A recent clinical trial led by researchers at the University of Pittsburgh indicates that low-dose oral lithium may slow the decline of verbal memory in older adults with mild cognitive impairment. The study, published in JAMA Neurology on March 2, focused on individuals aged 60 and above and included those showing signs of amyloid beta, a key biomarker for Alzheimer's disease.
The two-year trial, completed in August 2024, randomized participants to receive either low-dose lithium or a placebo. Participants underwent annual cognitive assessments, brain imaging, and biomarker evaluations. Results showed that those receiving lithium experienced a slower decline in verbal memory compared to the placebo group. However, overall differences between groups did not reach statistical significance.
Dr. Ariel Gildengers, professor of psychiatry at the University of Pittsburgh and geriatric psychiatrist at UPMC, led the study. He noted previous research linking long-term lithium use in older adults with bipolar disorder to better brain integrity. This background informed the rationale for testing lithium’s potential neuroprotective effects against Alzheimer’s-related decline.
Brain imaging revealed hippocampal shrinkage over time in both groups. Exploratory analyses suggested that participants positive for amyloid beta might benefit more from lithium treatment, though these findings require further investigation.
Safety was a central concern given the age of participants. The study found that low-dose lithium was safe and well tolerated when monitored closely.
"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."
When this trial began nearly ten years ago, blood-based tests for Alzheimer's biomarkers were unavailable; therefore, enrollment relied on clinical symptoms alone rather than confirmed amyloid status. Only some participants were later found to be amyloid-positive—a limitation that may have affected the strength of observed 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 team are now seeking support for a larger clinical trial using blood-based biomarkers to identify suitable candidates and determine whether lithium can meaningfully delay cognitive decline linked to 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."
