Study 1 Low-level lithium in drinking water and subsequent risk of dementia: A cohort study (Duthie et al. 2023).

This study was conducted in Scotland pooling from the general population by using the Scottish Mental Survey 1932 (MS1932), which included almost all school-aged children from June 1932. Most of these children had been born in 1921. Despite efforts to include all children, the study did exclude about 5.6% of them for failure to complete the survey. Later in life, 43% of these individuals were identified using medical and primary care records, as well as location.

Measurements of Li were collected from the “Scottish Water” database sampled in 2014. 285 Li samples were collected, and the remaining were gathered by using “idw ()” in R to interpolate values using inverse distance weighting. These values were then assigned to individuals based on their geographical location. Gathered standardized Li concentration levels were broken down into 5 quantiles.

The main outcome measured by the study was the risk of dementia. The authors controlled for the participants' IQ at age 11 and their sex. The study, however, did not consider dietary sources of Li, Li content in bottled water, access to health care, age of diagnosis or changes of address.

Study 2 Examining the Relationship between Trace Lithium in Drinking Water and the Rising Rates of Age-Adjusted Alzheimer’s Disease Mortality in Texas (Fajardo et al. 2017).

This study was conducted in all Texas counties. Data was gathered using the “Wonder’s Compressed Mortality Database”. Encompassing changes in mortality rates between years 2000–2006 and 2009–2015.

Li cationic levels were collected from the public water supply using the “Texas Water Development Board Groundwater Database”. This information was obtained from the database using the filters “quality” and “last 10 years”. Overall yielding 6180 water samples across 234 counties in Texas.

This study aimed to investigate the Li levels and Alzheimer’s mortality rates. To further inquire about this relationship, data on race, gender, and rural residence, were obtained from the Census Bureau’s Population Estimation Program; air pollution data from the CDC Wonder Environmental Database; and physical activity, obesity, and type 2 diabetes (T2D) from the National Diabetes Surveillance System. This study did not account for time individuals may have spent in other areas outside Texas or the length of Li exposure,.

Study 3 Lithium in drinking water and Alzheimer’s dementia: Epidemiological Findings from National Data Base of Japan (Muronaga et al. 2022).

This research was conducted in Japan, including 808 regions, containing 785 cities and 23 wards of Tokyo. 91% of the population living in these areas were included in the study. Information on AD individuals was compiled from anonymous AD claims to the Nippon Telegraph and Telephone (NTT) survey, the Ministry of Health, Labor, and Welfare of Japan database, and 2 major medical insurances (one for the early elderly and another for the later elderly). Despite including the 2 primary insurance companies in Japan, the research team was unable to find all anonymous claims, limiting their sample.

Lithium measurements came from 988 water samples congregated from the main rail station or municipal office between 2010 and 2015. A 3rd party used mass spectroscopy to analyze the levels of Li.

To investigate the prevalence of AD, researchers collected Li levels in water and AD incidence rates. 4 variables from the Statistics Bureau Ministry of Internal Affairs and Communications database were considered, including (1) the proportion of one-person households; (2) the proportion of people in primary industry employment; (3) the annual total sunshine hours between 2010 and 2015; and (4) the number of beds in psychiatric hospitals between the same period. The present study also failed to consider dietary sources of Li, use of NSAIDs, the difference of Li in mineral water in Japan when compared to other locations, gender, education, race, and metabolic factors (i.e. obesity, T2D) or changes of adress.

Study 4 Association of Lithium in Drinking Water with the Incidence of Dementia (Kessing et al. 2017).

This Danish population-based study pooled data from the population registry for individuals with dementia by obtaining information on Danish individuals from national reports (Statistics Denmark, the Danish National Patient Register—DNPR, and the Danish Register of Causes of Death—DPCRR) from 1986 to 2013. Control individuals were randomly assigned, and sex/age matched those of the dementia group. Individuals who lacked information on the municipality of residence between 1986 and the index were excluded from the study.

151 samples of the public water reservoirs were gathered between 2009–2010 and 2013. The researchers used these samples to estimate Li in water using the Kringing interpolation methods. This method accounted for individuals moving to different areas in Denmark during the time being analyzed.

To investigate the incidence of dementia and its relationship to Li exposure via drinking water, gathered demographic data from the population. The study did not adjust for accessibility to health care (as it was deemed similar across the board) and other environmental factors such as urbanicity.

Study 5 Association between groundwater lithium and the diagnosis of bipolar disorder and dementia in the United States (Parker et al. 2018).

An investigation on the association between groundwater Li and diagnosis of BD and dementia was conducted across the United States. Individuals’ inpatient hospital and long-term care data were gathered using the Truven Health Marketscan Commercial Claims & Encounters (2003–2010), Medicare recipients, and Medicaid Analytic eXtract (2011–2012). This generates potential for selection, and it was not exhaustive of the sampling population.

Lithium levels were obtained from the US Geological Survey from 3000 + drinking water wells from 1992 to 2003. The overlap between this sampling and the study population is not clear. To investigate the impacts of groundwater Li and dementia diagnosis, demographic data was collected from the Health Resources & Services Administration (HRSA) and the 2010 Area Health Resources Files (AHRF). The study considered median age, education, race, ethnicity, and the number of beds in primary care per 1000/individuals.

The study did not explain in detail the use of covariates on the association of dementia onset and Li levels in groundwater. This study was the least comprehensive and had the greatest potential for bias.

The sample size varied in the studies from 37,597 to 35 000 000. Lithium levels ranged from 0.002 to 0.027 (mg/L). The rates of dementia varied widely; in 3 studies the rates were between 5.8% and 9.6%, while in 1 study the rates were very low at 0.041% (See Table 1), likely reflecting marked selection bias.

4 of the 5 studies found a significant association between Li levels and lower risk of dementia or lower dementia mortality rates, when they did not control for any confounders. One study did not find any association between Li and dementia and reported one of the lowest Li levels (Duthie et al. 2023).

After controlling for available confounders, one found an association between Li levels and lower risk of dementia in both male and females (Kessing et al. 2017) and one study in females only (Muronaga et al. 2022). In contrast, the association between lithium and dementia disappeared when controlling for county demographics and healthcare resources (Parker et al. 2018), and physical inactivity, obesity and T2D (Fajardo et al. 2017). While all studies controlled for sex, the additional confounding factor varied between studies and surprisingly, age categories were not controlled in any of the studies.

The association between trace levels of Li and dementia outcomes was non-linear in at least one of the studies (Kessing et al. 2017).