stress, and Alzheimer’s disease. Front Aging Neurosci 677

  5. Patrone C, Eriksson O, Lindholm D (2014) Diabetes drugs and neurological disorders: new views and therapeutic possibilities. Lancet Diabetes Endocrinol 2(3):256–262

    Article  CAS  PubMed  Google Scholar 

  6. Biessels GJ, Strachan MW, Visseren FL, Kappelle LJ, Whitmer RA (2014) Dementia and cognitive decline in type 2 diabetes and prediabetic stages: towards targeted interventions. Lancet Diabetes Endocrinol 2(3):246–255

    Article  PubMed  Google Scholar 

  7. Geijselaers SL, Sep SJ, Stehouwer CD, Biessels GJ (2014) Glucose regulation, cognition, and brain MRI in type 2 diabetes: a systematic review. Lancet Diabetes Endocrinol

  8. Tuligenga RH, Dugravot A, Tabak AG, Elbaz A, Brunner EJ, Kivimaki M, Singh-Manoux A (2014) Midlife type 2 diabetes and poor glycaemic control as risk factors for cognitive decline in early old age: a post-hoc analysis of the Whitehall II cohort study. Lancet Diabetes Endocrinol 2(3):228–235

    Article  PubMed  PubMed Central  Google Scholar 

  9. Borza LR (2014) A review on the cause-effect relationship between oxidative stress and toxic proteins in the pathogenesis of neurodegenerative diseases. Rev Med Chir Soc Med Nat Iasi 118(1):19–27

    PubMed  Google Scholar 

  10. Ghaemi-Oskouie F, Shi Y (2011) The role of uric acid as an endogenous danger signal in immunity and inflammation. Curr Rheumatol Rep 13(2):160–166

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Alvarez-Lario B, Macarron-Vicente J (2011) Is there anything good in uric acid? QJM 104(12):1015–1024

    Article  CAS  PubMed  Google Scholar 

  12. Shih CY, Chen CY, Wen CJ, Liu HM, Kuo HK (2012) Relationship between serum uric acid and cerebral white matter lesions in the elderly. Nutr Metab Cardiovasc Dis 22(2):154–159

    Article  CAS  PubMed  Google Scholar 

  13. Vannorsdall TD, Jinnah HA, Gordon B, Kraut M, Schretlen DJ (2008) Cerebral ischemia mediates the effect of serum uric acid on cognitive function. Stroke 39(12):3418–3420

    Article  CAS  PubMed  Google Scholar 

  14. Maesaka JK, Wolf-Klein G, Piccione JM, Ma CM (1993) Hypouricemia, abnormal renal tubular urate transport, and plasma natriuretic factor(s) in patients with Alzheimer’s disease. J Am Geriatr Soc 41(5):501–506

    Article  CAS  PubMed  Google Scholar 

  15. Foy CJ, Passmore AP, Vahidassr MD, Young IS, Lawson JT (1999) Plasma chain-breaking antioxidants in Alzheimer’s disease, vascular dementia and Parkinson’s disease. QJM 92(1):39–45

    Article  CAS  PubMed  Google Scholar 

  16. Carantoni M, Zuliani G, Munari MR, D’Elia K, Palmieri E, Fellin R (2000) Alzheimer disease and vascular dementia: relationships with fasting glucose and insulin levels. Dement Geriatr Cogn Disord 11(3):176–180

    Article  CAS  PubMed  Google Scholar 

  17. Polidori MC, Mecocci P (2002) Plasma susceptibility to free radical-induced antioxidant consumption and lipid peroxidation is increased in very old subjects with Alzheimer disease. J Alzheimers Dis 4(6):517–522

    CAS  PubMed  Google Scholar 

  18. Rinaldi P, Polidori MC, Metastasio A, Mariani E, Mattioli P, Cherubini A, Catani M, Cecchetti R et al (2003) Plasma antioxidants are similarly depleted in mild cognitive impairment and in Alzheimer’s disease. Neurobiol Aging 24(7):915–919

    Article  CAS  PubMed  Google Scholar 

  19. Polidori MC, Mattioli P, Aldred S, Cecchetti R, Stahl W, Griffiths H, Senin U, Sies H et al (2004) Plasma antioxidant status, immunoglobulin g oxidation and lipid peroxidation in demented patients: relevance to Alzheimer disease and vascular dementia. Dement Geriatr Cogn Disord 18(3–4):265–270

    Article  CAS  PubMed  Google Scholar 

  20. Pulido R, Jimenez-Escrig A, Orensanz L, Saura-Calixto F (2005) Study of plasma antioxidant status in Alzheimer’s disease. Eur J Neurol 12(7):531–535

