It’s In Your Blood: A New Way to Detect Alzheimer’s
A blood test for brain-derived tau protein can change the way Alzheimer’s disease is diagnosed
Imagine a world where the familiar has become unfamiliar — family members are now strangers, and memories from years ago or even moments earlier easily escape you. For over six million Americans suffering from Alzheimer’s disease (AD), this is the daily reality caused by the physical degeneration of their brain.
While this is the sixth leading cause of death in the US, much is yet to be learned about the cause of the disease and how to diagnose it.
It used to be the case that Alzheimer’s could only be definitively diagnosed post-mortem, when researchers could physically look at the brain. Today, clinicians can make a diagnosis by testing a patient’s cerebrospinal fluid (CSF), the liquid found around the brain and spinal cord. However, this can be expensive and impractical.
What if Alzheimer’s could be diagnosed like so many other diseases — using a blood test?
ATN Framework
So far, several successful tests have been developed to help diagnose Alzheimer’s. These tests identify three biomarkers (molecules in the body that indicate disease): amyloid plaques, tau phosphorylation, and neurodegeneration. Using these biomarkers as a basis for diagnosis is called the ATN framework.
We have developed reliable tests for amyloid and tau phosphorylation, but at the time of this study, the test for neurodegeneration was not yet specific to Alzheimer’s. This meant that the ATN framework for diagnosing Alzheimer’s was incomplete.
Tau is a protein that helps neurons retain their structure, and can be found in neurons all over the body. It accumulates and forms tangles specifically in the brain during Alzheimer’s disease.
Measuring total tau (t-tau) levels in blood plasma has been suggested as a biomarker of neurodegeneration. However, the total amount of tau in the blood does not always reflect the amount of Alzheimer’s-causing tau protein in the brain.
Unlike with Alzheimer’s, some neurodegenerative diseases are caused by tau in the peripheral nervous system (nerves outside of the brain and spinal cord). Since t-tau shows the amount of tau in the central and peripheral nervous system, it can’t be used to make an accurate Alzheimer’s diagnosis.
Brain-Derived Tau Assay
In this study, researchers from the University of Pittsburgh set out to develop a test for brain-derived tau in the blood, in order to complete the ATN framework. The study was conducted with samples from over 600 patients.
They first identified that brain-derived tau (BD-tau) is structurally different from tau in the peripheral nervous system (PNS). Tau in the PNS has an extra exon, or coding region, in its genetic code.
Based on this observation, researchers used a monoclonal antibody that would specifically bind to the tau that didn’t contain the extra exon, thus only binding to BD-tau.
They then ran several tests to make sure that this assay, or procedure, could be reliably used to identify BD-tau.
- Dilution linearity: When the concentration of BD-tau was diluted, the amount identified by the test decreased by a proportional amount.
- Within-run and between-run validity: The test results were the same within a single run of the assay as well as when multiple measurements were taken.
- Spike recovery: A known amount of BD-tau was added, or “spiked,” to a sample. The test was conducted, and the measured and known amounts of BD-tau were compared.
Researchers also made sure that the BD-tau they measured in their blood test correlated with the amount of tau in the CSF. This confirmed that their test was specific to Alzheimer’s-causing tau, and not peripheral tau.
They also compared BD-tau levels in healthy control subjects without Alzheimer’s, and found that Alzheimer’s patients had a nearly 9-fold higher amount of BD-tau.
In brains where Alzheimer’s had been confirmed through an autopsy, BD-tau could distinguish AD from other neurodegenerative diseases.
Additionally, BD-tau levels were inversely correlated with scores on the Mini-Mental State Examination. This meant that as BD-tau levels increased, cognitive impairment increased.
Together with blood tests for amyloid plaques and tau phosphorylation, this test likely completes the ATN framework, making it simpler to test for Alzheimer’s and paving the way for further study of the disease.
