, Volume 16, Issue 1, pp 192–202 | Cite as

Supranutritional Sodium Selenate Supplementation Delivers Selenium to the Central Nervous System: Results from a Randomized Controlled Pilot Trial in Alzheimer’s Disease

  • Barbara R. CardosoEmail author
  • Blaine R. Roberts
  • Charles B. Malpas
  • Lucy Vivash
  • Sila Genc
  • Michael M. Saling
  • Patricia Desmond
  • Christopher Steward
  • Rodney J. Hicks
  • Jason Callahan
  • Amy Brodtmann
  • Steven Collins
  • Stephen Macfarlane
  • Niall M Corcoran
  • Christopher M. Hovens
  • Dennis Velakoulis
  • Terence J. O’Brien
  • Dominic J. HareEmail author
  • Ashley I. Bush
Original Article


Insufficient supply of selenium to antioxidant enzymes in the brain may contribute to Alzheimer’s disease (AD) pathophysiology; therefore, oral supplementation may potentially slow neurodegeneration. We examined selenium and selenoproteins in serum and cerebrospinal fluid (CSF) from a dual-dose 24-week randomized controlled trial of sodium selenate in AD patients, to assess tolerability, and efficacy of selenate in modulating selenium concentration in the central nervous system (CNS). A pilot study of 40 AD cases was randomized to placebo, nutritional (0.32 mg sodium selenate, 3 times daily), or supranutritional (10 mg, 3 times daily) groups. We measured total selenium, selenoproteins, and inorganic selenium levels, in serum and CSF, and compared against cognitive outcomes. Supranutritional selenium supplementation was well tolerated and yielded a significant (p < 0.001) but variable (95% CI = 13.4–24.8 μg/L) increase in CSF selenium, distributed across selenoproteins and inorganic species. Reclassifying subjects as either responsive or non-responsive based on elevation in CSF selenium concentrations revealed that responsive group did not deteriorate in Mini-Mental Status Examination (MMSE) as non-responsive group (p = 0.03). Pooled analysis of all samples revealed that CSF selenium could predict change in MMSE performance (Spearman’s rho = 0.403; p = 0.023). High-dose sodium selenate supplementation is well tolerated and can modulate CNS selenium concentration, although individual variation in selenium metabolism must be considered to optimize potential benefits in AD. The Vel002 study is listed on the Australian and New Zealand Clinical Trials Registry (, ID: ACTRN12611001200976.

Key words

Sodium selenate selenium Alzheimer’s disease supranutritional selenium supplementation randomized controlled trial 



Alzheimer’s disease


Apolipoprotein E


Central nervous system


Cerebrospinal fluid


Glutathione peroxidase


Inductively coupled plasma-mass spectrometry


Mini-Mental Status Examination


Magnetic resonance imaging










Serious adverse event


Size exclusion chromatography


Treatment emergent adverse event



The Florey Institute of Neuroscience and Mental Health wishes to acknowledge the Victorian Government’s Operational Infrastructure Support Program, as well as the assistance of the Cooperative Research Centre for Mental Health and the Neuroproteomics Facility.

Funding Information

Funded by Fellowships from the Brazilian Government Science Without Borders program (Ciência sem Fronteiras; BRC), Deakin University (BRC), and the Australian National Health and Medical Research Council (GNT1138673, BRR; GNT1105784, SC; GNT1122981, DJH; GNT1103703, AIB); a Program Grant from the Australian National Health and Medical Research Council (GNT1132604, AIB); and by Velacor Therapeutics. Agilent Technologies provided material and research support (BRR, DJH).

Supplementary material

13311_2018_662_MOESM1_ESM.pdf (1.2 mb)
ESM 1 (PDF 1224 kb)
13311_2018_662_MOESM2_ESM.pdf (1.2 mb)
ESM 2 (PDF 1224 kb)
13311_2018_662_MOESM3_ESM.docx (21 kb)
Supplementary Table 1 (DOCX 20 kb)


