JAMA Neurology | Low-Dose Lithium for Mild Cognitive Impairment: A Pilot Randomized Clinical Trial

Lithium deficiency, resulting from its sequestration by amyloid plaques, may contribute to neurodegeneration in Alzheimer’s disease. A growing body of evidence suggests that lithium may protect against dementia, but no randomized clinical trial had yet combined cognitive assessment, neuroimaging, and plasma biomarkers to test this rigorously in humans.

The Lithium as a Treatment to Prevent Impairment of Cognition in Elders (LATTICE) study was designed to address that gap. Investigators including Ariel Gildengers, MD (Professor of Psychiatry); Thomas Karikari, PhD (Associate Professor of Psychiatry); Andrea Weinstein, PhD (Assistant Professor of Psychiatry, Psychology, and Clinical and Translational Science); and Meryl Butters, PhD (Emeritus Professor of Psychiatry and Clinical and Translational Science), from Pitt Psychiatry conducted a single-site, randomized, double-blind, placebo-controlled pilot-feasibility clinical trial. The study tested whether daily low-dose lithium carbonate could delay cognitive decline in adults aged 60 and older with mild cognitive impairment (MCI).

As a pilot-feasibility trial, LATTICE was not designed to prove that lithium works. The results were encouraging but not definitive; verbal memory declined at approximately half the rate in the lithium group compared to placebo, though this did not meet the pre-specified significance threshold. The study, published in JAMA Neurology, confirmed that low-dose lithium was safe and well tolerated in older adults. Most importantly, it generated the methodological insights and effect size estimates needed to design a larger, adequately powered confirmatory trial, including the knowledge that future trials should enroll participants with confirmed Alzheimer’s pathology using blood-based biomarkers.

“This is the third independent study to suggest that lithium may slow cognitive decline in older adults with mild cognitive impairment or Alzheimer’s disease. That pattern across independent samples, different countries, and different populations is what warrants the next step: a larger, adequately powered confirmatory trial,” said Dr. Gildengers, the study’s corresponding author.

Low-Dose Lithium for Mild Cognitive Impairment: A Pilot Randomized Clinical Trial.

Gildengers AG, Ibrahim TS, Anderson SJ, Emanuel JE, Santini T, Diaz JL, Lopresti BJ, Royse SK, Lopez OL, Zeng X, de Almeida B, Alkhateeb SK, Chu C, Karikari TK, Lee L, Weinstein AM, Butters MA.

JAMA Neurology. Published online March 02, 2026. doi:10.1001/jamaneurol.2026.0072