Skip to main content

Advertisement

SpringerLink
Log in

What role do metals play in Alzheimer's disease?

  • Review
  • Published:
Journal of the Iranian Chemical Society Aims and scope Submit manuscript

Abstract

Alzheimer's disease is the most common neurodegenerative disorder that usually occurs after the age of 65 for which there is currently no cure. The predominant feature of this disease is the appearance of beta amyloid plaques next to the neurons in the brain. Numerous studies have investigated the possible causes of the disease and in particular the role of metals. In the present study, while briefly reviewing the effect of various lifestyle factors on the incidence and prevalence of the disease, by presenting the latest clinical reports and cohort studies regarding the role of metals in the disease, we try to provide a comprehensive overview of this issue to the reader. Some studies have shown changes in the concentration of metals in the brain or body fluids of AD patients, while others have not indicated any change. Therefore, it can be concluded that metals are not causative factor, but they are risk factor in certain conditions.

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

Similar content being viewed by others

References

  1. P.A. Adlard, A.I. Bush, Metals and Alzheimer’s disease: how far have we come in the clinic? J. Alzheimer’s Dis. 62, 1369–1379 (2018). https://doi.org/10.3233/JAD-170662

    Article  Google Scholar 

  2. C.J. Sarell, The Copper-Amyloid-Beta-Peptide Complex of Alzheimer’ s Disease : Affinity, Structure, Fibril Formation and Toxicity (University of London, London, 2010).

    Google Scholar 

  3. S. Bagheri, R. Squitti, T. Haertlé, M. Siotto, A.A. Saboury, Role of copper in the onset of Alzheimer’s disease compared to other metals. Front. Aging Neurosci. 9, 446 (2018). https://doi.org/10.3389/fnagi.2017.00446

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  4. X. Du, X. Wang, M. Geng, Alzheimer’s disease hypothesis and related therapies. Transl. Neurodegener. (2018). https://doi.org/10.1186/s40035-018-0107-y

    Article  PubMed  PubMed Central  Google Scholar 

  5. M.A. Zoroddu, J. Aaseth, G. Crisponi, S. Medici, M. Peana, V.M. Nurchi, The essential metals for humans: a brief overview. J. Inorg. Biochem. 195, 120–129 (2019). https://doi.org/10.1016/J.JINORGBIO.2019.03.013

    Article  PubMed  CAS  Google Scholar 

  6. A.A.A. Saad, A. El-Sikaily, H. Kassem, Essential, non-essential metals and human health. Pollut. Status Environ. Prot. Renew. Energy Prod. Mar. Syst. 3, 47 (2016)

    Google Scholar 

  7. M. Jaishankar, T. Tseten, N. Anbalagan, B.B. Mathew, K.N. Beeregowda, Toxicity, mechanism and health effects of some heavy metals. Interdiscip. Toxicol. 7, 60–72 (2014). https://doi.org/10.2478/intox-2014-0009

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. S.G. Schäfer, W. Forth, Excretion of metals into the rat intestine. Biol. Trace Elem. Res. 5, 205–217 (1983). https://doi.org/10.1007/BF02916624

    Article  PubMed  Google Scholar 

  9. A.T. Jan, M. Azam, K. Siddiqui, A. Ali, I. Choi, Q.M.R. Haq, Heavy metals and human health: mechanistic insight into toxicity and counter defense system of antioxidants. Int. J. Mol. Sci. 16, 29592–29630 (2015). https://doi.org/10.3390/ijms161226183

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. S.J. Genuis, M. Sears, G. Schwalfenberg, J. Hope, R. Bernhoft, Incorporating environmental health in clinical medicine. J. Environ. Public Health. (2012). https://doi.org/10.1155/2012/103041

    Article  PubMed  PubMed Central  Google Scholar 

  11. B. Dubois, H.H. Feldman, C. Jacova, H. Hampel, J.L. Molinuevo, K. Blennow, S.T. Dekosky, S. Gauthier, D. Selkoe, R. Bateman, S. Cappa, S. Crutch, S. Engelborghs, G.B. Frisoni, N.C. Fox, D. Galasko, M.O. Habert, G.A. Jicha, A. Nordberg, F. Pasquier, G. Rabinovici, P. Robert, C. Rowe, S. Salloway, M. Sarazin, S. Epelbaum, L.C. de Souza, B. Vellas, P.J. Visser, L. Schneider, Y. Stern, P. Scheltens, J.L. Cummings, Advancing research diagnostic criteria for Alzheimer’s disease: The IWG-2 criteria. Lancet Neurol. (2014). https://doi.org/10.1016/S1474-4422(14)70090-0

    Article  PubMed  Google Scholar 

  12. A.M. Fernandez, A. Santi, I. Torres Aleman, Insulin peptides as mediators of the impact of life style in Alzheimer’s disease. Brain Plast. 4, 3–15 (2018). https://doi.org/10.3233/bpl-180071

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. M. Baumgart, H.M. Snyder, M.C. Carrillo, S. Fazio, H. Kim, H. Johns, Summary of the evidence on modifiable risk factors for cognitive decline and dementia: a population-based perspective. Alzheimer’s Dement. 11, 718–726 (2015). https://doi.org/10.1016/j.jalz.2015.05.016

    Article  Google Scholar 

  14. M. Crous-Bou, C. Minguillón, N. Gramunt, J.L. Molinuevo, Alzheimer’s disease prevention: from risk factors to early intervention. Alzheimer’s Res. Ther. 9, 71 (2017). https://doi.org/10.1186/s13195-017-0297-z

    Article  CAS  Google Scholar 

  15. M.L. Daviglus, C.C. Bell, W. Berrettini, P.E. Bowen, E.S. Connolly, N.J. Cox, J.M. Dunbar-Jacob, E.C. Granieri, G. Hunt, K. McGarry, D. Patel, A.L. Potosky, E. Sanders-Bush, D. Silberberg, M. Trevisan, National Institutes of Health state-of-the-science conference statement: preventing Alzheimer disease and cognitive decline. Ann. Intern. Med. 153, 176–181 (2010). https://doi.org/10.7326/0003-4819-153-3-201008030-00260

    Article  PubMed  Google Scholar 

  16. D.E. Barnes, K. Yaffe, The projected impact of risk factor reduction on Alzheimer’s disease prevalence. Lancet Neurol. 10, 819–828 (2011). https://doi.org/10.1016/S1474-4422(11)70072-2

    Article  PubMed  PubMed Central  Google Scholar 

  17. B.R. Cardoso, C. Cominetti, S.M.F. Cozzolino, Importance and management of micronutrient deficiencies in patients with Alzheimer’s disease. Clin. Interv. Aging. 8, 531–542 (2013). https://doi.org/10.2147/CIA.S27983

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. A.G. Pacholko, C.A. Wotton, L.K. Bekar, Poor diet, stress, and inactivity converge to form a “Perfect Storm” that drives Alzheimer’s disease pathogenesis. Neurodegener. Dis. 19, 60–77 (2019). https://doi.org/10.1159/000503451

    Article  PubMed  Google Scholar 

  19. R.F. Gottesman, A.L.C. Schneider, Y. Zhou, J. Coresh, E. Green, N. Gupta, D.S. Knopman, A. Mintz, A. Rahmim, A.R. Sharrett, L.E. Wagenknecht, D.F. Wong, T.H. Mosley, Association between midlife vascular risk factors and estimated brain amyloid deposition. JAMA J. Am. Med. Assoc. (2017). https://doi.org/10.1001/jama.2017.3090

    Article  Google Scholar 

  20. J.K. Cataldo, J.J. Prochaska, S.A. Glantz, Cigarette smoking is a risk factor for Alzheimer’s disease: an analysis controlling for tobacco industry affiliation. J. Alzheimer’s Dis. 19, 465–480 (2010). https://doi.org/10.3233/JAD-2010-1240

    Article  Google Scholar 

  21. C. Wallin, S.B. Sholts, N. Österlund, J. Luo, J. Jarvet, P.M. Roos, L. Ilag, A. Gräslund, S.K.T.S. Wärmländer, Alzheimer’s disease and cigarette smoke components: effects of nicotine, PAHs, and Cd(II), Cr(III), Pb(II), Pb(IV) ions on amyloid-β peptide aggregation. Sci. Rep. 7, 14423 (2017). https://doi.org/10.1038/s41598-017-13759-5