  1. 1.
    Schweizer U, Bräuer AU, Köhrle J, Nitsch R, Savaskan NE. Selenium and brain function: a poorly recognized liaison. Brain Res Rev. 2004;45(3):164–78.CrossRefGoogle Scholar
  2. 2.
    Berr C, Balansard B, Arnaud J et al. Cognitive Decline Is Associated with Systemic Oxidative Stress: The EVA Study. J Am Geriatr Soc. 2000;48(10):1285–91.CrossRefGoogle Scholar
  3. 3.
    Cardoso BR, Ong TP, Jacob-Filho W et al. Nutritional status of selenium in Alzheimer's disease patients. Br J Nutr. 2010;103(6):803–6.CrossRefGoogle Scholar
  4. 4.
    Lin MT, Beal FM. Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature. 2006;443(7113):787–95.CrossRefGoogle Scholar
  5. 5.
    Barnham KJ, Masters CL, Bush AI. Neurodegenerative diseases and oxidative stress. Nat Rev Drug Discov. 2004;3(3):205–14.CrossRefGoogle Scholar
  6. 6.
    Loef M, Schrauzer GN, Walach H. Selenium and Alzheimer's disease: a systematic review. J Alzheimers Dis. 2011;26:81–104.CrossRefGoogle Scholar
  7. 7.
    da Silva S, Vellas B, Elemans S et al. Plasma nutrient status of patients with Alzheimer's disease: Systematic review and meta-analysis. Alzheimers Dement. 2014;10(4):485–502.CrossRefGoogle Scholar
  8. 8.
    Gao S, Jin Y, Hall KS et al. Selenium level and cognitive function in rural elderly Chinese. Am J Epidemiol. 2007;165(8):955–65.CrossRefGoogle Scholar
  9. 9.
    Reddy VS, Bukke S, Dutt N, Rana P, Pandey AK. A systematic review and meta-analysis of the circulatory, erythrocellular and CSF selenium levels in Alzheimer's disease: A metal meta-analysis (AMMA study-I). J Trace Elem Med Biol. 2017;42:68–75.CrossRefGoogle Scholar
  10. 10.
    Cardoso BR, Hare DJ, Lind M et al. The APOE ε4 Allele Is Associated with Lower Selenium Levels in the Brain: Implications for Alzheimer’s Disease. ACS Chem Neurosci. 2017;8:1459–64.CrossRefGoogle Scholar
  11. 11.
    Portet F, Ousset PJ, Visser PJ et al. Mild cognitive impairment (MCI) in medical practice: a critical review of the concept and new diagnostic procedure. Report of the MCI Working Group of the European Consortium on Alzheimer’s Disease. J Neurol Neurosurg Psychiatry. 2006;77(6):714–8.CrossRefGoogle Scholar
  12. 12.
    da Silva E, Mataveli L, Arruda M. Speciation analysis of selenium in plankton, Brazil nut and human urine samples by HPLC–ICP-MS. Talanta. 2013;110:53–7.CrossRefGoogle Scholar
  13. 13.
    Cardoso BR, Apolinario D, da Silva Bandeira V et al. Effects of Brazil nut consumption on selenium status and cognitive performance in older adults with mild cognitive impairment: a randomized controlled pilot trial. Eur J Nutr. 2016;55(1):107–16.CrossRefGoogle Scholar
  14. 14.
    Kryscio RJ, Abner EL, Caban-Holt A et al. Association of antioxidant supplement use and dementia in the prevention of alzheimer’s disease by vitamin e and selenium trial (preadvise). JAMA Neurol. 2017;74(5):567–573.CrossRefGoogle Scholar
  15. 15.
    van Eersel J, Ke YD, Liu X et al. Sodium selenate mitigates tau pathology, neurodegeneration, and functional deficits in Alzheimer's disease models. Proc Natl Acad Sci USA. 2010;107(31):13888–93.CrossRefGoogle Scholar
  16. 16.
    Corcoran NM, Martin D, Hutter-Paier B et al. Sodium selenate specifically activates PP2A phosphatase, dephosphorylates tau and reverses memory deficits in an Alzheimer's disease model. J Clin Neurosci. 2010;17(8):1025–33.CrossRefGoogle Scholar
  17. 17.
    Shultz SR, Wright DK, Zheng P et al. Sodium selenate reduces hyperphosphorylated tau and improves outcomes after traumatic brain injury. Brain. 2015;138(Pt 5):1297–313.CrossRefGoogle Scholar
  18. 18.
    Jin N, Zhu H, Liang X et al. Sodium selenate activated Wnt/beta-catenin signaling and repressed amyloid-beta formation in a triple transgenic mouse model of Alzheimer's disease. Exp Neurol. 2017;297:36–49.CrossRefGoogle Scholar
  19. 19.
    Lovell MA, Xiong S, Lyubartseva G, Markesbery WR. Organoselenium (Sel-Plex diet) decreases amyloid burden and RNA and DNA oxidative damage in APP/PS1 mice. Free Radic Biol Med. 2009;46(11):1527–33.CrossRefGoogle Scholar
  20. 20.
    Malpas CB, Vivash L, Genc S et al. A Phase IIa Randomized Control Trial of VEL015 (Sodium Selenate) in Mild-Moderate Alzheimer's Disease. J Alzheimers Dis. 2016;54(1):223–32.CrossRefGoogle Scholar
  21. 21.
    McKhann G, Drachman D, Folstein M et al. Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease. Neurology. 1984;34(7):939–44.CrossRefGoogle Scholar
  22. 22.
    Lothian A, Roberts BR. Standards for Quantitative Metalloproteomic Analysis Using Size Exclusion ICP-MS. J Vis Exp. 2016;
  23. 23.
    Hare DJ, Grubman A, Ryan TM et al. Profiling the iron, copper and zinc content in primary neuron and astrocyte cultures by rapid online quantitative size exclusion chromatography-inductively coupled plasma-mass spectrometry. Metallomics. 2013;5(12):1656–62.CrossRefGoogle Scholar
  24. 24.
