With the recent approval of two for Alzheimer’s disease, hope is growing for those at risk. However, diagnostic tests still need improvement. Earlier diagnosis would allow individuals to benefit from the drugs sooner, when they are most effective.
Current detection methods are challenging. Brain scans like PET scans can detect amyloid plaques, protein clumps indicative of the disease, but these appear after brain function has already declined. These scans are also costly and not universally available. Analyzing spinal fluid can offer more sensitive detection of amyloid and tau, another related protein, but requires a spinal tap, which is painful and potentially risky. Blood tests for these proteins are under expedited review by the FDA but have not yet been approved.
A new published in Nature Medicine details promising results from a blood test developed by researchers at Washington University in St. Louis. This test targets a different form of tau than existing tests, which they believe is a better indicator of the amount of damaging protein buildup in the brain and correlates with disease severity. Comparing the blood test results to brain scans, the team found the blood test to be 92% accurate in measuring tau levels.
Dr. Randall Bateman, professor of neurology at Washington University and the paper’s senior author, emphasizes that both amyloid and tau proteins must be present to diagnose Alzheimer’s. Amyloid plaques develop over years, and symptoms like memory loss and confusion only appear once sufficient clusters have formed. After amyloid aggregates form, tau begins to develop abnormally inside and outside brain neurons.
Outside the cell, tau forms phosphorylated tau, which current tests can detect. However, inside neurons of Alzheimer’s patients, tau breaks down further, becoming crystallized and forming tangled protein structures instead of the neat, linear forms seen in healthy individuals. “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 explains that this crystallized form of tau is more strongly linked to the cognitive decline associated with Alzheimer’s. Detecting early signs of this form could help doctors identify patients at risk of developing more severe memory and cognitive issues. “This is the first report of a tau tangle marker in the blood,” he states.
In 2023, Bateman and his team developed the for this crystallized tau form, but it required spinal fluid. Due to the inconvenience and risks of spinal taps, they shifted focus to finding the same crystallized tau signs in blood. After extensive screening of blood markers, they succeeded. “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 C2N Diagnostics to manufacture and provide the test for clinical trial research. This blood-based test could accelerate the development of anti-tau treatments for Alzheimer’s, enabling drug developers to quickly assess a compound’s effect on tau buildup with a blood sample. “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.”
An accessible method for tracking tau levels could also reveal new insights into Alzheimer’s progression and potential drug targets.
The relationship between phosphorylated tau outside neurons and crystallized tau inside cells is still unclear. It’s possible that phosphorylated tau buildup triggers the formation of destructive crystallized tau inside neurons. Another unknown is why certain crystallized tau fragments exit nerve cells. Understanding this process could lead to new strategies for controlling tau and slowing disease progression. “If we want better treatments for patients,” says Bateman, “then we have to understand what causes the disease.”