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. D. Laurin, R. Verreault, J. Lindsay, K. MacPherson, K. Rockwood, Physical activity and risk of cognitive impairment and dementia in elderly persons. Arch. Neurol. 58, 498–504 (2001). https://doi.org/10.1001/archneur.58.3.498

    Article  PubMed  CAS  Google Scholar 

  23. L.J. Podewils, E. Guallar, L.H. Kuller, L.P. Fried, O.L. Lopez, M. Carlson, C.G. Lyketsos, Physical activity, APOE genotype, and dementia risk: findings from the cardiovascular health cognition study. Am. J. Epidemiol. 161, 639–651 (2005). https://doi.org/10.1093/aje/kwi092

    Article  PubMed  Google Scholar 

  24. Y. Rolland, G. Abellan van Kan, B. Vellas, Physical activity and Alzheimer’s disease: from prevention to therapeutic perspectives. J. Am. Med. Dir. Assoc. 9, 390–405 (2008). https://doi.org/10.1016/j.jamda.2008.02.007

    Article  PubMed  Google Scholar 

  25. S. Sabia, A. Dugravot, J.F. Dartigues, J. Abell, A. Elbaz, M. Kivimäki, A. Singh-Manoux, Physical activity, cognitive decline, and risk of dementia: 28 year follow-up of Whitehall II cohort study. BMJ 357, j2709 (2017). https://doi.org/10.1136/bmj.j2709

    Article  PubMed  PubMed Central  Google Scholar 

  26. M. Weih, J. Wiltfang, J. Kornhuber, Non-pharmacologic prevention of Alzheimer’s disease: nutritional and life-style risk factors. J. Neural Transm. 114, 1187–1197 (2007). https://doi.org/10.1007/s00702-007-0704-x

    Article  PubMed  CAS  Google Scholar 

  27. A. Mendonça, R.A. Cunha, Therapeutic opportunities for caffeine in Alzheimer’s disease and other neurodegenerative disorders. J. Alzheimer’s Dis. (2010). https://doi.org/10.3233/JAD-2010-01420

    Article  Google Scholar 

  28. V. Flaten, C. Laurent, J.E. Coelho, U. Sandau, V.L. Batalha, S. Burnouf, M. Hamdane, S. Humez, D. Boison, L.V. Lopes, L. Buée, D. Blum, From epidemiology to pathophysiology: what about caffeine in Alzheimer’s disease? Biochem. Soc. Trans. 42, 587–592 (2014). https://doi.org/10.1042/BST20130229

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Y. Chern, N. Rei, J.A. Ribeiro, A.M. Sebastião, Adenosine and its receptors as potential drug targets in amyotrophic lateral sclerosis. J. Caffeine Adenosine Res. 9, 157–166 (2019). https://doi.org/10.1089/caff.2019.0016

    Article  CAS  Google Scholar 

  30. S.F. Akomolafe, The effects of caffeine, caffeic acid, and their combination on acetylcholinesterase, adenosine deaminase and arginase activities linked with brain function. J. Food Biochem. 41, e12401 (2017). https://doi.org/10.1111/jfbc.12401

    Article  CAS  Google Scholar 

  31. S.F. Akomolafe, A.J. Akinyemi, O.B. Ogunsuyi, S.I. Oyeleye, G. Oboh, O.O. Adeoyo, Y.R. Allismith, Effect of caffeine, caffeic acid and their various combinations on enzymes of cholinergic, monoaminergic and purinergic systems critical to neurodegeneration in rat brain—in vitro. Neurotoxicology. 62, 6–13 (2017). https://doi.org/10.1016/j.neuro.2017.04.008

    Article  PubMed  CAS  Google Scholar 

  32. K. Sharma, Cholinesterase inhibitors as Alzheimer’s therapeutics (Review). Mol. Med. Rep. 20, 1479–1487 (2019). https://doi.org/10.3892/mmr.2019.10374

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. S. Bagheri, A.A. Saboury, T. Haertlé, Adenosine deaminase inhibition. Int. J. Biol. Macromol. 141, 1246–1257 (2019). https://doi.org/10.1016/j.ijbiomac.2019.09.078

    Article  PubMed  CAS  Google Scholar 

  34. G. Ataie, S. Bagheri, A. Divsalar, A.A. Saboury, S. Safarian, S. Namaki, A.A. Moosavi-Movahedi, A kinetic comparison on the inhibition of adenosine deaminase by purine drugs. Iran. J. Pharm. Res. 6, 43–50 (2007)

    CAS  Google Scholar 

  35. S.V. Ovsepian, V.B. O’Leary, Can arginase inhibitors be the answer to therapeutic challenges in Alzheimer’s disease? Neurotherapeutics. 15, 1032–1035 (2018). https://doi.org/10.1007/s13311-018-0668-6

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. Y. Manivannan, B. Manivannan, T. Beach, R. Halden, Role of environmental contaminants in the etiology of Alzheimers disease: a review. Curr. Alzheimer Res. 12, 116–146 (2015). https://doi.org/10.2174/1567205012666150204121719

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. A.R. Armstrong, Risk factors for Alzheimer’s disease. Folia Neuropathol. 57, 87–105 (2019). https://doi.org/10.5114/fn.2019.85929

    Article  Google Scholar 

  38. F. Li, Z. Qiu, J. Zhang, W. Liu, C. Liu, G. Zeng, Investigation, pollution mapping and simulative leakage health risk assessment for heavy metals and metalloids in groundwater from a typical brownfield, middle China. Int. J. Environ. Res. Public Health. 14, 768 (2017). https://doi.org/10.3390/ijerph14070768

    Article  PubMed Central  CAS  Google Scholar 

  39. G. Azeh Engwa, P. Udoka Ferdinand, F. Nweke Nwalo, M. N. Unachukwu, Mechanism and Health Effects of Heavy Metal Toxicity in Humans, in Poisoning Mod World New Tricks an Old Dog? (2019). https://doi.org/10.5772/intechopen.82511.

  40. P. Chen, M.R. Miah, M. Aschner, Metals and Neurodegeneration. F1000Research. (2016). https://doi.org/10.12688/f1000research.7431.1

    Article  PubMed  PubMed Central  Google Scholar 

  41. WHO, Trace elements in human nutrition and health World Health Organization, World Heal. Organ. (1996).

  42. E. Inan-Eroglu, A. Ayaz, Is aluminum exposure a risk factor for neurological disorders? J. Res. Med. Sci. 2018, 23–51 (2018). https://doi.org/10.4103/jrms.JRMS_921_17

    Article  Google Scholar 

  43. Y.K. Gupta, M. Meenu, S.S. Peshin, Aluminium utensils: Is it a concern? Natl. Med. J. India. 32, 38–40 (2019). https://doi.org/10.4103/0970-258X.272116

    Article  PubMed  Google Scholar 

  44. D. Dordevic, H. Buchtova, S. Jancikova, B. Macharackova, M. Jarosova, T. Vitez, I. Kushkevych, Aluminum contamination of food during culinary preparation: case study with aluminum foil and consumers’ preferences. Food Sci. Nutr. 7, 3349–3360 (2019). https://doi.org/10.1002/fsn3.1204

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  45. S.A. Virk, G.D. Eslick, Brief report: meta-analysis of antacid use and Alzheimer’s disease: implications for the aluminum hypothesis. Epidemiology. 26, 769–773 (2015). https://doi.org/10.1097/EDE.0000000000000326

    Article  PubMed  Google Scholar 

  46. T.I. Lidsky, Is the aluminum hypothesis dead? J. Occup. Environ. Med. 56, 73–79 (2014). https://doi.org/10.1097/JOM.0000000000000063

    Article  CAS  Google Scholar 

  47. D.L. Marcus, D.L. Wong, M.L. Freedman, Dietary aluminum and alzheimer’s disease. J. Nutr. Elder. 12, 55–61 (1992). https://doi.org/10.1300/J052v12n02_04

    Article  PubMed  CAS  Google Scholar 

  48. H.P. Carr, E. Lombi, H. Küpper, S.P. McGrath, M.H. Wong, Accumulation and distribution of aluminium and other elements in tea (Camellia sinensis) leaves. Agronomie. 23, 705–710 (2003). https://doi.org/10.1051/agro:2003045

