Because the new imaging technique followed plaque formation in detail over many days, it could address this chicken-and-egg conundrum as previous approaches could not. “When you only have single snapshots of the process, it’s hard to be sure how to interpret causation,” says Hyman.
Hyman’s team found that plaque formation was indeed the first step in the process, with amyloid-beta protein depositing into an aggregate that appeared quickly and continued to grow. Next, immune cells called microglia were activated and flocked to the area. In the ensuing days, a halo of damage began to appear around the plaque. Nearby neurons became distended and twisted into abnormal, corkscrew-like shapes, likely hampering their ability to transport critical cell components and communicate with one another.
“The bottom line,” says Troncoso, “is that this study establishes that at least in the mouse, the plaque is the first step.” This kind of investigation would not be possible in humans for ethical reasons, and there’s no guarantee that the mechanism observed in mice is the same one that takes place in the brains of human Alzheimer’s patients. But Troncoso says that the results are relevant nonetheless. “These animal models are our best available tool to try to understand these types of processes,” he says.
Finkbeiner agrees that Hyman’s results implicate amyloid plaques as the instigators of the neural damage that surrounds them. “I think this study clearly establishes that the dystrophy that you see in association with plaques does occur after the plaque forms,” he says. But he contends that there is still no powerful evidence that such damage is to blame for the primary symptoms of Alzheimer’s.
“I don’t doubt for a minute that dystrophy does have deleterious consequences for the neurons involved,” says Finkbeiner. “But it probably doesn’t explain the majority of symptoms that people get with Alzheimer’s disease.”
Hyman maintains that the local damage associated with plaques could very well underlie the systemic disruption in neural function that characterizes the disease. “Ultimately, the types of changes that we see, I think, lead to a breakdown in the connections of the brain,” he says.
If that is the case, preventing amyloid buildup is likely to be a key strategy in treating Alzheimer’s. According to Troncoso, since the study “strongly suggests that amyloid is a very early event in the development of Alzheimer’s disease, the corollary would be that it becomes the therapeutic target of choice.”
Hyman plans to probe the plaque formation process in more detail, investigating how the amyloid-beta protein develops into a full-blown plaque, and how it brings about the observed changes in neighboring neurons.