Summary: Lithium has been a mainstay for treating bipolar disorder for over half a century, but new research suggests its benefits may extend deep into neuroprotection. A pilot clinical trial indicates that low-dose oral lithium may slow the decline of verbal memory—the ability to recall words and sentences—in older adults with Mild Cognitive Impairment (MCI).
The two-year study found that lithium’s protective signal was particularly strong in individuals who tested positive for amyloid-beta, a primary hallmark of Alzheimer’s disease. While not a cure, this finding positions lithium as a potential low-cost, accessible strategy to delay cognitive deterioration.
Key Facts
- Verbal Memory Protection: Participants taking low-dose lithium showed a significantly slower rate of decline in verbal memory, one of the first cognitive areas hit by Alzheimer’s.
- The Amyloid Connection: Exploratory analyses revealed that the neuroprotective effects were most pronounced in participants with confirmed amyloid-beta pathology.
- Safety in Aging: The trial confirmed that low-dose lithium is safe and well-tolerated in older adults when monitored, easing concerns about its use in aging populations.
- Longitudinal Signal: The study built on prior observations that long-term lithium users with bipolar disorder often maintain better brain integrity as they age.
- Slowing vs. Restoring: Researchers emphasize that lithium does not restore lost memory; rather, it appears to act as a “brake,” slowing down the rate of inevitable decline.
Source: University of Pittsburgh
Lithium—a decades-old treatment for bipolar disorder—may hold potential neuroprotective benefits beyond mood stabilization.
An exploratory clinical trial from the University of Pittsburgh suggests that low‑dose oral lithium may help slow the decline of verbal memory, or ability to remember and recall words and sentences, in older adults with mild cognitive impairment, particularly among those with evidence of amyloid beta—one of the hallmark biomarkers of Alzheimer’s disease.
The study, published in JAMA Neurology on March 2, was designed to answer a critical early question: Is lithium promising enough to justify a larger clinical trial aimed at slowing Alzheimer’s‑related cognitive decline?
A long‑standing question, tested rigorously
The study was led by Dr. Ariel Gildengers, professor of psychiatry at Pitt and a geriatric psychiatrist at UPMC known for his research on lithium’s effects on the aging brain. Gildengers’ prior work has shown that long‑term lithium use in older adults with bipolar disorder is associated with better brain integrity—a finding that helped shape the current trial’s scientific rationale.
“In a prior study, we observed that older adults with bipolar disorder who take lithium long‑term tend to show markers of better brain integrity,” Gildengers said. “The new question was whether those apparent neuroprotective effects might extend beyond mood disorders—and whether we could test that rigorously in a prospective clinical trial.”
To answer that question, the research team included experts in advanced brain imaging and cutting-edge Alzheimer’s biomarkers. The two‑year trial, completed in August 2024, enrolled adults aged 60 and older with mild cognitive impairment and randomized them to receive either a low dose of lithium or a placebo.
The researchers then followed participants annually through detailed cognitive testing, high‑resolution brain imaging and biomarker assessments.
What the study found—and what it didn’t
Over the two‑year study period, participants receiving lithium showed a slower rate of decline on a sensitive test of verbal memory, a cognitive domain known to deteriorate early in Alzheimer’s disease. While the results weren’t definitive, the study showed particularly encouraging signs when it came to verbal memory.
Brain imaging analyses showed that the hippocampus—a region critical for memory—shrank over time in both the lithium and placebo groups.
Although the overall difference between groups did not reach statistical significance, exploratory analyses suggested larger protective effects among participants who were positive for amyloid beta, pointing to a potential biological signal worth pursuing.
Importantly, the study confirmed that low‑dose lithium was safe and well tolerated in older adults when carefully monitored, addressing a major concern about testing the drug in aging populations.
“The key point is that lithium doesn’t restore lost memory,” Gildengers emphasized. “What it appears to do—if the signal holds up—is slow deterioration. That distinction matters enormously when you’re designing trials and interpreting results.”
What are the nest steps
When the trial was launched nearly a decade ago, blood‑based tests for Alzheimer’s pathology were not yet available. As a result, participants were enrolled based on clinical symptoms alone, and only a subset turned out to be amyloid‑positive—a limitation that may have diluted the study’s ability to detect stronger effects.
“If we were designing this study today, we would enroll participants based on amyloid status from the start,” Gildengers said. “That’s exactly what we’re planning for next.”
Gildengers and his collaborators are now seeking support for a larger, more definitive clinical trial informed by the pilot study’s findings.
The next phase would use blood‑based biomarkers to identify individuals most likely to benefit and would enroll enough participants to determine whether lithium can meaningfully delay cognitive and neurodegenerative changes associated with Alzheimer’s disease.