    Article  CAS  Google Scholar 

  49. S. Kakutani, H. Watanabe, N. Murayama, Green tea intake and risks for dementia, Alzheimer’s disease, mild cognitive impairment, and cognitive impairment: a systematic review. Nutrients. 11, 1165 (2019). https://doi.org/10.3390/nu11051165

    Article  PubMed Central  Google Scholar 

  50. M. Noguchi-Shinohara, S. Yuki, C. Dohmoto, Y. Ikeda, M. Samuraki, K. Iwasa, M. Yokogawa, K. Asai, K. Komai, H. Nakamura, M. Yamada, Consumption of green tea, but not black tea or coffee, is associated with reduced risk of cognitive decline. PLoS ONE 9, e96013 (2014). https://doi.org/10.1371/journal.pone.0096013

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  51. C.A. Polito, Z.Y. Cai, Y.L. Shi, X.M. Li, R. Yang, M. Shi, Q.S. Li, S.C. Ma, L.P. Xiang, K.R. Wang, J.H. Ye, J.L. Lu, X.Q. Zheng, Y.R. Liang, Association of tea consumption with risk of alzheimer’s disease and anti-beta-amyloid effects of tea. Nutrients. 10, 655 (2018). https://doi.org/10.3390/nu10050655

    Article  PubMed Central  CAS  Google Scholar 

  52. S.C. Sofuoglu, P. Kavcar, An exposure and risk assessment for fluoride and trace metals in black tea. J. Hazard. Mater. 158, 392–400 (2008). https://doi.org/10.1016/j.jhazmat.2008.01.086

    Article  PubMed  CAS  Google Scholar 

  53. T. Fei, J. Fei, F. Huang, T. Xie, J. Xu, Y. Zhou, P. Yang, The anti-aging and anti-oxidation effects of tea water extract in Caenorhabditis elegans. Exp. Gerontol. 97, 89–96 (2017). https://doi.org/10.1016/j.exger.2017.07.015

    Article  PubMed  CAS  Google Scholar 

  54. S. Peters, A. Reid, L. Fritschi, N. De Klerk, A.W. Musk, Long-term effects of aluminium dust inhalation. Occup. Environ. Med. (2013). https://doi.org/10.1136/oemed-2013-101487

    Article  PubMed  Google Scholar 

  55. S.A. Virk, G.D. Eslick, Occupational exposure to aluminum and Alzheimer disease a meta-analysis. J. Occup. Environ. Med. 57, 893–896 (2015). https://doi.org/10.1097/JOM.0000000000000487

    Article  PubMed  CAS  Google Scholar 

  56. S. Meshitsuka, D.A. Aremu, T. Nose, A risk of Alzheimer’s disease and aluminum in drinking water. Psychogeriatrics. 2, 263–268 (2002). https://doi.org/10.1111/j.1479-8301.2002.tb00039.x

    Article  Google Scholar 

  57. V. Rondeau, H. Jacqmin-Gadda, D. Commenges, C. Helmer, J.F. Dartigues, Aluminum and silica in drinking water and the risk of Alzheimer’s disease or cognitive decline: findings from 15-year follow-up of the PAQUID cohort. Am. J. Epidemiol. 169, 489–496 (2009). https://doi.org/10.1093/aje/kwn348

    Article  PubMed  Google Scholar 

  58. C.N. Martyn, D.N. Coggon, H. Inskip, R.F. Lacey, W.F. Young, Aluminum concentrations in drinking water and risk of Alzheimer’s disease. Epidemiology. 8, 281–286 (1997). https://doi.org/10.1097/00001648-199705000-00009

    Article  PubMed  CAS  Google Scholar 

  59. D.P. Forster, A.J. Newens, D.W.K. Kay, J.A. Edwardson, Risk factors in clinically diagnosed presenile dementia of the Alzheimer type: A case-control study in northern England. J. Epidemiol. Community Health. 49, 253–258 (1995). https://doi.org/10.1136/jech.49.3.253

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  60. G.A. Taylor, A.J. Newens, J.A. Edwardson, D.W.K. Kay, D.P. Forster, Alzheimer’s disease and the relationship between silicon and aluminium in water supplies in northern England. J. Epidemiol. Community Health. 49, 323–324 (1995). https://doi.org/10.1136/jech.49.3.323

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  61. X.L. Shen, J.H. Yu, D.F. Zhang, J.X. Xie, H. Jiang, Positive relationship between mortality from Alzheimer’s disease and soil metal concentration in mainland China. J. Alzheimer’s Dis. 42, 893–900 (2014). https://doi.org/10.3233/JAD-140153

    Article  CAS  Google Scholar 

  62. Z. Wang, X. Wei, J. Yang, J. Suo, J. Chen, X. Liu, X. Zhao, Chronic exposure to aluminum and risk of Alzheimer’s disease: a meta-analysis. Neurosci. Lett. 610, 200–206 (2016). https://doi.org/10.1016/j.neulet.2015.11.014

    Article  PubMed  CAS  Google Scholar 

  63. A. Mirza, A. King, C. Troakes, C. Exley, Aluminium in brain tissue in familial Alzheimer’s disease. J. Trace Elem. Med. Biol. 40, 30–36 (2017). https://doi.org/10.1016/j.jtemb.2016.12.001

    Article  PubMed  CAS  Google Scholar 

  64. S. Yumoto, S. Kakimi, A. Ohsaki, A. Ishikawa, Demonstration of aluminum in amyloid fibers in the cores of senile plaques in the brains of patients with Alzheimer’s disease. J. Inorg. Biochem. 103, 1579–1584 (2009). https://doi.org/10.1016/j.jinorgbio.2009.07.023

    Article  PubMed  CAS  Google Scholar 

  65. S. Bhattacharjee, Y. Zhao, J.M. Hill, F. Culicchia, T.P.A. Kruck, M.E. Percy, A.I. Pogue, J.R. Walton, W.J. Lukiw, Selective accumulation of aluminum in cerebral arteries in alzheimer’s disease (ad). J. Inorg. Biochem. 126, 35–37 (2013). https://doi.org/10.1016/j.jinorgbio.2013.05.007

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  66. L.M. Gaetke, H.S. Chow-Johnson, C.K. Chow, Copper: toxicological relevance and mechanisms. Arch. Toxicol. 88, 1929–1938 (2014). https://doi.org/10.1007/s00204-014-1355-y

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  67. I. of Medicine, Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc (2001). https://doi.org/10.17226/10026.

  68. A.A. Taylor, J.S. Tsuji, M.R. Garry, M.E. McArdle, W.L. Goodfellow, W.J. Adams, C.A. Menzie, Critical review of exposure and effects: implications for setting regulatory health criteria for ingested copper. Environ. Manage. 65, 131–159 (2020). https://doi.org/10.1007/s00267-019-01234-y

    Article  PubMed  Google Scholar 

  69. M.J. Ceko, J.B. Aitken, H.H. Harris, Speciation of copper in a range of food types by X-ray absorption spectroscopy. Food Chem. 164, 50–54 (2014). https://doi.org/10.1016/j.foodchem.2014.05.018

    Article  PubMed  CAS  Google Scholar 

  70. R.S. Ohgami, D.R. Campagna, A. McDonald, M.D. Fleming, The Steap proteins are metalloreductases. Blood 108, 1388–1394 (2006). https://doi.org/10.1182/blood-2006-02-003681

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  71. P.V.E. Van Den Berghe, L.W.J. Klomp, New developments in the regulation of intestinal copper absorption. Nutr. Rev. 67, 658–672 (2009). https://doi.org/10.1111/j.1753-4887.2009.00250.x

    Article  PubMed  Google Scholar 

  72. M. Bost, S. Houdart, M. Oberli, E. Kalonji, J.F. Huneau, I. Margaritis, Dietary copper and human health: Current evidence and unresolved issues. J. Trace Elem. Med. Biol. 35, 107–115 (2016). https://doi.org/10.1016/j.jtemb.2016.02.006

