Drugs & Aging

, Volume 29, Issue 5, pp 335–342 | Cite as

Does Lithium Prevent Alzheimer’s Disease?

  • Orestes V. ForlenzaEmail author
  • Vanessa J. de Paula
  • Rodrigo Machado-Vieira
  • Breno S. Diniz
  • Wagner F. Gattaz
Current Opinion


Lithium salts have a well-established role in the treatment of major affective disorders. More recently, experimental and clinical studies have provided evidence that lithium may also exert neuroprotective effects. In animal and cell culture models, lithium has been shown to increase neuronal viability through a combination of mechanisms that includes the inhibition of apoptosis, regulation of autophagy, increased mitochondrial function, and synthesis of neurotrophic factors. In humans, lithium treatment has been associated with humoral and structural evidence of neuroprotection, such as increased expression of anti-apoptotic genes, inhibition of cellular oxidative stress, synthesis of brain-derived neurotrophic factor (BDNF), cortical thickening, increased grey matter density, and hippocampal enlargement. Recent studies addressing the inhibition of glycogen synthase kinase-3 beta (GSK3B) by lithium have further suggested the modification of biological cascades that pertain to the pathophysiology of Alzheimer’s disease (AD). A recent placebo-controlled clinical trial in patients with amnestic mild cognitive impairment (MCI) showed that long-term lithium treatment may actually slow the progression of cognitive and functional deficits, and also attenuate Tau hyperphosphorylation in the MCI-AD continuum. Therefore, lithium treatment may yield disease-modifying effects in AD, both by the specific modification of its pathophysiology via inhibition of overactive GSK3B, and by the unspecific provision of neurotrophic and neuroprotective support. Although the clinical evidence available so far is promising, further experimentation and replication of the evidence in large scale clinical trials is still required to assess the benefit of lithium in the treatment or prevention of cognitive decline in the elderly.


Lithium Amyotrophic Lateral Sclerosis Mild Cognitive Impairment Neuroprotective Effect Hippocampal Neurogenesis 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



The authors have no conflicts of interest that are directly relevant to the content of this article.

Funding for the present work was provided by Conselho Nacional de Pesquisa Científica (CNPq, Project 554535/2005-0), Alzheimer’s Association (NIRG-08-90688), Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP, Project 02/13635-7 and 09/52825-8) and Associação Beneficente Alzira Denise Hertzog da Silva (ABADHS).


