A decline in lithium levels may be among the earliest changes that push ageing brains towards Alzheimer’s disease, researchers have said in a new study that has also found that lithium therapy can reverse such changes in mice.
The study by US researchers is the first to show that lithium, a trace metal, occurs naturally in the brain, but is depleted in people with mild cognitive impairment — a precursor to Alzheimer’s. Restoring lithium levels, the study found, reverses brain changes and memory loss in mice.
The findings, published in the journal Nature on Wednesday, provide a new theory for Alzheimer’s and point to a lithium-based strategy for early diagnosis, prevention and treatment, amid limited insights into the earliest molecular changes of the disease.
“You have to be careful about extrapolating from mouse models, and you never know until you try it in a controlled human clinical trial — but the results so far are very encouraging,” Bruce Yankner, professor of genetics and neurology at the Harvard Medical School, said in a media release.
Yankner and his colleagues at Harvard and the Rush University Medical Centre, Chicago, have generated multiple lines of evidence that suggest that lithium deficiency is a potential common mechanism for the degenerative changes in the brain leading to the onset of Alzheimer’s.
The researchers relied on postmortem brain tissues donated to science by thousands of study participants to measure the trace levels of about 30 metals in both healthy and impaired brains.
They found that among all the metals they measured, lithium was the only one that was significantly reduced in the brains of people who had mild cognitive impairment. The levels were lower even at the earliest stages of memory loss.
The scientists said their observations from the brain tissue banks were consistent with a population-based study in 2017 from Denmark that had found that the higher the trace levels of lithium in drinking water, the lower the incidence of dementia.
“Lithium turns out to be like other nutrients we get from the environment, such as iron or vitamin C,” Yankner said.
The researchers also found that feeding healthy mice a lithium-deficient diet lowered their brain lithium levels.
Lithium depletion accelerated the formation of protein fragments called amyloid-beta plaques and other structures associated with Alzheimer’s and activated inflammatory cells in the brain. This led to the loss of neuronal connectivity, cognitive decline and memory loss — all signatures of Alzheimer’s.
Most current therapies for Alzheimer’s target the buildup of toxic proteins in the brain, rather than the underlying drivers of the disease.
But a compound called lithium orotate given to the mice reversed such disease-related damage and restored the memory functions even in older mice with advanced disease.
The experiments on mice also showed that stable lithium levels in early life prevented the onset of Alzheimer’s-like diseases — another indicator implicating lithium in the disease mechanisms.
The scientists say that measuring lithium levels through routine blood tests might help identify people at the risk of Alzheimer’s who might benefit from treatment to prevent or delay the onset of the disease.
Yankner has cautioned that people should not take lithium compounds on their own because lithium has not yet been shown to be safe or effective in protecting humans from the degenerative brain changes linked to Alzheimer’s.
Lithium is currently used in the treatment of certain psychiatric disorders but at doses that raise lithium levels in the blood to over 1,000 times the natural level. In normal ageing mice, low levels of lithium preserve brain function, reduce inflammation and suppress brain tissue damage