    Article  PubMed  CAS  Google Scholar 

  73. H. Kessler, F.-G. Pajonk, D. Bach, T. Schneider-Axmann, P. Falkai, W. Herrmann, G. Multhaup, J. Wiltfang, S. Schafer, O. Wirths, T.A. Bayer, Effect of copper intake on CSF parameters in patients with mild Alzheimer’s disease: a pilot phase 2 clinical trial. J. Neural Transm. 115, 1181–1187 (2008). https://doi.org/10.1007/s00702-008-0080-1

    Article  PubMed  CAS  Google Scholar 

  74. M.C. Morris, D.A. Evans, C.C. Tangney, J.L. Bienias, J.A. Schneider, R.S. Wilson, P.A. Scherr, Dietary copper and high saturated and trans fat intakes associated with cognitive decline. Arch. Neurol. 63, 1085–1088 (2006). https://doi.org/10.1001/archneur.63.8.1085

    Article  PubMed  Google Scholar 

  75. G.J. Brewer, Copper toxicity in Alzheimer’s disease: cognitive loss from ingestion of inorganic copper. J. Trace Elem. Med. Biol. 26, 89–92 (2012). https://doi.org/10.1016/j.jtemb.2012.04.019

    Article  PubMed  CAS  Google Scholar 

  76. G.J. Brewer, S.H. Kanzer, E.A. Zimmerman, D.F. Celmins, S.M. Heckman, R. Dick, Copper and ceruloplasmin abnormalities in Alzheimer’s disease. Am. J. Alzheimers. Dis. Other Demen. 25, 490–497 (2010). https://doi.org/10.1177/1533317510375083

    Article  PubMed  Google Scholar 

  77. G.R. Behbehani, L. Barzegar, M. Mohebbian, A.A. Saboury, A comparative interaction between copper ions with Alzheimer’s amyloid peptide and human serum albumin. Bioinorg. Chem. Appl. (2012). https://doi.org/10.1155/2012/208641

    Article  PubMed  PubMed Central  Google Scholar 

  78. H.W. Hsu, S.C. Bondy, M. Kitazawa, Environmental and dietary exposure to copper and its cellular mechanisms linking to Alzheimer’s disease. Toxicol. Sci. 163, 338–345 (2018). https://doi.org/10.1093/toxsci/kfy025

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  79. I. Singh, A.P. Sagare, M. Coma, D. Perlmutter, R. Gelein, R.D. Bell, R.J. Deane, E. Zhong, M. Parisi, J. Ciszewski, R.T. Kasper, R. Deane, Low levels of copper disrupt brain amyloid-β homeostasis by altering its production and clearance. Proc. Natl. Acad. Sci. 110, 14771–14776 (2013). https://doi.org/10.1073/pnas.1302212110

    Article  PubMed  PubMed Central  Google Scholar 

  80. L. Pickart, J.M. Vasquez-Soltero, A. Margolina, The effect of the human peptide GHK on gene expression relevant to nervous system function and cognitive decline. Brain Sci. 7, 20 (2017). https://doi.org/10.3390/brainsci7020020

    Article  PubMed Central  CAS  Google Scholar 

  81. S.J. Bhathena, L. Recant, N.R. Voyles, K.I. Timmers, S. Reiser, J.C. Smith, A.S. Powell, Decreased plasma enkephalins in copper deficiency in man. Am. J. Clin. Nutr. 43, 42–46 (1986). https://doi.org/10.1093/ajcn/43.1.42

    Article  PubMed  CAS  Google Scholar 

  82. E.L. Sampson, N. White, K. Lord, B. Leurent, V. Vickerstaff, S. Scott, L. Jones, Pain, agitation, and behavioural problems in people with dementia admitted to general hospital wards: a longitudinal cohort study. Pain 156, 675–683 (2015). https://doi.org/10.1097/j.pain.0000000000000095

    Article  PubMed  PubMed Central  Google Scholar 

  83. Z. Cai, A. Ratka, Opioid system and Alzheimer’s disease. Neuromol. Med. 14, 91–111 (2012). https://doi.org/10.1007/s12017-012-8180-3

    Article  CAS  Google Scholar 

  84. L. Pirpamer, E. Hofer, B. Gesierich, F. De Guio, P. Freudenberger, S. Seiler, M. Duering, E. Jouvent, E. Duchesnay, M. Dichgans, S. Ropele, R. Schmidt, Determinants of iron accumulation in the normal aging brain. Neurobiol. Aging. 43, 149–155 (2016). https://doi.org/10.1016/j.neurobiolaging.2016.04.002

    Article  PubMed  CAS  Google Scholar 

  85. J. Stankiewicz, S.S. Panter, M. Neema, A. Arora, C.E. Batt, R. Bakshi, Iron in chronic brain disorders: imaging and neurotherapeutic implications. Neurotherapeutics. 4, 371–386 (2007). https://doi.org/10.1016/j.nurt.2007.05.006

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  86. B.B. Yavuz, M. Cankurtaran, I.C. Haznedaroglu, M. Halil, Z. Ulger, B. Altun, S. Ariogul, Iron deficiency can cause cognitive impairment in geriatric patients. J. Nutr. Heal. Aging. 16, 220–224 (2012). https://doi.org/10.1007/s12603-011-0351-7

    Article  CAS  Google Scholar 

  87. P.K. Lam, D. Kritz-Silverstein, E. Barrett-Connor, D. Milne, F. Nielsen, A. Gamst, D. Morton, D. Wingard, Plasma trace elements and cognitive function in older men and women: the Rancho Bernardo study. J. Nutr. Heal. Aging. 12, 22–27 (2008). https://doi.org/10.1007/BF02982160

    Article  CAS  Google Scholar 

  88. R.C. Shah, A.S. Buchman, R.S. Wilson, S.E. Leurgans, D.A. Bennett, Hemoglobin level in older persons and incident Alzheimer disease prospective cohort analysis. Neurology. 77, 219–226 (2011). https://doi.org/10.1212/WNL.0b013e318225aaa9

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  89. D.D. Li, W. Zhang, Z.Y. Wang, P. Zhao, Serum copper, zinc, and iron levels in patients with Alzheimer’s disease: a meta-analysis of case-control studies. Front. Aging Neurosci. 15, 300 (2017). https://doi.org/10.3389/fnagi.2017.00300

    Article  CAS  Google Scholar 

  90. A. Damulina, L. Pirpamer, M. Soellradl, M. Sackl, C. Tinauer, E. Hofer, C. Enzinger, B. Gesierich, M. Duering, S. Ropele, R. Schmidt, C. Langkammer, Cross-sectional and longitudinal assessment of brain iron level in Alzheimer disease using 3-T MRI. Radiology 296, 619–626 (2020). https://doi.org/10.1148/radiol.2020192541

    Article  PubMed  Google Scholar 

  91. S. Ayton, Y. Wang, I. Diouf, J.A. Schneider, J. Brockman, M.C. Morris, A.I. Bush, Brain iron is associated with accelerated cognitive decline in people with Alzheimer pathology. Mol. Psychiatry. 25, 2932–2941 (2020). https://doi.org/10.1038/s41380-019-0375-7

    Article  PubMed  CAS  Google Scholar 

  92. J. Everett, J. Brooks, F. Lermyte, P.B. O’Connor, P.J. Sadler, J. Dobson, J.F. Collingwood, N.D. Telling, Iron stored in ferritin is chemically reduced in the presence of aggregating Aβ(1–42). Sci. Rep. 10, 10332 (2020). https://doi.org/10.1038/s41598-020-67117-z

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  93. Z. Xie, H. Wu, J. Zhao, Multifunctional roles of zinc in Alzheimer’s disease. Neurotoxicology. 80, 112–123 (2020). https://doi.org/10.1016/j.neuro.2020.07.003

    Article  PubMed  CAS  Google Scholar 

  94. S.D. Gower-Winter, C.W. Levenson, Zinc in the central nervous system: From molecules to behavior. BioFactors 38, 186–193 (2012). https://doi.org/10.1002/biof.1012

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  95. J. Chaudhary, R. Jora, P. Sharma, R. Gehlot, A study of iron and zinc deficiency on short term memory in children & effect of their supplementation. Asian J. Biomed. Pharm. Sci. 5, 12–15 (2015). https://doi.org/10.15272/ajbps.v5i42.664