  1. 1.
    Cade JF. Lithium salts in the treatment of psychotic excitement. Med J Austr 1949; 2: 349–52Google Scholar
  2. 2.
    Young AH. More good news about the magic ion: lithium may prevent dementia. Br J Psychiatry 2011; 198 (5): 356–7CrossRefGoogle Scholar
  3. 3.
    Sarkar S, Floto RA, Berger Z, et al. Lithium induces autophagy by inhibiting inositol monophosphatase. J Cell Biol 2005; 170 (7): 1101–11PubMedCrossRefGoogle Scholar
  4. 4.
    Sarkar S, Rubinsztein DC. Inositol and IP3 levels regulate autophagy: biology and therapeutic speculations. Autophagy 2006; 2 (2): 132–4PubMedGoogle Scholar
  5. 5.
    Garcia-Arencibia M, Hochfeld W, Toh P, et al. Autophagy, a guardian against neurodegeneration. Semin Cell Dev Biol 2010; 7: 691–8Google Scholar
  6. 6.
    Chalecka-Franaszek E, Chuang DM. Lithium activates the serine/threonine kinase Akt-1 and suppresses glutamate-induced inhibition of Akt-1 activity in neurons. Proc Natl Acad Sci U S A 1999; 96: 8745–50PubMedCrossRefGoogle Scholar
  7. 7.
    Ryves WJ, Harwood AJ. Lithium inhibits glycogen synthase kinase-3 by competition for magnesium. Biochem Biophys Res Commun 2001 Jan 26; 280 (3): 720–5PubMedCrossRefGoogle Scholar
  8. 8.
    Zhang F, Phiel CJ, Spece L, et al. Inhibitory phosphorylation of glycogen synthase kinase-3 (GSK-3) in response to lithium: evidence for autoregulation of GSK-3. Biol Chem 2003; 278: 35067–77Google Scholar
  9. 9.
    Qu Z, Sun D, Young W. Lithium promotes neural precursor cell proliferation: evidence for the involvement of the non-canonical GSK-3b-NF-AT signaling. Cell Biosci 2011; 1 (1): 18PubMedCrossRefGoogle Scholar
  10. 10.
    Rao AS, Kremenevskaja N, Resch J, et al. Lithium stimulates proliferation in cultured thyrocytes by activating Wnt/beta-catenin signalling. Eur J Endocrinol 2005; 153 (6): 929–38PubMedCrossRefGoogle Scholar
  11. 11.
    Fornai F, Longone P, Cafaro L, et al. Lithium delays progression of amyotrophic lateral sclerosis. Proc Natl Acad Sci U S A 2008; 105 (6): 2052–7PubMedCrossRefGoogle Scholar
  12. 12.
    Su H, Chu TH, Wu W. Lithium enhances proliferation and neuronal differentiation of neural progenitor cells in vitro and after transplantation into the adult rat spinal cord. Exp Neurol 2007; 206 (2): 296–307PubMedCrossRefGoogle Scholar
  13. 13.
    Yasuda S, Liang MH, Marinova Z, et al. The mood stabilizers lithium and valproate selectively activate the promoter IV of brain-derived neurotrophic factor in neurons. Mol Psychiatry 2009; 14 (1): 51–9PubMedCrossRefGoogle Scholar
  14. 14.
    Jope RS, Roh MS. Glycogen synthase kinase-3 (GSK3) in psychiatric diseases and therapeutic interventions. Curr Drug Targets 2006; 7 (17100582): 1421–34PubMedCrossRefGoogle Scholar
  15. 15.
    Hong M, Chen DC, Klein PS, et al. Lithium reduces tau phosphorylation by inhibition of glycogen synthase kinase-3. J Biol Chem 1997; 272: 25326–32PubMedCrossRefGoogle Scholar
  16. 16.
    Su Y, Ryder J, Li B, et al. Lithium, a common drug for bipolar disorder treatment, regulates amyloid-beta precursor protein processing. Biochemistry 2004; 43: 6899–908PubMedCrossRefGoogle Scholar
  17. 17.
    Mendes CT, Mury FB, de Sá Moreira E, et al. Lithium reduces Gsk3b mRNA levels: implications for Alzheimer disease. Eur Arch Psychiatry Clin Neurosci 2009; 259 (1): 16–22PubMedCrossRefGoogle Scholar
  18. 18.
