Amyloid Hypothesis

Conduct any kind of research on Alzheimer’s disease and you’ll quickly learn the words amyloid beta. The words are synonymous with this disease. Amyloid beta is the sticky protein plaque (coupled with the tangles of tau, but we’ll leave tau out of this post) that take over the brain in Alzheimer’s patients, killing neurons and slowly destroying the brain.

Researchers in the 1980s leapt onto the amyloid-beta-causes-Alzheimer’s-disease bandwagon, forming the amyloid hypothesis, which basically runs as follows: Amyloid causes Alzheimer’s. Therefore removing existing amyloid and stopping its production in the future will cure it. Sounds pretty logical to me. So why haven’t we cured it ages ago? Because Alzheimer’s is far more complicated than just one simple cause/cure solution.

Yet, for some reason, researchers and pharmaceutical companies continue to cling to the amyloid hypothesis like dogma, despite decades of studies and clinical drug trials that have proven it doesn’t work.

“I don’t have to hedge or estimate when I tell you how many of the 200-plus experimental drugs have proven safe and effective enough in these trials — where effective means they have stopped the worsening or, even better, reversed Alzheimer’s disease — to be approved by the Food and Drug Administration. That number is zero,” Dr. Dale Bredesen, M.D., wrote in “The End of Alzheimer’s.”

The definition of insanity, as the saying goes, is repeating the same action over and over again, expecting different results. So many amyloid-removing drugs have been tried without success, and yet here we go again. I read in a recent CNN article that researchers are “cautiously optimistic” about a new drug that removes and prevents amyloid. Their test subjects, they claim, reported some cognitive improvement after the first phase of the study. But that’s only the first phase. In other words, they don’t know if the cognitive improvement will continue. I’ll venture a guess, and I’d even be willing to put some money on it: It won’t.

The article states the new test drug “is one of many potential drugs using ‘the amyloid hypothesis’ … . Various drug manufacturers have targeted beta amyloid by trying to stop its formation, train the immune system to kill it or remove it from the bloodstream and brain. Results to date had been poor.” The article then goes on to list drug trials that have crashed and burned, but later quotes Maria Carrillo, chief science officer for the nonprofit Alzheimer’s Association, saying, “The amyloid hypothesis remains an important therapeutic target to pursue in Alzheimer’s disease.” Really?

This is just my humble opinion, but maybe researchers need to start thinking a little more outside the box and, for Alzheimer’s at least, abandon the idea that “Big Pharm” will save us all — especially where amyloid beta is concerned. Instead of continuously painting amyloid beta as the be-all-to-end-all bad guy, let’s try looking at this protein from a different angle.

We’ve already discussed that amyloid beta is a sticky protein that accumulates in the brain, bringing on neuron death. Check. How does it form in the first place? According to The National Institute on Aging, it is created from the breakdown of a larger protein, amyloid precursor protein.

So what causes this breakdown to occur, bringing on amyloid beta’s formation? Now, that’s the question we need to be asking. In all my years of Alzheimer’s research, that question had never popped into my head, nor was it answered in any of the information I had found. The image of amyloid had only ever inspired in me something akin to “The Blob,” some terrible foreign mass that invades and destroys the brain. I had never realized the body was creating this mass and therefore had never thought to question why. That was until Bredesen posed that very question in “The End of Alzheimer’s.” In that moment, I actually put the book down, a little shocked. It was definitely a eureka moment for me.

“Neurons sport receptors called APP (amyloid precursor protein),” Bredesen wrote. “When APP grabs hold of a molecule called netrin-1 … it sends a signal to the neuron that keeps the neuron healthy and functional.”

When the environment in the brain does not support healthy function, when chronic inflammation or toxins are present or when hormones and nutrients are in short supply, netrin-1 becomes increasingly unavailable.

“When APP fails to grab netrin-1 and lacks proper trophic support, it defaults to a very different signal, telling the neuron to commit suicide,” Bredesen continued.

This suicide, believe it or not, is a defense mechanism. The neuron’s receive the signal that all is not well, so the lesser, “unnecessary” neurons begin to die off so all energy and protection can go to the more important parts of the brain — the brain stem, which controls heart rate, breathing, etc. — to help ensure survival.

The lack of netrin-1 also sets the stage for the APP receptors to be “cut,” creating the amyloid beta as a defense. Other APP receptors then start “grabbing” amyloid beta molecules instead of netrin-1, and this “unleashes a cascade of biochemical reactions,” Bredesen says, leading to more amyloid beta production. A vicious cycle is initiated.

According to Bredesen, amyloid precursor protein breaks down when an external threat to the neuron’s health and well-being is perceived. The resulting amyloid beta actually is a powerful defense mechanism — a “potent pathogen fighter,” Bredesen says — created to protect the brain from these toxic assaults.

“The amyloid that has been vilified for decades, the very amyloid that everyone has been trying to get rid of, is part of a protective response. No wonder trying to get rid of it hasn’t been very helpful to those with Alzheimer’s disease,” Bredesen wrote in “The End of Alzheimer’s.” “Contrary to the current dogma, therefore, what is referred to as Alzheimer’s disease is actually a protective response to, specifically, three different processes: inflammation, suboptimal levels of nutrients and other synapse-supporting molecules, and toxic exposures.”

A healthy brain, Bredesen says, responds to these three outside threats with amyloid beta, defeats them and goes on functioning as it should.

“The problem comes when those threats are chronic, multiple, unrelenting, and intense — so much so that these protective mechanisms cross the line into causing harm,” he wrote. “Therefore, to prevent and reverse cognitive decline, you must address potential infections, optimize your immune system’s ability to destroy pathogens, and reduce chronic inflammation that results from fighting these organisms for years.”

In other words, we need to focus on eliminating the threats to our health and stop trying to eliminate our natural defense mechanism to those threats.

The American health care system’s mainstream view is that sicknesses and injuries occur because the human body is a flawed, imperfect machine just counting the minutes until it begins to fall apart. I completely disagree. Except for cases of rare genetic mutations, the body is a fine-tuned, highly evolved machine. It doesn’t just turn against itself for no reason. Every single process in the body, right down the cellular level, happens for a good reason. However, the human body can only take so much abuse before things begin to spin out of control.

I believe we absolutely should support organizations like Alzheimer’s Association to help raise funds for the hard-working and brilliant researchers who continuously strive to unlock the secrets of Alzheimer’s and other diseases. But we can’t just stop there and leave the fate of our future — and even present — health in someone else’s hands. As they say, the buck stops here. To truly stop Alzheimer’s, every individual needs to stand up and say, “this is my body, and I’m going to fight for it.” Our fates are in our own hands, not in “Big Pharm” or in some cure-all pill.

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