Studies reinforce clinical relevance of lithium against Alzheimer’s disease

Experiments carried out at USP confirm that the medication used in the treatment of bipolar disorder alters pathogenic processes and has a preventive effect against manifestation of the degenerative disease.

By Fábio de Castro

Agência FAPESP – Research carried out at the Universidade de São Paulo (USP) reinforced the evidence that lithium, widely used in the treatment of bipolar disorder, can have a preventive effect against the manifestation of Alzheimer’s disease.

The study, the results of which were published in the British Journal of Psychiatry magazine in 2011, was led by Orestes Forlenza in the Neurosciences Laboratory at the Hospital das Clínicas Psychiatric Institute (IPq), which is part of USP. Forlenza presented the results in São Paulo during the Brazil-Canada Prion Science Workshop 2012, held by Hospital A.C. Camargo in March.

The study is the result of the Thematic Project “Neurobiology of Alzheimer’s disease: risk markers, prognosis and therapeutic response”, begun in 2010 and financed by FAPESP. The study was led by Wagner Gattaz, also from IPq.

According to Forlenza, the experiment was carried out with elderly people showing mildly compromised cognition. The results show the clinical relevance of the application of low doses of lithium in patients that have not yet reached the dementia phase of Alzheimer’s disease, reinforcing the hypothesis that the medication could be utilized to prevent the problem.

“The patients that received lithium not only remained more clinically stable from the functional and cognitive points of view, but also had less memory loss and less loss of cognitive functions,” Forlenza told Agência FAPESP.

In addition, the experiment showed evidence that one of the central pathogenic processes of Alzheimer’s was modified: hyperphosphorylation of the TAU protein, a process that destroys cell skeletons, leading to the death of neurons. Lithium inhibits the activity of the GSK 3-Beta enzyme, which phosphorylates TAU.

“This set of results shows that lithium may produce a modifying effect for the disease. Aside from the initial hypothesis, which was inhibition of the GSK 3-Beta enzyme, we looked at other possible participants of this effect,” said Forlenza.

The studies showed that there is an increase in the brain-derived neurotrophic factor (BDNF) of the mitochondrial function and in the activity of other enzymes. “All this lines up around a multiple mechanism of modification of many different pathogenic processes,” said the researcher.

Follow-ups

Science has been accumulating biological and experimental evidence for years—in animal models, cell cultures or neuroimaging extrapolations—in which lithium was able to have neurotrophic or neuroprotective actions. However, no one had proven that this action had any clinical significance or human benefit until recently.

“This proof began to come into being when we published a study in 2007 showing that when they get older, individuals with bipolar disorder—and who therefore receive lithium clinically for many years—have a lower rate of dementia than the bipolar individuals that were treated with other therapies,” said Forlenza.

Based on these experimental clinical hypotheses, the USP group performed a randomized study to evaluate, in a well-controlled manner, the neuroprotective effect of lithium in individuals at risk of having Alzheimer’s disease. The model chosen for evaluation was individuals with mildly compromised cognition.

“We had two studies to work from that were published (one in England, the other in Germany) using lithium to treat individuals with Alzheimer’s disease that was already in the dementia phase,” explained Forlenza.

He said that the British study was not successful because the patients did not tolerate the treatment. The doses of lithium were high, and there was a higher quit rate, which made it impossible to arrive at any conclusions. The other multi-center European study carried out in Germany performed an experiment with lithium with mild forms of Alzheimer’s disease for ten weeks. This study was also unsuccessful because no changes in the clinical or biological parameters were found.

“Based on this information, we designed our project not to treat Alzheimer’s patients already in the dementia stage but in a stage before it. Another different thing about our approach is that we used lithium in smaller doses than those used clinically. We showed that these doses are enough to inhibit the activity of an enzyme that we imagine must be associated with the process,” said Forlenza.

Another crucial difference in relation to the older studies, says Forlenza, was the follow-up period. “We followed-up for four years, at 12-, 24- and 36-month intervals. There were a total of 61 patients in the full sample. Not all reached the end of the four-year period, but in the first year, we had a 91% permanency rate in the study,” he said.

The Thematic Project will end in 2014. Until then, the researchers will continue with a line of study involving the application of lithium as an antagonist of Alzheimer’s disease. The scientists will now focus on parameters such as functional neuroimaging with positron emission tomography (PET) and structural neuroimaging to compare the two groups of patients and observe other outcomes.

“There are still many analyses that need to be made or completed, with variations of biomarkers and follow-up times, for example. We also want to start up a similar study, not with patients with mild cognitive impairment but with early onset family Alzheimer’s, which may be the ideal model for testing this pathogenic modification,” said Forlenza.