    Article  CAS  PubMed  Google Scholar 

  21. Kim TS, Pae CU, Yoon SJ, Jang WY, Lee NJ, Kim JJ, Lee SJ, Lee C et al (2006) Decreased plasma antioxidants in patients with Alzheimer’s disease. Int J Geriatr Psychiatry 21(4):344–348

    Article  PubMed  Google Scholar 

  22. Iuliano L, Monticolo R, Straface G, Spoletini I, Gianni W, Caltagirone C, Bossu P, Spalletta G (2010) Vitamin E and enzymatic/oxidative stress-driven oxysterols in amnestic mild cognitive impairment subtypes and Alzheimer’s disease. J Alzheimers Dis 21(4):1383–1392

    CAS  PubMed  Google Scholar 

  23. Can M, Varlibas F, Guven B, Akhan O, Yuksel GA (2013) Ischemia modified albumin and plasma oxidative stress markers in Alzheimer’s disease. Eur Neurol 69(6):377–380

    Article  CAS  PubMed  Google Scholar 

  24. Al-Khateeb E, Althaher A, Al-Khateeb M, Al-Musawi H, Azzouqah O, Al-Shweiki S, Shafagoj Y (2014) Relation between uric acid and Alzheimer’s disease in elderly Jordanians. J Alzheimers Dis

  25. Higgins JP, Thompson SG, Deeks JJ, Altman DG (2003) Measuring inconsistency in meta-analyses. BMJ 327(7414):557–560

    Article  PubMed  PubMed Central  Google Scholar 

  26. DerSimonian R, Laird N (1986) Meta-analysis in clinical trials. Control Clin Trials 7(3):177–188

    Article  CAS  PubMed  Google Scholar 

  27. Mantel N, Haenszel W (1959) Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst 22(4):719–748

    CAS  PubMed  Google Scholar 

  28. Zafrilla P, Mulero J, Xandri JM, Santo E, Caravaca G, Morillas JM (2006) Oxidative stress in Alzheimer patients in different stages of the disease. Curr Med Chem 13(9):1075–1083

    Article  CAS  PubMed  Google Scholar 

  29. Cankurtaran M, Yesil Y, Kuyumcu ME, Ozturk ZA, Yavuz BB, Halil M, Ulger Z, Cankurtaran ES et al (2013) Altered levels of homocysteine and serum natural antioxidants links oxidative damage to Alzheimer’s disease. J Alzheimers Dis 33(4):1051–1058

    CAS  PubMed  Google Scholar 

  30. Cervellati C, Cremonini E, Bosi C, Magon S, Zurlo A, Bergamini CM, Zuliani G (2013) Systemic oxidative stress in older patients with mild cognitive impairment or late onset Alzheimer’s disease. Curr Alzheimer Res 10(4):365–372

    Article  CAS  PubMed  Google Scholar 

  31. Cervellati C, Romani A, Seripa D, Cremonini E, Bosi C, Magon S, Passaro A, Bergamini CM et al (2014) Oxidative balance, homocysteine, and uric acid levels in older patients with late onset Alzheimer’s disease or vascular dementia. J Neurol Sci 337(1–2):156–161

    Article  CAS  PubMed  Google Scholar 

  32. Nazef K, Khelil M, Chelouti H, Kacimi G, Bendini M, Tazir M, Belarbi S, El Hadi CM et al (2014) Hyperhomocysteinemia is a risk factor for Alzheimer’s disease in an Algerian population. Arch Med Res 45(3):247–250

    Article  CAS  PubMed  Google Scholar 

  33. Euser SM, Hofman A, Westendorp RG, Breteler MM (2009) Serum uric acid and cognitive function and dementia. Brain 132(Pt 2):377–382

    CAS  PubMed  Google Scholar 

  34. Irizarry MC, Raman R, Schwarzschild MA, Becerra LM, Thomas RG, Peterson RC, Ascherio A, Aisen PS (2009) Plasma urate and progression of mild cognitive impairment. Neurodegener Dis 6(1–2):23–28

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Wu Y, Zhang D, Pang Z, Jiang W, Wang S, Tan Q (2013) Association of serum uric acid level with muscle strength and cognitive function among Chinese aged 50–74 years. Geriatr Gerontol Int 13(3):672–677

    Article  PubMed  Google Scholar 

  36. Shang X, Zhang F, Meng L, Zhang W, Lin M, Xue Y (2009) Relationship between the level of serum uric acid and Alzheimer’s disease [article in Chinese]. J China Med Univ 38(5):333–334

    CAS  Google Scholar 

  37. Huang D, Lu Z, Tan S, Yang H, Yang Y (2012) Study on the correlation of uric acid levels with Alzheimer’s disease [article in Chinese]. Guangxi Med Univ 34(11):1483–1485

    CAS  Google Scholar 

  38. Zhou Y, Tan H, Wang A (2012) Study on the relationship between uric acid and various cognitive functions in Alzheimer’s disease [article in Chinese]. J Chin Physician 14(7):904–906