    Article  Google Scholar 

  96. J.E. De Moura, E.N.O. De Moura, C.X. Alves, S.H. De Lima Vale, M.M.G. Dantas, A. De Araújo Silva, M. Das Graças Almeida, L.D. Leite, J. Brandão-Neto, Oral zinc supplementation may improve cognitive function in schoolchildren. Biol. Trace Elem. Res. 155, 23–28 (2013). https://doi.org/10.1007/s12011-013-9766-9

    Article  PubMed  CAS  Google Scholar 

  97. E. Khodashenas, A. Mohammadzadeh, M. Sohrabi, A. Izanloo, The effect of zinc supplementation on cognitive performance in schoolchildren. Int. J. Pediatr. 3, 1033–1038 (2015). https://doi.org/10.22038/ijp.2015.5617

    Article  Google Scholar 

  98. R.P. Tupe, S.A. Chiplonkar, Zinc supplementation improved cognitive performance and taste acuity in indian adolescent girls. J. Am. Coll. Nutr. 28, 388–396 (2009). https://doi.org/10.1080/07315724.2009.10718101

    Article  PubMed  CAS  Google Scholar 

  99. Y. Xu, G. Xiao, L. Liu, M. Lang, Zinc transporters in Alzheimer’s disease. Mol. Brain. 12, 1–12 (2019). https://doi.org/10.1186/s13041-019-0528-2

    Article  Google Scholar 

  100. V. Tõugu, A. Karafin, K. Zovo, R.S. Chung, C. Howells, A.K. West, P. Palumaa, Zn(II)- and Cu(II)-induced non-fibrillar aggregates of amyloid-β (1–42) peptide are transformed to amyloid fibrils, both spontaneously and under the influence of metal chelators. J. Neurochem. 110, 1784–1795 (2009). https://doi.org/10.1111/j.1471-4159.2009.06269.x

    Article  PubMed  CAS  Google Scholar 

  101. J. Mutter, A. Curth, J. Naumann, R. Deth, H. Walach, Does inorganic mercury play a role in Alzheimer’s disease? A systematic review and an integrated molecular mechanism. J. Alzheimer’s Dis. 22, 357–374 (2010). https://doi.org/10.3233/JAD-2010-100705

    Article  CAS  Google Scholar 

  102. T. Sanders, Y. Liu, V. Buchner, P.B. Tchounwou, Neurotoxic effects and biomarkers of lead exposure: a review. Rev. Environ. Health. 24, 15–45 (2009). https://doi.org/10.1515/REVEH.2009.24.1.15

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  103. T.W. Clarkson, L. Magos, G.J. Myers, The toxicology of mercury—current exposures and clinical manifestations. N. Engl. J. Med. 349, 1731–1737 (2003). https://doi.org/10.1056/NEJMra022471

    Article  PubMed  CAS  Google Scholar 

  104. M.R. Basha, W. Wei, S.A. Bakheet, N. Benitez, H.K. Siddiqi, Y.W. Ge, D.K. Lahiri, N.H. Zawia, The fetal basis of amyloidogenesis: exposure to lead and latent overexpression of amyloid precursor protein and β-amyloid in the aging brain. J. Neurosci. 25, 823–829 (2005). https://doi.org/10.1523/JNEUROSCI.4335-04.2005

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  105. J. Wu, M.R. Basha, B. Brock, D.P. Cox, F. Cardozo-Pelaez, C.A. McPherson, J. Harry, D.C. Rice, B. Maloney, D. Chen, D.K. Lahiri, N.H. Zawia, Alzheimer’s Disease (AD)-like pathology in aged monkeys after infantile exposure to environmental metal lead (Pb): evidence for a developmental origin and environmental link for AD. J. Neurosci. 28, 3–9 (2008). https://doi.org/10.1523/JNEUROSCI.4405-07.2008

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  106. S.W. Bihaqi, Early life exposure to lead (Pb) and changes in DNA methylation: relevance to Alzheimer’s disease. Rev. Environ. Health. (2019). https://doi.org/10.1515/reveh-2018-0076

    Article  PubMed  Google Scholar 

  107. L.H. Mason, J.P. Harp, D.Y. Han, Pb neurotoxicity: Neuropsychological effects of lead toxicity. Biomed. Res. Int. 2014, 840547 (2014). https://doi.org/10.1155/2014/840547

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  108. H. Gu, P.R. Territo, S.A. Persohn, A.A. Bedwell, K. Eldridge, R. Speedy, Z. Chen, W. Zheng, Y. Du, Evaluation of chronic lead effects in the blood brain barrier system by DCE-CT. J. Trace Elem. Med. Biol. 62, 126648 (2020). https://doi.org/10.1016/j.jtemb.2020.126648

    Article  PubMed  CAS  Google Scholar 

  109. X. Shen, L. Xia, L. Liu, H. Jiang, J. Shannahan, Y. Du, W. Zheng, Altered clearance of beta-amyloid from the cerebrospinal fluid following subchronic lead exposure in rats: Roles of RAGE and LRP1 in the choroid plexus. J. Trace Elem. Med. Biol. 61, 126520 (2020). https://doi.org/10.1016/j.jtemb.2020.126520

    Article  PubMed  CAS  Google Scholar 

  110. D.J. Hare, N.G. Faux, B.R. Roberts, I. Volitakis, R.N. Martins, A.I. Bush, Lead and manganese levels in serum and erythrocytes in Alzheimer’s disease and mild cognitive impairment: results from the Australian Imaging, biomarkers and lifestyle Flagship study of ageing. Metallomics (2016). https://doi.org/10.1039/c6mt00019c

    Article  PubMed  Google Scholar 

  111. L. Xu, W. Zhang, X. Liu, C. Zhang, P. Wang, X. Zhao, Circulatory levels of toxic metals (aluminum, cadmium, mercury, lead) in patients with Alzheimer’s disease: a quantitative meta-analysis and systematic review. J. Alzheimer’s Dis. 62, 361–372 (2018). https://doi.org/10.3233/JAD-170811

    Article  CAS  Google Scholar 

  112. B.R. Roberts, T.M. Ryan, A.I. Bush, C.L. Masters, J.A. Duce, The role of metallobiology and amyloid-β peptides in Alzheimer’s disease. J. Neurochem. 120, 149–166 (2012). https://doi.org/10.1111/j.1471-4159.2011.07500.x

    Article  PubMed  CAS  Google Scholar 

  113. C. Wallin, M. Friedemann, S.B. Sholts, A. Noormägi, T. Svantesson, J. Jarvet, P.M. Roos, P. Palumaa, A. Gräslund, S.K.T.S. Wärmländer, Mercury and alzheimer’s disease: Hg(II) ions display specific binding to the amyloid-β peptide and hinder its fibrillization. Biomolecules. 10, 44 (2020). https://doi.org/10.3390/biom10010044

    Article  CAS  Google Scholar 

  114. D. Meleleo, G. Notarachille, V. Mangini, F. Arnesano, Concentration-dependent effects of mercury and lead on Aβ42: possible implications for Alzheimer’s disease. Eur. Biophys. J. 48, 173–187 (2019). https://doi.org/10.1007/s00249-018-1344-9

    Article  PubMed  CAS  Google Scholar 

  115. D.A. Geier, J.K. Kern, K.G. Homme, M.R. Geier, A cross-sectional study of blood ethylmercury levels and cognitive decline among older adults and the elderly in the United States. J. Alzheimer’s Dis. 72, 901–910 (2019). https://doi.org/10.3233/JAD-190894

    Article  Google Scholar 

  116. G. Bjørklund, A.A. Tinkov, M. Dadar, M.M. Rahman, S. Chirumbolo, A.V. Skalny, M.G. Skalnaya, B.E. Haley, O.P. Ajsuvakova, J. Aaseth, Insights into the Potential Role of Mercury in Alzheimer’s Disease. J. Mol. Neurosci. 67, 511–533 (2019). https://doi.org/10.1007/s12031-019-01274-3

    Article  PubMed  CAS  Google Scholar 

  117. G. Bjørklund, B. Hilt, M. Dadar, U. Lindh, J. Aaseth, Neurotoxic effects of mercury exposure in dental personnel. Basic Clin. Pharmacol. Toxicol. 124, 568–574 (2019). https://doi.org/10.1111/bcpt.13199

