Can Lithium Supplements Slow Cognitive Ageing?

In a few weeks, a clinical trial is set to launch in order to test the safety of oral lithium supplements (or more precisely, lithium orotate salt) in participants with early stage Alzheimer’s disease. Scientists hope that lithium might be able to help treat or prevent dementia and perhaps even improve some aspects of cognitive function. But what’s special about this metal, and is it worth considering taking lithium supplements as a way to reduce your risk of dementia?

Lithium and the Brain

Lithium is a silvery-white metal and is the lightest metal in the periodic table. It’s also very reactive and so doesn’t naturally occur in its pure form – rather, it is found as part of mineral compounds in rocks and water. While lithium is best known for its use in batteries, lithium salts have well established medical uses in psychiatry, primarily in the treatment of bipolar disorder.

Scientists don’t fully understand the mechanisms of action of lithium in the brain, but one of the most relevant effects for the purposes of this article involves an enzyme called glycogen synthase kinase-3β (GSK-3β). This enzyme is overactive in bipolar disorder but is inhibited by lithium, which helps to stabilise mood. GSK-3β can modify over 100 different proteins in order to alter their activity, including proteins involved in glucose storage, inflammation and circadian rhythms. It is not known exactly how inhibiting GSK-3β with lithium stabilises mood.

As its name implies, one of the proteins that is modified by GSK-3β is glycogen synthase, an enzyme that converts glucose (sugar) into glycogen – the main form of glucose storage in the body. GSK-3β inhibits glycogen synthase, which means that muscle tissue and the liver store less glucose as glycogen, which in turn results in more glucose in the blood. Because of this, GSK-3β is implicated in the progression of many diseases in which high blood sugar plays a role. The most obvious of these is of course type II diabetes, but other age-related diseases are also closely linked to high blood sugar, including Alzheimer’s.

This should come as no surprise given that the brain relies nearly exclusively on glucose for energy under normal circumstances. Chronically high blood sugar drives resistance to insulin, the hormone that promotes the uptake of glucose by cells. If the brain becomes resistant to insulin, neurons are deprived of their primary source of energy. Insulin also promotes the production of brain-derived neurotrophic factor (BDNF), a key neuroprotective growth factor. In addition to this, GSK-3β also modifies signalling molecules that affect inflammation and the deposition of misfolded proteins (amyloid β and tau). This means that there are multiple mechanisms to suggest that inhibiting GSK-3β with lithium might protect against neurodegenerative disease and cognitive decline.

More Scientific Clues

The possible neuroprotective effects of lithium are more than just a theory – there’s some real world evidence to back them up. Starting with the observational evidence, researchers have found that lithium content in the brains of people with mild cognitive impairment and Alzheimer’s is significantly lower than normal. The same study also found that depleting lithium from the diets of mice accelerated the progression of Alzheimer’s-like disease. Another study found that regions of the US that had more lithium in their drinking water had lower rates of dementia.

Correlation isn’t causation and none of these findings prove that lithium deficiency causes dementia in humans. However, given these correlations, the plausible mechanistic explanations, and the fact that animal studies have found that blocking GSK-3β can reduce the build-up of amyloid plaques (a key feature of Alzheimer’s), the justification for human clinical trials was strong.

Lithium Treatments in Humans

The most commonly used lithium compound in the treatment of bipolar disorder is called lithium carbonate, and so this was the natural starting point for clinical trials. Unfortunately, results have so far been mixed. Some earlier trials reported improved cognitive scores and reduced amyloid plaque in participants taking lithium carbonate compared to those taking placebo. However, the longest-lasting trial to date, the results of which were published earlier this year, found no significant benefit to lithium carbonate treatment. This trial randomised 80 participants with mild cognitive impairment to receive either lithium carbonate or a control treatment for two years. Though cognitive scores among those taking the placebo did decline faster, this was not found to be statistically significant.

While this may be discouraging, there is still cause for optimism. The problem with lithium carbonate is that it can be absorbed by amyloid plaques, which effectively reduces the amount of lithium that is available to reach neurons where it could have a therapeutic effect. However, a study published last year found that a different lithium salt – lithium orotate – had significantly less amyloid binding compared to lithium carbonate and was effective at treating Alzheimer’s-like disease in mice. Additionally, they found that ageing mice treated with lithium orotate from 12 to 24 months of age had significantly improved learning and memory compared to controls, suggesting that supplementation might protect against some age-related cognitive decline.

Are Lithium Supplements A Good Idea?

Unlike lithium carbonate, lithium orotate supplements are available to buy over the counter, so should you be taking them in order to stave off cognitive ageing and Alzheimer’s disease? Given that there is currently no evidence that lithium orotate reduces the risk of Alzheimer’s or improves cognition in humans, taking it for this purpose is a hard sell. On the other hand, taking too much lithium can have serious side effects including thyroid and kidney damage. The risk of this occurring in the short term is low as it would require taking many times more lithium than the recommended supplement dose. The lithium orotate dose used in the mouse study showing improved cognitive function used low doses, so it is possible that such low doses would be effective in humans as well. However, there’s no human safety data for long-term, low dose lithium.

In summary, there’s currently not much evidence to go on when it comes to the effects of lithium orotate supplements on human brain health. Given that plenty of other interventions thought to improve cognitive function and prevent dementia (such as dietary changes and exercise) have convincing evidence behind them, there are probably other things you could be doing to improve cognitive health with a higher level of confidence in their impact. Hopefully the upcoming clinical trial will prove successful and will lead to further research into the potential benefits of lithium supplements on cognitive ageing.