The discovery of lithium's essential role in Alzheimer's opens a hopeful avenue for treating the disease.

Lithium deficiency is a possible cause of Alzheimer's, suggests a pivotal study that provides a new theory of the disease and a novel treatment strategy. The authors, from Harvard University (USA), have shown that lithium, a metallic chemical element rare in the Earth's crust, plays an essential role in brain function. The researchers also observed that administering a salt, lithium orotate, to mice prevents memory loss and the characteristic pathological changes of dementia . The signatories urge citizens not to take supplements on their own, as they can be extremely dangerous, but urge the launch of clinical trials to investigate the effect of lithium orotate on humans. Their results were published this Wednesday in the journal Nature , one of the most prestigious scientific publications in the world.

Research leader Bruce Yankner compares Alzheimer's to a chaotic battlefield covered in corpses after a war. There is so much destruction that it's hard to know how it all began. Yankner himself discovered in 1990 that a protein that is deposited in the brains of people with Alzheimer's, called beta amyloid , can cause neuron degeneration. Another protein, called tau, forms tangles inside the brain cells of these patients. And the activation of immune cells maintains chronic neuroinflammation that damages neurons and deteriorates their connections. The battlefield in the brain is so confusing that, more than a century after the discovery of the disease in a German woman with memory loss, the scientific community still doesn't understand how Alzheimer's arises. "Lithium deficiency is the breakdown in communication that leads to war," Yankner explains to EL PAÍS.

The Harvard team wanted to shed light on the possible role of some thirty metallic chemical elements, such as iron and copper, in the enigmatic process that leads to Alzheimer's. The researchers analyzed human samples stored in the Rush University Brain Bank in Chicago, a collection of donations from thousands of healthy individuals or those in various stages of cognitive decline. After measuring the minute traces of these metals with unprecedented precision, the group found that only lithium levels declined dramatically as Alzheimer's progressed. The finding was consistent with previous studies that had observed a surprising fact: drinking water with higher amounts of lithium is associated with a lower incidence of dementia in the population. In Denmark, this effect was seen in a 2017 analysis of 800,000 people .

Yankner's group explains that characteristic deposits of beta amyloid protein bind to lithium and sequester it, impeding its natural function in the brain. This drop in the metal's levels affects all key brain cells, the neurologist emphasizes. "Lithium deficiency is a possible common mechanism for the multisystem degeneration of the brain that leads to dementia," he notes. The finding is momentous, Harvard University emphasized in a statement . "The idea that lithium deficiency may be a cause of Alzheimer's is novel and suggests a different therapeutic approach," Yankner concludes.

Lithium's role as a mood stabilizer is well known—it was already an ingredient in the original recipe for the popular American soft drink 7UP a century ago—and it is used as a treatment for people with bipolar disorder, depression, or schizophrenia. The most common drug is lithium carbonate, a toxic substance that can cause kidney failure and seizures. Yankner's team has discovered that another compound, lithium orotate, is effective at one-thousandth of the usual dose and does not become trapped in the deposits of the beta amyloid protein. This salt—made up of five carbon atoms, three hydrogen atoms, one lithium atom, two nitrogen atoms, and four oxygen atoms (C₅H₃LiN₂O₄)—prevents pathological changes and memory loss in both naturally aging mice and those genetically modified to mimic the effects of Alzheimer's, according to experiments conducted at Harvard.

“As a neuroscientist, it’s fascinating to explore the functions of lithium in the brain. Our genetic analysis suggests that lithium affects all major brain cell types. I suspect we’ve barely scratched the surface,” says Yankner, who continues research to pave the way for future clinical trials of lithium orotate in humans.

The idea that lithium deficiency may be a cause of Alzheimer's is new and suggests a different therapeutic approach.

Bruce Yankner, Harvard neuroscientist

A Spanish study, led by biologists Javier Vitorica and Antonia Gutiérrez , showed in 2013 that lithium carbonate slowed the progression of Alzheimer's in transgenic mice and improved their memory. Vitorica emphasizes that the Harvard team has now opted for a seemingly less toxic compound, but insists that no one should take it on their own. "Lithium is very dangerous; the dose must be carefully controlled," warns the researcher, a professor at the University of Seville. Vitorica applauds the new study but remains cautious until these encouraging results are confirmed in human trials. "It's not going to be the drug that cures Alzheimer's, but it may mitigate its symptoms," he opines.

Her colleague Antonia Gutiérrez highlights that the Harvard study has established a relationship between lithium deficiency and the activation of a pro-inflammatory state in microglia , the brain's immune cells discovered in 1918 by the Spanish neuroscientist Pío del Río Hortega . The dysfunction of these cells prevents them from removing harmful deposits of beta amyloid protein, which in turn would cause the neurodegenerative process to progress through inflammation, the accumulation of tau protein tangles, and the loss of connections between neurons. "The results of this study support the idea that lithium could be a modulator of the microglial state and, from this perspective, open a way to modulate disease progression," celebrates the biologist, a professor at the University of Malaga.

Gutiérrez, however, is skeptical that lithium deficiency is a cause of Alzheimer's. "The suggestion that lithium is a key factor in the origin of the disease is somewhat speculative. The work does not determine whether lithium deficiency is a consequence or a primary factor of the disease," the professor believes. "Extrapolation of the results of this study to human pathology requires further scientific support. Most of the experiments were conducted in transgenic animal models, and direct causality has not been demonstrated in humans," Gutiérrez warns. "If confirmed, the main challenge would be finding a safe and effective dose, since lithium can have toxic effects, especially in people with compromised kidney function," she adds.

Pathologist Alberto Rábano directs the CIEN Foundation's brain bank in Madrid, which has over a thousand donated organs. "The relationship between lithium and Alzheimer's has a long history, but this study is truly new and important," he says. Rábano particularly values the fact that the Harvard team analyzed post-mortem human tissue, because "it reveals the importance of brain donation." His foundation is always looking for donors , both healthy and those with neurological or psychiatric illnesses.

Rábano points out that two treatments already exist, lecanemab and donanemab , which slow cognitive decline in Alzheimer's patients by between 27% and 35%, but they are very expensive— more than €20,000 per patient per year—and cause serious side effects. The pathologist emphasizes that the lithium orotate proposed by Yankner's team could complement the modest efficacy of these two therapies, if their activity in humans is confirmed. "This is excellent news in the field of Alzheimer's," Rábano celebrates.