Diabetes drug for Alzheimer’s explored

“A common diabetes drug could be redeveloped as a new treatment for Alzheimer's,” reported the BBC. It said that metformin may help prevent the formation of “tau tangles”, a key brain abnormality linked to the disease.

This study investigated whether metformin has any effect on the tau proteins that form these tangles. In studies of mouse cells, metformin increased the activity of an enzyme that can counteract the development of the tangles. Similar findings were also seen in live mice given the drug.

These are promising findings, but this is early research and many questions still need answering. It is not known if the drug can prevent or treat the brain changes seen in Alzheimer’s in humans or if it can help with memory, cognition and recognition problems. Also, the doses used in these experiments on mice were much higher than the equivalent doses used to treat diabetes in humans. It is not known if an equivalent human dose would be safe.

Where did the story come from?

This study was carried out by researchers from the Max-Planck Institute, the Charité Medical School, the German Centre for Neurodegenerative Diseases, and the University of Dundee and the University of Innsbruck in Scotland. It was published by the peer-reviewed journal Proceedings of the National Academy of Sciences.

The study was funded by the Volkswagen Stiftung, Tenovus, the Tyrolian Future Foundation, and the Integrated Center of Research and Therapy of the Medical University of Innsbruck.

The BBC covered the story accurately, noting this is early stage research not yet carried out in humans. The source of the Daily Mail’s claim that metformin could be administered in combination with resveratrol is unclear, as the researchers did not use resveratrol in their study, nor do they make any specific recommendations of combination treatments. Therefore, the claim that this research 'brings hope of a brighter future for millions' is premature.

What kind of research was this?

The aim of this study was to investigate whether metformin, a drug approved for the treatment of diabetes, had any effect on levels of proteins in the brain associated with Alzheimer’s disease. This laboratory study was on mouse cells and healthy mice without Alzheimer’s disease.

A sign of Alzheimer’s disease is the formation of clumps of protein, known as plaques and tangles, in the brain. Tangles are mostly made up of a protein called tau.

In healthy brains without Alzheimer’s, the tau protein plays an essential role in cell function. However, in Alzheimer’s disease, an abnormal version of tau is produced. Linked to this abnormal tau is a biological process called ‘phosphorylation’. In Alzheimer’s brains, this process does not work properly, and too much phosphorylation occurs, disrupting the normal activity of tau proteins and leading to the formation of tangles.

An enzyme called PP2A is known to reduce levels of phosphorylation and it has been discovered that, in people with Alzheimer’s disease, PP2A activity may be reduced.

Previous research has suggested that metformin can interact with PP2A. These researchers wanted to see whether metformin can reduce the extent of tau phosphorylation by increasing the activity of PP2A.

What did the research involve?

The researchers began by investigating whether PP2A was able to remove phosphorylation from tau in living cells. They then investigated whether metformin could increase activity of PP2A and whether this increase could lead to a reduction in phosphorylation in mouse neurone cells.

The researchers then confirmed that metformin influenced levels of tau phosphorylation through PP2A, and explored how the drug might be acting on PP2A. Finally, they looked at the effects of metformin on tau phosphorylation levels in living mice.

What were the basic results?

Metformin was found to increase the activity of PP2A in cells in the laboratory. Cells in which PP2A activity was stimulated by metformin had lower levels of tau phosphorylation. This applied to normal mouse cells, as well as cells from mice that had been genetically modified to produce the human form of the tau protein. The researchers confirmed that the metformin was indeed acting on tau phosphorylation through the activity of PP2A.

Finally, they found the mice that had been given metformin in their drinking water had reduced levels of tau phosphorylation.

How did the researchers interpret the results?

The researchers describe how metformin reduced the levels of tau phosphorylation in both cells and in live mice. They say their findings ‘suggest a potential beneficial effect of long-term metformin treatment and raise the hope that metformin would have a neuroprotective and prophylactic effect in patients with a predisposition to Alzheimer’s disease’.

Conclusion

This was an early stage laboratory study in healthy mice without Alzheimer’s disease, which gives insight into the biochemical effect that metformin has within nerve cells. These are promising findings but this study does not tell us whether metformin has the same effect on tau proteins in humans, what dose is safe and effective, and whether it would work in all patients.

It should be noted that this study used doses of metformin that were much higher than the equivalent doses used in people with diabetes. If further laboratory studies show that metformin is effective at preventing or treating Alzheimer’s disease in animal models, the next stage would be to start clinical trials. As metformin is already licensed for use in diabetes, the process of assessing its safety in humans could be shortened. However, identifying a safe and effective dose for dementia, and checking whether such a dose would have any additional side effects or possible harms, would still be necessary.