Lithium, long used as a mood stabilizer for people with bipolar disorder, has diverse actions in the brain. Some controversial studies suggest that even the ultra-low doses that occur naturally in tap water affect behavior, including suicide and criminality. Now, a study from Lars Kessing and colleagues from the University of Copenhagen in Denmark suggests that minuscule amounts of the element, ingested over a lifetime, may protect against dementia. In a study published online August 23 in JAMA Psychiatry, the investigators compared health records, water analysis data, and information on place of residence for more than 800,000 Danes. Their analysis revealed that people exposed to the highest levels of lithium had the lowest incidence of dementia. The differences were small, translating into a maximum risk reduction of 17 percent.
“The protective effect is modest, but interesting, given the substantial preclinical literature suggesting lithium’s salutary effects on the biology of Alzheimer’s disease or neurodegeneration,” said Lon Schneider of the Keck School of Medicine of the University of Southern California in Los Angeles. He noted clinical trials of lithium in people with Alzheimer’s disease or mild cognitive impairment have been poorly designed, small, short, and inconclusive. “This is one more observational study that suggests there might be something there,” he said. It offers clues to designing better trials in the future that may yield more definitive results, Schneider told Alzforum.
New approaches to prevent dementia are critically needed, but the results by themselves do not support spiking water supplies with lithium, as many communities do with fluoride for tooth decay, researchers emphasized. In an editorial accompanying the paper, John McGrath, Queensland University, and Michael Berk, University of Melbourne, both in Australia, ask, “Can we convert lithium, a simple metal used as a mood stabilizer, into a golden public health intervention that could prevent dementia?” They say this will depend on what the next generation of epidemiologic studies and clinical trials reveal.
Other scientists expressed deep skepticism that vanishingly low levels of lithium, thousands of times lower than the doses used to treat bipolar disorder or tested in AD, and just a fraction of what’s taken in with food, could produce a meaningful biological effect. The authors suggest that a cumulative effect of low levels over a lifetime might add up to protection against dementia.
The anti-Alzheimer’s effects of lithium show up clearly in animal models: Lithium inhibits glycogen synthase kinase-3 (GSK3), a key regulator of tau hyperphosphorylation and Aβ production (May 2003 news). GSK3 is a potential target for Alzheimer drugs (Nov 2016 news). Lithium’s many diverse actions also include neurotrophic and anti-inflammatory activities that could protect against AD.
Previously, Kessing studied people with bipolar disorder, who have a two to three times higher risk of developing dementia, and in particular Alzheimer’s disease. Those who used lithium had lower rates of dementia than those who took other medications (Kessing et al., 2010). Unfortunately, the lithium doses effective against bipolar disorder cause liver and neurotoxicity in elderly people. A handful of small trials using lower-dose lithium in people with Alzheimer’s disease or mild cognitive impairment produced mixed results (reviewed in Forlenza et al., 2016).
The new study asked a different question: If lithium affects neurodegenerative processes, would life-long exposure to small amounts of it lessen the risk of dementia in the general population? Lithium occurs naturally in ground water, in low amounts that vary with geography. In Denmark, the government had measured or imputed lithium concentrations for wells across the country, and kept a residence history of every citizen in the country going back to 1986. Those pieces of data allowed Kessing to estimate a lithium exposure for virtually every Danish resident for the last 30 years.
From medical registries, the investigators identified all dementia diagnoses in Denmark between 1995 and 2013. For each of the 79,731 cases found, they compared lithium exposure to roughly 10 age- and sex-matched controls, for a total sample size of 813,384 subjects. The people with dementia had significantly less lithium in their drinking water, with a median of 11.5 micrograms per liter (μg/L), compared to 12.2 for controls. The results suggest that water-borne lithium might protect against dementia.
However, the dose relationship was not straightforward. Compared to the lowest dose level (2-5 μg/L), the incidence of dementia went up slightly but significantly in those exposed to 5-10 μg/L (risk ratio of 1.22). Dementia was back down in those exposed to 10-15 μg/L, and then decreased significantly in those exposed to the highest level (15 μg/L or higher, risk ratio of 0.83). The pattern held up when the investigators looked at either Alzheimer disease or vascular dementia, which have very different etiologies.
