Tag Archives: clinical trials

The Villain of Alzheimer’s Disease Could Actually Be a Hero

The toxic amyloid-beta protein has long been considered the cause of Alzheimer’s disease–but what if it’s actually been a hero all along?

If you were to look inside the brain of someone with Alzheimer’s disease, you’d immediately see that something has gone terribly wrong. The first thing you’d notice is that it’s much smaller than a healthy brain, appearing shriveled up like a raisin. Upon closer examination, you’d see that the brain is filled with large, dark clumps of protein. That protein, called amyloid-beta, can stick to itself and form toxic aggregates that poison the brain from within. Your first instinct would probably be the same as most scientists: in order to cure Alzheimer’s disease, we need to get rid of these amyloid-beta clumps.

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Artistic rendition of amyloid-beta plaques surrounding neurons in the brain. Image Source

It’s a reasonable assumption. These clumps of amyloid-beta, formally known as senile plaques, are among the most recognizable hallmarks of Alzheimer’s disease, and they’re toxic to brain cells in high doses. So it makes sense to think that getting rid of them will be the key for curing Alzheimer’s.

For three decades now, that’s exactly what scientists have been trying to do. They created drugs that targeted and destroyed amyloid-beta, or prevented it from being formed in the first place. They invented vaccines to help our own immune systems recognize amyloid-beta, and inhibitors that stopped amyloid-beta from sticking together to form toxic clumps. Yet, despite hundreds of scientists and billions of dollars devoted to the research, these efforts failed. Of the more than 200 drug candidates for Alzheimer’s disease that have reached clinical trials in the past 30 years, not a single one successfully cured the disease or slowed its progression. The drugs currently on the market for Alzheimer’s disease offer some patients a small improvement in their cognitive symptoms, but since they do not treat the underlying pathology, their effects are temporary and they cannot prevent the patient’s deterioration.

Even worse than the poor efficacy of these drugs were the severe side effects they often created. Many patients involved in these trials developed a condition called Amyloid-Related Imaging Abnormalities (ARIA), which results from leaky blood vessels bleeding into the brain. Other patients experienced dangerous infections or skin cancer, and a few even saw their cognition decline faster than patients who weren’t taking the drug at all.

The disastrous results of these clinical trials have shaken the field of neuroscience to its core. A few companies, including the pharma giant Pfizer, have even given up their Alzheimer’s research programs entirely. Yet I would argue that there is still hope for a cure to Alzheimer’s disease, and it lies by viewing the toxic amyloid-beta protein in a new light. In fact, I think that amyloid-beta might actually turn out to be a powerful ally in the fight against Alzheimer’s.

The Evolutionary Riddle of Amyloid-Beta

I’m a geneticist by training, and that means I think a lot about evolution. And so the first question that came to my mind when I first learned about amyloid-beta was, why do we have it in the first place? After all, the core premise of natural selection is that harmful traits tend to disappear from a population over evolutionary time. If amyloid-beta is nothing more than a toxic substance that makes us sick, then we’d expect it to become rarer as our species evolved, and eventually disappear completely.

Yet when you actually look at the data, the opposite seems to be true. In fact, every vertebrate species (including mammals, birds, and reptiles) produces a version of amyloid-beta that’s almost identical to our own. It’s even been found in sea anemones and hydra, meaning that amyloid-beta has been around for at least 600 million years.

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The hydra, a tiny invertebrate often found in ponds, has its own version of amyloid-beta. This suggests that the protein has been remarkably conserved across evolutionary time. Image Source

From an evolutionary perspective, this makes no sense. Why would a toxic, harmful protein have been conserved for so many years across such diverse species? The most likely explanation is that there’s more to amyloid-beta than meets the eye. Specifically, it must be serving some kind of beneficial purpose that’s caused it to be maintained for so long.

The idea that amyloid-beta could actually serve some kind of biological function was originally met with controversy, but as more evidence has emerged, the scientific community has begun to accept this shift in view. In fact, the more we look at amyloid-beta, the more functions we seem to uncover.

The Hero We Never Knew We Had

The beneficial roles of amyloid-beta have become something of a fascination for me. One of its coolest functions is within the immune system. Amazingly, the properties that allow amyloid-beta to aggregate into toxic clumps in the brains of Alzheimer’s patients can also be used to trap harmful microbes, preventing them from spreading. Once the microbes are stuck, amyloid-beta can kill them by tearing holes in their cell membranes. In fact, amyloid-beta’s chemical properties suggest that it’s part of a family of immune proteins called antimicrobial peptides, which all utilize a similar manner of clumping and ripping microbes to protect the body from infection.

In addition to its role in the immune system, amyloid-beta has many other functions. Some research suggests that it may suppress the growth of cancer cells, which could explain why people with Alzheimer’s disease tend to have a lower risk of developing cancer. Others propose that amyloid-beta could help prevent leaks in the brain’s blood vessels by clumping into a kind of “scab” that restricts bleeding. It also seems to be helpful in recovery from neuronal injuries, as mice that are unable to produce amyloid-beta have worse outcomes from traumatic brain injuries, spinal cord injuries, strokes, and even multiple sclerosis. Finally, recent evidence has suggested that amyloid-beta helps to regulate the signaling activity of neurons, which is extremely important for learning and memory.

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This figure, adapted from our recent publication in Frontiers in Aging Neuroscience, summarizes some of amyloid-beta’s possible roles in human biology.

