LITHIUM treatment may modestly slow memory decline in older adults with mild cognitive impairment, according to pilot trial findings that provide early effect size estimates.
Rationale for Lithium Treatment in MCI
Lithium treatment has long been used in psychiatry, but growing evidence suggests lithium deficiency may contribute to Alzheimer disease pathogenesis. Mild cognitive impairment represents a high-risk state for progression to dementia, yet disease modifying options remain limited. Researchers therefore evaluated whether low dose lithium treatment could delay cognitive decline and influence neuroimaging and plasma biomarkers. Establishing feasibility, safety, and preliminary efficacy is essential before advancing to definitive phase three trials in this vulnerable population.
Lithium Treatment Outcomes Over Two Years
This single site randomized, double blind, placebo-controlled pilot trial enrolled 80 participants aged 60 years or older. Mean age was 72.93 8.77 years in the lithium group and 71.22 6.47 years in the placebo group, with 56% female overall. None of the 6 coprimary outcomes met the prespecified significance threshold. For verbal memory, scores declined 1.42 points annually in the placebo group vs 0.73 points in the lithium group difference, 0.69 points per year; 95% CI, 0.01-1.37; P = .05. Hippocampal and cortical volumes declined in both groups without significant treatment × time interactions. Serious adverse events occurred in 12 of 41 29% receiving lithium vs 9 of 39 23% receiving placebo; none were definitely treatment related.
Clinical Implications and Future Directions
Although lithium treatment did not meet primary statistical thresholds, the observed difference in verbal memory decline suggests a potential signal warranting further investigation. Safety and retention targets were achieved, supporting feasibility in older adults. Notably, tolerability challenges emerged at doses above 300 mg daily, indicating future trials should consider 150 mg to 300 mg regimens. Longer study durations may also be required to detect cognitive effects in mild cognitive impairment. Larger confirmatory studies will be essential to determine whether lithium treatment can meaningfully delay progression toward dementia.
Featured image: jroballo on Adobe Stock
Reference
Gildengers AG et al. Low-dose lithium for mild cognitive impairment: a pilot randomized clinical trial. JAMA Neurol. 2026;DOI:10.1001/jamaneurol.2026.0072.
