When doctors suspect Alzheimer's, they can order a blood test to learn whether a patient's brain contains the sticky amyloid plaques that are a hallmark of the disease.
But the results of that test won't tell the whole story, says Dr. Randall Bateman, a neurology professor at Washington University in St. Louis.
"People can have a head full of amyloid, but no dementia or memory loss," Bateman says.
So he and a team of scientists have developed a new blood test that can show whether Alzheimer's has actually begun to affect a person's thinking and memory.
It joins another new test, this one of spinal fluid, that can predict whether the brain changes associated with Alzheimer's are likely to affect cognitive function.
"It's a strong indicator of memory impairment," says Tony Wyss-Coray, a neurology professor at Stanford University.
Both tests, described in the journal Nature Medicine, could help doctors identify patients who are likely to benefit from drugs that can clear the brain of amyloid plaques. Both were developed with funding from the National Institutes of Health.
Looking beyond amyloid
The blood test is the result of a search for better Alzheimer's biomarkers — measurable substances in the body that indicate the presence of a disease.
Bateman and his team had been studying tau tangles, the abnormal clumps of protein that form inside the neurons of people with Alzheimer's. These tangles are considered a hallmark of the disease, along with amyloid plaques.
The team noticed that one region of the tau protein seemed to play a critical role in damaging neurons and causing memory loss. And they found a biomarker for this region called MTBR-tau243.
Compared with biomarkers of amyloid plaques, MTBR-tau243 "was much more related to memory loss, symptom onset, dementia stage, all the things that patients care about," Bateman says.
At first, the team had to use spinal fluid to reliably measure levels of the new biomarker. But eventually, they developed a test that could use blood samples.
The blood test indicates how much abnormal tau is in a patient's brain, Bateman says, "and it only goes up when people are symptomatic."
When the test becomes available commercially, Bateman says, it will give doctors a fast and easy way to tell whether the amyloid plaques sitting in a patient's brain are actually affecting their memory and thinking.
It will also indicate whether Alzheimer's has progressed past the point where drug treatment is likely to help, he says.
"We can now make a much more informed choice about: How much benefit are you likely to get if you undergo a treatment to remove the amyloid plaques?" Bateman says.
A measure of synapses
Another new test, this one of spinal fluid, comes from a team led by Wyss-Coray of Stanford.
He says they set out to answer a simple question related to aging: "Can we find proteins that change if a person's memory is not working well?"
The team studied more than 7,000 proteins in the spinal fluid of more than 3,000 people. Two proteins emerged as potential biomarkers.
Levels of one protein rose dramatically in people with memory problems, while levels of the other fell sharply.
"So we made a ratio between the two, and that ratio turns out to be a very good indicator of whether a person's memory is OK or not," Wyss-Coray says.
The ratio also could be used to predict eventual memory loss in people who have a genetic predisposition to Alzheimer's.
"In these individuals, [the ratio] goes up 10 to 20 years before they get the actual disease diagnosis," Wyss-Coray says, because that's when the first subtle signs of cognitive impairment appear.
Both proteins in the test are involved in regulating synapses, the connections between neurons, says Dr. Paul Worley, a professor of neuroscience at Johns Hopkins University. So it makes sense that levels of these proteins change when Alzheimer's begins to affect brain function.
"The exciting thing here is that this is a process that seems to anticipate the development of cognitive decline 10, 20, 30 years later," Worley says. That means it should be possible to start treatment long before symptoms of Alzheimer's start to appear, he says.
Worley was part of a team that showed how the loss of one of the two proteins used in the test disrupts synapses and leads to memory loss in Alzheimer's. His team also found that people could remain cognitively normal despite amyloid plaques so long as their brains had normal levels of this protein.
The importance of synapses in Alzheimer's suggests that preserving their function — perhaps by increasing levels of this protein — could be one way to treat or prevent the disease, Worley says.
"The fundamental biology supports that," he says.
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