Blood vessel discovery points to alternative cause of Alzheimer’s dementia

Blood vessel discovery points to alternative cause of Alzheimer’s dementia
New research hypothesizes narrowing blood vessels in the brain plays a role in the cognitive decline associated with Alzheimer's disease
New research hypothesizes narrowing blood vessels in the brain plays a role in the cognitive decline associated with Alzheimer's disease
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New research hypothesizes narrowing blood vessels in the brain plays a role in the cognitive decline associated with Alzheimer's disease
New research hypothesizes narrowing blood vessels in the brain plays a role in the cognitive decline associated with Alzheimer's disease

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

How did the anti-amyloid treatments fail? Did they fail to break up the amyloid protein or did they break it up and this made no difference? A rather significant distinction to take in before deciding to give up on this treatment approach. Also, is this new 'discovery' not just a slightly different version of the Zamboni MS hypothesis?

One hopes not but what's old sure seems new again.
Best of luck in the new direction, UoM. Finding the cause and putting down Alzheimers and other forms of dementia is critical.
I am a Designer not a Doctor or Scientist so unqualified to judge the worth of my idea to clear amyloid proteins from the vascular system, but, as they are present as blockages in diseases affecting blood flow to the vitals, they are negatively influencing health. Why not trial a treatment where the Patients own white blood cells are cultured and altered to recognize these proteins then reintroduced to let these "micro machines" do what comes naturally as the "bouncers" of the blood? Best of all drug free!
The brain does a cleaning process during sleep. What opens up tiny blood vessels? I feel like a bedtime niacin type drug will be invented soon.

With all due respect to Gene Kranz (a TRUE American hero!) that is not true in this case. Failures are how we learn!

It has become apparent (to me) that the many failures associated with Alzheimer's research indicate, not just a misunderstanding of the root causes of this problem, but, more likely, a reflection of the case that causality of Alzheimer's is manifold, not a unitary situation. So many studies have targeted amyloid plaques as the villain, while other approaches indicate that there may be a spectrum of issues behind this most cruel of diseases.

Thank God that this new report expands the search for likely causes, not just of "Alzheimer's", but many other forms of dementia.

If my suspicions are correct, there are MANY causes of brain malfunction, and eachone requires a different approach.

One size does NOT fit all.