Low-Dose Lithium Shows Promise for Mild Cognitive Impairment

Mild cognitive impairment (MCI) is a condition in which individuals demonstrate cognitive impairment with minimal impairment of instrumental activities of daily living (IADL).¹ IADL are depicted in Table 1.² Individuals are asked to choose the description that most closely matches their highest functional level, which is scored as either 1 (can complete the task) or 0 (cannot complete the task). MCI can be the first cognitive manifestation of Alzheimer disease (AD) but may also result from other neurologic, neurodegenerative, systemic, or psychiatric disorders.

There are currently no well-established pharmacologic agents proven to prevent progression of MCI, which is why new medications as well as repurposing strategies for existing medications are being used.

Lithium, a mood stabilizer long used for bipolar disorder, has gained interest as a potential treatment for MCI. This stems from its neuroprotective effects, thought to be caused by 2 mechanisms: glycogen synthase kinase-3 (GSK-3) a/b inhibition, an enzyme implicated in amyloid-β production and tau phosphorylation, two hallmarks of AD; and upregulation of brain-derived neurotrophic factor (BDNF) expression, a plasma biomarker that supports neuronal survival and plasticity.³

In the double-blind, randomized, national, single center, pilot LATTICE (The Lithium as a Treatment to Prevent Impairment of Cognition in Elders) trial (NCT03185208), 41 patients were assigned to receive lithium carbonate (150 mg or 300 mg daily or every other day, titrated weekly to the maximum tolerated dose), and 42 patients were assigned to receive a matching placebo. Patients were followed over a period of 2 years. Eligible participants were aged 60 years or older with MCI defined per Petersen criteria (cognitive performance 1-2 standard deviations below age- and education-adjusted norms in ³1 cognitive domain) and preserved ADL. Exclusion criteria included major psychiatric illness, major neurologic illness, contraindications to lithium, and those with nonremediable sensory or motor impairments that would impair their ability to complete neuropsychological testing (ie, blindness).³

The study evaluated 6 coprimary outcomes: verbal memory, visual memory, overall cognitive performance, hippocampal volume, cortical gray matter volume, and BDNF levels. GSK-3 a/b activity was originally planned as an additional biomarker outcome, but the assays failed quality control and could not be assessed. The objective was to determine whether low-dose lithium could delay cognitive decline and preserve brain structure in older adults with MCI. The study hypothesized that participants randomized to take low-dose lithium for 2 years would better maintain cognitive function, primarily in memory vs those in the placebo group, which would be associated with changes in GSK-3 a/b activity and BDNF levels. This study was the first of its kind to combine cognitive outcomes, neuroimaging, and plasma biomarker end points.³

Eighty patients were needed to provide 80% power at a 2-sided α-level of 0.05 to detect a medium effect size. The primary analyses used a more conservative 2-sided α-level of 0.01 to account for multiple outcomes. None of the 6 coprimary outcomes met the prespecified significance threshold. Still, one cognitive measure, verbal memory, showed a numerically slower decline with lithium vs placebo. Scores declined by 0.73 points per year in the lithium group vs 1.42 points per year in the placebo group, a difference that reached clinical significance but did not meet the stricter threshold set for the primary analysis.³

Lithium treatment is associated with initial nausea, vomiting, diarrhea, tiredness, muscle weakness, polydipsia, polyuria, and fine hand tremor. Long-term adverse effects include renal toxicity, hypothyroidism, cardiac effects, leukocytosis, skin effects, increased weight, and neurologic disturbances. In the trial serious adverse events occurred in 29% (12/41) of patients in the lithium vs 23% (9/39) of patients in the placebo group. Adverse effects in the lithium vs placebo group included diarrhea (29% [12/41] vs 15% [6/39]), tiredness (29% [12/41] vs 15% [6/39]), and tremor (24% [10/41] vs 15% [6/39]), while increased creatinine levels were comparable between groups (29% [12/41] vs 31% [12/39]).³

In conclusion, low-dose lithium did not meet the prespecified primary outcomes in patients with MCI, though it may have shown a modest signal for preservation of verbal memory. These findings are currently not strong enough to support routine use of lithium for MCI prevention or treatment in clinical practice. From a practice standpoint, lithium’s narrow therapeutic index, need for close laboratory monitoring, and adverse effect profile must also be taken into consideration.

REFERENCES

1. Petersen RC, Lopez O, Armstrong MJ, et al. Practice guideline update summary: mild cognitive impairment [RETIRED]: report of the guideline development, dissemination, and implementation subcommittee of the American Academy of Neurology. Neurology. 2018;90(3):126-135. doi:10.1212/WNL.00000000004826

2. Graf C. The Lawton instrumental activities of daily living scale. Am J Nurs. 2008;108(4):52-62. doi:10.1097/01.NAJ.0000314810.46029.74

3. Gildengers AG, Ibrahim TS, Anderson SJ, et al. Low-dose lithium for mild cognitive impairment: a pilot randomized clinical trial. JAMA Neurol. 2026;83(4):310-319. doi:10.1001/jamaneurol.2026.0072