Researchers Discover Lithium’s Role in Alzheimer’s Disease

After nearly ten years of research, a team from Harvard Medical School has unveiled a significant finding regarding Alzheimer’s disease and brain aging—specifically, the role of lithium.

Historically, lithium has been recognized mainly as a mood stabilizer for individuals with bipolar disorder and depression, receiving FDA approval in the 1970s yet used for mood ailments for almost a century before that.

Interestingly, this research indicates that lithium occurs naturally in the body, playing a vital role similar to that of essential nutrients like vitamin C or iron, and is crucial for maintaining brain health.

A series of experiments published in the journal Nature revealed that removing lithium from the diets of normal mice led to brain inflammation and aging-related changes.

Notably, mice bred to exhibit Alzheimer’s-like changes showed an increased accumulation of harmful proteins when on a low-lithium diet, which significantly sped up memory loss.

Conversely, keeping lithium levels stable in those mice seemed to guard against Alzheimer’s-related brain alterations.

If further studies validate these findings, they might pave the way for new treatments and diagnostic methods for Alzheimer’s, which currently impacts around 6.7 million older adults in the U.S., according to the CDC.

This research offers a cohesive theory that could elucidate many enigmas scientists have sought to solve for years.

Dr. Bruce Yankner, a professor of genetics at Harvard and study leader, remarked, “It’s a potential candidate for a common mechanism leading to multisystem degeneration in the brain that can precede dementia.” He also emphasized the need for further science to discern if this forms a singular common pathway or is one among multiple pathways to Alzheimer’s, stating, “The data are very intriguing.”

In an editorial in Nature, Dr. Ashley Bush, a neuroscientist at the University of Melbourne, noted that the researchers present convincing evidence suggesting lithium has a physiological role and that normal aging could hinder lithium regulation in the brain. He was not involved in the study.

The study involved thorough examinations of brain tissues and accompanying genetic investigations, revealing that beta amyloid plaques bind to lithium, depriving nearby cells—including crucial scavenger cells known as microglia—of this metal.

In healthy brains, microglia serve as waste managers, clearing excess beta amyloid before it can build up harmfully. Yet, tests of microglia from lithium-deficient mice showed diminished ability to remove beta amyloid.

Yankner suggested this creates a troubling cycle, where accumulating beta amyloid absorbs more lithium, further reducing the brain’s capacity to eliminate it.

He and his team also explored various lithium compounds, discovering that lithium orotate doesn’t bind to beta amyloid.

When administered to mice showing Alzheimer’s signs, lithium orotate reduced both beta amyloid plaques and tau tangles, enhancing their ability to navigate mazes and recognize new objects, in contrast to placebos, which showed no improvement.

In its natural state, lithium is a soft, silvery-white metal, present in our environment, food, and water.

While it’s known for its mood-enhancing properties, the exact mechanism remained elusive until recently. Interestingly, 7Up once contained lithium, marketed as a mood-enhancer for various uses, and some mineral-rich hot springs have been believed to have healing properties due to lithium.

However, those taking prescription lithium—usually at higher doses—may face potential risks, such as thyroid or kidney issues. Encouragingly, mice receiving lower lithium orotate doses showed no adverse effects.

This is promising, but Yankner cautioned against self-medication with lithium supplements. He emphasized, “A mouse is not a human. Nobody should take anything based just on mouse studies.” He underscored the necessity for human replication of findings and the need to pinpoint appropriate dosages.

Normal lithium levels found in our bodies tend to be around 1,000 times less than therapeutic doses usually given for bipolar disorder. Yankner hopes for upcoming trials assessing toxicity in lithium salts, assuring that neither he nor his collaborators have a financial stake in the outcome.

The National Institutes of Health significantly funded this research, supported by private foundation grants. Yankner acknowledged, “NIH support was absolutely critical for this work.”

This study aligns with earlier investigations suggesting lithium’s importance in Alzheimer’s. A 2017 Danish research indicated that individuals with higher lithium levels in drinking water had a reduced dementia diagnosis risk, while a 2022 UK study pointed out that those prescribed lithium were about half as likely to develop Alzheimer’s compared to those who weren’t.

Yankner noted that lithium’s psychiatric applications led to a narrow perception of its therapeutic potential, and it wasn’t fully recognized for its significance in normal physiology.

Partially, this oversight occurred because the body’s lithium levels were too minimal to measure until recently, and innovative technology was necessary for this task.

In the study’s initial phase, researchers analyzed brain tissue and blood from older patients to detect trace levels of 27 metals. Although most metals presented no variation, lithium was consistently lower in patients experiencing cognitive impairments compared to cognitively healthy individuals, which amounted to a smoking gun, according to Yankner.

He initially met these results with skepticism, but further validation came from assessing samples from other brain banks.

To investigate if this lithium drop had biological significance, the researchers designed an experiment to evaluate the consequences of lowering lithium in mice diets. Surprisingly, a 50% reduction resulted in rapidly developing Alzheimer’s features in their brains.

#”The neurons began to degenerate, and the brain’s immune cells reacted with increased inflammation, resembling more advanced Alzheimer’s symptoms,” Yankner reported.

The study also identified a similarity in gene expression profiles between lithium-deficient mice and individuals suffering from Alzheimer’s.

Investigating why this lithium reduction occurs, Yankner noted an initial decrease in lithium uptake from blood to brain, with many contributing factors likely involved, including dietary changes and genetics.

Common lithium dietary sources include leafy greens, nuts, legumes, and spices such as turmeric and cumin. Interestingly, many foods known to be healthy may also provide lithium benefits.

Yankner mused, “Often in science, we perceive an effect and believe we understand its cause, only to later find out we were mistaken about the reasons.”