Pilot Study Investigates Low-Dose Lithium for Mild Cognitive Impairment
KEY TAKEAWAYS
- Low-dose lithium treatment for people with mild cognitive impairment was feasible and generally well tolerated over 2 years.
- The study did not meet any coprimary endpoints, with no significant differences in cognition, brain volume, or biomarkers vs placebo.
- A nominal signal toward slower verbal memory decline and exploratory findings in amyloid-positive participants support further study.
Results from a pilot randomized clinical trial (NCT03185208) published in JAMA Neurology demonstrated the feasibility of recruitment, retention, and longitudinal evaluation of low-dose lithium therapy for people with mild cognitive impairment. The treatment was generally well tolerated over the study period, and outcomes showed a nominal signal toward slower verbal memory decline for lithium treatment vs placebo, though statistical significance was not reached. Although the study was not designed to establish efficacy, and none of the coprimary end points were met, the results support further investigation of low-dose lithium treatment as a potential disease-modifying therapy.
The single-site, double-blind study enrolled 83 adults aged 60 years or older with mild cognitive impairment, with 80 initiating treatment. Participants received daily low-dose lithium carbonate (n=41) or placebo (n=39) for 2 years. The trial assessed six coprimary outcomes spanning cognition, brain structure, and a plasma biomarker.
Key findings:
- None of the coprimary endpoints met the prespecified threshold for statistical significance.
- Verbal memory decline was slower with lithium vs placebo (−0.73 vs −1.42 points per year; difference, 0.69; 95% CI, 0.01 to 1.37; nominal P=.05), but this did not meet the adjusted significance threshold.
- No significant between-group differences were observed for global cognition, visuospatial memory, hippocampal volume, cortical gray matter volume, or brain-derived neurotrophic factor.
- Brain volume declined over time in both groups, consistent with expected disease progression.
Safety findings were broadly comparable between groups. Serious adverse events occurred in 29% of lithium-treated participants and 23% of those receiving placebo, with none considered treatment related.
Although efficacy was not demonstrated, exploratory analyses suggested larger effects among amyloid-positive participants. The authors noted that the trial provides effect size estimates and supports further investigation of lithium in larger, biomarker-enriched populations.
Sources
Gildengers AG, Ibrahim TS, Anderson SJ, et al. Low-Dose Lithium for Mild Cognitive Impairment: A Pilot Randomized Clinical Trial. JAMA Neurol. Published online March 02, 2026. doi:10.1001/jamaneurol.2026.0072