Following yet another failed clinical trial testing a novel drug designed to break up the aggregations of toxic proteins thought to be the cause of Alzheimer’s disease, a new study suggests we look to a different part of the brain in the hopes of finding a treatment. Led by researchers from the University of Manchester the new study found disruptions to blood vessels in the brain may be contributing to the neurodegeneration seen in Alzheimer’s.

For decades the leading hypothesis driving most Alzheimer’s research looked at finding ways to reduce the build-up of toxic amyloid proteins in the brain. Perhaps the most common pathological sign of Alzheimer’s disease are known as amyloid plaques, accumulations of proteins thought to be the fundamental cause of neurodegeneration.

But every drug designed to either prevent the accumulation of these plaques, or dismantle pre-existing aggregations, has failed at some stage of human clinical trials. And just recently yet another anti-amyloid drug has failed in Phase 2 human trials.

Called crenezumab, and developed with backing from pharma giant Roche, this new anti-amyloid failure has led many experts to express frustration at the excessive time and money being funneled into research based on a hypothesis that seems to be consistently proven wrong. Chemist and pharma commentator Derek Lowe summed up the merry-go-round of frustration in the Alzheimer’s research community in a blog post asking, “How long are we going to keep doing this?”.

“I do not believe that targeting amyloid is going to lead to a useful Alzheimer’s therapy, and watching these trials feels to me like watching someone trying to put out an oil well fire by dumping duffel bags of money onto it from helicopters,” Lowe frankly professed. “Hell, that would probably be cheaper. I don’t know what the answer to Alzheimer’s is, but at this point, as far as I’m concerned, it isn’t amyloid.”

There are, however, growing numbers of researchers developing alternative hypotheses. Earlier this month, for example, a team from New York University published a study that indicated declining acidity in cellular cleaning organelles called lysosomes may be an early pathological sign of Alzheimer’s. And restoring acidity in those lysosomes could be a way to prevent Alzheimer’s decline in its earliest stages.

Another alternative hypothesis published recently in the journal PNAS comes from researchers at the University of Manchester. This team focused on the relationship between reduced blood flow in the brain and Alzheimer’s disease.

Using mouse models the new research found arteries in the brain can be narrowed by a type of amyloid protein called Amyloid-β 1-40. It is suspected that when these arteries narrow the brain doesn’t get enough oxygen or nutrients, and this mechanism may play a role in the cognitive decline associated with Alzheimer’s.

“To date, over 500 drugs have been trialled as a cure for Alzheimer’s disease,” said Adam Greenstein, lead researcher on the new study. “All of them have targeted the nerves in the brain and none of them have been successful. By showing exactly how Alzheimer’s disease affects the small blood vessels, we have opened the door to new avenues of research to find an effective treatment.”

Hypothetically, if this vascular dysfunction could be prevented, or reversed, then healthy cerebral blood flow could be maintained and the cognitive dysfunction seen in Alzheimer’s could be reduced. Of course, it’s all speculation and animal studies at this point. The first step will be to find out if this same mechanism plays out in humans and then work out a pharmacological way to restore normal function.

It’s all very early, proof-of-concept stuff, but considering the constant parade of failed anti-amyloid Alzheimer’s treatments it is crucial for alternative hypotheses to be investigated. Metin Avkiran, from the British Heart Foundation, points to the urgency of cracking the Alzheimer’s mystery as cases of this neurodegenerative disease are rising from year to year.

“This research is an important step forward in our understanding of Alzheimer’s disease,” said Avkiran. “More than half a million people in the UK are living with the condition, and that number is set to rise as our population gets older. These findings could lead to a desperately needed treatment for this devastating condition.”

The new study was published in the journal PNAS.

Source: University of Manchester