Lithium deficiency in the brain could be a cause of Alzheimer’s disease—and a new potential target for treatment.
Ten years in the making, this is the finding of researchers at Harvard Medical School who have revealed how lithium plays an essential role in brain function and may provide resistance against brain aging and Alzheimer’s.
Lithium is a chemical element, currently used as medicine to treat mood disorders like mania and bipolar disorder.
“Most people associate lithium with psychiatric treatment. Our study shows, for the first time, that naturally occurring lithium plays a crucial role in maintaining brain health during aging—even at concentrations far below those used in clinical psychiatry,” study authors Bruce Yankner and Liviu Aron told Newsweek.
The findings are based on a series of experiments in mice and on analyses of human brain tissue and blood samples from individuals in various stages of cognitive health.
“We found that lithium is uniquely depleted in the brains of people with mild cognitive impairment—a precursor to Alzheimer’s. This makes lithium deficiency one of the earliest biochemical signs of the disease, possibly years before clinical symptoms appear,” the duo explained.
“We also saw that higher endogenous lithium levels were associated with preserved cognitive function even in individuals without Alzheimer’s. So, this isn’t just about preventing disease—it’s about supporting healthy brain aging in general.
The new revelation helps to explain why some people with Alzheimer’s-like abnormalities in the brain don’t go on to develop the disease. While genetic and environmental factors play a role, scientists also haven’t been able to suggest why some people with the same risk factors might develop it and others don’t—until now.
The scientists unearthed that lithium loss in the human brain is one of the earliest changes leading to Alzheimer’s. In mice, meanwhile, similar lithium depletion accelerated brain pathology (disease or abnormality) and memory decline.
They also found reduced lithium levels stemmed from binding to amyloid plaques (misfolded proteins found between nerve cells found in the brains of people with Alzheimer’s) and impaired uptake in the brain.
In their final set of experiments, they found a new lithium compound that avoids “capture” by amyloid plaques restored memory in mice.
“In people that start experiencing memory loss, the so-called mild cognitive impairment, lithium gets trapped by amyloid plaques—reducing its availability just when it’s most needed to protect against inflammation and neurodegeneration,” Yankner and Aron explained.
“This creates a self-perpetuating feedback loop of worsening pathology and accelerating disease progression and memory loss.”
This all ties together decades-long observations in patients and provides a new theory of the disease and strategy for early diagnosis, prevention and treatment, according to the researchers.
Recently developed treatments that target amyloid beta (a key component of the amyloid plaques) typically don’t reverse memory loss and only modestly reduce the rate of decline.
“The idea that lithium deficiency could be a cause of Alzheimer’s disease is new and suggests a different therapeutic approach,” said Yankner in a statement.
Researchers had previously found lithium to be the only metal that had markedly different levels across people with and without Alzheimer’s at different stages. But Yankner added in a statement, “Lithium turns out to be like other nutrients we get from the environment, such as iron and vitamin C.
“It’s the first time anyone’s shown that lithium exists at a natural level that’s biologically meaningful without giving it as a drug.”
Previous population studies have shown that higher lithium levels in the environment, including in drinking water, tracked with lower rates of dementia.
Yankner’s team demonstrated in mice that lithium depletion isn’t just linked to Alzheimer’s, it actually helps drive it.
This raises hope that one day lithium could be used to treat the disease in its entirety rather than focusing on a single factor like amyloid beta or tau (another Alzheimer’s-associated protein), Yankner said.
Crucially, the researchers discovered that as amyloid beta begins to form deposits in the early stages of dementia in both humans and mouse models, it binds to lithium, reducing lithium’s function in the brain. The reduced levels of lithium affect all major brain cell types and, in mice, lead to changes similar to those seen in Alzheimer’s disease, including memory loss.
Treating mice with the most potent amyloid-evading compound, called lithium orotate, reversed Alzheimer’s pathology, prevented brain cell damage and restored memory.
While the findings need to be confirmed in humans through clinical trials, they suggest that measuring lithium levels could help screen for early Alzheimer’s. They also highlight the importance of testing amyloid-evading lithium compounds for treatment or prevention.
While other lithium compounds are already used to treat bipolar disorder and clinical depression, they are given at much higher concentrations that can be toxic to some people, the researchers flag. Yankner’s team discovered lithium orotate is effective at one-thousandth that dose— enough to mimic the natural level of lithium in the brain.
Mice treated for nearly their entire adult lives showed no evidence of toxicity, the study found.
If further studies confirm these findings, the researchers say lithium screening through routine blood tests may one day offer a way to identify individuals at risk for Alzheimer’s who would benefit from treatment to prevent or delay disease onset.
“Our study adds to growing evidence that Alzheimer’s may be preventable—with something as simple as keeping brain lithium at healthy levels as we age,” said Yankner and Aron.
“Clinical trials [on humans] could test the impact of low-dose supplementation on cognitive health and dementia risk.”
Before lithium is proved to be safe and effective in protecting against neurodegeneration in humans, Yankner emphasized that people should not take lithium compounds on their own.
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Reference
Aron, L., Ngian, Z. K., Qiu, C., Choi, J., Liang, M., Drake, D. M., Hamplova, S. E., Lacey, E. K., Roche, P., Yuan, M., Hazaveh, S. S., Lee, E. A., Bennett, D. A., & Yankner, B. A. (2025). Lithium deficiency and the onset of Alzheimer’s disease. Nature. https://doi.org/10.1038/s41586-025-09335-x
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