    Thomson CD. Assessment of requirements for selenium and adequacy of selenium status: a review. Eur J Clin Nutr. 2004;58(3):391–402.CrossRefGoogle Scholar
  25. 25.
    Kipp AP, Strohm D, Brigelius-Flohé R et al. Revised reference values for selenium intake. J Trace Elem Med Biol. 2015;32:195–9.CrossRefGoogle Scholar
  26. 26.
    Xia Y, Hill KE, Li P et al. Optimization of selenoprotein P and other plasma selenium biomarkers for the assessment of the selenium nutritional requirement: a placebo-controlled, double-blind study of selenomethionine supplementation in selenium-deficient Chinese subjects. Am J Clin Nutr. 2010;92(3):525–31.CrossRefGoogle Scholar
  27. 27.
    Cardoso BR, Hare DJ, Bush AI et al. Selenium Levels in Serum, Red Blood Cells, and Cerebrospinal Fluid of Alzheimer's Disease Patients: A Report from the Australian Imaging, Biomarker & Lifestyle Flagship Study of Ageing (AIBL). J Alzheimers Dis. 2017;57(1):183–93.CrossRefGoogle Scholar
  28. 28.
    Haratake M, Hongoh M, Miyauchi M et al. Albumin-mediated selenium transfer by a selenotrisulfide relay mechanism. Inorg Chem. 2008;47(14):6273–80.CrossRefGoogle Scholar
  29. 29.
    Bishop DP, Hare DJ, Clases D, Doble PA. Applications of liquid chromatography-inductively coupled plasma-mass spectrometry in the biosciences: a tutorial review and recent developments. TrAC Trends in Analytical Chemistry. 2018;104:11–21.CrossRefGoogle Scholar
  30. 30.
    Delafiori J, Ring G, Furey A. Clinical applications of HPLC–ICP-MS element speciation: A review. Talanta. 2016;153:306–31.CrossRefGoogle Scholar
  31. 31.
    Onning G, Bergdahl IA. Fractionation of soluble selenium compounds from fish using size-exclusion chromatography with on-line detection by inductively coupled plasma mass spectrometry. Analyst. 1999;124(10):1435–8.CrossRefGoogle Scholar
  32. 32.
    Palacios Ò, Lobinski R. Investigation of the stability of selenoproteins during storage of human serum by size-exclusion LC–ICP-MS. Talanta. 2007;71(4):1813–6.CrossRefGoogle Scholar
  33. 33.
    Ganrot K, Laurell CB. Measurement of IgG and albumin content of cerebrospinal fluid, and its interpretation. Clin Chem. 1974;20(5):571–3.Google Scholar
  34. 34.
    Solovyev N, Berthele A, Michalke B. Selenium speciation in paired serum and cerebrospinal fluid samples. Anal Bioanal Chem. 2013;405(6):1875–84.CrossRefGoogle Scholar
  35. 35.
    Vinceti M, Mandrioli J, Borella P et al. Selenium neurotoxicity in humans: Bridging laboratory and epidemiologic studies. Toxicol Lett. 2014;230(2):295–303.CrossRefGoogle Scholar
  36. 36.
    Cold F, Winther KH, Pastor-Barriuso R et al. Randomised controlled trial of the effect of long-term selenium supplementation on plasma cholesterol in an elderly Danish population. Br J Nutr. 2015;114(11):1807–18.CrossRefGoogle Scholar
  37. 37.
    Rayman M, Winther KH, Pastor-Barriuso R et al. Effect of long-term selenium supplementation on mortality: results from a multiple-dose, RCT. The 11st International Symposium on Selenium in Biology and Medicine and The 5th International Conference on Selenium in the Environment and Human Health (Se2017); Stockholm 2017. p.p. 44. Abstract.Google Scholar
  38. 38.
    Morris J, Crane SB. Selenium Toxicity from a Misformulated Dietary Supplement, Adverse Health Effects, and the Temporal Response in the Nail Biologic Monitor. Nutrients. 2013;5(4):1024–57.CrossRefGoogle Scholar
  39. 39.
    MacFarquhar JK, Broussard DL, Melstrom P et al. Acute selenium toxicity associated with a dietary supplement. Arch Intern Med. 2010;170(3):256–61.CrossRefGoogle Scholar
  40. 40.
    Jäger T, Drexler H, Göen T. Human metabolism and renal excretion of selenium compounds after oral ingestion of sodium selenate dependent on trimethylselenium ion (TMSe) status. Arch Toxicol. 2016;90(1):149–58.CrossRefGoogle Scholar
  41. 41.
    Rayman MP. Selenium and human health. Lancet. 2012;379(9822):1256–68.CrossRefGoogle Scholar
  42. 42.
    Cardoso B, Roberts BR, Bush AI, Hare DJ. Selenium, selenoproteins and neurodegenerative diseases. Metallomics 2015;7(8):1213–28.CrossRefGoogle Scholar
  43. 43.
    Cardoso B, Hare D, Bush A, Roberts B. Glutathione peroxidase 4: a new player in neurodegeneration? Mol Psychiatry. 2017;22(3).Google Scholar
  44. 44.
    Dixon SJ, Lemberg KM, Lamprecht MR et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell. 2012;149(5):1060–72.CrossRefGoogle Scholar
  45. 45.
    Dixon SJ, Stockwell BR. The role of iron and reactive oxygen species in cell death. Nat Chem Biol. 2014;10(1):9–17.CrossRefGoogle Scholar
  46. 46.
    Stockwell BR, Angeli J, Bayir H et al. Ferroptosis: A Regulated Cell Death Nexus Linking Metabolism, Redox Biology, and Disease. Cell. 2017;171(2):273–85.CrossRefGoogle Scholar
  47. 47.
    Xiong S, Markesbery WR, Shao C, Lovell MA. Seleno-L-Methionine Protects Against β-Amyloid and Iron/Hydrogen Peroxide-Mediated Neuron Death. Antioxid Redox Signal. 2007;9(4):457–67.CrossRefGoogle Scholar

