Alzheimer's disease 'wonder drug' claims are premature

"Millions could be offered wonder drug to prevent Alzheimer's before symptoms appear," is the overhyped headline in the Daily Express. 

The "wonder drug" in question, bexarotene, has only been tested in worms as part of this latest Alzheimer's research.

In this study, researchers tried to identify drugs able to prevent the formation of abnormal clumps of beta-amyloid proteins, known as aggregates, inside the brain. Aggregates are thought to contribute to the damage to nerve cells seen in people with Alzheimer's disease.

The researchers tested drugs on nerve cells in the laboratory, as well as in genetically modified worms, and found the cancer drug bexarotene had a beneficial effect. The drug is currently used in the treatment of a rare type of non-Hodgkin lymphoma.

Bexarotene was found to slow down the sticking together of aggregates and reduce toxic effects on nerve cells. It was also able to prevent the effects of beta-amyloid accumulation in genetically modified worms if it was given early on in their life cycle. But the drug didn't have this effect if given to worms already showing the effects of beta-amyloid accumulation.

The side effects of bexarotene weren't discussed in this study. Common side effects include skin damage, fatigue, and raised cholesterol levels.

The big question is would otherwise healthy people be willing to tolerate these side effects on the off-chance bexarotene prevents Alzheimer's?

Human studies are required to provide a better understanding of the risks and benefits of bexarotene for Alzheimer's to better answer this question. 

Where did the story come from?

The study was carried out by researchers from the University of Cambridge, which also provided funding.

It was published in the peer-reviewed journal Science Advances on an open-access basis, so you can read it online for free.

This study has been widely covered by the UK media, but only BBC News provided an appropriate summary of the research.

The BBC included a warning from the Alzheimer's Society that it is still early days for the research. The story also pointed out the side effects associated with bexarotene and how we don't yet know if it is safe for people with Alzheimer's to take this drug. 

All of the other UK news outlets largely ignored these warnings. Headlines heralding a "wonder drug" for Alzheimer's seem extremely premature – especially given the study involved worms, not humans.   

What kind of research was this?

This is a laboratory study that largely used nerve cells and genetically modified worms. It aimed to identify drugs that could be used to suppress the formation of toxic accumulations of beta-amyloid, which are linked to Alzheimer's disease.

This study has provided us with very early-stage findings that need to be confirmed in further animal models of the disease before any of the drugs could be tested in humans.

In 2012, bexarotene was used in mice genetically engineered to develop Alzheimer's-like symptoms. While the initial results were encouraging, the results were not replicated in other studies. It seems researchers are going "back to basics" by using worms in this study.  

What did the research involve?

The researchers first identified various small molecules that have been reported to bind to beta-amyloid protein pieces. They then identified compounds that contained these molecules, some of which are drugs already in use.

One such compound was the cancer drug bexarotene, which is used to treat a rare form of lymphoma (a cancer of the lymphatic system). The researchers started by studying its effects further.

They first looked at whether bexarotene could stop beta-amyloid protein pieces sticking together in the lab. They then tested whether the effect could slow down the toxic effects of beta-amyloid aggregates on nerve cells in the lab.

The researchers then looked at microscopic worms that had been genetically modified to produce a form of beta-amyloid that forms aggregates easily. As a result, these worms experience increasing paralysis as they age.

The researchers looked at what happened if they exposed the worms to bexarotene. They specifically looked at how many body bends the worms made, as fewer body bends shows more serious paralysis. 

What were the basic results?

Bexarotene reduced the ability of beta-amyloid protein pieces to stick together. The results suggest the drug had this effect in the early stages of Alzheimer's, when beta-amyloid protein pieces started to form small aggregates. This slowed down the formation of larger aggregates of beta-amyloid, which are toxic to nerve cells.

This means that adding bexarotene to beta-amyloid for up to four hours before adding it to nerve cells in the lab reduced the number of nerve cells that were killed by the amyloid.

However, as the bexarotene only slowed down the formation of beta-amyloid aggregates, this beneficial effect was not seen if the drug was added to the beta-amyloid for seven hours – that is, if the amyloid was given longer to form the toxic aggregates.

Over two days, the researchers found the genetically modified beta-amyloid-producing worms reduced the number of body bends they made. This suggests they were beginning to experience paralysis.

If the worms were exposed to a high concentration of bexarotene from early on in their lives, they were able to maintain a level of movement similar to normal worms over their nine-day lifespan. If the worms were exposed to bexarotene later in life (at two days), it did not slow down paralysis.  

How did the researchers interpret the results?

The researchers concluded their results suggest preventing the early stages of beta-amyloid aggregation using drugs such as bexarotene "could potentially reduce the risk of onset of Alzheimer's disease".

They also say their methods could be used to identify other drugs that could be used to treat diseases affecting nerve cells. 

Conclusion

The number of people with Alzheimer's disease is increasing as the global population ages. Researchers have estimated 44 million people currently have the condition, and this number will grow to more than 135 million by 2050.

It's believed the condition is caused at least in part by the accumulation of toxic aggregates of beta-amyloid protein pieces in the brain. Researchers hope stopping this aggregation could be a way to prevent or treat the disease, but have not yet found successful ways of doing this.

This piece of research looked at nerve cells and microscopic worms genetically modified to develop beta-amyloid aggregates. The researchers aimed to develop a way to identify chemicals that could suppress the formation of toxic amyloid aggregates. They identified the cancer drug bexarotene as one drug that could do this.

The main limitation of this study is it only provides very early-stage findings, which are so far in nerve cells and a short-lived worm model. As worms are much simpler organisms than humans, the next step would be confirming these findings in more complex animal models, like mice, before considering testing in humans.

Bexarotene has been investigated before in animals, with mixed results. The drug only appears to slow the formation of beta-amyloid aggregates, so even if it does show an effect in further studies, it may not be able to prevent Alzheimer's completely.

In addition, the drug did not show an effect in worms if given once the beta-amyloid had taken hold, which suggests it needs to be given early on. This is supported by the fact the drug has also been found to be ineffective in people with established Alzheimer's disease.

But targeting very early-stage disease or using the drug in people without Alzheimer's has not been studied.

Researchers will need to think about how they might target people for trials of this drug in a preventative capacity. Many people may not be willing to take a drug for a long period of time to prevent a disease they may or may not get.

Also, bexarotene has a number of undesirable side effects, including increasing blood cholesterol levels, which can increase the risk of heart disease.

Would healthy people be willing to reduce the risk of one chronic disease while raising the risk of another? Targeting people who have a higher risk of developing the disease is likely to be more feasible.

It's also likely bexarotene would need to be refined in some way to reduce its side effects before it could ever be used as a "statin for the brain".