Lithium exposure and risk of dementia and Alzheimer's disease: A systematic review and meta-analysis

BackgroundAlzheimer's disease (AD) is the most common cause of dementia, affecting over 55 million people worldwide with no established disease-modifying treatments. Lithium has emerged as a potential neuroprotective agent through multiple molecular mechanisms, and observational studies suggest reduced dementia risk among users, but evidence synthesis is needed.ObjectiveTo evaluate the association between lithium exposure and dementia incidence through systematic review and meta-analysis.MethodsWe conducted a systematic review following PRISMA 2020 guidelines, searching major databases through December 2024. Random-effects meta-analyses with Hartung-Knapp-Sidik-Jonkman adjustment were performed.ResultsTwenty-three primary studies with original data (n > 1.2 million) were included in qualitative synthesis; 11 provided extractable quantitative data, including 8 individual-level and 3 ecological studies. Four cohort studies showed a pooled hazard ratio (HR) of 0.633 (95% CI: 0.517-0.775; p = 0.003), indicating ∼37% lower dementia risk with lithium. Two individual-level studies showed HR 0.656 (95% CI: 0.427-1.009; p = 0.052) for AD diagnosis. Three randomized controlled trials (RCTs) of cognitive outcomes yielded SMD -0.410 (95% CI: -0.810 to -0.020; p = 0.040) based on 229 participants. Two ecological studies using incidence rate ratios (IRR 0.830, 95% CI: 0.810-0.850) were directionally consistent. Substantial heterogeneity reflected clinical diversity, with consistent protective effects across subgroups.ConclusionsLithium exposure was consistently associated with reduced dementia risk. While observational evidence precludes definitive causal inferences, the magnitude, consistency, and biological plausibility support lithium as a promising candidate for dementia prevention research. Large-scale, long-term RCTs are needed to establish causality.