title: Does lithium prevent Alzheimer's disease?
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.
authors.affiliation: Laboratory of Neuroscience (LIM-27), Department and Institute of Psychiatry, University of São Paulo, São Paulo, Brazil. forlenza@usp.br
authors.forename: Orestes V
authors.initials: OV
authors.lastname: Forlenza
authors.forename: Vanessa J
authors.initials: VJ
authors.lastname: de Paula
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Machado-Vieira
authors.forename: Breno S
authors.initials: BS
authors.lastname: Diniz
authors.forename: Wagner F
authors.initials: WF
authors.lastname: Gattaz
mesh_terms: D000368:Aged; D000544:Alzheimer Disease / Q000503:physiopathology / Q000517:prevention & control*; D000818:Animals; D003072:Cognition Disorders / Q000188:drug therapy / Q000209:etiology; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D018020:Lithium Compounds / Q000494:pharmacology*; D018696:Neuroprotective Agents / Q000494:pharmacology*
chemical_list: D018020:Lithium Compounds; D018696:Neuroprotective Agents; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3