The study shows an association, not cause and effect, and the authors say the findings should be interpreted cautiously. They can’t rule out that other, unknown regional variables besides lithium might explain the association.
To replicate the findings, scientists will need to look beyond Denmark, said Orestes Forlenza, University of São Paulo in Brazil. “Denmark has relatively low lithium levels in water, there are other places in Europe and around the world that have higher levels, and we might want to look into those,” he said.
The exposures overall from water are indeed minuscule: the median lithium level in Demark was 11.6 μg/L, with a range from 0.6 μg/L in the western part of the country, to 30.7 μg/L in eastern Denmark. For comparison, the dose for treating bipolar disorder is 900 to 1,800 mg per day—the equivalent of drinking 30,000 liters or more of water. The lowest exposure that gave some hint of efficacy in a small Alzheimer’s trial was 300 μg per day, or the content of 30 liters of water at the average lithium concentration (Nunes et al., 2013).
That presents a problem for thinking about mechanism, say several commentators.
Peter Klein of the University of Pennsylvania in Philadelphia calls it “implausible” that this concentration acutely affects of any of the known targets of lithium. “People talk about the pleiotropic effects of lithium, but there are not that many known direct targets, and most are inhibited at about 1,000 times more lithium than they find in the water,” he said. “You have to invoke either a new target, or an integration of the chronic exposure over a long period of time. It’s possible that lithium could accumulate in some areas of the brain and have a higher effective concentration.” So far there is no evidence for that in people.
Jim Woodgett, Lunenfeld-Tanenbaum Research Institute, Toronto, agreed that the levels in drinking water are likely insufficient to significantly inhibit GSK3, or other known targets of lithium. “While these are not ‘homeopathic’ doses (they are measurable!) I wonder if the variances in natural levels in water are surrogates for some other difference that accounts for the variation in incidence?” he wrote in an email to Alzforum.
Ashley Bush, University of Melbourne in Australia, and Peng Lei, Sichuan University, China, don’t think lithium accounts for the association of geography with dementia. They point out that the intake of lithium from food sources, reportedly in the range of 0.6 to 3.1 milligrams per day in the United States in 1985, dwarfs the 90 μg estimated from daily consumption of three liters of water. “Therefore, the contribution of water-sourced lithium to the total daily intake of lithium would be marginal. This observation alone argues that the protective or hazardous effects associated with lithium intake from water sources are unlikely to be mediated by the pharmacological effect of lithium itself, but rather, mediated by some other agent in the water that co-enriches with lithium or by some other regional environmental factor,” Bush and Lei wrote in an email to Alzforum. They also noted that there is no data correlating drinking water concentrations with the level of lithium in the blood.
If the results can be replicated, even a modest effect makes the case for better-designed human trials of lithium for AD, said Schneider. “Reducing incidence by even a few percent, or delaying onset by a couple of years, is a big deal,” he said. Any trial will need to test low doses, for a reasonable period of time, and in enough people to detect what could be a small effect, he said.—Pat McCaffrey
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- Kessing LV, Forman JL, Andersen PK. Does lithium protect against dementia?. Bipolar Disord. 2010 Feb;12(1):87-94. PubMed.
- Forlenza OV, Aprahamian I, de Paula VJ, Hajek T. Lithium, a Therapy for AD: Current Evidence from Clinical Trials of Neurodegenerative Disorders. Curr Alzheimer Res. 2016;13(8):879-86. PubMed.
- Nunes MA, Viel TA, Buck HS. Microdose lithium treatment stabilized cognitive impairment in patients with Alzheimer�s disease. Curr Alzheimer Res. 2012 Jun 29; PubMed.
- Kessing LV, Gerds TA, Knudsen NN, Jørgensen LF, Kristiansen SM, Voutchkova D, Ernstsen V, Schullehner J, Hansen B, Andersen PK, Ersbøll AK. Association of Lithium in Drinking Water With the Incidence of Dementia. JAMA Psychiatry. 2017 Oct 1;74(10):1005-1010. PubMed.
- McGrath JJ, Berk M. Could Lithium in Drinking Water Reduce the Incidence of Dementia?. JAMA Psychiatry. 2017 Aug 23; PubMed.