    Noble W, Planel E, Zehr C, et al. Inhibition of glycogen synthase kinase-3 by lithium correlates with reduced tauopathy and degeneration in vivo. Proc Natl Acad Sci 2005; 102: 6990–5PubMedCrossRefGoogle Scholar
  19. 19.
    Li Q, Li H, Roughton K, et al. Lithium reduces apoptosis and autophagy after neonatal hypoxia-ischemia. Cell Death Dis 2010; 1: e56PubMedCrossRefGoogle Scholar
  20. 20.
    Chen G, Rajkowska G, Du F, et al. Enhancement of hippocampal neurogenesis by lithium. J Neurochem 2000; 75: 1729–34PubMedCrossRefGoogle Scholar
  21. 21.
    Silva R, Mesquita AR, Bessa J, et al. Lithium blocks stress-induced changes in depressive-like behavior and hippocampal cell fate: the role of glycogen-synthase-kinase-3beta. Neuroscience 2008; 152 (18291594): 656–69PubMedCrossRefGoogle Scholar
  22. 22.
    Chen CL, Lin CF, Chiang CW, et al. Lithium inhibits ceramide- and etoposide-induced protein phosphatase 2A methylation, Bcl-2 dephosphorylation, caspase-2 activation, and apoptosis. Mol Pharmacol 2006; 70 (2): 510–7PubMedCrossRefGoogle Scholar
  23. 23.
    Senatorov VV, Ren M, Kanai H, et al. Short-term lithium treatment promotes neuronal survival and proliferation in rat striatum infused with quinolinic acid, an excitotoxic model of Huntington’s disease. Mol Psychiatry 2004; 9 (4): 371–85PubMedCrossRefGoogle Scholar
  24. 24.
    Hooper C, Markevich V, Plattner F, et al. Glycogen synthase kinase-3 inhibition is integral to long-term potentiation. Eur J Neurosci 2007; 25 (1): 81–6PubMedCrossRefGoogle Scholar
  25. 25.
    Zhang X, Heng X, Li T, et al. Long-term treatment with lithium alleviates memory deficits and reduces amyloid-beta production in an aged Alzheimer’s disease transgenic mouse model. J Alzheimers Dis 2011; 24 (4): 739–49PubMedGoogle Scholar
  26. 26.
    Wada A. Lithium and neuropsychiatric therapeutics: neuroplasticity via glycogen synthase kinase-3beta, beta-catenin, and neurotrophin cascades. J Pharmacol Sci 2009; 110 (1): 14–28PubMedCrossRefGoogle Scholar
  27. 27.
    Riadh N, Allagui MS, Bourogaa E, et al. Neuroprotective and neurotrophic effects of long term lithium treatment in mouse brain. Biometals 2011; 24 (4): 747–57PubMedCrossRefGoogle Scholar
  28. 28.
    Rametti A, Esclaire F, Yardin C, et al. Lithium down-regulates tau in cultured cortical neurons: a possible mechanism of neuroprotection. Neurosci Lett 2008; 434: 93–8PubMedCrossRefGoogle Scholar
  29. 29.
    Phiel CJ, Wilson CA, Lee VM, et al. GSK-3alpha regulates production of Alzheimer’s disease amyloid-beta peptides. Nature 2003; 423: 435–9PubMedCrossRefGoogle Scholar
  30. 30.
    Fiorentini A, Rosi MC, Grossi C, et al. Lithium improves hippocampal neurogenesis, neuropathology and cognitive functions in APP mutant mice. PLoS One 2010; 5 (12): e14382PubMedCrossRefGoogle Scholar
  31. 31.
    Machado-Vieira R, Manji HK, Zarate Jr CA. The role of lithium in the treatment of bipolar disorder: convergent evidence for neurotrophic effects as a unifying hypothesis. Bipolar Disord 2009; 11 Suppl. 2: 92–109PubMedCrossRefGoogle Scholar
  32. 32.
    Geddes JR, Goodwin GM, Rendell J, et al. Lithium plus valproate combination therapy versus monotherapy for relapse prevention in bipolar I disorder (BALANCE): a randomised open-label trial. Lancet 2010; 375 (9712): 385–95PubMedCrossRefGoogle Scholar
  33. 33.
    Lam RW, Kennedy SH, Grigoriadis S, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) clinical guidelines for the management of major depressive disorder in adults: III. Pharmacotherapy. J Affect Disord 2009; 117 Suppl. 1: S26–43PubMedCrossRefGoogle Scholar