In light of amyloid-beta’s newly-discovered functions, the side effects that occurred in Alzheimer’s clinical trials begin to make more sense. By removing amyloid-beta from the patients’ brains and bodies, these drugs may have inadvertently led to ARIA, infections, and other harmful outcomes.

A New Dawn for Alzheimer’s Research

So what do the beneficial roles of amyloid-beta mean for the future? Well, if the last 30 years of clinical trials tell us anything, it’s that our current approaches aren’t working, and the functions of amyloid-beta may explain why.

Of course, the fact remains that amyloid-beta is toxic to neurons, and it tends to accumulate within the brains of Alzheimer’s patients. But I would argue that getting rid of amyloid-beta outright is not the answer. Instead, we need to consider what might have caused it to start accumulating in the first place.

For example, maybe the amyloid-beta clumps are actually a protective barrier surrounding infectious microbes that have infiltrated the brain, or a scab that prevents blood from leaking into the brain. As we get older, brain infections and leaky blood vessels become more common, which might explain why amyloid-beta levels tend to increase over time. Perhaps after a certain threshold, the amyloid-beta that’s responding to these issues becomes more harmful than helpful to the brain. It’s doing its job too well–there are too many microbes or leaky blood vessels for amyloid-beta to clump around without its toxic properties damaging the brain in the process.

We can’t just get rid of amyloid-beta at this stage, because then the microbes or vascular leaks that it was protecting us from in the first place will be left unchecked. Instead, we need to first treat the underlying cause of the problem. Only once that has been resolved can we then go back with anti-amyloid-beta drugs and remove the toxic clumps from patients’ brains.

I want to be entirely clear here: at this point, everything I’ve said in this last section is pure speculation. We don’t know if all amyloid-beta plaques are caused by some other factor, or whether resolving that factor will make our drugs more effective. However, a few early studies have provided tantalizing hints that this hypothesis may be correct. For example, one study found that among Alzheimer’s patients who were infected with H. pylori, a common type of bacteria that causes stomach ulcers, treating this infection with antibiotics resulted in a 65% lower risk of Alzheimer’s progression after one year.

The study of amyloid-beta’s biological functions is still in its infancy, and we have a lot to learn about the true role that it plays in Alzheimer’s disease. But if additional research can confirm that amyloid-beta is a side effect of the disease instead of its root cause, it could usher in a new age of Alzheimer’s research and bring us one step closer to finding a cure.

 

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New Alzheimer’s Drug Shows Promise in Clinical Trials

One of the main hallmarks of Alzheimer’s disease is the accumulation of toxic protein clumps called amyloid-beta plaques inside the brain (for more detail see Alzheimer’s Disease: A General Overview). For the past several decades, the predominant theory among neuroscientists has been that these plaques are the main cause of the disease, and that removing them is the key to a cure. This is known as the amyloid cascade hypothesis.

A recent study published in Nature, one of the world’s premier scientific journals, reported promising results from a phase 1b clinical trial of a new drug called aducanumab. This drug works by selectively targeting amyloid-beta aggregates and marking them for destruction by the body’s immune system, an approach known as immunotherapy. The researchers demonstrated using mice that the drug is able to penetrate the blood-brain barrier and reduce levels of amyloid-beta plaques.

Various doses of the drug were injected into patients with mild Alzheimer’s disease once per month for one year. PET scans showed that the 125 subjects who completed the trial had reduced amyloid-beta levels in their brains compared to controls who were given a placebo. This reduction was enhanced the longer the drug was administered and the higher the dose. The subjects given the drug also had higher scores on tests of cognitive function. Notably, the drug slowed but did not prevent or reverse cognitive decline in these subjects, and the effects varied substantially based on the dosage.

Dozens of previous immunotherapeutic drug candidates for Alzheimer’s disease have failed early in clinical trials, and so these positive results are very exciting. However, this drug is far from being declared a cure, and there are several important caveats to keep in mind.

Problematic side effects have plagued Alzheimer’s drug trials for decades, and unfortunately this one was no exception. Nearly 25% of the subjects withdrew from the trial due to side effects, which included headache, urinary tract infection, upper respiratory infection, and an interesting phenomenon known as amyloid-related imaging abnormalities (ARIA). ARIA are small abnormalities that appear on MRI scans and are believed to be the result of cerebral microhemorrhages (“mini-strokes”). ARIA is a common side affect of amyloid-beta immunotherapy and is considered to be a serious condition. 41% of subjects given the highest dose of aducanumab experienced ARIA, compared to zero controls. Several subjects were also diagnosed with another type of serious hemorrhaging called superficial siderosis of the central nervous system. No deaths due to side effects were reported.

Additionally, it’s important to note that all of the subjects in the study were only in the earliest stages of Alzheimer’s disease, so it’s not clear how well this drug will work with patients in later stages. The trial was also relatively short-term and only in phase 1b. It’s not uncommon for drugs to succeed in early clinical trials but fail when they reach the final phase 3 trials, which is was happened with a promising Alzheimer’s drug candidate earlier this year.

The final point I want to make is that the success of aducanumab hinges on the amyloid cascade hypothesis being correct. The theory was considered dogmatic for years, but lately it has been experiencing scrutiny, due in large part to the discovery that nearly 1 in 3 elderly people have high levels of amyloid-beta in their brains despite being cognitively normal (for a deeper look at this controversy, see Where’s our cure to Alzheimer’s disease?). Though the majority of mainstream neuroscientists still support the amyloid cascade hypothesis, it’s important to keep its criticisms in mind. The scientific community will wait with bated breath for the drug’s phase 3 trial results.

 

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