Lithium, used widely to treat bipolar disorder, does double duty as a neuroprotective and neurotrophic agent. Low levels of lithium, found naturally in drinking water, seem to ward off psychiatric disease, but whether they do the same for dementia is controversial. In a new study of groundwater lithium concentrations and dementia incidence across the U.S., William Parker and colleagues at the University of Chicago find that, at first blush, high lithium levels do accompany a lower incidence of dementia. However, the association disappears when the researchers control for demographic factors like age, ethnicity, and access to health care. Their results appear in a letter in the May 23 JAMA Psychiatry.
- Epidemiological data questioned if low levels of lithium in tap water reduce dementia incidence.
- In the U.S., the link vanishes when scientists control for differences in health care access and demographics.
- Lithium in drinking water is unlikely to affect dementia risk.
The results run contrary to a large study linking high lithium concentrations with lower dementia incidence in Denmark (Aug 2017 news), and a more recently reported inverse relationship between lithium levels and AD-related mortality in Texas (Fajardo et al., 2018). Importantly, those studies did not control for the variables the Parker group did.
In the new study, the investigators collated data on lithium in groundwater from 3,000 drinking water wells in 174 counties across the U.S., sampled between 1992 and 2003. They tallied diagnoses of dementia in the same counties using insurance claim data covering 4.2 million adults. In 32 high-lithium counties, where the mean lithium exposure reached 141 μg/L, dementia prevalence was significantly lower compared to low-lithium counties, where the mean exposure was 6 μg/L. The same was true for bipolar disorder, previously linked to groundwater lithium concentrations. The association also held for three “negative control” conditions with no known link to lithium in drinking water, namely major depressive disorder, myocardial infarction, and prostate cancer.
However, the researchers found significant differences between the high- and low-lithium counties in terms of health care resources. The high-lithium areas had fewer hospital beds, primary care physicians, and psychiatrists per capita, a disparity that could result in lower rates of diagnosis of dementia. In addition, the residents of the high-lithium counties were younger, less educated, and more were Hispanic. When the investigators adjusted for those differences, the association between lithium and dementia, or any of the other diseases, disappeared.
“This indicates the purported association of high lithium concentrations in drinking water with mental health disorders is driven by unaccounted variation in demographics, health care resources, and diagnostic practices,” the authors concluded.
At therapeutic doses, lithium potently inhibits glycogen synthase kinase-3, decreases tau phosphorylation, lowers amyloid deposition, and improves cognition in animal models of AD. In a clinical study, lithium slowed cognitive decline and reduced levels of CSF tau in people with mild cognitive impairment (Forlenza et al., 2011). But as the authors point out, people in the highest lithium counties would have to drink more than 1,000 liters of water every day to ingest the 150 mg dose that elicited those effects.
Still, the debate goes on. Studies employing microdoses of lithium, equivalent to the amount present in just a few liters of water, or novel formulations, hint at benefits of sub-therapeutic doses in people (Nunes et al., 2012) and in animal models (Nunes et al., 2015; Wilson et al., 2017; Habib et al., 2017).
How low is too low? Jun Tan and Roland Shytle, University of South Florida, Tampa, said they agreed with the authors that concentrations of lithium in drinking water were unlikely to benefit those suffering with dementia. Nonetheless, they wrote in an email to Alzforum, “These findings should in no way reduce the enthusiasm for recent research exploring the possible therapeutic benefits of lithium … at broader and safer dose ranges lower than those already well-established for the treatment of bipolar disorder.”—Pat McCaffrey
- Fajardo VA, Fajardo VA, LeBlanc PJ, MacPherson RE. Examining the Relationship between Trace Lithium in Drinking Water and the Rising Rates of Age-Adjusted Alzheimer's Disease Mortality in Texas. J Alzheimers Dis. 2018;61(1):425-434. PubMed.
- Forlenza OV, Diniz BS, Radanovic M, Santos FS, Talib LL, Gattaz WF. Disease-modifying properties of long-term lithium treatment for amnestic mild cognitive impairment: randomised controlled trial. Br J Psychiatry. 2011 May;198(5):351-6. 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.
- Nunes MA, Schöwe NM, Monteiro-Silva KC, Baraldi-Tornisielo T, Souza SI, Balthazar J, Albuquerque MS, Caetano AL, Viel TA, Buck HS. Chronic Microdose Lithium Treatment Prevented Memory Loss and Neurohistopathological Changes in a Transgenic Mouse Model of Alzheimer's Disease. PLoS One. 2015;10(11):e0142267. Epub 2015 Nov 25 PubMed.
- Wilson EN, Do Carmo S, Iulita MF, Hall H, Ducatenzeiler A, Marks AR, Allard S, Jia DT, Windheim J, Cuello AC. BACE1 inhibition by microdose lithium formulation NP03 rescues memory loss and early stage amyloid neuropathology. Transl Psychiatry. 2017 Aug 1;7(8):e1190. PubMed.
- Habib A, Sawmiller D, Li S, Xiang Y, Rongo D, Tian J, Hou H, Zeng J, Smith A, Fan S, Giunta B, Mori T, Currier G, Shytle DR, Tan J. LISPRO mitigates β-amyloid and associated pathologies in Alzheimer's mice. Cell Death Dis. 2017 Jun 15;8(6):e2880. PubMed.
No Available Further Reading
- Parker WF, Gorges RJ, Gao YN, Zhang Y, Hur K, Gibbons RD. Association Between Groundwater Lithium and the Diagnosis of Bipolar Disorder and Dementia in the United States. JAMA Psychiatry. Published online May 23, 2018.