  34. 34.
    Shulman KI. Lithium for older adults with bipolar disorder: should it still be considered a first-line agent? Drugs Aging 2010; 27 (8): 607–15PubMedCrossRefGoogle Scholar
  35. 35.
    Machado-Vieira R, Andreazza AC, Viale CI, et al. Oxidative stress parameters in unmedicated and treated bipolar subjects during initial manic episode: a possible role for lithium antioxidant effects. Neurosci Lett 2007; 421 (1): 35–6CrossRefGoogle Scholar
  36. 36.
    Machado-Vieira R, Dietrich MO, Leke R, et al. Decreased plasma brain derived neurotrophic factor levels in unmedicated bipolar patients during manic episode. Biol Psychiatry 2007; 61 (2): 142–4PubMedCrossRefGoogle Scholar
  37. 37.
    Barbosa IG, Huguet RB, Neves FS, et al. Impaired nerve growth factor homeostasis in patients with bipolar disorder. World J Biol Psychiatry 2011; 12 (3): 228–32PubMedCrossRefGoogle Scholar
  38. 38.
    Diniz BS, Teixeira AL, Talib L, et al. Interleukin-1beta serum levels is increased in antidepressant-free elderly depressed patients. Am J Geriatr Psychiatry 2010; 18: 172–6PubMedCrossRefGoogle Scholar
  39. 39.
    Diniz BS, Teixeira AL, Talib LL, et al. Serum brain-derived neurotrophic factor level is reduced in antidepressant-free patients with late-life depression. World J Biol Psychiatry 2010; 11 (3): 550–5PubMedCrossRefGoogle Scholar
  40. 40.
    Diniz BS, Teixeira AL, Talib LL, et al. Increased soluble TNF receptor 2 in antidepressant-free patients with late-life depression. J Psychiatr Res 2010; 44 (14): 917–20PubMedCrossRefGoogle Scholar
  41. 41.
    Berk M, Kapczinski F, Andreazza AC, et al. Pathways underlying neuroprogression in bipolar disorder: focus on inflammation, oxidative stress and neurotrophic factors. Neurosci Biobehav Rev 2011; 35 (3): 804–17PubMedCrossRefGoogle Scholar
  42. 42.
    Pandey GN, Ren X, Rizavi HS, et al. Glycogen synthase kinase-3beta in the platelets of patients with mood disorders: effect of treatment. J Psychiatr Res 2010; 44: 143–8PubMedCrossRefGoogle Scholar
  43. 43.
    Polter A, Beurel E, Yang S, et al. Deficiency in the inhibitory serine-phosphorylation of glycogen synthase kinase-3 increases sensitivity to mood disturbances. Neuropsychopharmacology 2010; 35 (8): 1761–74PubMedGoogle Scholar
  44. 44.
    Li X, Friedman AB, Zhu W, et al. Lithium regulates glycogen synthase kinase-3beta in human peripheral blood mononuclear cells: implication in the treatment of bipolar disorder. Biol Psychiatry 2007; 61: 216–22PubMedCrossRefGoogle Scholar
  45. 45.
    Rybakowski JK, Suwalska A. Excellent lithium responders have normal cognitive functions and plasma BDNF levels. Int J Neuropsychopharmacol 2010; 13 (5): 617–22PubMedCrossRefGoogle Scholar
  46. 46.
    de Sousa RT, van de Bilt MT, Diniz BS, et al. Lithium increases plasma brain-derived neurotrophic factor in acute bipolar mania: a preliminary 4-week study. Neurosci Lett 2011; 494 (1): 54–6PubMedCrossRefGoogle Scholar
  47. 47.
    Suwalska A, Sobieska M, Rybakowski JK. Serum brain-derived neurotrophic factor in euthymic bipolar patients on prophylactic lithium therapy. Neuropsychobiology 2010; 62 (4): 229–34PubMedCrossRefGoogle Scholar
  48. 48.
    Hashimoto R, Takei N, Shimazu K, et al. Lithium induces brain-derived neurotrophic factor and activates TrkB in rodent cortical neurons: an essential step for neuroprotection against glutamate excitotoxicity. Neuropharmacology 2002; 43 (7): 1173–9PubMedCrossRefGoogle Scholar
