Lithium for Alzheimer’s? A Hype-Free Explainer

The original formula for Coca-Cola contained cocaine. And when soft drink 7-Up debuted in 1929, its makers went for another mood-stabilizing drug: lithium, calling it the Bib-Label Lithiated Lemon-Lime Soda. Drugs were eventually removed from soft drinks. But lithium went on to become an effective treatment for bipolar disorder and depression. Today, researchers are still studying its effects on the brain — this time, in lab mice engineered to model Alzheimer’s disease.

Now, thanks to a new study published in Nature, lithium is back in the spotlight. News outlets are abuzz with optimism that it could play a role in healthy brain aging. In the study, lithium appeared to slow cognitive decline and disease progression in Alzheimer’s mouse models.

“The idea that lithium deficiency could be a cause of Alzheimer’s disease is new and suggests a different therapeutic approach,” said senior author Bruce Yankner, professor at Harvard Medical School, in a press release. “One of the most galvanizing findings for us was that there were profound effects at this exquisitely low dose.”

So far, the approach has been scantly studied in humans.

But Dr. A. Claudio Cuello, a professor at McGill University, who wasn’t involved in the study, said this rodent study provides “strong validation for a potential long-term, preventive therapeutic for Alzheimer’s.” Cuello has studied the protective effects of a microdose of lithium in rat models of Alzheimer’s. While he noted that the potential of lithium in treating the disease isn’t new in the neuroscience field, the finding that age-related loss of lithium in the brain increases susceptibility to the disease may be “transformational.” 

Lithium: what is it good for?

Trace amounts of lithium — like many other metals — play key physiological roles in the body, though scientists don’t fully understand each metal’s function. Research has suggested that people with Alzheimer’s may have abnormal levels of these trace metals in key brain regions.

Observational studies have found that people living in areas with higher natural lithium levels in drinking water have a lower dementia risk. Others found that people who take lithium for other conditions were more than 40 percent less likely to develop Alzheimer’s or other dementias.

In the new study, Yankner’s team measured 27 metals in autopsied brains, comparing healthy controls, people with mild cognitive impairment (MCI), and people with Alzheimer’s. Only lithium levels were consistently reduced in both MCI and Alzheimer’s.

The researchers found that as beta-amyloid plaques formed, they absorbed lithium, leaving less available for healthy brain function. In genetically engineered mice prone to amyloid buildup, the same pattern appeared.

When the mice ate lithium-deficient food, plaques and tau accumulated faster, cognitive performance worsened, and brain gene activity shifted. Immune cells called microglia entered a pro-inflammatory state, making them less effective at clearing plaques.

Lithium, like sodium, is a metal that forms salts to become stable (e.g., sodium chloride). The researchers tested various lithium salts to see which resisted plaque absorption. Lithium orotate was the clear winner.

When added back to the mouse diet, lithium orotate slowed amyloid and tau accumulation, slowed cognitive decline, and restored microglia’s plaque-clearing ability — echoing findings from earlier rat studies. Even healthy aging mice saw brain benefits from small amounts of lithium orotate.

Uncharted territory

Because lithium is already FDA-approved for mental health conditions, it could reach Alzheimer’s trials faster. Still, past trials of lithium in Alzheimer’s were small, inconsistent, and used doses potentially toxic for older adults.

According to Cuello, once extrapolated to humans, the doses in this recent study are much smaller than what was tested in previous trials, and the lithium is formulated specifically to get to the brain.

“Our years of work [in rats] have shown no adverse side effects after continued administration,” said Cuello, who noted that in his studies, microdosing lithium also stops tau accumulation. “Tau is the killer, because once tauopathy begins, it will continue to progress and cannot be stopped by any current treatment.”

Although the potential benefits of lithium for Alzheimer’s have been probed before, there haven’t been any large, definitive human studies of the treatment. Drug companies don’t stand to profit much from lithium, said Cuello, because available forms of lithium are off-patent and available as a generic medicine. As a result, funding for larger trials — especially those testing whether lithium could prevent Alzheimer’s before symptoms start — is hard to secure.

Treating lab mice with lithium orotate (top row) lowered beta-amyloid (left) and tau (right) far more dramatically than lithium carbonate (bottom row). IMAGE: Yankner Lab

More research is on the way. Alzamend Neuro is developing a proprietary lithium formulation for Alzheimer’s, though a Phase 3 trial hasn’t been announced. At the University of Pittsburgh, researchers are running an 80-person trial testing lithium carbonate for MCI — though most participants don’t have amyloid plaques. 

But these approaches might be treating the problem when it’s already too late, according to Cuello. Based on his rat studies, Cuello believes that lithium needs to be administered before the onset of symptoms.

“There are larger human clinical trials in the works, in several labs all over the world, but this is slowed down owing to the constant need for funding, as well as the time needed to recruit adequate patient populations,” said Cuello. “I am struggling to raise one million for a phase one/two trial in preclinal Alzheimer’s.”

Why research doesn’t always translate to humans

Humans are not mice, and rodent models of Alzheimer’s disease are far from perfect. Since mice and rats don’t normally develop the disease, scientists need to modify their genetic code to make them produce amyloid plaques. They help scientists develop new ideas and understand the mechanisms behind the disease. But for the most part, treatments that have succeeded in these rodent models, as a result, have failed in human trials.

Autopsy studies also have limits. While this study analyzed more than 250 brains, researchers must confirm the findings in other brain banks. Past examples show why: taurine once looked promising for age-related decline, but larger studies found no such drop with age.

Observational studies can mislead, too. Some have suggested anti-herpes drugs, over-the-counter anti-inflammatories, and cholesterol-lowering medications might reduce Alzheimer’s risk — but so far, at least, clinical trials have shown no benefit.

Lithium orotate may help mice, but that doesn’t mean it will help humans. The researchers caution against microdosing supplements now. Researchers who study supplements have found that they may not contain the same dosage as advertised on the label, and in some cases, could include adulterated or illegal ingredients. With lithium, there are extra risks involved. Even when it’s used in a medical setting, it comes with side effects, including nausea, diarrhea, and in rare cases, kidney problems.

“You have to be careful about extrapolating from mouse models,” Yankner said. “And you never know until you try it in a controlled human clinical trial.

UPDATED 12 August, 2025, 00:01 EST. This article was updated with a first-hand interview with Dr. Cuello, a third-party expert who has studied the protective effects of lithium in rat models of Alzheimer’s.