Copyright information

© The American Society for Experimental NeuroTherapeutics, Inc. 2018

Authors and Affiliations

  • Barbara R. Cardoso
    • 1
    Email author
  • Blaine R. Roberts
    • 2
  • Charles B. Malpas
    • 3
    • 4
    • 5
    • 6
  • Lucy Vivash
    • 3
    • 6
  • Sila Genc
    • 5
    • 7
  • Michael M. Saling
    • 4
  • Patricia Desmond
    • 8
  • Christopher Steward
    • 8
  • Rodney J. Hicks
    • 8
    • 9
  • Jason Callahan
    • 9
  • Amy Brodtmann
    • 2
    • 10
  • Steven Collins
    • 3
    • 11
  • Stephen Macfarlane
    • 12
  • Niall M Corcoran
    • 13
  • Christopher M. Hovens
    • 13
  • Dennis Velakoulis
    • 14
  • Terence J. O’Brien
    • 3
    • 6
  • Dominic J. Hare
    • 2
    Email author
  • Ashley I. Bush
    • 2
  1. 1.Institute for Physical Activity and Nutrition (IPAN), School of Exercise and Nutrition SciencesDeakin UniversityGeelongAustralia
  2. 2.Melbourne Dementia Research Centre, The Florey Institute of Neuroscience and Mental HealthThe University of MelbourneParkvilleAustralia
  3. 3.Department of MedicineRoyal Melbourne HospitalMelbourneAustralia
  4. 4.Melbourne School of Psychological SciencesThe University of MelbourneParkvilleAustralia
  5. 5.Developmental ImagingMurdoch Children’s Research InstituteMelbourneAustralia
  6. 6.Departments of Neuroscience and Neurology, The Central Clinical School and The Alfred HospitalMonash UniversityMelbourneAustralia
  7. 7.Department of PaediatricsThe University of MelbourneParkvilleAustralia
  8. 8.Department of Radiology, Royal Melbourne HospitalUniversity of MelbourneMelbourneAustralia
  9. 9.Centre for Molecular Imaging, Peter MacCallum Cancer CentreMelbourneAustralia
  10. 10.Eastern Cognitive Disorders Clinic, Department of Neurology, Eastern HealthMonash UniversityMelbourneAustralia
  11. 11.Department of Clinical Neurosciences and Neurological ResearchSt Vincent’s HospitalFitzroyAustralia
  12. 12.Caulfield HospitalAlfred HealthCaulfieldAustralia
  13. 13.Department of SurgeryRoyal Melbourne HospitalMelbourneAustralia
  14. 14.Department of PsychiatryThe University of MelbourneParkvilleAustralia

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