Low-dose lithium may slow verbal memory decline, exploratory clinical trial suggests

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, 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 next 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.”