Lithium deficiency may result from its sequestration within amyloid plaques, which could contribute to the neurodegeneration observed in Alzheimer’s disease (AD). Evidence from epidemiological, clinical, animal, and cellular studies suggests that lithium may serve as a protective agent against dementia.
A 2015 systematic literature review and meta-analysis of three randomized controlled trials involving 232 patients with mild cognitive impairment (MCI) or AD found that lithium significantly reduced the cognitive decline process when compared to placebo. However, findings across studies are not consistent; lithium deficiency may represent a modifiable risk factor for AD. The neuroprotective effects of lithium are associated with inhibition of glycogen synthase kinase (GSK)-3α/β and increased activity of brain-derived neurotrophic factor (BDNF), but clinical trials combining plasma biomarkers, cognitive assessment, and neuroimaging are limited.
Lithium as a treatment to prevent impairment of cognition in elders (LATTICE) pilot randomized clinical trial evaluated whether two years of lithium treatment in individuals with MCI could preserve cognition, influence biomarkers, and reduce the brain structural decline.
The LATTICE was a single-center, double-blind, placebo-controlled, randomized, pilot feasibility clinical study that was conducted at the University of Pittsburgh School of Medicine between February 2, 2018, and August 5, 2022. A total of 80 patients with mild MCI were included in this study. They were randomized to receive lithium carbonate (n = 41, mean age = 72.93±8.77 years, female = 56%, male = 44%, White = 93%) or placebo (n = 39, mean age = 71.22±6.47 years, female = 56%, male = 44%, White = 85%) for two years with dose adjustment and regular monitoring of lithium levels, compliance, adverse events, and safety using spontaneous reporting of adverse effects (SRSE), brief adherence rating scale (BARS), and udvalg for kliniske undersØgelser (UKU).
Six co-primary endpoints included plasma BDNF, hippocampal volume, visual memory, cortical gray matter volume, verbal memory (California verbal learning test-II [CVLT-II]), and overall cognition (preclinical Alzheimer cognitive composite [PACC]). Activity of GSK-3 was not determined due to assay failure. Cognitive assessments, magnetic resonance imaging (MRI), positron emission tomography (PET), biomarker analyses, and additional clinical evaluations were conducted periodically to measure cognitive outcomes, alterations in brain structure, and biological markers that are associated with AD progression. All statistical analyses were carried out using SAS, version 9.4, and R, version 4.4.2.
Among 80 participants, the mean daily lithium dose was found to be 195±150 mg, which produced a mean serum level of 0.17±0.13 mEq/L with 98% pill compliance, whereas placebo participants showed 97% compliance. One death was reported in the placebo group, while none occurred in the lithium group. Additionally, a total of 41 serious adverse events were reported (lithium group: 29% of participants; placebo group: 23%), none of which were considered related to the study medication.
The most common adverse events included tremors (24% with lithium vs 15% with placebo), diarrhea (29% vs 15%), increased levels of creatinine (29% vs 31%), and tiredness (29% vs 15%).
There was a significant decline observed in neuroimaging measures and CVLT-II. Only CVLT-II showed nominal treatment significance, with an annual decline of 0.69 points (95% confidence interval [CI]: 0.01-1.37) and p-value of 0.05, but this was not met with the prespecified threshold of p <0.01. Cortical volume and hippocampal volume were decline of 352 mm3/year (95% CI: -2866 to 2162, p = 0.78) and 59 mm3/year (95% CI: -9 to 127, p = 0.09), respectively. Measures of BDNF, BVMT-R, and PACC showed no statistically significant treatment effects. However, exploratory analyses suggested larger effects among amyloid-positive participants.
This study’s limitations include being conducted during the COVID-19 pandemic, which affected in-person assessments and medication adherence. Furthermore, participants with syndromic MCI were enrolled without biomarker confirmation of AD pathology, which may have diluted the treatment effects.
In conclusion, this study demonstrated the safety and tolerability of low-dose lithium use among older adults with MCI. This supports the larger clinical trials to evaluate its potential neuroprotective effects.
Reference: Gildengers AG, Ibrahim TS, Anderson SJ, et al. Low-Dose Lithium for Mild Cognitive Impairment: A Pilot Randomized Clinical Trial. JAMA Neurol. 2026. doi:10.1001/jamaneurol.2026.0072
