A salt for preventing Alzheimer’s? Lithium seems to be!

To the Editor

Lithium has played a phenomenal role in the development of psychiatry. Its proven and re-proven role as a mood stabilizer in acute and maintenance management of bipolar disorder along with its anti-suicidal and neuroprotective roles has chartered the course of biological psychiatry (Malhi, 2017). Once again, with the demonstration of its efficacy in preventing the progression of mild cognitive impairment (MCI) to Alzheimer’s disease (AD), lithium has reaffirmed its key position in the psychopharmacological armamentarium (Forlenza et al., 2019). The recent Randomized Controlled Efficacy Trial of Lithium on the cognitive and functional outcomes of community-dwelling elderly with MCI has reiterated its neuroprotective effects and added to the sheen of this humble metal. The disease-modifying property of lithium on AD is further supported by its favorable effects on the cerebrospinal fluid (CSF) levels of AD-related biomarkers.

Epidemiological studies have demonstrated a negative association between lithium levels in drinking water and incidence of dementia in a Danish population. A meta-analysis of randomized placebo-controlled trials of lithium in MCI and AD has also favored beneficial effects of lithium on cognition but not on CSF biomarkers (Matsunaga et al., 2015). The current randomized controlled trial (RCT) on amnestic mild cognitive impairment (aMCI) subgroup of elderly has shown an increase in AD biomarker CSF Aβ_1-42 after continuing lithium at sub-therapeutic dose for 3 years (Forlenza et al., 2019). This finding has re-ignited the hope of preventing aMCI early in its course.

Amyloid-β42 deposition in extracellular spaces and phosphorylation of τ proteins in intracellular spaces are known to contribute to amyloid plaques and neurofibrillary tangles of AD. These protein deposits are understood as a result of the failure of autophagic processes inside the neurons. Lithium through its actions on intracellular signaling pathways and gene regulation causes upregulation of autophagy. Also, through its glycogen synthase kinase 3β (GSK3β) inhibition, lithium improves synaptic plasticity. Facilitatory impact on neurotrophic factors, reduction of proinflammatory processes, oxidative stress modulation and mitochondrial upregulation are speculated reasons for the reported increase in cortical thickness and volumetric increase in hippocampus and amygdala following long-term lithium dosing.

Although there was no between-group significant difference in conversion rates to AD, the cognitive and functional stability of the lithium group is welcome news. This trial adds to the existing evidence of efficacy of lithium in preventing dementia in aMCI provided it is started early, given in optimal doses and continued for a long time. Lithium seems to prevent the progression of MCI at least in the subgroup with high CSF Aβ_1-42.