Higher long-term lithium exposure from drinking water may be associated with a lower incidence of dementia, a large population-based study suggests.

"This is the first study ever investigating the association between lithium in drinking water and onset of dementia," Lars Vedel Kessing, MD, DMSc, from the University of Copenhagen, Denmark, told Medscape Medical News.

"If confirmed by others, tablets of lithium in microdose could be used among individuals at high risk of developing Alzheimer's disease, including those with a family history or certain genetic variations," Dr Kessing added.

The study was published online August 23 in JAMA Psychiatry.

Neuroprotective Potential

The neuroprotective potential of lithium has been demonstrated in preclinical and some clinical studies. Animal studies have shown that lithium improves learning and memory, and observational studies suggest lithium may reduce the risk for dementia in patients with bipolar disorder.

In addition, a randomized placebo-controlled trial showed that daily treatment with subtherapeutic doses (150 to 600 mg) of lithium has stabilizing effects in adults with mild cognitive impairment, while a separate controlled trial showed that a microdose (300 µg/d) of lithium stabilized cognitive impairment in patients with Alzheimer's disease.

Using a nationwide, population-based, nested case-control study design, the researchers investigated whether the incidence of dementia in the general Danish population varied with long-term exposure to microlevels of lithium in drinking water.

In addition to vegetables, drinking water is a major source of human lithium intake. Levels of lithium in ground water and drinking water are most likely to remain stable over time, the investigators note.

Study participants included 73,731 patients with dementia and 733,653 controls. The analysis included individualized data on lithium exposure based on residence over up to 28 years of exposure (from 1986 to 2013) and drinking water lithium samples from 151 waterworks sampled from 2009 to 2010 and in 2013, spatially covering all of Denmark, combined with hospital data on incident dementia up to 19 years (1995 to 2013).

The mean lithium level in drinking water was 11.6 µg/L and ranged from 0.6 µg/L in western Denmark to 30.7 µg/L in eastern Denmark. Mean lithium exposure significantly differed between patients with dementia and controls (median, 11.5 µg/L vs 12.2 µg/L; P < .001).

In Cox proportional hazards regression models, the incidence rate ratio (IRR) of dementia was lower in individuals exposed to 10.1 µg/L of lithium or more compared with their peers exposed to 2.0 to 5.0 µg/L, reaching statistical significance among those exposed to greater than 15.0 µg/L of lithium (P < .001). However, exposure to 5.1 to 10.0 µg/L of lithium was associated with an increased IRR of dementia compared with 2.0 to 5.0 µg/L (P < .001).

Table. Lithium Exposure and Rates of Dementia

Mean Lithium Exposure (μg/L) IRR (95% Confidence Interval) 2.0 - 5.0 1 (Reference) 5.1 - 10.0 1.22 (1.19 - 1.25) 10.1 - 15.0 0.98 (0.96 - 1.01) 15.1 - 27.0 0.83 (0.81 - 0.85)

This nonlinear pattern remained unchanged when the analyses excluded data for individuals with partly missing information on municipality of residence and the pattern was confirmed when the analysis was adjusted for living in an urban area. However, the investigators note that confounding from other factors associated with municipality of residence cannot be excluded.

"Overall, we confirmed the hypothesis that higher long-term lithium exposure from drinking water may be associated with a lower incidence of dementia, although the association was nonlinear," write Dr Kessing and colleagues.

Crucial Contribution

The hypothesis that a low lithium concentration in drinking water may protect against dementia is "mechanistically plausible" as lithium effects many biological pathways linked to neuroprogressive and neurodegenerative disorders, say the authors of an accompanying editorial.

"If the findings of Kessing and colleagues are supported in future studies, even a marginal reduction in the incidence of dementia could result in major societal and economic gains," write John McGrath, MD, PhD, from Queensland Brain Institute in Brisbane, Australia, and Michael Berk, PhD, from University of Melbourne, Victoria, Australia.

"However, we also need to consider the political and social landscape regarding augmentation of drinking water (such as the ongoing debate around fluoride and dental caries). In the spirit of alchemy, could we convert lithium, a simple metal used as a mood stabilizer, into a golden public health intervention that could prevent dementia? This will depend on what the next generation of epidemiologic studies and clinical trials reveal," Dr McGrath and Dr Berk conclude.

Commenting on the study for Medscape Medical News, Tomas Hajek, MD, PhD, from Dalhousie University, Halifax, Nova Scotia, Canada, noted that lithium is "not widely tested in treatment of Alzheimer dementia or amnestic mild cognitive impairment, despite some promising initial findings from randomized controlled trials. This is in part related to concerns about side effects of lithium, which are dose dependent and may be particularly bothersome in elderly patients."

"The study by Kessing et al," Dr Hajek said, "is a crucial contribution to the literature. It suggests that perhaps much lower doses of lithium than those used for treatment of mood disorders may be sufficient in treatment of dementia. It provides strong rationale for studies testing the effects of long-term microdose lithium preparations in patients with Alzheimer dementia or amnestic mild cognitive impairment."

However, Dr Hajek noted drug companies are "unlikely to invest in clinical studies of lithium, since it cannot be patented and has never made a large profit. So having a strong piece of evidence for beneficial effects of microlevels of lithium on incidence of dementia is a key argument which could help in obtaining grant funding for such much-needed studies."

The study had no commercial funding. Dr Kessing has worked as a consultant for Lundbeck, AstraZeneca, and Sunovion. The other authors have disclosed no relevant financial relationships.

JAMA Psychiatry. Published online August 23, 2017. Study full text, Editorial