A doctor points to results of a PET scan that are part of Alzheimer’s disease research. Much of the work in this area focuses on a substance called beta-amyloid. A new study could test whether this is the right target.

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A doctor points to results of a PET scan that are part of Alzheimer’s disease research. Much of the work in this area focuses on a substance called beta-amyloid. A new study could test whether this is the right target.

Evan Fauci/AFP

An idea that has driven Alzheimer’s disease research for more than 30 years is nearing its reckoning day.

Scientists have launched a study designed to make or break the hypothesis that Alzheimer’s is caused by a sticky substance called beta-amyloid. The study will give an experimental anti-amyloid drug to people under 18 who have the genetic mutations that often lead to Alzheimer’s disease in their 30s or 40s.

The study comes after several experimental drugs failed to prevent memory and thinking decline despite their success in removing amyloid from the brains of patients in the early stages of Alzheimer’s disease. These failures eroded support for the idea that amyloid is responsible for a chain of events that ultimately leads to the death of brain cells.

“A lot of us think this is the ultimate test of the amyloid hypothesis. If that doesn’t work, then nothing will work,” says Dr. Randall Pittman, professor of neurology at Washington University School of Medicine in St. Louis.

The new trial, called the DIAN-TU Primary Prevention Trial, is due to begin enrolling patients by the end of the year.

Explanation with history

The amyloid hypothesis can be traced back to Dr. Alois Alzheimer, the pathologist who first described the disease that would bear his name in 1906.

Alzheimer’s was working in a psychiatric clinic in Munich, where he had the opportunity to perform an autopsy on a woman who died at the age of 50 after suffering from memory loss, confusion and hallucinations. He noted that the woman’s brain suffers from an “unusual disease of the cerebral cortex,” including an “aging plaque” that typically appears in older adults.

In the 1980s, scientists showed that these plaques are made of beta-amyloid, a substance found in many forms in the brain, from free-floating molecules to the large clumps that make up the sticky plaques reported by Alzheimer’s disease.

Since this discovery, most efforts to treat Alzheimer’s disease have involved drugs that target different forms of amyloid. This approach still makes sense, Pittman says.

“We have 30 years of solid data, thousands of studies that all say this is enough to cause Alzheimer’s disease,” he says.

But doubts about the amyloid hypothesis are growing as the list of drug failures has grown in the past decade.

For example, Batman and a team of researchers were unable to stop Alzheimer’s disease in a study of patients who received the amyloid anti-amyloid drug gantenirumab.

“What we found was that it reversed amyloid plaques in their brains,” Pittman says. “We had no evidence of the benefit of thinking memory.”

However, Pittman and many other scientists believe that it is too early to abandon the amyloid hypothesis.

“Penicillin, a great achievement, failed in its first two clinical trials,” Pittman says. “Fortunately, people haven’t said, oh, the antibiotic theory is a bad idea and we should give it up.”

Helpful hints

Pittman was encouraged by the results of recent studies of anti-amyloid drugs, even those that did not prevent cognitive decline.

For example, Gantenerumab seemed to delay many of the brain changes associated with brain cell death, he says.

The experimental drug lecanemab appeared to slow memory loss and thinking in a study of nearly 1,800 people with early-onset Alzheimer’s disease, according to a statement from the drug’s manufacturer.

Many studies of anti-amyloid drugs may have failed because they were given to people who already had amyloid plaques in their brains. At this point, Pittman says, it may not be possible to stop the process that ultimately kills brain cells.

So Pittman is optimistic about the upcoming prevention trial, which will start treatment early.

“My expectation is that it will work, and it will work fantastically,” he says. “If we can really prevent the plaques from taking off and taking off and those changes downstream, my expectation is that these people will never have Alzheimer’s disease.”

The prevention study is based on the idea that when amyloid begins to build up, it causes a cascade of changes in the brain, says Dr. Eric McDaid, a professor of neuroscience at the University of Washington who will lead the trial.

These changes include the appearance of toxic tau tangles within neurons, loss of connections between neurons, inflammation, and eventually the death of brain cells responsible for thinking and memory.

“What we’re trying to do is prevent the development of amyloid diseases in the first place,” McDaid says.

However, this type of prevention means starting treatment long before symptoms appear.

“The moment someone develops symptoms, we now know they likely have had amyloid in their brain for a decade,” McDaid says.

So the four-year study will enroll about 160 people from families with autosomal dominant Alzheimer’s disease. This type of dementia results from rare, inherited gene mutations that cause Alzheimer’s disease to develop in middle age, often in your 30s and 40s.

“The earliest they can get to is 25 years before we can expect them to start showing symptoms,” McDaid says. “For most of these families, that puts them in their mid-20s when we start this experiment.”

Like the previous study that failed, this study will use the anti-amyloid drug gantenerumab.

The short-term goal is to make sure that no amyloid plaques develop. Next, researchers will look to see if this prevents other signs of Alzheimer’s disease from appearing on the brain.

One such sign is the presence of neurofibrillary tangles, a toxic version of a protein called tau that forms disorganized strands inside neurons. These internal tangles disrupt the cell’s ability to move chemicals and nutrients from one place to another and to maintain connections with other cells.

Another sign is cerebral atrophy, which is a shrinkage of one or more areas of the brain due to the loss of neurons and the connections between them.

“If we prevent the development of amyloid pathology and these other signs continue to develop and show up, that would be one of the best ways to say, and listen, amyloid isn’t really what we should be targeting,” McDaid says.

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