Low-Dose Lithium Trial Sets the Stage for Future Alzheimer’s Studies

Last year, researchers reported that in the brains of people with Alzheimer’s and in mouse models, lithium deficiency might be driving the disease, renewing the field’s interest in pursuing different formulations of lithium as a treatment. 

The researchers behind that study are working on developing a drug using a microdose of a formulation called lithium orotate. 

In the meantime, others are running trials to repurpose the form of lithium used to stabilize mood in bipolar disorder, called lithium carbonate. The results of a trial piloting a low-dose of this form of lithium for treating mild cognitive impairment (MCI) were recently published in JAMA Neurology. In the study, designed to test safety and feasibility,  the treatment group didn’t show a statistically significant benefit, but researchers still think it warrants more trials.

“We observed that verbal memory declined at about half the rate in the lithium group compared with placebo over two years,“ Dr. Ariel Gildengers, a geriatric psychiatrist at UPMC and professor at the University of Pittsburgh, who authored the lithium carbonate study, told Being Patient.

 Several other small lithium studies also found potential signals, albeit not statistically significant, which, he said, “suggest the results are unlikely to be random and reinforces the importance of further research.” 

Putting lithium to the test

Researchers have trialled lithium carbonate and other proprietary forms for cognitive impairment before, but Gildengers’ study of lithium carbonate is the first randomized trial to combine cognitive assessments with brain imaging and blood biomarkers. The goal of the study wasn’t to prove that lithium could slow Alzheimer’s, rather to show that a larger trial would be safe and feasible to run. 

Gildengers and his team recruited 80 participants who were on average in the early 70s with MCI, though only 21 had MCI caused by Alzheimer’s. Many other causes include treatable conditions like sleep apnea, vitamin or hormone deficiencies, and depression. 

Participants were randomized to receive 150mg per day of lithium carbonate or a placebo, with the doses titrated up to a maximum of 300mg. The researchers wanted to reach the highest dose where individuals could tolerate the side effects. Due to side effects like diarrhea or tremor, 29 of the 80 participants dropped out of the study. 

The researchers looked at six main outcomes besides safety to look for potential signals of effectiveness: Three different tests of cognitive ability, two brain metrics of brain imaging, and a blood biomarker called BDNF. After two years of treatment there was no significant difference between the lithium carbonate and placebo group on any of the outcomes. 

Although the results did not meet the statistical threshold, there was a slowing of decline on verbal memory. 

“That is what you would expect from a pilot feasibility study of this size, which was not designed to prove efficacy,” said Gildengers.

However, there was a trend showing the treatment may have an effect in people who were amyloid-positive, though this would need to be confirmed in additional trials. “If lithium’s potential effects are more closely related to Alzheimer’s biology, then including participants without amyloid pathology could dilute the overall signal,” said Gildengers.

Though he believes the data is promising, he would “strongly caution” against using lithium supplements to boost brain health as the findings do not yet support its use. “Over-the-counter lithium supplements, including lithium orotate,” Gildengers said, “are not regulated the same way and should not be used for brain health.” 

Several more lithium trials are on the way

Gildengers is in the process of designing a larger follow-up study to test whether lithium is effective. “A major focus will be enrolling participants based on biological markers of Alzheimer’s disease, which we believe is key to better understanding whether lithium has a meaningful role,” he said. 

The Atlanta-based drug company Alzamend Neuro is developing a proprietary lithium formulation, AL001 for Alzheimer’s. The company’s form of lithium is engineered in a way to enter the brain more easily. Alzamend Neuro has completed some Phase 2 studies, though a pivotal Phase 3 trial hasn’t been announced. 

Bruce Yankner, the Harvard Medical School professor, who authored the lithium deficiency study last year is also planning to trial a different form, called lithium orotate, in the coming years. 

Meanwhile, Dr. A. Claudio Cuello, a professor at McGill University, who wasn’t involved in the lithium carbonate or lithium orotate studies, thinks lithium trials need to target people earlier — before tau tangles form and cognitive impairment starts — to see an effect. “MCI is already too late,” he told Being Patient. “Lithium has a chance to be a preventative therapy that should be applied in the preclinical stages.”

In unpublished results from his lab, microdoses of lithium far smaller than what was trialled in Gildengers’ carbonate study, could slow early tau pathology in rat models of Alzheimer’s. His team is in the process of securing funding for a preventative lithium trial. 

With many more lithium trials on the way, we may know soon whether lithium could prevent or treat Alzheimer’s.