    Article  PubMed  CAS  Google Scholar 

  118. N. Nagpal, S.S. Bettiol, A. Isham, H. Hoang, L.A. Crocombe, A review of mercury exposure and health of dental personnel. Saf. Health Work. 8, 1–10 (2017). https://doi.org/10.1016/j.shaw.2016.05.007

    Article  PubMed  Google Scholar 

  119. N. Attiya, R. Fattahi, A. El-Haidani, N. Lahrach, M.Y. Amarouch, Y. Filali-Zegzouti, Mercury exposure and dentists’ health status in two regions of centrall Morocco: Descriptive cross-sectional survey. Pan Afr. Med. J. 36, 1–13 (2020). https://doi.org/10.11604/pamj.2020.36.110.19623

    Article  Google Scholar 

  120. N. Mikhailichenko, K. Yagami, J.Y. Chiou, J.Y. Huang, Y.H. Wang, J.C.C. Wei, T.J. Lai, Exposure to dental filling materials and the risk of dementia: a population-based nested case control study in Taiwan. Int. J. Environ. Res. Public Health. 16, 3283 (2019). https://doi.org/10.3390/ijerph16183283

    Article  PubMed Central  CAS  Google Scholar 

  121. R. Siblerud, J. Mutter, E. Moore, J. Naumann, H. Walach, A hypothesis and evidence that mercury may be an etiological factor in alzheimer’s disease. Int. J. Environ. Res. Public Health. 16, 5152 (2019). https://doi.org/10.3390/ijerph16245152

    Article  PubMed Central  CAS  Google Scholar 

  122. B.A. Racette, M. Aschner, T.R. Guilarte, U. Dydak, S.R. Criswell, W. Zheng, Pathophysiology of manganese-associated neurotoxicity. Neurotoxicology. 33, 881–886 (2012). https://doi.org/10.1016/j.neuro.2011.12.010

    Article  PubMed  CAS  Google Scholar 

  123. A.W. Dobson, K.M. Erikson, M. Aschner, Manganese neurotoxicity. Ann. N. Y. Acad. Sci. 1012, 115–128 (2004). https://doi.org/10.1196/annals.1306.009

    Article  PubMed  CAS  Google Scholar 

  124. M.A. Verity, Manganese neurotoxicity: a mechanistic hypothesis. Neurotoxicology. 20, 489–497 (1999)

    PubMed  CAS  Google Scholar 

  125. K. Du, M. Liu, Y. Pan, X. Zhong, M. Wei, Association of serum manganese levels with Alzheimer’s disease and mild cognitive impairment: a systematic review and meta-analysis. Nutrients. 9, 231 (2017). https://doi.org/10.3390/nu9030231

    Article  PubMed Central  CAS  Google Scholar 

  126. L. Gerhardsson, T. Lundh, L. Minthon, E. Londos, Metal concentrations in plasma and cerebrospinal fluid in patients with Alzheimer’s disease. Dement. Geriatr. Cogn. Disord. 25, 508–515 (2008). https://doi.org/10.1159/000129365

    Article  PubMed  CAS  Google Scholar 

  127. I.M. Balmu, S.A. Strungaru, A. Ciobica, M.N. Nicoara, R. Dobrin, G. Plavan, C. Tefǎnescu, Preliminary data on the interaction between some biometals and oxidative stress status in mild cognitive impairment and Alzheimer’s disease patients. Oxid. Med. Cell. Longev. 2017, 7156928 (2017). https://doi.org/10.1155/2017/7156928

    Article  CAS  Google Scholar 

  128. D.B. Milne, R.L. Sims, N.V.C. Ralston, Manganese content of the cellular components of blood. Clin. Chem. 36, 450–452 (1990). https://doi.org/10.1093/clinchem/36.3.450

    Article  PubMed  CAS  Google Scholar 

  129. Y. Tong, H. Yang, X. Tian, H. Wang, T. Zhou, S. Zhang, J. Yu, T. Zhang, D. Fan, X. Guo, T. Tabira, F. Kong, Z. Chen, W. Xiao, D. Chui, High manganese, a risk for Alzheimer’s disease: high manganese induces amyloid-β related cognitive impairment. J. Alzheimer’s Dis. 42, 865–878 (2014). https://doi.org/10.3233/JAD-140534

    Article  CAS  Google Scholar 

  130. D. Gandhi, S. Sivanesan, K. Kannan, Manganese-induced neurotoxicity and alterations in gene expression in human neuroblastoma SH-SY5Y cells. Biol. Trace Elem. Res. 183, 245–253 (2018). https://doi.org/10.1007/s12011-017-1153-5

    Article  PubMed  CAS  Google Scholar 

  131. V. Venkataramani, T.R. Doeppner, D. Willkommen, C.M. Cahill, Y. Xin, G. Ye, Y. Liu, A. Southon, A. Aron, H.Y. Au-Yeung, X. Huang, D.K. Lahiri, F. Wang, A.I. Bush, G.G. Wulf, P. Ströbel, B. Michalke, J.T. Rogers, Manganese causes neurotoxic iron accumulation via translational repression of amyloid precursor protein and H-Ferritin. J. Neurochem. 147, 831–848 (2018). https://doi.org/10.1111/jnc.14580

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  132. A.C. Martins, P. Morcillo, O.M. Ijomone, V. Venkataramani, F.E. Harrison, E. Lee, A.B. Bowman, M. Aschner, New insights on the role of manganese in alzheimer’s disease and parkinson’s disease. Int. J. Environ. Res. Public Health. 16, 3546 (2019). https://doi.org/10.3390/ijerph16193546

    Article  PubMed Central  CAS  Google Scholar 

  133. H. Vural, H. Demirin, Y. Kara, I. Eren, N. Delibas, Alterations of plasma magnesium, copper, zinc, iron and selenium concentrations and some related erythrocyte antioxidant enzyme activities in patients with Alzheimer’s disease. J. Trace Elem. Med. Biol. 24, 169–173 (2010). https://doi.org/10.1016/j.jtemb.2010.02.002

    Article  PubMed  CAS  Google Scholar 

  134. A.E. Çilliler, Ş Öztürk, Ş Özbakır, Serum magnesium level and clinical deterioration in Alzheimer’s disease. Gerontology. 53, 419–422 (2007). https://doi.org/10.1159/000110873

    Article  PubMed  Google Scholar 

  135. E. Andrási, S. Igaz, Z. Molnár, S. Makó, Disturbances of magnesium concentrations in various brain areas in Alzheimer’s disease. Magnes. Res. 13, 189–196 (2000)

    PubMed  Google Scholar 

  136. E. Andrási, N. Páli, Z. Molnár, S. Kösel, Brain aluminum, magnesium and phosphorus contents of control and Alzheimer-diseased patients. J. Alzheimer’s Dis. 7, 273–284 (2005). https://doi.org/10.3233/JAD-2005-7402

    Article  Google Scholar 

  137. N. Veronese, A. Zurlo, M. Solmi, C. Luchini, C. Trevisan, G. Bano, E. Manzato, G. Sergi, R. Rylander, Magnesium status in Alzheimer’s disease: a systematic review. Am. J. Alzheimers. Dis. Other Demen. 31, 208–213 (2016). https://doi.org/10.1177/1533317515602674

    Article  PubMed  Google Scholar 

  138. G. Liu, J.G. Weinger, Z.L. Lu, F. Xue, S. Sadeghpour, Efficacy and safety of MMFS-01, a synapse density enhancer, for treating cognitive impairment in older adults: a randomized, double-blind, placebo-controlled trial. J. Alzheimer’s Dis. 49, 971–990 (2015). https://doi.org/10.3233/JAD-150538

    Article  CAS  Google Scholar 

  139. B.C.T. Kieboom, S. Licher, F.J. Wolters, M.K. Ikram, E.J. Hoorn, R. Zietse, B.H. Stricker, M.A. Ikram, Serum magnesium is associated with the risk of dementia. Neurology. 89, 1716–1722 (2017). https://doi.org/10.1212/WNL.0000000000004517

