Early Study of Lithium in Mild Cognitive Impairment Yields Mixed Outcomes

In a pilot randomized clinical trial published in JAMA Neurology, results showed that low-dose lithium was safe among patients with mild cognitive impairment (MCI), but did not lead to significant outcomes on any of the 6 coprimary end points. Investigators did conclude that the study provided effect size estimates and methodological insights on how a future confirmatory trial may be conducted.¹

This single-site, randomized, double-blind, placebo-controlled feasibility trial otherwise known as LATTICE included 80 participants aged 60 years or older with MCI who were randomized to either low-dose lithium (n = 41) or placebo (n = 39) for a 2-year treatment period. The study included 6 coprimary end points– cognitive performance (California Verbal Learning Test-II [CVLT-II] delayed recall, Brief Visuospatial Memory Test-Revised (BVMT-R), preclinical Alzheimer cognitive composite), hippocampal volume, cortical gray matter volume, and brain-derived neurotrophic factor.

Among cognitive outcomes, CVLT-II showed the largest effect size, as patients on placebo demonstrated declines of 1.42 points per year vs 0.73 for those on lithium (difference, 0.69 points per year; 95% CI, 0.01-1.37; P = .05). Despite this, differences in CVLT-II were only nominal, and did not meet the prespecified threshold of P <.01. Led by Ariel G. Gildengers, MD, a professor of psychiatry at the University of Pittsburgh, neither BVMT-R nor PACC showed significant change over time in either group, limiting interpretation of treatment effects on these measures.

“Conducting this trial provided knowledge and experience to inform future trials of low-dose lithium in MCI,” Gildengers et al wrote. “Most importantly, we observed that older adults have substantial difficulty tolerating doses greater than 300 mg daily. Thus, future trials should use doses of lithium carbonate in the range of 150 mg to 300 mg daily.”

The literature on lithium in MCI and neurodegenerative diseases such as Alzheimer disease (AD) has expanded significantly over the past decade, with growing evidence suggesting lithium deficiency may be a modifiable risk factor for AD. A notable 2025 study published in Nature Medicine further supported this concept, with preclinical findings demonstrating the physiological role of endogenous lithium in the brain and identifying disruption of lithium homeostasis as a potential early event in AD pathogenesis. The authors concluded that lithium replacement using amyloid-evading salts may represent a potential strategy for AD prevention and treatment.

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In the pilot study, low-dose lithium was considered safe and well tolerated, with common adverse events (AEs) that included creatinine, diarrhea, tiredness, and tremor. There were no deaths in the lithium group and 1 death in the placebo group that was considered not study related. Overall, investigators recorded 41 serious AEs (25 lithium vs 16 placebo), with none definitely related to the study medication.

Additional data showed no significant between-group differences on outcomes such as hippocampal volume (difference in annual decline, 59 mm3 per year; 95% CI, –9 to 127; P = .09). Furthermore, cortical gray matter volume showed no treatment x time interaction (difference in annual decline, –352 mm3 per year; 95% CI, –2866 to 2162; P = .78).

Prespecified analyses were conducted among participants who completed the study, with results in the overall completer cohort—including both amyloid-positive (Aβ+) and amyloid-negative (Aβ−) individuals—consistent with the intention-to-treat findings. In exploratory subgroup analyses stratified by amyloid status, sample sizes were limited; however, effect sizes were notably larger among Aβ+ completers, with Hedges g values of 0.74 for verbal memory, 0.82 for hippocampal volume, and 0.81 for hippocampal percentage change. In contrast, corresponding effect sizes in Aβ− completers were 0.32, 0.09, and 0.12, respectively.

Gildengers et al concluded that, “This pilot randomized clinical trial established the feasibility of recruitment and retention and confirmed the safety and tolerability of low-dose lithium treatment in older adults with MCI. The trial generated preliminary effect size estimates across cognitive and neuroimaging outcomes. Together with findings from prior independent longer-term trials, these results support further investigation of lithium in adequately powered trials to assess its potential neuroprotective properties in MCI.”

REFERENCES
1. 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 2, 2026. doi:10.1001/jamaneurol.2026.0072
2. Aron L, Ngian ZK, Qiu C, et al. Lithium deficiency and the onset of Alzheimer’s disease. Nature. 2025;645:712-721. doi:10.1038/s41586-025-09335-x