For decades, a single overriding hypothesis has guided the majority of research into Alzheimer's disease, but after a string of failed major clinical trials, a small group of scientists is starting to question this mainstream belief. A new study from a team of researchers at the University at Buffalo is suggesting a protein called presenilin could be a more effective target for potential treatments.

Around a century ago, German scientist Aloysius Alzheimer first described the condition we now know as Alzheimer's disease. While early investigations into the condition noted a correlation between the build-up of amyloid plaques in the brain and dementia, it wasn't until the 1980s that a causal hypothesis was proposed.

Known as the "amyloid hypothesis," this idea suggested that a build-up of plaques, composed of a protein called beta-amyloid, contributes to the fundamental degenerative characteristics of the disease. Through the 1980s, interest in these plaques generated a flurry of research and by the end of the decade scientists had developed neurological targets for treatment with a newfound laser-sharp focus.

The hypothesis suggested that as these amyloid plaques built up, they systematically destroyed neurons and then synapses, contributing to the degenerative cognitive effects of the disease. So scientists started to focus on ways to either remove or inhibit these amyloid plaques as a way to thwart the disease.

Fast forward to now, and while the amyloid hypothesis is still the primary driver of most Alzheimer's research, it has suffered a series of major set backs in recent years. A decidedly bad run of failed clinical trials has started to raise doubts over whether amyloid plaques are the correct treatment target.

A striking 2014 study examined over a decade of clinical trials for Alzheimer's drugs, most targeting amyloid in one way or another. Out of 413 trials examined, the study concluded almost all had failed at some phase, with an overall failure rate of 99.6 percent.

Since then, the news hasn't got much better, with several major pharmaceutical companies completely pulling out of Alzheimer's research after some high-profile clinical trial failures. Last year, one of Merck's big Alzheimer's drug candidates, verubecestat, was revealed to be failing Phase 3 clinical trials, so the pharma giant quickly shut down research into the compound. And early this year, Pfizer announced it was stopping all research into Alzheimer's drugs, presumably due to the ongoing clinical failures.

The amyloid hypothesis is not entirely dead, however. A number of major clinical trials are still underway targeting the protein using different methods and at different stages of disease onset. But a small vanguard of scientists are also exploring alternate targets in the hope that they can find a more effective way to treat this devastating condition.

Shermali Gunawardena at the University at Buffalo studies axonal transport, the system that controls the movement of a variety of compounds within neurons. Gunawardena's work hypothesizes that breakdowns within this transportation system are what potentially could result in the formation of amyloid plaques, and targeting this process could result in more effective Alzheimer's treatments.

"We are looking at processes that occur before cell death, before you start to see plaques in the brain," says Gunawardena. "A lot of the treatments being developed for Alzheimer's are targeting beta-amyloid, but maybe we should be targeting processes that happen earlier on, before plaques are formed."

Gunawardena and her team have been focusing on a protein called presenilin for over five years. The protein was initially found to play a prominent early role in the generation of amyloid plaques, but further research has revealed presenilin as being much more important that just regulating amyloid formation.

"We are curious about the normal function of presenilin," says Gunawardena. "What does this protein normally do? In the past, we have thought of it as being implicated in the production of beta-amyloid, but in fact, presenilin appears to also have a very different function independent of this. As we learn more about presenilin, it's possible that our research will result in new, more targeted opportunities for treating or preventing Alzheimer's disease."

It will be a few years yet before enough clinical trials can offer clarity on whether targeting amyloid directly will be an effective Alzheimer's treatment. Science is, after all, a cumulative process, whereby failures offer as much valuable data as successes. It is undeniably clear that the build-up of amyloid plaques in the brain correlate with Alzheimer's disease, but whether this amyloid clumping is the root cause of the condition is not yet clear.

Some scientists are suggesting treatments that target amyloid build-ups need to be started early to be effective. Some ongoing trials are examining subjects that are healthy but at a high genetic risk of developing the condition, while others are testing compounds on subjects with early elevated levels of amyloid in the brain before any symptoms of dementia have appeared.

Dealing with slow, degenerative neurological conditions make this kind of research a very long game. So, while some researchers, in the minority, are suggesting the amyloid hypothesis is already dead, there is undoubtably a great deal of work still to be done before this scientific story has a conclusion.

The new University at Buffalo research was published in the journal Human Molecular Genetics.