  49. 49.
    Aliyazicioglu R, Kural B, Colak M, et al. Treatment with lithium, alone or in combination with olanzapine, relieves oxidative stress but increases atherogenic lipids in bipolar disorder. Tohoku J Exp Med 2007; 213 (1): 79–87PubMedCrossRefGoogle Scholar
  50. 50.
    Foland LC, Altshuler LL, Sugar CA, et al. Increased volume of the amygdala and hippocampus in bipolar patients treated with lithium. Neuroreport 2008; 19 (2): 221–4PubMedCrossRefGoogle Scholar
  51. 51.
    Germana C, Kempton MJ, Sarnicola A, et al. The effects of lithium and anticonvulsants on brain structure in bipolar disorder. Acta Psychiatr Scand 2010; 122 (6): 481–7PubMedCrossRefGoogle Scholar
  52. 52.
    Yucel K, McKinnon MC, Taylor VH, et al. Bilateral hippocampal volume increases after long-term lithium treatment in patients with bipolar disorder: a longitudinal MRI study. Psychopharmacology (Berl) 2007; 195 (3): 357–67CrossRefGoogle Scholar
  53. 53.
    Moore GJ, Cortese BM, Glitz DA, et al. A longitudinal study of the effects of lithium treatment on prefrontal and subgenual prefrontal gray matter volume in treatment-responsive bipolar disorder patients. J Clin Psychiatry 2009; 70 (5): 699–705PubMedCrossRefGoogle Scholar
  54. 54.
    Dunn N, Holmes C, Mullee M. Does lithium therapy protect against the onset of dementia? Alzheimer Dis Assoc Disord 2005; 19: 20–2PubMedCrossRefGoogle Scholar
  55. 55.
    Forester BP, Finn CT, Berlow YA, et al. Brain lithium, N-acetyl aspartate and myo-inositol levels in older adults with bipolar disorder treated with lithium: a lithium-7 and proton magnetic resonance spectroscopy study. Bipolar Disord 2008; 10 (6): 691–700PubMedCrossRefGoogle Scholar
  56. 56.
    Silverstone PH, Wu RH, O’Donnell T, et al. Chronic treatment with lithium, but not sodium valproate, increases cortical N-acetyl-aspartate concentrations in euthymic bipolar patients. Int Clin Psychopharmacol. 2003; 18 (2): 73–9PubMedCrossRefGoogle Scholar
  57. 57.
    Nunes PV, Forlenza OV, Gattaz WF. Lithium and risk for Alzheimer’s disease in elderly patients with bipolar disorder. Br J Psychiatry 2007; 190: 359–60PubMedCrossRefGoogle Scholar
  58. 58.
    Kapusta ND, Mossaheb N, Etzersdorfer E, et al. Lithium in drinking water and suicide mortality. Br J Psychiatry 2011; 198 (5): 346–50PubMedCrossRefGoogle Scholar
  59. 59.
    Ohgami H, Terao T, Shiotsuki I, et al. Lithium levels in drinking water and risk of suicide. Br J Psychiatry 2009; 194 (5): 464–5PubMedCrossRefGoogle Scholar
  60. 60.
    Macdonald A, Briggs K, Poppe M, et al. A feasibility and tolerability study of lithium in Alzheimer’s disease. Int J Geriatr Psychiatry 2008; 23 (7): 704–11PubMedCrossRefGoogle Scholar
  61. 61.
    Hampel H, Ewers M, Burger K, et al. Lithium trial in Alzheimer’s disease: a randomized, single-blind, placebo-controlled, multicenter 10-week study. J Clin Psychiatry 2009; 70 (6): 922–31PubMedCrossRefGoogle Scholar
  62. 62.
    Leyhe T, Eschweiler GW, Stransky E, et al. Increase of BDNF serum concentration in lithium treated patients with early Alzheimer’s disease. J Alzheimers Dis 2009; 16: 649–56PubMedGoogle Scholar
  63. 63.
    Straten G, Saur R, Laske C, et al. Influence of lithium treatment on GDNF serum and CSF concentrations in patients with early Alzheimer’s disease. Curr Alzheimer Res 2011 Dec; 8 (8): 853–9PubMedCrossRefGoogle Scholar
