The research suggests a new approach to preventing and treating the mind-robbing disease.
“It seems to somehow turn back the clock,” said the team’s senior author, Dr. Bruce Yankner, co-director of the Paul F. Glenn Center for the Biology of Aging Research, and professor of genetics and neurology at Harvard.
The findings come amid a rising tide of Alzheimer’s and growing urgency to pinpoint an effective treatment for the roughly 7 million Americans living with the disease, a number that is projected to reach nearly 13 million by 2050.
For years, researchers believed the buildup of sticky clumps of protein, known as amyloid plaques, fueled the devastating cascade of brain degeneration in Alzheimer’s. But new medications designed to clear the plaques have not reversed memory loss and have had only modest success slowing decline, which suggests there’s some other spark that is igniting the disease.
Yankner now believes that may be a lithium deficiency.
Lithium has long been used to treat mental health conditions, particularly bi-polar disorder. But the form of lithium typically used for such treatments, lithium carbonate, is different than the one used by the Yankner team, which employed lithium orotate.
His team studied brain tissue donated from about 400 people post mortem, as well as blood samples and a battery of memory tests performed yearly before their death. The participants ranged from cognitively healthy at the time of their death to having full-blown Alzheimer’s.
The scientists found higher levels of lithium in cognitively healthy people. But as amyloid began forming in the early stages of dementia, in both humans and in mice, the amyloid bound to the lithium, restraining it and reducing its availability to surrounding brain cells. That depleted the lithium even in parts of the brain that were amyloid free, essentially reducing lithium’s protective function.
To test whether lithium depletion was driving the disease or simply a byproduct of it, they fed healthy mice a lithium-restricted diet, draining their lithium levels. This appeared to accelerate their brain aging process, creating inflammation and reducing the ability of nerve cells to communicate. That spurred memory loss in the mice, as measured by their diminished performance in several laboratory memory tests.
The researchers then fed a restricted-lithium diet to mice that were genetically engineered to develop Alzheimer’s-like amyloid plaques and abnormal tangles of another protein, called tau, and witnessed a dramatic acceleration of the disease.
But they were able to reverse the disease-related damage and restore memory function, even in older mice with advanced disease, by returning lithium to their diet. (Lithium orotate, the compound the scientists used, can evade capture by Alzheimer’s amyloid plaques).
Other scientists not involved in the research said the findings create a new approach to designing medications to treat and prevent Alzheimer’s.
“This study is looking at it from a novel angle,” said Li-Huei Tsai, director of the Picower Institute for Learning and Memory at the Massachusetts Institute of Technology.
“I didn’t expect that the lithium level [in our body] would be this critical,” she said. “I just hadn’t thought about it this way.”
The amount of lithium in medications used for mental health conditions is very high and can be toxic to elderly patients. But the amount of lithium used by Yankner’s team was one-thousandth the level, essentially mimicking the amount naturally found in the brain.
Indeed, mice fed tiny amounts throughout their adult life showed no signs of toxicity.
Earlier research has suggested a link between sustained intake of lithium and lower levels of dementia. Notably, a 2017 nationwide Danish study that tracked the lithium levels in the drinking water of 800,000 people, aged 50 to 90, found that those diagnosed with dementia had lived in areas with lower levels of lithium in the drinking water.
Saul Villeda, an associate professor and associate director of the Bakar Aging Research Institute at the University of California, San Francisco, said the new Harvard study is intriguing because the safety profile of lithium is already well known, giving a potential lithium-based Alzheimer’s medication a leg up.
“When we’re thinking about the therapeutics of a replacement, if you’re lowering something, you just have to replace it back to the natural levels,” he said. “That seems a lot safer than introducing something that our body is not used to, or doesn’t already need in order to function. ”
“That’s a really good rationale for pursuing it,” he said.
A number of factors are linked through research to a higher risk of Alzheimer’s and dementia including advanced age, family history, and genetics, as well as several modifiable factors such as diet, smoking, hypertension and diabetes. A recent large study found that simple lifestyle changes, including improved nutrition, increased physical activity, and more time with friends, led to improved cognition.
Many foods already touted for their health benefits naturally contain higher amounts of lithium — seafood, grains, nuts, some vegetables, and mineral water.
Matt Kaeberlein, an adjunct professor at the University of Washington who studies the biology of aging, said Alzheimer’s is typically a disease of aging and the Harvard findings build on earlier research that has suggested lithium can slow signs of aging in worms and some animals.
But Kaeberlein and other researchers said the real test of the Harvard team’s findings would be a large clinical trial in people, with half of the participants receiving small doses of lithium orotate and the others a sham substance, to compare the findings. Kaeberlein said the safety track record of this form of lithium, which showed no toxicity in animals, may help speed trials in people.
The Harvard findings “line up with a lot of earlier work, both in the brain and in normal aging,” Kaeberlein said.
And he added something rarely heard from scientists when discussing cutting-edge research and a potential medication that may fundamentally change the course of a dreaded disease.
This work, he said, “feeds my optimism that this will lead to potential therapeutics.”
But one obstacle to advancing the research is the freeze on nearly all federal funding to Harvard imposed by the Trump administration earlier this year. The National Institutes of Health was a major supporter, “and this support has been terminated as part of the overall termination of federal grant support to Harvard,” said Yankner. ”Unfortunately, this will significantly limit our progress going forward.”
Kay Lazar can be reached at kay.lazar@globe.com Follow her @GlobeKayLazar.
