An Overview of the Effects of Lithium on Alzheimer's Disease: A Historical Perspective

Abstract

Lithium was introduced into psychiatric practice in the late nineteenth century and has since become a standard treatment for severe psychiatric disorders, particularly those characterized by psychotic agitation. It remains the most effective agent for managing acute mania and preventing relapses in bipolar disorder. Despite potential adverse effects, lithium's use should be carefully considered relative to other treatment options, as these alternatives may present distinct safety and tolerability profiles. The World Health Organization classifies lithium salts as 'essential' medications for inclusion in global healthcare systems. Over the past two decades, the growing recognition of lithium's efficacy-extending beyond mood stabilization to include reducing suicide risk and inducing neuroprotection-has led to its incorporation into clinical practice guidelines. Current research, particularly from translational models, suggests that lithium's pleiotropic effects benefit not only mental and brain health but also other organs and systems. This supports its potential as a therapeutic candidate for neurological conditions, particularly those associated with neurodegenerative processes. This article will discuss the historical background, discovery, and early experimentation of lithium in psychiatry. We will also review its mechanisms of action and discuss its potential in the treatment and prevention of neurodegenerative disorders, focusing on Alzheimer's disease.

Keywords: Alzheimer’s disease; lithium salts; lithium therapy; neurodegenerative diseases; neuroprotection.

Figure 1

Molecular mechanisms of lithium in Alzheimer’s Disease. Alzheimer’s disease (AD) is characterized by the accumulation of senile plaques and neurofibrillary tangles (NFTs) in the brain, disrupting normal neuronal function. Lithium modulates the production and clearance of amyloid-beta (Aβ) by inhibiting β-site APP cleaving enzyme 1 (BACE1) mRNA expression and decreasing γ-secretase activity, thereby reducing amyloid precursor protein (APP) cleavage and Aβ production. Additionally, lithium reduces NFT formation by lowering tau mRNA expression and inhibiting glycogen synthase kinase-3 beta (GSK-3β), which in turn decreases tau phosphorylation levels and results in neuroprotection. At the same time, through the inhibition of GSK-3β, lithium induces the activation of protein kinase B (Akt) and cyclic adenosine monophosphate (cAMP) response element-binding protein (CREB) signaling pathways, thereby upregulating the mRNA expression and protein levels of nuclear factor erythroid 2-related factor 2 (NRF-2), neurosecretory protein VGF, brain-derived neurotrophic factor (BDNF), B-cell lymphoma 2 (Bcl-2), and other neuroprotective molecules. Conversely, by this same pathway, lithium downregulates the mRNA expression and protein levels of Bcl-2–associated X protein (BAX), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), tumor necrosis factor-alpha (TNF-α), and other molecules involved in neuroinflammation and apoptosis. Furthermore, by inhibiting protein phosphatase 2 (PP2A) and inositol monophosphatase (IMPase), lithium reinforces GSK-3β inactivation, promoting neuroprotective responses.