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With two new treatments for Alzheimer’s disease approved in recent years, there’s growing hope for people at risk of the memory-robbing condition. But tests to detect the condition still lag behind. Earlier diagnosis would mean that people could take advantage of the drugs sooner, when the medicines are most effective.
Detection is currently tricky. Brain scans like PET can pick up amyloid plaques, the clumps of protein that are the hallmark of the disease, but by the time these form, people’s brain function is already declining. The scans are also expensive and not available at all hospitals. More sensitive ways to detect amyloid and tau, another protein related to the disease, are possible by analyzing spinal fluid, but that requires a painful and potentially dangerous spinal tap. Blood tests for the two proteins have not yet been approved by the U.S. Food and Drug Administration—although they have received breakthrough designation from the agency, which means they are getting expedited review as studies of the tests are completed.
In a new study published in Nature Medicine, researchers led by a group at Washington University in St. Louis report promising results of a blood test they developed to detect a different from of tau than the one that existing tests target. This form, they say, is a better indicator of how much of the damaging protein has built up in patients’ brains—and those levels correlate with the severity of a person’s disease. By comparing the results from the blood test to those from brain scans, the team determined that the blood test was 92% accurate in its readings of tau.
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Dr. Randall Bateman, professor of neurology at Washington University and senior author of the paper, says that the presence of both amyloid and tau proteins in patients’ brains is essential to diagnosing Alzheimer’s. Amyloid plaques take years to develop, and it’s not until sufficient clusters of the protein have formed that symptoms like memory loss, confusion, and disorientation occur. Once amyloid aggregates form, then tau starts to develop abnormally both inside and outside of brain neurons.
Outside of the cell, tau forms what scientists call phosphorylated tau—what current tests can detect. But inside of brain neurons, tau in Alzheimer’s patients breaks down further, and instead of adopting neat, linear forms as it does in people without Alzheimer’s, it becomes crystalized and forms a mess of protein resembling tangled yarn. “Tau tangles are most associated with a person’s dementia symptoms,” says Bateman. “Plaques are like the fuel driving a lot of changes that we observe [in patients] over time. But not until the fire ignites, with the spread of tau tangles, does the brain really fall apart.”
He says that the crystalized form of tau is more strongly linked to cognitive decline associated with Alzheimer’s, so detecting the first signs of this form of tau would help doctors to identify patients on the brink of developing more severe memory and cognitive problems. “This is the first report of a tau tangle marker in the blood," he says.
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In 2023, Bateman and his team developed the first test for this crystalized form of tau, but in the spinal fluid. Because of the inconvenience and risk of spinal taps, the team then focused on looking for the same telltale signs of crystalized tau in the blood. After tediously screening a variety of blood markers, they finally found it. “We went through molecule by molecule, atom by atom, looking for the exact structure of the forms of tau that [we knew] existed, and then discovered the form that was uniquely identified with the presence of tangles.”
Bateman founded a company, C2N Diagnostics, to manufacture and provide the test to researchers for use in clinical trials. The blood-based test could speed development of anti-tau treatments for Alzheimer’s, since drug developers can fairly quickly determine whether a compound they are testing is having any effect on the amount of tau building up in a patient’s brain from a vial of blood. “A lot of us think that if we can slow down or reverse the formation of tau tangles, then it’s a good strategy to slow down or reverse Alzheimer’s,” says Bateman. “[The test] can accelerate how quickly new treatments are developed.”
Having a relatively easy way to track tau levels in Alzheimer’s could also provide new clues about how the disease progresses, and potentially provide new targets for drugs.
It’s not clear yet how the phosphorylated forms of tau that exist outside of neurons are related to the crystalized forms that cells generally harbor inside, but it’s possible that at some point, the buildup of phosphorylated tau triggers the formation of destructive crystalized tau inside neurons. Another unanswered question is why some fragments of the crystalized tau make their way outside of the nerve cells. Understanding that process could lead to new strategies for controlling tau and perhaps slowing the progression of the disease. “If we want better treatments for patients," says Bateman, "then we have to understand what causes the disease."
