About this Research Topic
It has been known for some time that lithium is an inhibitor of the enzyme GSK3, amongst several other molecular targets. GSK3 inhibitors have been touted as potential treatments for Alzheimer’s disease (AD) due to an association between high GSK3 activity and AD pathology. Indeed, several rodent studies have provided evidence that GSK3 inhibitors, including lithium, can reduce severity and progression of AD pathology. Whether this translates to human disease remains to be discovered. However, recent population-based, albeit retrospective, analysis in people with bipolar disorder indicated that lithium may offer some protection against development of dementia compared to other treatments or no treatment. In addition, there have been several reports associating higher lithium levels in drinking water with lower rates of dementia incidence. All of these findings are intriguing, yet there is still a great deal of resistance against performing randomized clinical trials with lithium. This appears primarily due to safety concerns around lithium toxicity, as well as worries about the lethality of GSK3 ablation. Importantly, it remains unclear what dose of lithium would be appropriate for clinical studies in dementia, whether it would be that used in bipolar disease, and whether it is really GSK3 or one of the other known targets of lithium that mediates its actions on bipolar disease or dementia.
We propose that the time is right to bring together papers, perspectives and reviews on the state of the art of lithium as a potential treatment for neurodegenerative disease, focusing on what are the missing pieces of evidence (mechanistic and clinical) required to justify randomized clinical trials, and what are the main barriers to the initiation of such trials on dementia with lithium.
We propose to cover what is known about the many molecular actions of lithium and evidence for target engagement associating with clinical efficacy from animal models and pre-clinical studies. We shall review the data from population studies on benefits of lithium on cognition and effects in the environment; discuss lessons from clinical trial using lithium in other neurological disorders, along with the pharmacogenetics of lithium response; question what biomarkers of lithium efficacy are feasible and appropriate (molecular and imaging); debate what dose of lithium would be both safe and required for target engagement in such trials, and in what trial population; and aim to address the real problems designing a clinical trial with lithium in each target population.
The overall aim is to challenge the somewhat entrenched negative attitude to the potential repurposing of lithium for neurodegenerative disease, but at the same time generate a database of impartial opinions on how one would go about safely testing the hypothesis that lithium could have clinical benefit in neurodegenerative disease.
Important Note: All contributions to this Research Topic must be within the scope of the section and journal to which they are submitted, as defined in their mission statements. Frontiers reserves the right to guide an out-of-scope manuscript to a more suitable section or journal at any stage of peer review.