Lithium, a decades-old treatment for bipolar disorder, may have potential neuroprotective effects beyond mood stabilization.
An exploratory clinical trial at the University of Pittsburgh suggests that low doses of oral lithium may help slow the decline in verbal memory, the ability to remember and recall words and sentences, in older adults with mild cognitive impairment, especially those with evidence of amyloid beta 1, a hallmark biomarker of Alzheimer’s disease.
This study JAMA Neurology The paper, published March 2, was designed to answer a key early question: Is lithium promising enough to warrant large-scale clinical trials aimed at slowing Alzheimer’s disease-related cognitive decline?
Rigorous testing of long-standing questions
The study was led by Dr. Ariel Gildengers, a professor of psychiatry at Pitt and a geriatric psychiatrist at UPMC known for her work on the effects of lithium on the aging brain. Gildengarth’s previous research has shown that long-term use of lithium in older adults with bipolar disorder is associated with improved brain health, and this finding helped form the scientific basis for the current trial.
Previous studies have observed that older adults with bipolar disorder tend to show better markers of brain integrity when they take lithium long-term. An emerging question was whether these apparent neuroprotective effects extend beyond mood disorders and whether it could be rigorously tested in prospective clinical trials. ”
Dr. Ariel Gildengers, Professor of Psychiatry at Pitt and Geriatric Psychiatrist at UPMC
To answer that question, the research team included experts in advanced brain imaging and cutting-edge Alzheimer’s disease biomarkers. The two-year trial, completed in August 2024, enrolled adults aged 60 and older with mild cognitive impairment and randomly assigned them to receive either low-dose lithium or a placebo. The researchers then followed up the participants annually through detailed cognitive tests, high-resolution brain imaging, and biomarker assessments.
What the research found and what it didn’t find
Over the two-year study period, participants who received lithium showed slower declines in sensitive tests of verbal memory, a cognitive domain known to deteriorate early in Alzheimer’s disease. Although the results were inconclusive, the study showed some encouraging signs, especially regarding verbal memory.
Brain imaging analysis showed that the hippocampus, an area important for memory, shrank over time in both the lithium and placebo groups. Although the overall difference between groups did not reach statistical significance, exploratory analyzes suggested a greater protective effect among amyloid beta-positive participants, pointing to a potential biological signal worth pursuing.
Importantly, this study confirms that low-dose lithium is safe and well-tolerated in older adults when carefully monitored, resolving major concerns about testing drugs in older populations.
“The important point is that lithium does not restore lost memories,” Gildengarth emphasized. “If the signal persists, it appears to degrade slowly. This distinction is very important when planning trials and interpreting results.”
What is a nest step
When this trial began nearly a decade ago, blood-based tests for the pathology of Alzheimer’s disease were not yet available. As a result, participants were enrolled based solely on clinical symptoms, and only some were found to be amyloid positive, a limitation that may have weakened the study’s ability to detect a stronger effect.
“If we were planning this study now, we would enroll participants based on their amyloid status from the beginning,” Gildengarth said. “That’s exactly what we’re planning next.”
Gildengarth and his colleagues are now seeking support for a larger, more definitive clinical trial based on the results of the pilot study. The next step will be to use blood-based biomarkers to identify individuals who are most likely to benefit, and to enroll a sufficient number of participants to determine whether lithium can significantly slow the cognitive and neurodegenerative changes associated with Alzheimer’s disease.
“This study shows that this approach is feasible, safe, and worth pursuing,” Gildengarth said. “But it also reminds us why careful and well-researched trials are essential, especially when the stakes are this high.”
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Reference magazines:
Gildengars, A.G.; others. (2026). Low-dose lithium for mild cognitive impairment. JAMA Neurology. DOI: 10.1001/jamaneurol.2026.0072. https://jamanetwork.com/journals/jamaneurology/fullarticle/2845746