    Article  PubMed  CAS  Google Scholar 

  140. X. Zhu, A.R. Borenstein, Y. Zheng, W. Zhang, D.L. Seidner, R. Ness, H.J. Murff, B. Li, M.J. Shrubsole, C. Yu, L. Hou, Q. Dai, Ca: Mg ratio, APOE cytosine modifications, and cognitive function: results from a randomized trial. J. Alzheimer’s Dis. 75, 85–98 (2020). https://doi.org/10.3233/jad-191223

    Article  CAS  Google Scholar 

  141. J. Liu, W. Zhao, E.B. Ware, S.T. Turner, T.H. Mosley, J.A. Smith, DNA methylation in the APOE genomic region is associated with cognitive function in African Americans. BMC Med. Genom. 11, 43 (2018). https://doi.org/10.1186/s12920-018-0363-9

    Article  CAS  Google Scholar 

  142. B. Wu, H. Cai, S. Tang, Y. Xu, Q. Shi, L. Wei, L. Meng, N. Zhang, X. Wang, D. Xiao, Y. Zou, X. Yang, X. Li, C. Lu, Methionine-mediated protein phosphatase 2A catalytic subunit (PP2Ac) methylation ameliorates the tauopathy induced by manganese in cell and animal models. Neurotherapeutics. (2020). https://doi.org/10.1007/s13311-020-00930-6

    Article  PubMed  PubMed Central  Google Scholar 

  143. D. Zhu, J. You, N. Zhao, H. Xu, Magnesium regulates endothelial barrier functions through TRPM7, MagT1, and S1P1. Adv. Sci. 6, 1901166 (2019). https://doi.org/10.1002/advs.201901166

    Article  CAS  Google Scholar 

  144. C. Smorgon, E. Mari, A.R. Atti, E. Dalla Nora, P.F. Zamboni, F. Calzoni, A. Passaro, R. Fellin, Trace elements and cognitive impairment: an elderly cohort study. Arch. Gerontol. Geriatr. 9, 393–402 (2004). https://doi.org/10.1016/j.archger.2004.04.050

    Article  CAS  Google Scholar 

  145. J. Siuda, A. Gorzkowska, M. Patalong-Ogiewa, E. Krzystanek, E. Czech, B. Wiechuła, W. Garczorz, A. Danch, B. Jasińska-Myga, G. Opala, From mild cognitive impairment to Alzheimer’s disease—Influence of homocysteine, vitamin B 12 and folate on cognition over time: Results from one-year follow-up. Neurol. Neurochir. Pol. 43, 321–329 (2009)

    PubMed  CAS  Google Scholar 

  146. C.I. Prodan, L.D. Cowan, J.A. Stoner, E.D. Ross, Cumulative incidence of vitamin B12 deficiency in patients with Alzheimer disease. J. Neurol. Sci. 284, 144–148 (2009). https://doi.org/10.1016/j.jns.2009.05.005

    Article  PubMed  CAS  Google Scholar 

  147. C. Guan, R. Dang, Y. Cui, L. Liu, X. Chen, X. Wang, J. Zhu, D. Li, J. Li, D. Wang, Characterization of plasma metal profiles in Alzheimer’s disease using multivariate statistical analysis. PLoS ONE 12, e0178271 (2017). https://doi.org/10.1371/journal.pone.0178271

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  148. S. Rafiee, K. Asadollahi, G. Riazi, S. Ahmadian, A.A. Saboury, Vitamin B12 inhibits tau fibrillization via binding to cysteine residues of tau. ACS Chem. Neurosci. 8, 2676–2682 (2017). https://doi.org/10.1021/acschemneuro.7b00230

    Article  PubMed  CAS  Google Scholar 

  149. N.V. Gorantla, E. Balaraman, S. Chinnathambi, Cobalt-based metal complexes prevent repeat tau aggregation and nontoxic to neuronal cells. Int. J. Biol. Macromol. 152, 171–179 (2020). https://doi.org/10.1016/j.ijbiomac.2020.02.278

    Article  PubMed  CAS  Google Scholar 

  150. K.F. Roberts, C.R. Brue, A. Preston, D. Baxter, E. Herzog, E. Varelas, T.J. Meade, Cobalt(III) Schiff base complexes stabilize non-fibrillar amyloid-β aggregates with reduced toxicity. J. Inorg. Biochem. 213, 111265 (2020). https://doi.org/10.1016/j.jinorgbio.2020.111265

    Article  PubMed  CAS  Google Scholar 

  151. E.A. Bajema, K.F. Roberts, T.J. Meade, Cobalt-schiff base complexes: preclinical research and potential therapeutic uses. Met. Ions Life Sci. NLM (Medline) (2019). https://doi.org/10.1515/9783110527872-017

    Article  Google Scholar 

  152. A.H. Smith, P.A. Lopipero, M.N. Bates, C.M. Steinmaus, Arsenic epidemiology and drinking water standards. Science 296, 2145–2146 (2002). https://doi.org/10.1126/science.1072896

    Article  PubMed  CAS  Google Scholar 

  153. S.S. Tao, P.M. Bolger, Dietary arsenic intakes in the United States: FDA total diet study, September 1991-December 1996. Food Addit. Contam. 16, 465–472 (1999). https://doi.org/10.1080/026520399283759

    Article  PubMed  CAS  Google Scholar 

  154. L. Baum, I.H.S. Chan, S.K.K. Cheung, W.B. Goggins, V. Mok, L. Lam, V. Leung, E. Hui, C. Ng, J. Woo, H.F.K. Chiu, B.C.Y. Zee, W. Cheng, M.H. Chan, S. Szeto, V. Lui, J. Tsoh, A.I. Bush, C.W.K. Lam, T. Kwok, Serum zinc is decreased in Alzheimer’s disease and serum arsenic correlates positively with cognitive ability. Biometals 23, 173–179 (2010). https://doi.org/10.1007/s10534-009-9277-5

    Article  PubMed  CAS  Google Scholar 

  155. B.I. Giasson, D.M. Sampathu, C.A. Wilson, V. Vogelsberg-Ragaglia, W.E. Mushynski, V.M.Y. Lee, The environmental toxin arsenite induces tau hyperphosphorylation. Biochemistry 41, 15376–15387 (2002). https://doi.org/10.1021/bi026813c

    Article  PubMed  CAS  Google Scholar 

  156. N.N. Dewji, C. Do, R.M. Bayney, Transcriptional activation of Alzheimer’s β-amyloid precursor protein gene by stress. Mol. Brain Res. 33, 245–253 (1995). https://doi.org/10.1016/0169-328X(95)00131-B

    Article  PubMed  CAS  Google Scholar 

  157. S. Zarazúa, S. Bürger, J.M. Delgado, M.E. Jiménez-Capdeville, R. Schliebs, Arsenic affects expression and processing of amyloid precursor protein (APP) in primary neuronal cells overexpressing the Swedish mutation of human APP. Int. J. Dev. Neurosci. 29, 389–396 (2011). https://doi.org/10.1016/j.ijdevneu.2011.03.004

    Article  PubMed  CAS  Google Scholar 

  158. S. Gharibzadeh, S.S. Hoseini, Arsenic exposure may be a risk factor for alzheimer’s disease. J. Neuropsychiatry Clin. Neurosci. 20, 501 (2008). https://doi.org/10.1176/jnp.2008.20.4.501

    Article  PubMed  Google Scholar 

  159. X.L. Li, R.Q. Zhan, W. Zheng, H. Jiang, D.F. Zhang, X.L. Shen, Positive association between soil arsenic concentration and mortality from alzheimer’s disease in mainland China. J. Trace Elem. Med. Biol. 59, 126452 (2020). https://doi.org/10.1016/j.jtemb.2020.126452

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  160. M. Edwards, L. Johnson, C. Mauer, R. Barber, J. Hall, S. Obryant, Regional specific groundwater arsenic levels and neuropsychological functioning: a cross-sectional study. Int. J. Environ. Health Res. 24, 546–557 (2014). https://doi.org/10.1080/09603123.2014.883591

    Article  PubMed  PubMed Central  Google Scholar 

  161. S.E. O’Bryant, M. Edwards, C.V. Menon, G. Gong, R. Barber, Long-term low-level arsenic exposure is associated with poorer neuropsychological functioning: a project FRONTIER study. Int. J. Environ. Res. Public Health. 8, 861–874 (2011). https://doi.org/10.3390/ijerph8030861

