Antibodies Able to Detect Alzheimer’s Protein in Blood

Caption: The protein tau (green) aggregates abnormally in a brain cell (blue). Tau spills out of the cell and enters the bloodstream (red).
Research shows that antibodies (blue) can capture tau in the blood that reflects its levels in the brain.
Credit: Sara Moser

Age can bring moments of forgetfulness. It can also bring concern that the forgetfulness might be a sign of early Alzheimer’s disease. For those who decide to have it checked out, doctors are likely to administer brief memory exams to assess the situation, and medical tests to search for causes of memory loss. Brain imaging and spinal taps can also help to look for signs of the disease. But an absolutely definitive diagnosis of Alzheimer’s disease is only possible today by examining a person’s brain postmortem. A need exists for a simple, less-invasive test to diagnose Alzheimer’s disease and similar neurodegenerative conditions in living people, perhaps even before memory loss becomes obvious.

One answer may lie in a protein called tau, which accumulates in abnormal tangles in the brains of people with Alzheimer’s disease and other “tauopathy” disorders. In recent years, researchers have been busy designing an antibody to target tau in hopes that this immunotherapy approach might slow or even reverse Alzheimer’s devastating symptoms, with promising early results in mice [1, 2]. Now, an NIH-funded research team that developed one such antibody have found it might also open the door to a simple blood test [3].

Scientists know that tau loosened from abnormal tangles exits the brain and enters the bloodstream. Testing for the protein in blood has been extremely difficult because it disappears almost immediately. But the team has discovered that tau proteins bound to antibodies remain in the bloodstream much longer, allowing them to reach easily detectable levels. Importantly, they show that those blood levels of tau provide a good indication of abnormal tau levels in the brain. The discovery suggests a simple blood test for tau could one day be used to screen patients for early signs of tau-associated conditions, including Alzheimer’s disease and a brain injury known as chronic traumatic encephalopathy (CTE) that can affect football players and boxers who have suffered repeated concussions.

In a study published in Science Translational Medicine, the team led by David Holtzman at Washington University, St. Louis, showed that an infusion of its anti-tau antibody into people and mice causes blood levels of tau to rise within a day or two. In fact, during studies of three people with a rare neurodegenerative disease called progressive supranuclear palsy, they found that a single dose of antibody caused tau levels to remain high for up to 2 weeks.

Further study showed that the antibody increases blood levels of tau by stabilizing the protein and not allowing it to disappear so quickly. When tau alone was injected into the bloodstream, half of it vanished in less than 10 minutes. But when tau was injected along with the antibody, the protein remained in the blood for more than 3 hours. In other words, the antibody acts as a caretaker, making tau easier to measure by amplifying the time it stays in the bloodstream.

Of course, tau levels in the blood would only be useful if they provide an accurate indication of what’s going on in the brain. To find out, the researchers tested tau levels in mice with brain injuries. The injuries caused an increase in tau in the brain fluid that also appeared in their blood. Similarly, in mice genetically modified to develop less tau in brain fluid with age, the researchers found that blood levels of the protein indeed declined as the animals got older.

While lots of work remains to be done, Holtzman notes that the next logical step is to pair this promising new blood test with clinical trials to prevent or slow Alzheimer’s disease. One promising partner would be the Accelerating Medicines Partnership-Alzheimer’s Disease (AMP-AD) Biomarkers Project, which has brought together four pharmaceutical companies and NIH’s National Institute on Aging. AMP-AD is already incorporating tau imaging into trials of several promising therapies, and adding the blood test could be a powerful way to assess its clinical utility.

References:

[1] Anti-tau antibodies that block tau aggregate seeding in vitro markedly decrease pathology and improve cognition in vivo. Yanamandra K, Kfoury N, Jiang H, Mahan TE, Ma S, Maloney SE, Wozniak DF, Diamond MI, Holtzman DM. Neuron. 2013 Oct 16;80(2):402-14.

[2] Anti-tau antibody reduces insoluble tau and decreases brain atrophy.Yanamandra K, Jiang H, Mahan TE, Maloney SE, Wozniak DF, Diamond MI, Holtzman DM. Ann Clin Transl Neurol. 2015 Mar;2(3):278-88.

[3] Anti-tau antibody administration increases plasma tau in transgenic mice and patients with tauopathy. Yanamandra K, Patel TK, Jiang H, Schindler S, Ulrich JD, Boxer AL, Miller BL, Kerwin DR, Gallardo G, Stewart F, Finn MB, Cairns NJ, Verghese PB, Fogelman I, West T, Braunstein J, Robinson G, Keyser J, Roh J, Knapik SS, Hu Y, Holtzman DM. Sci Transl Med. 2017 Apr 19;9(386)

Sources:

About Alzheimer’s Disease: Diagnosis (National Institute on Aging/NIH)

Holtzman Lab (Washington University School of Medicine, St. Louis)

Accelerating Medicines Partnership (NIH)

NIH Workshop Report on the Trans-Agency Blood-Brain Interface Workshop 2016