  64. 64.
    Forlenza OV, Diniz BS, Radanovic M, et al. Disease-modifying properties of long-term lithium treatment for amnestic mild cognitive impairment: randomised controlled trial. Br J Psychiatry 2011; 198 (5): 351–6PubMedCrossRefGoogle Scholar
  65. 65.
    Petersen RC, Doody R, Kurz A, et al. Current concepts in mild cognitive impairment. Arch Neurol 2001; 58: 1985–92PubMedCrossRefGoogle Scholar
  66. 66.
    Gordon PH. Amyotrophic lateral sclerosis: pathophysiology, diagnosis and management. CNS Drugs 2011; 25 (1): 1–15PubMedCrossRefGoogle Scholar
  67. 67.
    Zinman L, Cudkowicz M. Emerging targets and treatments in amyotrophic lateral sclerosis. Lancet Neurol 2011; 10 (5): 481–90PubMedCrossRefGoogle Scholar
  68. 68.
    Fornai F, Longone P, Ferrucci M, et al. Autophagy and amyotrophic lateral sclerosis: the multiple roles of lithium. Autophagy 2008; 4 (4): 527–30PubMedGoogle Scholar
  69. 69.
    Caldero J, Brunet N, Tarabal O, et al. Lithium prevents excitotoxic cell death of motoneurons in organotypic slice cultures of spinal cord. Neuroscience 2010; 165 (4): 1353–69PubMedCrossRefGoogle Scholar
  70. 70.
    Feng HL, Leng Y, Ma CH, et al. Combined lithium and valproate treatment delays disease onset, reduces neurological deficits and prolongs survival in an amyotrophic lateral sclerosis mouse model. Neuroscience 2008; 155 (3): 567–72PubMedCrossRefGoogle Scholar
  71. 71.
    Chio A, Borghero G, Calvo A, et al. Lithium carbonate in amyotrophic lateral sclerosis: lack of efficacy in a dose-finding trial. Neurology 2010; 75 (7): 619–25PubMedCrossRefGoogle Scholar
  72. 72.
    Aggarwal SP, Zinman L, Simpson E, et al. Safety and efficacy of lithium in combination with riluzole for treatment of amyotrophic lateral sclerosis: a randomised, double-blind, placebo-controlled trial. Lancet Neurol 2010; 9 (5): 481–8PubMedCrossRefGoogle Scholar
  73. 73.
    Yong Y, Ding H, Fan Z, et al. Lithium fails to protect dopaminergic neurons in the 6-OHDA model of Parkinson’s disease. Neurochem Res 2011; 36 (3): 367–74PubMedCrossRefGoogle Scholar
  74. 74.
    Youdim MB, Arraf Z. Prevention of MPTP (N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) dopaminergic neuro-toxicity in mice by chronic lithium: involvements of Bcl-2 and Bax. Neuropharmacology 2004; 46 (8): 1130–40PubMedCrossRefGoogle Scholar
  75. 75.
    Wei H, Qin ZH, Senatorov VV, et al. Lithium suppresses excitotoxicity-induced striatal lesions in a rat model of Huntington’s disease. Neuroscience 2001; 106 (3): 603–12PubMedCrossRefGoogle Scholar
  76. 76.
    Wood NI, Morton AJ. Chronic lithium chloride treatment has variable effects on motor behaviour and survival of mice transgenic for the Huntington’s disease mutation. Brain Res Bull 2003; 61 (4): 375–83PubMedCrossRefGoogle Scholar
  77. 77.
    Kessing LV, Söndergard L, Forman JL, et al. Lithium treatment and risk of dementia. Arch Gen Psychiatry 2008; 65: 1351–5CrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2012

Authors and Affiliations

  • Orestes V. Forlenza
    • 1
    Email author
  • Vanessa J. de Paula
    • 1
  • Rodrigo Machado-Vieira
    • 1
  • Breno S. Diniz
    • 1
  • Wagner F. Gattaz
    • 1
  1. 1.Laboratório de Neurociências (LIM-27)Instituto de Psiquiatria do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, Rua Dr. Ovídio Pires de CamposSão Paulo, SPBrazil

Personalised recommendations