Research on reversing Alzheimer’s reveals lithium as potential key

Seven years of investigation by scientists at Harvard Medical School have revealed that the loss of the metal lithium plays a powerful role in Alzheimer’s disease, a finding that could lead to earlier detection, new treatments and a broader understanding of how the brain ages.

Researchers led by Bruce A. Yankner, professor of genetics and neurology at Harvard Medical School, reported that they were able to reverse the disease in mice and restore brain function with small amounts of the compound lithium orotate, enough to mimic the metal’s natural level in the brain. Their study appeared Wednesday in the journal Nature.

“The obvious impact is that because lithium orotate is dirt cheap, hopefully we will get rigorous, randomized trials testing this very, very quickly,” said Matt Kaeberlein, former director of the Healthy Aging and Longevity Research Institute at the University of Washington, who did not participate in the study. “And I would say that it will be an embarrassment to the Alzheimer’s clinical community if that doesn’t happen right away.”

Yankner, who is also co-director of the Paul F. Glenn Center for Biology of Aging Research at Harvard, said: “I do not recommend that people take lithium at this point, because it has not been validated as a treatment in humans. We always have to be cautious because things can change as you go from mice to humans.” He added that the findings still need to be validated by other labs.

Although there have been recent breakthroughs in the treatment of Alzheimer’s, no medication has succeeded in stopping or reversing the disease that afflicts more than 7 million Americans, a number projected to reach almost 13 million by 2050, according to the Alzheimer’s Association.

Lithium is widely prescribed for patients with bipolar disorder, and previous research indicated that it held potential as an Alzheimer’s treatment and an anti-aging medication. A 2017 study in Denmark suggested the presence of lithium in drinking water might be associated with a lower incidence of dementia.

However, the new work is the first to describe the specific roles that lithium plays in the brain, its influence on all of the brain’s major cell types and the effect that its deficiency later in life has on aging.

Results of the study by Yankner’s lab and researchers at Boston Children’s Hospital and the Rush Alzheimer’s disease Center in Chicago also suggest that measuring lithium levels might help doctors screen people for signs of Alzheimer’s years before the first symptoms begin to appear. Yankner said doctors might be able to measure lithium levels in the cerebrospinal fluid or blood, or through brain imaging.

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How our brains use lithium

In a healthy brain, lithium maintains the connections and communication lines that allow neurons to talk with one another. The metal also helps form the myelin that coats and insulates the communication lines and helps microglial cells clear cellular debris that can impede brain function.

“In normal aging mice,” Yankner said, “lithium promotes good memory function. In normal aging humans,” higher lithium levels also correspond to better memory function.

The depletion of lithium in the brain plays a role in most of the deterioration in several mouse models of Alzheimer’s disease.

Loss of lithium accelerates the development of harmful clumps of the protein amyloid beta and tangles of the protein tau that resemble the structures found in people with Alzheimer’s. Amyloid plaques and tau tangles disrupt communication between nerve cells.

The plaques in turn undermine lithium by trapping it, weakening its ability to help the brain function.

Lithium depletion is involved in other destructive processes of Alzheimer’s: decay of brain synapses, damage to the myelin that protects nerve fibers and reduced capacity of microglial cells to break down amyloid plaques.

Lithium’s pervasive role comes despite the fact that our brains contain only a small amount of it. After examining more than 500 human brains from Rush and other brain banks, Yankner’s team discovered the naturally occurring lithium in the brain is 1,000 times less than the lithium provided in medications to treat bipolar disorder.

Li-Huei Tsai, director of the Picower Institute for Learning and Memory at Massachusetts Institute of Technology who was not involved in the new study, called it “very exciting,” especially when many in the field, including her own lab, have focused on genetic risk factors for Alzheimer’s.

“But clearly genetic risk factors are not the only things,” said Tsai, who is also Picower professor of neuroscience. “There are a lot of people walking around carrying these risk genes, but they are not affected by Alzheimer’s disease. I feel this study provides a very important piece of the puzzle.”

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Pathways for treatment

Alzheimer’s treatments mostly help to manage symptoms and slow the decline in thinking and functioning. Aducanumab, lecanemab, and donanemab, all lab-made antibodies, bind to the harmful amyloid plaques and help remove them.

Donepezil, rivastigmine and galantamine ― all in the class of medications known as cholinesterase inhibitors ― work by replenishing a chemical messenger called acetylcholine, which is diminished in Alzheimer’s. Acetylcholine plays an important role in memory, muscle movement and attention.

Yankner and his team found that when they gave otherwise healthy mice a reduced-lithium diet, the mice lost brain synapses and began to lose memory. “We found that when we administered lithium orotate to aging mice [that had] started losing their memory, the lithium orotate actually reverted their memory to the young adult, six month level,” he said.

Lithium orotate helped the mice reduce production of the amyloid plaques and tau tangles, and allowed the microglial cells to remove the plaques much more effectively.

Yankner said one factor that might help lithium orotate reach clinical trials sooner is the small amount of treatment needed, which could greatly reduce the risk of harmful side effects, such as kidney dysfunction and thyroid toxicity.

Aside from its potential in treating Alzheimer’s, Yankner said lithium orotate might also have implications for the treatment of Parkinson’s disease, an area his lab is investigating.

“That needs to be rigorously examined,” he said. “But we’re looking at a whole slew of disorders.”