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Publishing in JAMA Psychiatry, researchers have looked into the association of Lithium in drinking water with incidence of dementia, reporting that long-term increased lithium exposure in drinking water may be associated with a lower incidence of dementia but the relationship was not linear.
Prof David Smith, Professor Emeritus of Pharmacology, University of Oxford, said:
“This is a high-quality study in a large population. The association between the levels of lithium in drinking water and a diagnosis of dementia was significant, however, it was not a linear relationship: the relative risk of dementia increased by 22% when the lithium level increased slightly and then decreased by 17% when the level became much higher. Thus, the study does not have any public health implications: we should not be adding lithium salts to our tap water because we would not know what amount to use.
“Similar findings of a non-linear relationship have been reported for calcium in drinking water in a Chinese study. It is a pity the authors did not look at the association with calcium since this might have been a confounder.
“The findings are consistent with basic research on some of the possible brain mechanisms leading to dementia and are consistent with human MRI studies: administration of lithium salts increases the volume of parts of the brain that are involved in Alzheimer’s disease.”
Dr James Pickett, Head of Research at Alzheimer’s Society said:
“Lithium triggers a number of useful responses in brain cells that means, theoretically, it might work as a treatment for Alzheimer’s disease. However, despite some success in animals, there hasn’t been enough positive research of lithium in people with dementia to yet convince us that it works.
“This large, well conducted study explores the potential of lithium in drinking water to prevent, rather than treat, dementia by looking at how cases of dementia vary with natural changes in lithium exposure across Denmark. Although people exposed to the highest levels of lithium appear to be slightly protected, those exposed to intermediate levels had higher rates of dementia than those with the lowest levels of lithium in their water.
“It’s almost too good to be true that something as cheap and plentiful as Lithium might have a role in future prevention of Alzheimer’s disease. However, more research including clinical trials are needed, and until then we should not consider increasing lithium in drinking water. In high doses, or even at low doses in some people, lithium can be toxic so it is important that people consult with their doctor before they consider taking it as a supplement.”
Prof Allan Young, Professor of Mood Disorders, King’s College London’s Institute of Psychiatry, Psychology & Neuroscience, said:
Q: Is this good quality research? Are the conclusions backed up by solid data?
“This is high quality research from the Danish national medical records linked system. The conclusions are backed by data but, because of the nature of the study, can only show association not causality.”
Q: How does this work fit with the existing evidence?
“This study fits well with previous evidence which shows that environmental lithium may have health benefits and lithium may prevent dementia.”
Q: Have the authors accounted for confounders? Are there important limitations to be aware of?
“A study of this nature is always likely to have confounding factors. Although the authors have tried to control for these replication in further, independent, studies is needed.”
Q: How big an impact does the lithium have on dementia?
“At a population level the effects would be considerable as even if lithium only delayed the onset of dementia by months for each person, over the nation that would amount to a lot of healthier months.”
Q: Are there side-effects of having these levels of lithium?
“There do not seem to be any associated problems, nevertheless this needs to be rigorously examined in an on-going manner.”
Q: Is there now a growing case for adding lithium to water?
“Although some may say that lithium should be “added to the water” the first step might be to conduct clinical trials to examine the preventative effects of lithium first.”
Prof Simon Lovestone, Prof of Translational Neuroscience, Department of Psychiatry, University of Oxford, said:
“This is a really intriguing study from Denmark where scientists have looked at the amount of lithium, a natural chemical found in water, in more than 70,000 people with dementia compared to 700,000 people who remained free from dementia as they got older. The results are not completely straightforward but at slightly higher, naturally occurring, amounts of lithium there seemed to be some protective effect – a reduction of risk of getting dementia. This is interesting, as lithium is known to reduce the activity of an enzyme called Glycogen Synthase Kinase 3 (GSK-3), which seems to be involved in Alzheimer’s disease. In neurons in a dish and in mouse and fruit-fly models of Alzheimer’s disease lithium has been shown to be protective. Not only that but lithium is used to treat people with bipolar disorder and some studies have suggested that people on lithium for this reason, often for life, might also be protected from Alzheimer’s.
“However, there are three important cautionary notes here. First, the amount of lithium in the water supply in Denmark – and this is true for other countries as well – is more than 1,000 or even 10,000 times lower than the amount given to people with bipolar disorder or to mice in laboratory experiments. We really do not know what Lithium does at such miniscule amounts and whether the findings in this paper relate to the previous research on lithium and Alzheimer’s disease is very much open to question. Secondly, the results were not straightforward in this study from Denmark. Although there was a protective effect at somewhat higher amounts in the water supply, this then was reduced as the amounts rose to the highest level. It’s very difficult to understand this, given what we know about lithium. Thirdly, it is important to realize that the protective effect these scientists have seen is really very small indeed.