    CAS  Google Scholar 

  39. Sun X, Pan F, Huang G (2013) Relationship between the cognitive function and the level of serum uric acid in Alzheimer’s disease [article in Chinese]. Geriatr Health Care 19(6):380–382

    CAS  Google Scholar 

  40. Yang J (2014) Uric acid test for Alzheimer’s disease and vascular dementia patients [article in Chinese]. Mod Diagn Treat 25(1):161–162

    CAS  Google Scholar 

  41. Fitzsimons CP, van Bodegraven E, Schouten M, Lardenoije R, Kompotis K, Kenis G, van den Hurk M, Boks MP et al (2014) Epigenetic regulation of adult neural stem cells: implications for Alzheimer’s disease. Mol Neurodegener 925

  42. Marr RA, Hafez DM (2014) Amyloid-beta and Alzheimer’s disease: the role of neprilysin-2 in amyloid-beta clearance. Front Aging Neurosci 6187

  43. Montine TJ, Koroshetz WJ, Babcock D, Dickson DW, Galpern WR, Glymour MM, Greenberg SM, Hutton ML et al (2014) Recommendations of the Alzheimer’s disease-related dementias conference. Neurology 83(9):851–860

    Article  PubMed  PubMed Central  Google Scholar 

  44. Poirier J, Miron J, Picard C, Gormley P, Theroux L, Breitner J, Dea D (2014) Apolipoprotein E and lipid homeostasis in the etiology and treatment of sporadic Alzheimer’s disease. Neurobiol Aging 35(Suppl 2):S3–S10

    Article  CAS  PubMed  Google Scholar 

  45. Cukierman-Yaffe T, Bosch J, Diaz R, Dyal L, Hancu N, Hildebrandt P, Lanas F, Lewis BS et al (2014) Effects of basal insulin glargine and omega-3 fatty acid on cognitive decline and probable cognitive impairment in people with dysglycaemia: a substudy of the ORIGIN trial. Lancet Diabetes Endocrinol 2(7):562–572

    Article  CAS  PubMed  Google Scholar 

  46. Martinez-Finley EJ, Avila DS, Chakraborty S, Aschner M (2011) Insights from Caenorhabditis elegans on the role of metals in neurodegenerative diseases. Metallomics 3(3):271–279

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Sultana R, Butterfield DA (2009) Oxidatively modified, mitochondria-relevant brain proteins in subjects with Alzheimer disease and mild cognitive impairment. J Bioenerg Biomembr 41(5):441–446

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Squadrito GL, Cueto R, Splenser AE, Valavanidis A, Zhang H, Uppu RM, Pryor WA (2000) Reaction of uric acid with peroxynitrite and implications for the mechanism of neuroprotection by uric acid. Arch Biochem Biophys 376(2):333–337

    Article  CAS  PubMed  Google Scholar 

Download references

Conflict of interest

The authors declare that they have no competing interest.

Author information

Author notes

    Authors and Affiliations

    1. Department of Endocrinology, Affiliated Hospital of Qingdao University, 16 Jiangsu Road, Qingdao, 266003, China

      Na Du, Xu Hou, Xuejia Song, Cancan Liu, Ying Chen & Yangang Wang

    2. Department of Rheumatology, Affiliated Hospital of Weifang Medical University, Weifang, 261031, China

      Donghua Xu

    3. Department of Physiology, Functional Laboratory of Weifang Medical University, Weifang, 261031, China

      Xin Li

    Authors
    1. Na Du
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. Donghua Xu
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. Xu Hou
      View author publications

      You can also search for this author in PubMed Google Scholar

    4. Xuejia Song
      View author publications

      You can also search for this author in PubMed Google Scholar

    5. Cancan Liu
      View author publications

      You can also search for this author in PubMed Google Scholar

    6. Ying Chen
      View author publications

      You can also search for this author in PubMed Google Scholar

    7. Yangang Wang
      View author publications

      You can also search for this author in PubMed Google Scholar

    8. Xin Li
      View author publications

      You can also search for this author in PubMed Google Scholar

    Corresponding authors

    Correspondence to Yangang Wang or Xin Li.

    Additional information

    Na Du, Donghua Xu, and Xu Hou contributed equally to this work.

    Rights and permissions

    Reprints and permissions

    About this article

    Check for updates. Verify currency and authenticity via CrossMark

    Cite this article

    Du, N., Xu, D., Hou, X. et al. Inverse Association Between Serum Uric Acid Levels and Alzheimer’s Disease Risk. Mol Neurobiol 53, 2594–2599 (2016). https://doi.org/10.1007/s12035-015-9271-6

    Download citation

    • Received:

    • Accepted:

    • Published:

    • Issue Date:

    • DOI: https://doi.org/10.1007/s12035-015-9271-6

    Keywords

    Search

    Navigation