The article by Forlenza et al ^{Reference Forlenza, Diniz, Radanovic, Santos, Talib and Gattaz1} is a useful addition to the literature. Disease-modifying drugs for dementia, and in particular Alzheimer’s disease, are sorely needed. Despite very strong preclinical science, translational studies have been relatively limited, so this sort of interventional trial is welcome.

The authors highlight the inhibition of glycogen synthase kinase-3 beta (GSK-3B), a serine/threonine kinase involved in the regulation of numerous intracellular signalling pathways, as the likely mechanism for any neuroprotective effects. Although it is true that there is a literature supporting this pathway, other potential disease-modifying pathways are influenced by lithium. For example, up-regulation of autophagy, an intracellular protein degradation pathway which is able to degrade mutant proteins associated with neurodegeneration, can rescue a variety of animal models of neurodegenerative disease. ^{Reference Garcia-Arencibia, Hochfeld, Toh and Rubinsztein2} In fact, GSK-3B inhibition inhibits autophagy via its effect on the mTOR (mammalian target of rapamycin) pathway. Despite this, lithium ultimately induces autophagy via a dominant mechanism involving inositol monophsphatase inhibition. ^{Reference Sarkar, Floto, Berger, Imarisio, Cordenier and Pasco3} These distinctions are not trivial, as understanding the interactions of these pathways allows for more rational treatment design. For example, lithium and rapamycin (a drug which inhibits mTOR) provides greater neuroprotection in fly models of Huntington’s disease than either drug alone. ^{Reference Sarkar, Krishna, Imarisio, Saiki, O'Kane and Rubinsztein4} Furthermore, numerous US Food and Drug Administration-approved drugs which are autophagy up-regulators have been identified. Many of these may have a more favourable side-effect profile than lithium, and preclinical work suggests their efficacy in animal models of neurodegenerative disease. ^{Reference Williams, Sarkar, Cuddon, Ttofi, Saiki and Siddiqi5}

The potential mechanisms for neuroprotection by lithium extend well beyond inhibition of GSK-3B. Working out which are most important is of more than scientific interest as it is likely to allow rational drug design and better selection of currently available drugs with neuroprotective potential.