ABU DHABI (ALETIHAD)
A decade of investigation by scientists at Harvard Medical School have revealed that the loss of the metal lithium plays a powerful role in Alzheimer’s disease, a finding that could lead to earlier detection and new treatments for the disease that affects memory and cognitive functioning.
Researchers led by Bruce A. Yankner, 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 Wednesday in the journal Nature.
The findings are based on a series of experiments in mice and on analyses of human brain tissue and blood samples from individuals in various stages of cognitive health.
The scientists found that lithium loss in the human brain is one of the earliest changes leading to Alzheimer’s, while in mice, similar lithium depletion accelerated brain pathology and memory decline.
The team further found that reduced lithium levels stemmed from binding to amyloid plaques and impaired uptake in the brain.
In a final set of experiments, the team found that a novel lithium compound that avoids capture by amyloid plaques restored memory in mice.
The results unify decades-long observations in patients, providing a new theory of the disease and a new strategy for early diagnosis, prevention, and treatment.
Affecting an estimated 400 million people worldwide, Alzheimer’s disease involves an array of brain abnormalities — such as clumps of the protein amyloid beta, neurofibrillary tangles of the protein tau, and loss of a protective protein called REST — but these never explained the full story of the disease.
For instance, some people with such abnormalities show no signs of cognitive decline. And recently developed treatments that target amyloid beta typically don’t reverse memory loss and only modestly reduce the rate of decline.
It is also clear that genetic and environmental factors affect risk of Alzheimer’s, but scientists haven’t figured out why some people with the same risk factors develop the disease while others do not.
Lithium, the study authors said, may be a critical missing link.
“The idea that lithium deficiency could be a cause of Alzheimer’s disease is new and suggests a different therapeutic approach,” said senior author Bruce Yankner, professor of genetics and neurology in the Blavatnik Institute at HMS, who in the 1990s was the first to demonstrate that amyloid beta is toxic.
The study raises hopes that researchers could one day use lithium to treat the disease in its entirety rather than focusing on a single facet such as amyloid beta or tau, he said.
One of the main discoveries in the study is that as amyloid beta begins to form deposits in the early stages of dementia in both humans and mouse models, it binds to lithium, reducing lithium’s function in the brain. The lower lithium levels affect all major brain cell types and, in mice, give rise to changes recapitulating Alzheimer’s disease, including memory loss.
The authors identified a class of lithium compounds that can evade capture by amyloid beta. Treating mice with the most potent amyloid-evading compound, called lithium orotate, reversed Alzheimer’s disease pathology, prevented brain cell damage, and restored memory.
Although the findings need to be confirmed in humans through clinical trials, they suggest that measuring lithium levels could help screen for early Alzheimer’s. Moreover, the findings point to the importance of testing amyloid-evading lithium compounds for treatment or prevention.
Other lithium compounds are already used to treat bipolar disorder and major depressive disorder, but they are given at much higher concentrations that can be toxic, especially to older people.
Yankner’s team found that lithium orotate is effective at one-thousandth that dose — enough to mimic the natural level of lithium in the brain. Mice treated for nearly their entire adult lives showed no evidence of toxicity.
Since lithium has not yet been shown to be safe or effective in protecting against neurodegeneration in humans, Yankner emphasises that people should not take lithium compounds on their own. But he expressed cautious optimism that lithium orotate or a similar compound will move forward into clinical trials in the near future and could ultimately change the story of Alzheimer’s treatment.
“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,” he said.