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Scientists in the UK and Sweden believe they have come up with an unprecedented breakthrough in Alzheimer's disease research: a method for developing new drugs that can target the roots of the deadly disease. Although the latest published work is truly intriguing, outside experts are concerned that the researchers' claims to the public are too grandiose.
Alzheimer's disease is the most common form of dementia, affecting 5.7 million Americans, according to the Alzheimer's Association. There is still much we do not understand about the exact sequence of events that lead to Alzheimer's disease, but we are pretty sure that a brain protein called beta-amyloid plays a vital role.
In its normal state, beta-amyloid seems to play an unknown but important role in the brain (some scientists believe that it could protect us from infections). But when beta-amyloid molecules do not bend properly, they can clump together and damage the brain. At a time when symptoms such as memory loss and confusion appear, a person's brain is littered with fiber-like amyloid fiber plates. The accumulation of another protein called tau – called entanglement – could damage the brain and cause the symptoms of Alzheimer's disease, but it is thought that the flood of beta-amyloid appears first and causes the progression of the disease .
Scientists have attempted to create drugs that delay or prevent Alzheimer's disease by eliminating these plaques, but clinical trials of these treatments have failed. One theory behind this failure has been that the drugs are used too late. At the moment when the brain is loaded with plaques, the damage is already done. This has led some scientists to start testing their anti-amyloid beta drugs in high-risk people who are not yet visibly ill.
In recent years, however, research has shown that if beta-amyloid accumulation can cause Alzheimer's disease, it does not actually cause plaque damage. Before they turn into plaques, the misfolded beta-amyloid molecules cluster into smaller groups called oligomers. And it is these oligomers, not the plaques, that appear to be the most toxic to the surrounding brain cells.
Researchers typically look for potential drugs based on their ability to bind to the particle structure they target. But according to the study's lead author, Michele Vendruscolo, a molecular chemist at the University of Cambridge in the UK, this approach can not work with beta-amyloid oligomers because oligomers are unstable, decompose and constantly reform.
Instead, his team says they have developed a technique to search for potentially useful compounds based on their ability to slow oligomer formulation.
"The drug candidates identified with our method can significantly reduce the number of oligomers produced during protein aggregation," Vendruscolo said via e-mail to Gizmodo. "This is a game changer."
In a press release from the University of Cambridge, Vendruscolo also described the technique as "world first". The title of the press release reads: "Scientists in Cambridge have presented an innovative plan to target Alzheimer's disease.
Vendruscolo and his team published Monday an article in Proceedings of the National Academy of Sciences detailing their method, known as SKAR (acronym for Structure-Kinetic Activity-Relationship).
Alzheimer's disease is one of many neurological disorders caused by protein folding – others include Parkinson's disease and Creutzfeldt-Jakob disease – and the Vendruscolo team believes that its approach could be used to find anti-oligomeric drugs.
The hype surrounding oligomers as the real cause of Alzheimer's disease and other similar disorders is real, according to James Hendrix, director of the Global Science Initiatives at the Alzheimer's Association. But it's not yet fully confirmed, he said.
Scientists are currently testing antibodies that target these oligomers in clinical trials on humans, said Hendrix, but if these tests fail, it is unlikely that the research of Vendruscolo and his team will elicit much attention. Warning. And if these trials show promising results, the team will still have to prove that their molecules can do a better job than experimental antibodies.
Vendruscolo and his team co-founded a biotechnology company called Wren Therapeutics, based at the University of Cambridge, to help them develop these drugs. He told Gizmodo that they had already tested some drug candidates discovered via their method on worms, and that they were currently testing them on mice. The results of the mouse should be published next year. He also said they would like to start testing the molecules in humans in the next two years.
According to Hendrix, the time it takes us to know if an experimental drug against Alzheimer's disease can actually work in people, from beginning to end, is more than 10 years old.
"Overall, I think this paper is interesting for medicinal chemists and could be a useful strategy for targeting oligomers in general," Hendrix said. "However, the Alzheimer's association is concerned that the press release accompanying the magazine article is not realistic about the novelty and short-term usefulness of this technique in the development of drugs against Alzheimer's disease.
Of course, because Alzheimer's disease can be devastating, not only for people with Alzheimer's disease but also for people who love it, any research that could help us develop treatment one day should be welcomed. But the story behind the development of drugs for Alzheimer's disease is sadly marked by a promising start that ends in disappointment. So, if nothing else, all the announcements of revolutionary discoveries in this area must be treated with skepticism at the beginning.
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