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Does Lithium Prevent Alzheimer’s Disease?

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Abstract

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.

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Acknowledgements

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).

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  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 Campos, 785, 3rd floor, 05403-010, São Paulo, SP, Brazil

    Orestes V. Forlenza, Vanessa J. de Paula, Rodrigo Machado-Vieira, Breno S. Diniz & Wagner F. Gattaz

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  1. Orestes V. Forlenza
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  2. Vanessa J. de Paula
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  3. Rodrigo Machado-Vieira
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Correspondence to Orestes V. Forlenza.

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Forlenza, O.V., de Paula, V.J., Machado-Vieira, R. et al. Does Lithium Prevent Alzheimer’s Disease?. Drugs Aging 29, 335–342 (2012). https://doi.org/10.2165/11599180-000000000-00000

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