Lithium deficiency appears as a hidden driver of Alzheimer’s

What is the early spark that ignings the course of Alzheimer’s disease? Why do some people with alzheimer’s brain -like changes never continue to develop dementia? These questions have been neuroscientists for decades.

Now, a team of researchers at Harvard Medical School may have found an answer: Lithium deficiency in the brain.

The work, published in nature, shows for the first time that lithium appears naturally in the brain, protects it from neurodegeneration and maintains the normal functioning of all large types of brain cells. The findings – 10 years in construction – are based on a series of experiments in mice and analyzes of human brain tissues and blood samples from people at various stages of cognitive health.

Scientists have found that lithium loss in the human brain is one of the first changes to lead to Alzheimer’s, while in mice, a similar exhaustion of lithium accelerates brain pathology and memory reduction. The group further found that reduced lithium levels came from commitment to amyloid plates and weakening the intake in the brain. In a final set of experiments, the team found that a new lithium union that avoids arresting the amyloid plates that restore memory in mice.

“The idea that lithium deficiency could be a cause of Alzheimer’s disease is new and proposes a different therapeutic approach,” said senior writer Bruce Yankner, a professor of genetics and neurology at the Blavatnik Institute in HMS, who was the first 1990.

The study increases the hopes that researchers could one day use lithium to cure the disease as a whole instead of focusing on a single appearance such as amyloid beta or tau, he said.

One of the main discoveries in the study is that as the amyloid beta begins to form deposits in the early stages of dementia in both humans and mice, it is associated with lithium, reducing the function of lithium in the brain. Lower levels of lithium affect all important types of brain cells and, in mice, create changes in recapitalization of Alzheimer’s disease, including memory loss.

The authors have recognized a category of lithium compounds that can avoid conception by amyloid beta. Facing mice with the most powerful amyloid union, called Lithium HIV, reverses the pathology of Alzheimer’s disease, prevented brain damage and restored memory.

Although the findings should be confirmed to people through clinical trials, they suggest that lithium -measuring levels could help promote Alzheimer’s early disease. In addition, the findings indicate the importance of testing lithium compounds that cause amyloid for treatment or prevention.

Other lithium compounds are already used to treat bipolar disorder and high depressive disorder, but are given at much higher concentrations that may be toxic, especially in the elderly. Yankner’s team found that lithium’s orotate is effective in one millimeter that the dose-to-make a dose to mimic the natural level of lithium in the brain. The mice undergoing treatment for almost their entire adult life showed no evidence of toxicity.

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

Lithium exhaustion is an early sign of Alzheimer’s

Yankner began to be interested in lithium while using it to study the neuroprotective protein rest. Finding whether lithium is in the human brain and if its levels change as neurodegeneration develops and evolves, however, it requires access to the brain tissue, which generally cannot overtake living people.

Thus, the workshop worked with the Rush memory and aging project, which has a post -mortem brain tissue bank that donates thousands of participants in the study throughout the spectrum of cognitive health and diseases.

Having this breadth was crucial because trying to study the brain in the late stages of Alzheimer’s is like looking at a battlefield after a war, Yankner said. There is a lot of damage and it is difficult to say how it all started. But in the early stages, “before the brain is poorly damaged, you can get significant indications,” he said.

Led by the first writer Liviu Aron, a senior research partner in the Yankner Laboratory, the team used an advanced type of mass spectroscopy to measure the trace elements of about 30 different metals in the brain and blood of well -known healthy people, Alzheimer’s.

Lithium was the only metal that had remarkably different levels between the groups and changed in the early stages of memory loss. Its levels were high in the known healthy donors, but were largely reduced to those with mild weakening or full chain.

The team reproduces its findings in samples taken from multiple brain banks at national level.

The results have been consolidating decades of observations to patients, providing a new theory of the disease and a new strategy for early diagnosis, prevention and treatment.

