Two key studies have unlocked the role lithium possibly plays in Alzheimer's and other neurological diseases, offering a route for potential new treatments and broader understanding of how the brain works, writes MedicalBrief.
In the US, seven years of investigation by scientists at Harvard Medical School has revealed that the loss of the metal lithium plays a powerful role in Alzheimer’s disease, , reports The Washington Post.
And researchers led by the University of Cambridge, United Kingdom, have reached similar conclusions, linking lithium to a reduced risk of developing dementia by studying the medical records of 30 000 British volunteers (see story below).lithium, most of whom received it as a treatment for bipolar disorder.
The US researchers led by Bruce Yankner, a 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 in the journal Nature.
Lithium orotate is a salt with orotate, a naturally-occurring substance in the body. Patients taking lithium orotate experience far fewer side effects than with lithium medication. This may simply be because lithium orotate is prescribed at much lower doses than the medication.
“The obvious impact is that because lithium orotate is dirt cheap, hopefully we will get rigorous, randomised trials testing this very, very quickly,” said Matt Kaeberlein, former director of the Healthy Ageing and Longevity Research Institute at the University of Washington, who did not participate in the study.
Yankner, who is also the co-director of the Paul F Glenn Centre for Biology of Ageing 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.
Lithium is naturally present at low, micromolar concentrations in the blood and brain, observed Ashley Bush, MBBS, PhD, of the University of Melbourne in Australia, in an accompanying commentary. “Its pharmacological effects have historically been considered a quirk for a metal ion with no obvious physiological purpose.”
However, reports Medpage Today, this study presents “compelling evidence that lithium does in fact have a physiological role, and that normal ageing might impair the regulation of lithium levels in the brain”, Bush wrote.
“The work opens up a world of possible functions for lithium at micromolar concentrations – for example, (lithium) could be a signalling ion similar to copper (Cu+), which was reported a few years ago to have a signalling role at trace concentrations,” he added.
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 7m Americans, a number projected to reach almost 13m 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-ageing 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 ageing.
Results of the study by Yankner’s lab and researchers at Boston Children’s Hospital and the Rush Alzheimer’s Disease Centre 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.
How our brains use lithium
In a healthy brain, lithium maintains the connections and communication lines that allow neurons to talk to 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 ageing mice,” Yankner told The Washington Post, “lithium promotes good memory function. In normal ageing 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 fibres 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 and who was not involved in the 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.”
Pathways for treatment
Alzheimer’s treatments mostly help to manage symptoms and slow the decline it causes 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 ageing mice (that had) started losing their memory, it 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 the 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.”
Reduced dementia
Meanwhile, across the pond, researchers led by the University of Cambridge, United Kingdom, have reached similar conclusions, linking lithium to a reduced risk of developing dementia.
For their research, published in the journal PLOS, they looked back at medical records from nearly 30 000 British volunteers, including 548 people exposed to lithium, most of whom received it as a treatment for bipolar disorder.
In those exposed to lithium, 9.7% of patients were also subsequently diagnosed with dementia. In those who weren’t exposed to lithium, 11.2% went on to develop dementia.
Lithium conferred this beneficial effect even when people were exposed to it for less than one year.
Dr Sara Imarisio, head of research from Alzheimer’s Research UK, said the results suggest that people prescribed lithium were less likely to develop dementia.
“The researchers analysed data from users of mental health services, and only a small number of participants were taking lithium. While we need to be careful before we generalise the findings to the wider population, the results do highlight the possible link between the two, and further work is ongoing.
“Alzheimer’s Research UK is now funding science at the University of Newcastle to see whether lithium could be a future treatment for Alzheimer’s disease using a new brain imaging technique.
“This project will help lay the groundwork for careful clinical trials, which are ultimately the only way to know if lithium could be an effective treatment for people with Alzheimer’s.”
She added that there was a desperate need for new dementia treatments and “where there is evidence that an existing, widely used, relatively safe and inexpensive drug could help, it is vital that researchers follow up on this as quickly as possible”.
Medpage Today – Lithium May Combat Alzheimer's Disease, Data Suggest (Open access)
The Washington Post article – Research on reversing Alzheimer’s reveals lithium as potential key
See more from MedicalBrief archives:
Natural lithium in drinking water linked with lower suicide rates
Lithium reduces re-hospitalisation risk in bipolar patients