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  162. S. Alboghobeish, M. Pashmforosh, L. Zeidooni, A. Samimi, M. Rezaei, High fat diet deteriorates the memory impairment induced by arsenic in mice: a sub chronic in vivo study. Metab. Brain Dis. 34, 1595–1606 (2019). https://doi.org/10.1007/s11011-019-00467-4

    Article  PubMed  CAS  Google Scholar 

  163. N. Medda, R. Patra, T.K. Ghosh, S. Maiti, Neurotoxic mechanism of arsenic: synergistic effect of mitochondrial instability, oxidative stress, and hormonal-neurotransmitter impairment. Biol. Trace Elem. Res. 198, 8–15 (2020). https://doi.org/10.1007/s12011-020-02044-8

    Article  PubMed  CAS  Google Scholar 

  164. Y.-W. Yang, S.-H. Liou, Y.-M. Hsueh, W.-S. Lyu, C.-S. Liu, H.-J. Liu, M.-C. Chung, P.-H. Hung, C.-J. Chung, Risk of Alzheimer’s disease with metal concentrations in whole blood and urine: a case–control study using propensity score matching. Toxicol. Appl. Pharmacol. 356, 8–14 (2018). https://doi.org/10.1016/j.taap.2018.07.015

    Article  PubMed  CAS  Google Scholar 

  165. C. Garza-Lombó, A. Pappa, M.I. Panayiotidis, M.E. Gonsebatt, R. Franco, Arsenic-induced neurotoxicity: a mechanistic appraisal. J. Biol. Inorg. Chem. 24, 1305–1316 (2019). https://doi.org/10.1007/s00775-019-01740-8

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  166. S. Satarug, D.A. Vesey, G.C. Gobe, Health risk assessment of dietary cadmium intake: do current guidelines indicate how much is safe? Environ. Health Perspect. 125, 284–288 (2017). https://doi.org/10.1289/EHP108

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  167. K.M. Bakulski, Y.A. Seo, R.C. Hickman, D. Brandt, H.S. Vadari, H. Hu, S.K. Park, Heavy metals exposure and Alzheimer’s disease and related dementias. J. Alzheimers. Dis. 76, 1215–1242 (2020). https://doi.org/10.3233/JAD-200282

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  168. H. Li, Z. Wang, Z. Fu, M. Yan, N. Wu, H. Wu, P. Yin, Associations between blood cadmium levels and cognitive function in a cross-sectional study of US adults aged 60 years or older. BMJ Open. 8, e020533 (2018). https://doi.org/10.1136/bmjopen-2017-020533

    Article  PubMed  PubMed Central  Google Scholar 

  169. J.Y. Min, K.B. Min, Blood cadmium levels and Alzheimer’s disease mortality risk in older US adults. Environ. Heal. A Glob. Access Sci. Source. 15, 69 (2016). https://doi.org/10.1186/s12940-016-0155-7

    Article  CAS  Google Scholar 

  170. J.R. Bondier, G. Michel, A. Propper, P.M. Badot, Harmful effects of cadmium on olfactory system in mice. Inhal. Toxicol. 20, 1169–1177 (2008). https://doi.org/10.1080/08958370802207292

    Article  PubMed  CAS  Google Scholar 

  171. J.J.V. Branca, M. Maresca, G. Morucci, T. Mello, M. Becatti, L. Pazzagli, I. Colzi, C. Gonnelli, D. Carrino, F. Paternostro, C. Nicoletti, C. Ghelardini, M. Gulisano, L.D.C. Mannelli, A. Pacini, Effects of cadmium on ZO-1 tight junction integrity of the blood brain barrier. Int. J. Mol. Sci. 20, 6010 (2019). https://doi.org/10.3390/ijms20236010

    Article  PubMed Central  CAS  Google Scholar 

  172. M. Forcella, P. Lau, M. Oldani, P. Melchioretto, A. Bogni, L. Gribaldo, P. Fusi, C. Urani, Neuronal specific and non-specific responses to cadmium possibly involved in neurodegeneration: a toxicogenomics study in a human neuronal cell model. Neurotoxicology. 76, 162–173 (2020). https://doi.org/10.1016/j.neuro.2019.11.002

    Article  PubMed  CAS  Google Scholar 

  173. T.M. Frisoli, R.E. Schmieder, T. Grodzicki, F.H. Messerli, Salt and hypertension: Is salt dietary reduction worth the effort? Am. J. Med. 125, 433–439 (2012). https://doi.org/10.1016/j.amjmed.2011.10.023

    Article  PubMed  CAS  Google Scholar 

  174. D. Mohan, K.H. Yap, D. Reidpath, Y.C. Soh, A. McGrattan, B.C.M. Stephan, L. Robinson, N. Chaiyakunapruk, M. Siervo, Link between dietary sodium intake, cognitive function, and dementia risk in middle-aged and older adults: a systematic review. J. Alzheimers. Dis. 76, 1347–1373 (2020). https://doi.org/10.3233/JAD-191339

    Article  PubMed  PubMed Central  Google Scholar 

  175. E. Koseoglu, R. Koseoglu, M. Kendirci, R. Saraymen, B. Saraymen, Trace metal concentrations in hair and nails from Alzheimer’s disease patients: Relations with clinical severity. J. Trace Elem. Med. Biol. 39, 124–128 (2017). https://doi.org/10.1016/j.jtemb.2016.09.002

    Article  PubMed  CAS  Google Scholar 

  176. K. Higuchi, T. Sato, Y.D. Bhutia, V. Ganapathy, Involvement of a Na+-coupled oligopeptide transport system for β-amyloid peptide (Aβ1–42) in brain cells. Pharm. Res. 37, 98 (2020). https://doi.org/10.1007/s11095-020-02835-7

    Article  PubMed  CAS  Google Scholar 

  177. G. Faraco, K. Hochrainer, S.G. Segarra, S. Schaeffer, M.M. Santisteban, A. Menon, H. Jiang, D.M. Holtzman, J. Anrather, C. Iadecola, Dietary salt promotes cognitive impairment through tau phosphorylation. Nature 574, 686–690 (2019). https://doi.org/10.1038/s41586-019-1688-z

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  178. G. Paglia, O. Miedico, A. Cristofano, M. Vitale, A. Angiolillo, A.E. Chiaravalle, G. Corso, A. Di Costanzo, Distinctive pattern of serum elements during the progression of Alzheimer’s disease. Sci. Rep. 6, 22769 (2016). https://doi.org/10.1038/srep22769

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  179. B.R. Roberts, J.D. Doecke, A. Rembach, L.F. Yévenes, C.J. Fowler, C.A. McLean, M. Lind, I. Volitakis, C.L. Masters, A.I. Bush, D.J. Hare, Rubidium and potassium levels are altered in Alzheimer’s disease brain and blood but not in cerebrospinal fluid. Acta Neuropathol. Commun. 4, 119 (2016). https://doi.org/10.1186/s40478-016-0390-8

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  180. K. Schofield, The metal neurotoxins: an important role in current human neural epidemics? Int. J. Environ. Res. Public Health. 14, 1511 (2017). https://doi.org/10.3390/ijerph14121511

    Article  PubMed Central  CAS  Google Scholar 

  181. C.E. Cicero, G. Mostile, R. Vasta, V. Rapisarda, S.S. Signorelli, M. Ferrante, M. Zappia, A. Nicoletti, Metals and neurodegenerative diseases. A systematic review. Environ. Res. 159, 82–94 (2017). https://doi.org/10.1016/j.envres.2017.07.048

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The authors would like to thank the Vice Chancellor for Research and Technology, Kermanshah University of Medical Sciences, for providing suitable conditions to conduct this study.

Author information

Authors and Affiliations

  1. Medical Biology Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran

    Soghra Bagheri

  2. Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran

    Ali A. Saboury

Authors
  1. Soghra Bagheri
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ali A. Saboury
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Soghra Bagheri.

Ethics declarations

Conflict of interest

It is declared that we do not have any conflicts of interest regarding the present study.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Bagheri, S., Saboury, A.A. What role do metals play in Alzheimer's disease?. J IRAN CHEM SOC 18, 2199–2213 (2021). https://doi.org/10.1007/s13738-021-02181-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13738-021-02181-4

Keywords

Search

Navigation