A quarter century after scientists proposed an idea that profoundly influenced the arc of Alzheimer’s research, they might finally find out whether they are correct. A new antibody drug called aducanumab appears to sweep the brain clean of sticky amyloid-beta protein. The drug may or may not become a breakthrough Alzheimer’s treatment — it’s too soon to say — but either way it will probably answer a key question: Have researchers been aiming at the right target?
According to the proposal, called the amyloid hypothesis, Alzheimer’s disease, estimated to affect more than 5 million people in the United States alone, is caused by abnormal buildup of A-beta protein in the brain. The buildup chokes vital brain areas and destroys nerve cells. Despite amassing much support in recent decades, the proposal hasn’t managed to shake off its detractors. Aducanumab offers a seemingly reliable and safe way to lower A-beta levels and thus test the amyloid hypothesis.
Over the course of a year, aducanumab entered the brains of people with early Alzheimer’s disease and cleared out the A-beta, scientists reported in September in Nature (SN: 10/1/16, p. 6). The trial was small — only 165 people. Yet in these people’s brains, amyloid-beta clearly declined. The higher the dose, the more A-beta cleanup.
There were hints that people on higher doses of the drug had cognitive improvements, too. If confirmed in larger studies, those cognitive benefits “would be a game changer for the field,” says Alzheimer’s researcher Eric Reiman of the Banner Alzheimer’s Institute in Phoenix. But those results “need to be treated agnostically for now,” at least until the larger studies currently under way are completed, he cautions.
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There is already strong evidence that A-beta is a disease culprit: Rare genetic mutations in genes related to A-beta almost always come with Alzheimer’s, an observation that has been confirmed in mice. A-beta is toxic to nerve cells in dishes, damaging their communication abilities before eventually killing the cells outright. “All the basic science work and natural history work supports it,” says neuroscientist John Hardy of University College London, who is among those who proposed the amyloid hypothesis.
Yet contradictions exist. Cognitively healthy people have been found with A-beta accumulation in their brain (SN: 12/10/16, p. 13). And so far, scientists have found only a weak correlation between A-beta plaques and cognition, results that have led some scientists to look elsewhere — to inflammation, overzealous pruning of brain cell connections called synapses and changes to the protein tau, which is known to accumulate inside nerve cells in people with Alzheimer’s. Each of these cellular processes has also been implicated as a driver of the disease.
Identifying the true cause of Alzheimer’s is difficult because all of these processes are closely related and occur simultaneously, making it nearly impossible to study their effects in isolation. What’s more, many of the key changes might happen years, or even decades, before symptoms begin to appear. Hardy concedes that in the years since he and others introduced the amyloid hypothesis, scientists have struggled to put together a full picture of Alzheimer’s. “It is tougher than we all thought it would be,” he says.
There won’t be clear answers for several years yet. In August of 2015, larger clinical trials of aducanumab began enrolling patients around the world with the goal of finishing by 2022. As more people with Alzheimer’s are tested, researchers hope to see obvious signs of mental improvement that track reductions in brain A-beta. It’s possible that aducanumab will lower A-beta in the brain yet fail to bring meaningful improvements in symptoms. Such a result might appear to be a strike against the amyloid hypothesis, a contradiction that could prod some researchers to explore other ideas more deeply. Either way, people with Alzheimer’s and their loved ones are waiting anxiously.
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