Common drug shows potential to treat Alzheimer’s

People with Alzheimer’s disease have been found to have lower lithium levels in their brains. A recent study showed that giving lithium to mice with Alzheimer’s-like symptoms helped restore their memory and thinking skills.

The research suggests that maintaining sufficient lithium levels might be important for healthy brain function and potentially for preventing or treating Alzheimer’s. 

Previous studies were unclear

Past research hinted at this connection. A 2022 study reported that patients who were taking lithium had nearly half the risk of developing Alzheimer’s compared to those who were not. Another study linked lithium in drinking water with a lower risk of dementia.

However, the studies faced uncertainty. “The trouble with these studies is that other hidden factors might explain the associations,” said Bruce Yankner of Harvard University.

Yankner noted that other metals, such as magnesium, could be influencing dementia risk instead.

To investigate further, his team examined brain samples from 285 deceased individuals. Of these, 94 had Alzheimer’s, 58 had mild cognitive impairment, and the rest showed no cognitive decline.

Lower lithium in Alzheimer’s brains

The prefrontal cortex, vital for memory and decision-making, showed lithium levels about 36 percent lower in people with Alzheimer’s compared to healthy individuals. For mild cognitive impairment, the drop was about 23 percent.

“We suspect that’s due to a number of environmental factors: dietary intake, genetics and so forth,” Yankner said.

An unexpected finding emerged. Amyloid plaques in Alzheimer’s brains contained nearly three times as much lithium as plaque-free regions.

“Lithium becomes sequestered in these plaques,” noted Yankner. “We have two things going on: impaired uptake of lithium very early on and then, as the disease progresses, the lithium that is in the brain is further diminished by being bound to amyloid.”

Memory loss tied to low lithium

To understand the effects of low lithium, the team fed a lithium-deficient diet to 22 genetically engineered mice prone to Alzheimer’s-like symptoms.

After eight months, these mice performed worse on memory tests compared to 16 mice on a normal diet.

In a water maze, lithium-deficient mice took around 10 seconds longer to find a hidden platform, even after several days of training. Their brains had nearly 2.5 times more amyloid plaques.

Genetic analysis revealed increased activity in genes associated with neurodegeneration. The mice also showed greater brain inflammation and a reduced ability to clear plaques – changes similar to those seen in humans with Alzheimer’s disease.

Lithium aids brain performance

The team tested various lithium compounds for their tendency to bind to amyloid. Lithium orotate, a naturally occurring compound in the body, appeared least likely to get trapped in plaques. Nine months of treatment with lithium orotate significantly reduced plaques in Alzheimer’s-like mice.

These treated mice performed as well as healthy mice on memory tests, showing marked improvements in learning, spatial navigation, and recall. The compound also preserved synaptic integrity and reduced inflammation in the brain.

The treatment improved myelin maintenance, supported healthier neuronal connections, and enhanced the microglial ability to clear amyloid deposits.

Researchers believe its lower plaque-binding tendency allows more lithium to remain available in brain tissue, enhancing its protective and restorative effects over time and slowing disease progression.

Safe lithium awaits human trials

Lithium is already used in high doses to treat conditions like bipolar disorder, but those doses can harm the kidneys and thyroid.

“One major limitation of lithium treatment in aging individuals is that, given the high doses that are used, people often run into kidney and thyroid toxicity,” Yankner said.

The doses in the mice study were about 1,000 times lower than psychiatric treatment doses, and no kidney or thyroid problems were observed during the study. Clinical trials will be essential before any human application.

“The challenge is, how do you determine whether somebody needs lithium?” said Rudolph Tanzi of Massachusetts General Hospital. “Because you wouldn’t want to overload the body with lithium. That could lead to severe side effects.”

Preventing cognitive decline

A growing body of evidence suggests that lithium plays a critical role in brain health, influencing processes that protect against Alzheimer’s-related damage. Lithium orotate, with its ability to evade plaque sequestration, stands out as a promising low-dose therapeutic option.

By preserving lithium availability in the brain, it may help reduce toxic protein buildup, curb inflammation, and protect neural connections.

While these findings in mice are encouraging, translating them into safe, effective treatments for humans will require carefully designed clinical trials.

If successful, this approach could provide a new strategy to slow – or even prevent – the devastating cognitive decline associated with Alzheimer’s disease.

The study is published in the journal Nature.

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