Lithium, new hope against Alzheimer's: a Harvard study reveals the link between the metal and the disease.

Researchers at Harvard Medical School in the United States have discovered that lithium loss in the brain accelerates memory decline , contributing to Alzheimer 's disease, and have opened up the possibility that this compound could help treat a disease that affects nearly 400 million people worldwide.

Alzheimer's disease involves a series of brain abnormalities, such as accumulations of the amyloid-beta protein, neurofibrillary tangles of the tau protein, and the loss of a protective protein called REST. However, these do not fully explain the onset of the disease, as some people with these conditions show no signs of cognitive decline, and drugs targeting amyloid-beta fail to reverse memory loss.

The work, published in Nature and conducted over 10 years, reveals that lithium could be the key to completing the Alzheimer's story. It demonstrates for the first time that lithium is produced naturally in the brain, protects it from neurodegeneration, and maintains the normal function of all major types of neurons.

The research team used an advanced form of mass spectroscopy to measure levels of approximately 30 different metals in the brains and blood of cognitively healthy individuals, those in early stages of dementia, and those with advanced Alzheimer's disease. To do so, they used a bank of postmortem brain tissue from the Rush Memory and Aging Project in Chicago.

Lithium was the only metal whose levels were notably different between groups and that was altered in the early stages of memory loss. Its levels were elevated in cognitively healthy donors, but greatly reduced in those with mild impairment or advanced Alzheimer's. These findings were replicated in samples obtained from multiple brain banks across the country.

An experiment on mice subsequently revealed that, in animals, lithium deficiency is not only linked to Alzheimer's disease, but actually contributes to its development .

Researchers found that feeding healthy mice a lithium-restricted diet reduced their brain lithium levels to levels similar to those of Alzheimer's patients. This appeared to accelerate the aging process, causing brain inflammation, loss of synaptic connections between neurons, and cognitive decline.

In mouse models of Alzheimer's disease, lithium deficiency dramatically accelerated the formation of beta-amyloid plaques and neurofibrillary tangle-like structures. Lithium deficiency also activated microglia, an inflammatory cell in the brain, reducing their ability to break down amyloid; caused the loss of synapses, axons, and myelin, which protects neurons; and accelerated cognitive decline and memory loss, all hallmarks of Alzheimer's disease.

Furthermore, these experiments showed that lithium altered the activity of genes known to increase or decrease the risk of Alzheimer's, including the most well-known gene, APOE.

Based on these results, the researchers decided to test the effects of administering treatment with lithium , specifically lithium orotate, on the memory impairment in mice. This reversed the disease-related damage and restored memory function, even in older mice with advanced disease.

Another finding highlighted that maintaining stable lithium levels in the early stages of life prevented the onset of Alzheimer's, confirming that this compound drives the pathological process.

Researchers have said that, if replicated in further studies, screening for lithium through routine blood tests could one day offer a way to identify individuals at risk for Alzheimer's who would benefit from treatment to prevent or delay the onset of the disease.

Since the safety and efficacy of lithium treatment against neurodegeneration in humans has not yet been demonstrated, the study's authors have warned the public not to start taking these compounds on their own.

Marc Suárez Calvet, a researcher at the Barcelonabeta Brain Research Center and the Neurology Department at Hospital del Mar (Barcelona), stressed in a statement to SMC Spain that the results of this study are "promising," but that caution is needed because clinical trials in patients are still needed to confirm the efficacy and safety of lithium before initiating its therapeutic use.

Along the same lines, Jordi Pérez-Tur, a research scientist at the CSIC's Institute of Biomedicine of Valencia, has urged us not to become overly optimistic and to continue advancing rigorously along this path.

"It needs to be confirmed that the same thing happens in humans as has been seen in animal models, which, let's remember, are imperfect because these animals don't develop the same disease as humans. If this is confirmed, it's necessary to establish what doses are necessary and safe to have an effect , as well as to determine whether significant side effects may occur. The use of this metal in the treatment of a neurological condition, however, gives hope that this last part will be relatively rapid," he noted.