Affecting some 50 million and 400 million people worldwide, Alzheimer’s disease includes a series of brain abnormalities – such as protein amyloid bits, neuroinidal t -shirts of the Tau protein and the loss of protein. For example, some people with such anomalies show no signs of cognitive decline. And recently developed treatments aimed at amyloid beta usually do not reverses memory loss and only reduce the rate of decline.

It is also clear that genetic and environmental factors affect the risk of Alzheimer’s, but scientists have not understood why some people with the same risk factors develop the disease, while others do not.

Lithium, the authors of the study said, may be a critical missing link.

The observation was aligned with previous population studies showing that higher levels of lithium in the environment, including drinking water, which is monitored with lower rates of dementia.

But the new study went beyond the immediate observation of lithium in the brains of people who had not received lithium as a treatment, creating a range that is normal levels and proving that lithium plays an essential role in the physiology of the brain.

“Lithium proves to be other nutrients we get from the environment, such as iron and vitamin C,” Yankner said. “This is the first time someone has shown that lithium exists on a natural level that is biological meaning without giving it as a medicine.”

Then Yankner and his colleagues made things one step further. They have shown in mice that lithium depletion is not just associated with Alzheimer’s disease – helps driving.

Lithium loss causes the range of changes associated with Alzheimer

Researchers found that the diet of healthy mice of a limited lithium diet brought their lithium levels to a level similar to that in patients with Alzheimer’s disease. This appeared to accelerate the aging process, creating inflammation of the brain, loss of synaptic connections between neurons and cognitive decline.

In Alzheimer’s mice models, the exhausted lithium dramatically accelerates the formation of plates and amyloid-gear structures that resemble neuroinidal tangles. Lithium exhaustion also activated inflammatory cells in the brain called microtics, reducing their ability to degrade amyloid. It caused the loss of synapses, neurons and myelin that protects neurons. and accelerated cognitive decline and memory loss – all the characteristics of Alzheimer’s disease.

Mouse experiments further revealed that lithium has changed the activity of genes known to increase or lower risk of Alzheimer’s, including the most famous APOE.

The replenishment of the lithium giving the mice lithium in their water reverses the damage associated with the disease and the recovery of memory function, even in older mice with advanced disease. Specifically, maintaining constant levels of lithium in early life prevented Alzheimer’s onset – a finding that confirmed that the lithium supplies the process of the disease.

“What impresses me most about lithium is the widespread result it has at the various events of Alzheimer’s.

A promising way to treat Alzheimer’s

Some limited clinical trials of lithium for Alzheimer’s disease have shown some efficacy, but lithium compounds they have used – such as clinical standard, carbonate lithium – may be toxic to the aging of humans in high doses used in the clinic.

The new research explains why: The amyloid beta removes these other lithium compounds before they can work. Yankner and his colleagues found the Lithium Orotate by developing a sorting platform looking for a library of compounds for those who can bypass the amyloid beta. Other researchers can now use the platform to search for additional lithium compounds that evolve with amyloid that may be even more effective.

“One of the most galvanized findings for us was that there were deep results in this extremely low dose,” Yankner said.

If they are reproduced in further studies, researchers say that controlling lithium through usual blood tests can one day offer a way to identify people who are at risk for Alzheimer’s who will benefit from treatment to prevent or delay the onset of the disease.

Studying lithium levels in people who are resistant to Alzheimer’s, as age can help scientists create a level of target that could help patients maintain to prevent the disease from appearing, Yankner said.

Since lithium has not yet been proven to be safe or effective in protecting people in humans, Yankner emphasizes that people should not receive lithium compounds on their own. But he expressed the careful optimism that the HIV -positive lithium or similar union would take clinical trials in the near future and could eventually change the history of Alzheimer’s treatment.

“My hope is that lithium will do something more fundamental than anti-ammmyloid or anti-tau treatments, not only reducing, but also reversing the cognitive decline and the improvement of patients’ lives,” he said.