In a fresh study published in Nature, researchers have discovered that a depletion of lithium in the brain may play a key role in the early stages of Alzheimer’s disease. The study establishes a strong connection between brain lithium levels and the onset of neurodegeneration.

Alzheimer’s disease is known for the build-up of amyloid plaques and hyperphosphorylated tau tangles — protein structures that prevent proper neuron function. However, the molecular changes that lead to their formation are not fully understood. To explore this, scientists from Harvard Medical School, Boston Children’s Hospital, and the Rush Alzheimer’s Disease Center investigated whether trace metals, particularly lithium, might influence the onset and progression of the disease.

Low Lithium Levels Found in People with Alzheimer’s Disease

The team analyzed the concentration of 27 different metals in the prefrontal cortex of brain tissue and blood samples from three groups: those with no cognitive impairment, those with mild cognitive impairment, and those with Alzheimer’s disease. Among all of the metals measured, only the levels of lithium were shown to be significantly reduced in the mild cognitive impairment and Alzheimer’s disease groups as compared to the healthy control. Lithium was also found to accumulate inside amyloid plaques, suggesting it was being trapped there and made unavailable to surrounding brain tissues.

Researchers ran two independent cohorts. The first one included 285 individuals and showed the initial pattern of lithium depletion. The second cohort of 79 individuals confirmed the result.

Mouse Models of Alzheimer’s Disease Help Reveal Mechanism

To understand the mechanism, the researchers conducted experiments on healthy mice and mice with human gene mutations known to cause forms of Alzheimer’s.

As the genetically modified mice age, they develop amyloid plaques and tau tangles.

These abnormal protein accumulations are linked to disrupted neural communication and cognitive decline, both in mice and humans. Tracking changes in the brains and behavior of genetically modified mice helps researchers better understand similar changes in human brains.

Mice Fed a Lithium-Deficient Diet Show Cognitive Decline

Healthy mice and genetically modified mice were each further divided into two subgroups: one received a lithium-deficient diet and the other was given a control diet with standard lithium levels.

Even in healthy mice, the lithium-deficient diet caused early signs of neural damage, including synapse and myelin loss, as well as memory impairment. In the genetically modified mice, the effects of lithium deficiency were much more severe and included early onset of amyloid plaque formation, increased levels of phosphorylated tau, increased neuroinflammation, and more pronounced cognitive decline.

Amyloid plaques in Alzheimer’s mouse models: on a normal lithium diet (left) and a lithium-deficient diet (right). Image: Yankner Lab

Tangle protein tau in Alzheimer’s mouse models: on a normal lithium diet (left) and a lithium-deficient diet (right). Image: Yankner Lab

Lithium Salts Can Reverse Neural Damage

Next, researchers explored whether feeding mice lithium could reverse these negative effects and whether different types of lithium salts had different outcomes. 

The inorganic salts, such as lithium carbonate, had high conductivity, meaning they quickly released free lithium ions that bonded to amyloid plaques, which reduced their availability in the brain. In contrast, organic salt lithium orotate had lower conductivity, released lithium more slowly, and did not bind to amyloid plaques significantly.

Lithium orotate restored lithium levels in the brain, reversed Alzheimer’s-related brain damage, reduced neuroinflammation, and restored memory performance in both Alzheimer’s-prone and healthy wild-type mice.  

Scientists Are Optimistic About The Use of Lithium In Human Patients

“You have to be careful about extrapolating from mouse models, and you never know until you try it in a controlled human clinical trial,” said one of the researchers, Bruce Yankner. “But so far the results are very encouraging.”

When given at a low dose that mimics natural lithium levels found in the brain, lithium orotate did not cause kidney or thyroid toxicity, which is a major concern with high-dose lithium treatments in elderly patients.

“My hope is that lithium will do something more fundamental than anti-amyloid or anti-tau therapies, not just lessening but reversing cognitive decline and improving patients’ lives,” Yankner said.

Read more in the original article.