“This study tells us that the approach is feasible, safe and worth pursuing,” Gildengers said. “But it also reminds us why careful, adequately powered trials are essential—especially when the stakes are this high.”
Key Questions Answered:
A: Not yet. While the results are promising, this was a small pilot study. Lithium requires careful medical monitoring because even at low doses, it can affect kidney and thyroid function. You should wait for the results of the larger, definitive clinical trials currently being planned.
A: Lithium is known to influence several pathways involved in brain health, including reducing inflammation and inhibiting an enzyme called GSK-3, which is linked to the formation of tau tangles. Essentially, it helps stabilize the brain’s internal environment, making it more resilient to disease.
A: It’s the same element, but in a purified, pharmaceutical salt form (usually lithium carbonate). In medicine, it has been used for over 70 years. Because it is a generic, naturally occurring mineral, it could eventually become a very affordable treatment option if proven effective in larger trials.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- Journal paper reviewed in full.
- Additional context added by our staff.
About this neuropharmacology and Alzheimer’s disease research news
Author: Anastasia Gorelova
Source: University of Pittsburgh
Contact: Anastasia Gorelova – University of Pittsburgh
Image: The image is credited to Neuroscience News
Original Research: Open access.
“Low-Dose Lithium for Mild Cognitive Impairment” by Ariel G. Gildengers, Tamer S. Ibrahim, Stewart J. Anderson, James E. Emanuel, Tales Santini, Jihui L. Diaz, Brian J. Lopresti, Sarah K. Royse, Oscar L. Lopez, Xuemei Zeng, Bruno de Almeida, Salem K. Alkhateeb, Cong Chu, Thomas K. Karikari, Laisze Lee, Andrea M. Weinstein, and Meryl A. Butters. JAMA Neurology
DOI:10.1001/jamaneurol.2026.0072
Abstract
Low-Dose Lithium for Mild Cognitive Impairment
Importance
Lithium deficiency may contribute to Alzheimer disease pathogenesis. No randomized clinical trial has examined lithium’s effects on cognition, neuroimaging, and plasma biomarkers in mild cognitive impairment (MCI).
Objective
To examine the feasibility, safety, and preliminary efficacy of lithium carbonate for delaying cognitive decline in older adults with MCI.
Design, Setting, and Participants
This single-site, randomized, double-blind, placebo-controlled pilot feasibility clinical trial was conducted at the University of Pittsburgh School of Medicine from February 2018 to August 2024, with 2-year follow-up. Analyses used linear mixed-effects models in the intention-to-treat population.
Adults aged 60 years or older with MCI who were free of major psychiatric or neurologic illness and contraindications to lithium were included. Of 170 individuals assessed, 83 were randomized (41 lithium vs 42 placebo), with 80 starting treatment (41 lithium vs 39 placebo). Data were analyzed from August 2024 to December 2025.
Intervention
Daily low-dose lithium carbonate or placebo for 2 years.
Main Outcomes and Measures
Six prespecified coprimary outcomes included cognitive performance (California Verbal Learning Test-II [CVLT-II] delayed recall, Brief Visuospatial Memory Test-Revised, preclinical Alzheimer cognitive composite), hippocampal volume, cortical gray matter volume, and brain-derived neurotrophic factor.
Results
Among 80 participants (mean [SD] age, lithium: 72.93 [8.77] years; placebo: 71.22 [6.47] years; 56% female), none of the 6 coprimary outcomes met the prespecified significance threshold. Mean (SD) CVLT-II baseline scores were 7.95 (3.4) for lithium and 7.90 (3.9) for placebo; scores declined 1.42 points annually in the placebo group vs 0.73 points in the lithium group (difference, 0.69 points per year; 95% CI, 0.01-1.37; P = .05). Hippocampal and cortical volumes showed a decline over time in both groups, but no significant treatment × time interactions.
Serious adverse events occurred in 12 of 41 (29%) receiving lithium vs 9 of 39 (23%) receiving placebo; none were definitely treatment related. One death occurred in the placebo group. Common adverse events included increased creatinine levels (12 of 41 [29%] with lithium vs 12 of 39 [31%] with placebo), diarrhea (12 of 41 [29%] vs 6 of 39 [15%]), tiredness (12 of 41 [29%] vs 6 of 39 [15%]), and tremor occurrence (10 of 41 [24%] vs 6 of 39 [15%]).
Conclusions and Relevance
This pilot randomized clinical trial established feasibility, confirmed safety and tolerability, and generated effect size estimates for future trials of low-dose lithium in MCI. None of the coprimary outcomes met the prespecified significance threshold.
Trial Registration
ClinicalTrials.gov Identifier: NCT03185208
