In a major new discovery over almost a decade of making, Harvard Medical School researcher Let’s say they find a key that may unlock many mysteries of Alzheimer’s disease and brain aging, many mysteries of humble metallic lithium.
Lithium is best known for its medication as a mood stabilizer given to people with bipolar disorder and depression. It was approved by the US Food and Drug Administration in 1970, but doctors used it to treat mood disorders for nearly a century.
Now, researchers have shown for the first time that lithium is naturally present in the body, and that cells need to function properly, like vitamin C and iron. It also appears to play an important role in maintaining brain health.
In a series of experiments reported Wednesday in the journal Nature, researchers from Harvard and Rush University found that depleting lithium in normal mice diet caused the brain to develop inflammation and cause changes related to accelerated aging.
In mice specially raised to develop brain changes of the same type as Alzheimer’s disease humans, a low-lithium diet avoided the accumulation of sticky proteins that form plaque and tangles in the brain, a characteristic of the disease. It also promoted memory loss.
However, maintaining normal lithium levels when mice aging protected them from brain changes associated with Alzheimer’s disease.
According to the U.S. Centers for Disease Control and Prevention, further research supports the findings, opening the door to new treatments and diagnostic tests for Alzheimer’s disease, which could affect an estimated 6.7 million seniors in the United States.
This study provides a unified theory that will help explain the many puzzle pieces that scientists have been trying to fit together for decades.
“This is a potential candidate for a common mechanism that leads to multisystem degeneration of the brain that precedes dementia,” said Dr. Bruce Jankner, professor of genetics at Harvard Medical School. “It takes more science to determine if this is a common route…or one of several routes,” he added. “The data is very interesting.”
In an editorial published in nature, Dr. Ashley Bush, a neuroscientist who directs the Melbourne Dementia Research Centre at the University of Melbourne in Australia, said the researchers “present compelling evidence that lithium actually plays a physiological role and that normal aging can impair the regulation of lithium levels in the brain.” He was not involved in the research.
Along with in-depth examination of human and animal brain tissue and genetic investigations of the study, beta-amyloid plaques – sticky sediments that gum up the brains of Alzheimer’s patients bind to and retain lithium. This binding depletes available lithium in nearby cells, including a key scavenger known as microglia.
If your brain is healthy and functioning properly, microglia are the waste managers and clean up beta amyloid before it accumulates and causes harm. In our team’s experiments, microglia from the brains of lithium-deficient mice showed a reduced ability to wipe out and degrade beta-amyloid.
Yankner believes this creates a downward spiral. The accumulation of beta amyloid increases the absorption of lithium, further impairing the brain’s ability to clean it up.
He and his colleagues have tested different lithium compounds and discovered one – lithium orotium – that does not bind to amyloid beta.
These changes were reversed when they fed orotium to mice with signs of Alzheimer’s disease in the brain: reduced beta-amyloid plaque and tau tangles that had choked the brain’s memory center. The lithium-treated mice were able to learn to navigate the maze again and identify new objects, but those who got the placebo showed no change in memory and thought deficits.
In its natural form, lithium is an element, a soft, silvery metal that easily binds to other elements to form compounds and salts. It is naturally present in an environment that contains food and water.
Scientists were not entirely aware of how it works to improve mood. The original formula of 7UP Soda contained lithium – it was called 7UP Lithy Lemon Soda and was advertised as “hospital or home use” as a hangover cure and mood lifter. Several hot springs known to contain lithium-filled mineral water were sought wellness destinations for their therapeutic potential.
Still, people taking prescription drugs with lithium, much higher than the doses used in new research, can develop thyroid or kidney toxicity.
Examination of mice receiving low-dose orotium showed no signs of damage.
Jankner said, but that doesn’t mean people shouldn’t try to take lithium supplements themselves.
“Mice are not human. No one should take them based solely on mouse studies,” Jankner said.
“The lithium treatment data we have is mouse and needs to be replicated in humans. We need to find the correct dose in humans,” he added.
The concentrations given to mice with the normal amounts of lithium in our body are small – about 1,000 times lower than the dose administered to treat bipolar disorder, Yankner points out.
Yankner said he hopes that toxicity testing for lithium salts will begin soon. Neither he nor his co-authors have financial interest in the findings of the research, he said.
The National Institutes of Health, along with grants from the Private Foundation, was the leading funder of the research.
“NIH support was absolutely important to this task,” Jankner said.
New research supports previous studies suggesting that lithium may be important for Alzheimer’s disease. A large Danish study published in 2017 found that people with higher levels of lithium in drinking water are less likely to be diagnosed with dementia than people with naturally low lithium levels in tap water. Another large study published in 2022 from the UK found that people who were prescribed lithium were more likely to be diagnosed with Alzheimer’s disease, suggesting the protective benefits of the drug.
However, the use of lithium in psychiatry has made it a type of cast as a treatment, Yankner said. No one realized that it was important to the normal physiology of the body.
It occurred because the amount of lithium circulating in the body is usually so small that it could not be quantified until recently. Yankner and his team had to adapt new technology to measure it.
In the first phase of the study, scientists tested brain tissue and blood from elderly patients collected at trace levels of 27 metals by the Rush University Brain Bank. Some patients have no history of memory loss, while others suffered from early memory decline and declared Alzheimer’s disease. There was no change in the levels of most metals they measured, with lithium being the exception. Lithium levels were consistently lower in patients with mild cognitive impairment or Alzheimer’s disease compared to patients with normal brain function. The patient’s Alzheimer’s brain also showed increased levels of zinc and decreased levels of copper. This is something scientists have observed before.
Consistently discovering low lithium levels in the brains of people with amnesia has become a smoking gun, according to Jankner.
“At first, we were skeptical of the outcome because, frankly, it wasn’t expected,” Jankner said.
But even when they checked samples from Massachusetts General Hospital, Duke and other brain banks at Washington University, it held up.
“We wanted to know if this lithium drop was biologically meaningful, so we devised an experimental protocol that allows us to selectively take lithium from our mouse diet and see what happens,” Jankner said.
By giving mice a low-lithium diet and simply dropping their natural levels by 50%, their brains quickly developed the characteristics of Alzheimer’s disease.
“The neurons began to degenerate. The immune cells in the brain became wild in terms of increased inflammation and worsening maintenance functions of surrounding neurons, appearing like advanced Alzheimer’s patients,” Jankner said.
The team also found that gene expression profiles in lithium-deficient mice are very similar to those in people with Alzheimer’s disease.
Researchers then began to consider how this drop in lithium occurs. Yankner said early stages reduce the brain’s lithium uptake from the blood. They still don’t know exactly how or why it occurs, but it is likely from a variety of things, including reduced dietary intake and genetic and environmental factors.
For most people, their diet is the main source of lithium. Among the most lithium-rich foods are lush green vegetables, nuts, legumes, and spices such as turmeric and cumin. Some minerals are abundant sources.
In other words, Yankner said many foods that are already healthy and have already been proven to reduce the risk of dementia could be beneficial due to their lithium content.
“I often discover in science that things might work and I think you know exactly why, but then it turns out to be completely wrong about why,” he said.
