Drinking Water Lithium Exposure and Risk of Dementia in the United States

Abstract Although experimental and clinical studies suggest that lithium has neuroprotective effects at therapeutic doses, evidence regarding low-level environmental lithium exposure and dementia remains limited and inconclusive. We examined associations between estimated drinking water lithium exposure and incident dementia. We included 162,728 participants without a prior recorded dementia diagnosis who enrolled in the All of Us Research Program. Data were collected between May 31, 2017, and June 30, 2022. Incident dementia was ascertained through October 1, 2023. Area-level drinking water lithium concentrations were retrospectively assigned by linking participants’ residential 3-digit ZIP Code areas (ZIP3) to modeled public water system lithium concentrations based on measurements collected from January 2023 through June 2025 under the U.S. Environmental Protection Agency’s Fifth Unregulated Contaminant Monitoring Rule (UCMR 5). Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated for all-cause dementia (N = 1,591), Alzheimer’s disease (N = 415), and vascular dementia (N = 288), using Cox proportional hazards regression. We also conducted exploratory analyses stratified by sex, age, and apolipoprotein E (APOE) ε4 status. Compared with concentrations <9 μg/L, estimated drinking-water lithium concentrations ≥17.7 μg/L were associated with lower hazards of all-cause dementia and vascular dementia. Restricted cubic spline analyses indicated lower estimated hazards of all-cause dementia, Alzheimer’s disease, and vascular dementia across an intermediate exposure range. Exploratory subgroup analyses suggested effect modification by APOE ε4 status for all-cause dementia. Higher estimated drinking-water lithium concentrations may be associated with lower dementia hazards, although confirmation using more temporally and spatially resolved exposure assessments is needed.