For decades, scientists have known that Alzheimer's disease is accompanied by the buildup of clumps of amyloid protein between brain cells. Could these plaques be causing the disease?
That's been a prevailing theory driving Alzheimer's research for years. But a new study suggests the strategy could be wrong.
Amyloid may not come first
Researchers reporting in the journal Neurology have found that early declines in memory and thinking seen in Alzheimer's patients tend to occur before amyloid plaques begin to appear in the brain, not after.
"Our research was able to detect subtle thinking and memory differences in study participants and these participants had faster amyloid accumulation on brain scans over time, suggesting that amyloid may not necessarily come first in the Alzheimer's disease process," study author Kelsey Thomas explained in a journal news release.
"Much of the research exploring possible treatments for Alzheimer's disease has focused on targeting amyloid, but based on our findings, perhaps that focus needs to shift to other possible targets," said Thomas, who conducts research at the VA San Diego Healthcare System.
This isn't the first indication that amyloid plaques might not cause Alzheimer's disease.
In April, clinical trial data on an experimental Alzheimer's drug called verubecestat was published in the New England Journal of Medicine. The drug reduced amyloid plaque levels in patients' brains and spinal fluid.
However, despite those reductions, patients showed no easing or slowing of their disease.
Those negative results present "pretty strong evidence that amyloid-lowering is the wrong target," Dr David Knopman, a professor of neurology with the Mayo Clinic in Rochester, Minnesota, said at the time. "They hit the target and yet people got worse, consistently worse, both in terms of brain structure and brain cognition," he added.
Similar poor results were seen with another amyloid-focused drug, aducanumab. Studies on the drug were halted earlier this year because it didn't appear to be effective. However, in December it was announced that research into aducanumab might resume.
In the new study, Thomas and her team tracked the neurological health of 747 people, average age 72 years. Everyone got a barrage of tests to spot and follow any changes – even subtle ones – in their memory and thinking skills.
Based on test results, 305 people were deemed to have normal thinking and memory skills, 153 had very subtle thinking and memory differences, and 289 people had mild cognitive impairment – often a precursor to Alzheimer's disease.
The participants also underwent high-tech brain scans at the beginning of the study and then yearly scans over the next four years, looking for signs of amyloid plaque buildup.
The investigators found that amyloid plaque accumulation occurred no faster in people with mild cognitive impairment than it did in people with normal thinking and memory skills.
Other brain changes were seen in conjunction with mild cognitive impairment, however, such as faster thinning of the brain's entorhinal cortex, as well as brain shrinkage of the hippocampus. Both brain regions are key to memory.
And there could be another culprit at work in Alzheimer's development, Thomas said.
"From prior research, we know that another biomarker of Alzheimer's disease, a [brain] protein called tau, shows a consistent relationship with thinking and memory symptoms," she said. "Therefore, more research is needed to determine if tau is already present in the brain when subtle thinking and memory differences begin to appear."
The study might lead to a better way to calculate a person's risk for Alzheimer's, Thomas added.
Numerous other factors
"Our study demonstrated a method to successfully detect subtle differences in thinking and memory either before or during the phase when amyloid is accumulating at a faster rate," she explained. "This could lead to non-invasive screenings that may be able to detect very early who is at risk of developing Alzheimer's disease."
One neurologist unconnected to the new study agreed that it helps point to new and potentially fruitful avenues of research.
The thinking that amyloid plaque buildup "leads to clinical problems is no longer a valid one, as this study demonstrates," said Dr Gayatri Devi, a neurologist and psychiatrist at Lenox Hill Hospital in New York City.
"Subtle symptoms accompanying or even preceding brain pathology suggest that numerous other factors are involved in the complex risk mixture that leads to Alzheimer's disease," Devi said.
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