“For now though, this study is encouraging and suggests that the research on lithium and Alzheimer’s is going in the right direction. Clearly, there isn’t much we can or should do about naturally occurring lithium. But we should be doing studies to see if very small amounts of lithium could be given, not as a treatment for dementia, but to try and prevent dementias such as Alzheimer’s disease. The results of this study do not suggest that we should add lithium to water supplies to combat dementia, and it’s important to remember that the lithium levels in water is usually 10-50ug/l, whereas when used as a drug it’s usually 500-1500 mg/day i.e. at least 1000x more.”
Prof Tara Spires-Jones, UK Dementia Research Institute Programme Lead and Deputy Director, Centre for Discovery Brain Sciences, University of Edinburgh, said:
“This paper reports a nationwide study in Denmark of 73 731 people with dementia and 733 653 healthy individuals examining whether measurements of lithium levels in the drinking water in the area where people lived was associated with their risk of developing dementia. The data from this large study robustly support the conclusion that higher levels of lithium in the drinking water in the area where people live are associated with a lower risk of developing dementia. However, this association does not necessarily mean that the lithium itself reduces dementia risk. There could be other environmental factors in the area that could be influencing dementia risk. Nonetheless, this is an interesting result that will prompt more research into whether lithium levels in the diet or drinking water may modify risk of dementia.”
Dr David Reynolds, Chief Scientific Officer of Alzheimer’s Research UK, said:
“While, overall, this research pointed to lower rates of dementia in areas with higher levels of lithium in the water supply, this relationship was not straight forward and the study does not suggest that regular doses of lithium that may be prescribed for conditions like bipolar disorder could reduce the risk of dementia. Previous studies investigating whether lithium could treat or affect the risk of dementia have been mixed and we need to see much more research before we can tell if lithium could benefit people’s lives in this way.
“This well-conducted study was able to take advantage of comprehensive health and address records for hundreds of thousands of people in Denmark to determine how much lithium each participant was exposed to through the water supply. Large population-based studies like this are extremely useful for identifying factors linked with dementia risk, but they can’t tell us what the root cause of an association might be. A number of factors relating to where someone lives could play a role in how many people go on to develop dementia and this study did not take differences in access to healthcare across the country into account, nor does it look at how financially well-off people are in these different areas– a factor that is closely interwoven with many aspects of our health.
“It is potentially exciting that low doses of a drug already available in the clinic could help limit the number of people who develop dementia. Analysis carried out by Alzheimer’s Research UK suggests that a treatment that could delay dementia by just five years would mean that 666,000 fewer people develop dementia by 2050 and save the economy billions every year. It is crucial that we see continued investment in dementia research so that scientists are able to evaluate and realise the clinical potential of interesting findings like this.”
Prof Rob Howard, Professor of Old Age Psychiatry, UCL, said:
“Lithium, long used in mental health as a highly effective mood stabiliser, has been on the radar as a potential disease modifying treatment for Alzheimer’s disease with positive evidence from preclinical studies and a number of small clinical trials.
“This study provides further support for a role for lithium in Alzheimer’s disease modification, but the story is complicated.
“In a large and well-conducted epidemiological study, the authors uncovered a significant association between the concentration of lithium in the drinking water of an area in Denmark and the risk of developing dementia. Broadly, the higher the lithium concentration in the drinking water, the lower the risk of dementia.
“Higher concentrations of lithium reduced the risk of developing dementia by about 20% and this effect applied to both Alzheimer’s disease and vascular dementia.
“The curious relationship observed between water lithium concentration and dementia risk – the risk initially increased as lithium increased before decreasing with subsequent rises in lithium concentration – together with the extremely small amounts of lithium involved are difficult to explain. The brain concentrations of lithium that result from the tiny amounts of the element in drinking water are between a hundredth and a thousandth of those seen in patients with mood disorders treated with lithium and much of the preclinical and trial evidence for lithium’s potential anti-dementia activity comes from use of these higher doses.
“These results represent another important piece of evidence for lithium’s potential as a treatment for Alzheimer’s disease. We now need clinical trials of lithium in patients with Alzheimer’s disease to determine once and for all whether this cheap and well-tolerated element can slow dementia progression.”
* ‘Association of Lithium in Drinking Water With the Incidence of Dementia’ by Kessing et al. was published in JAMA Psychiatry on Wednesday 23rd August.
Declared interests
Prof Lovestone: “SL has received grants from research agencies for more than 20 years to study GSK3 and Alzheimer’s disease. He has worked with companies including Astra-Zeneca and Noscira on collaborative projects that have used GSK3 inhibitors. In the past five years he provided consultancy to Eisai, J&J, OptumLabs and SomaLogic and has research funding from AstraZeneca and J&J and from the EU in collaborative public-provate pre-competitive programmes through the IMI scheme. He has in the past been named as senior inventor in patents held by KCL and Oxford University. None of these constitute a conflict in relation to the current study.”
Prof Spires-Jones: “I am employed by the University of Edinburgh and am a member of the Grant Review Board for Alzheimer’s Research UK.”
Dr Reynolds: “No relevant interests to declare.”
Prof Howard: None received