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Alzheimer's blood test shows promise

“A new technique could lead to a blood test for detecting Alzheimer’s,” BBC News has reported.

This news story is based on research that has developed a new method to screen blood for antibodies, a range of proteins that the body creates in response to specific diseases. The technique involved passing blood samples over special slides coated with a synthetic substance designed to identify antibodies found only in people with a specific disease. Researchers first refined the test in mice and then focused on Alzheimer’s disease in humans. They found that there were raised levels of two antibodies in the blood of 16 people with Alzheimer’s disease but not in 14 unaffected people.

This promising technique may eventually lead to blood tests for conditions such as Alzheimer’s disease. However, this research is in its early stages and now needs testing in much larger groups of people to confirm that these two antibodies are actual markers of Alzheimer’s. Additionally, the study did not determine at what point in the disease levels of these antibodies become raised, so we cannot presently tell if it can detect early-stage Alzheimer’s disease.

Where did the story come from?

The study was carried out by researchers from the Scripps Research institute in Florida and was funded by the US National Institutes of Health. It was published in Cell,peer-reviewed scientific journal.

This research was generally covered adequately by the media, with most newspapers highlighting the preliminary nature of the research. However, as yet, the researchers have not determined how early in the course of Alzheimer’s disease the antibody changes could be detected. At present, it is not possible to say whether this test would be able to detect Alzheimer’s disease any earlier than current diagnostic tests, as some newspapers have prematurely suggested.

What kind of research was this?

When the body mounts an immune response to disease or infection, it may produce antibodies. These are specific proteins that help the body neutralise the threat it has encountered. Once antibodies are created to deal with a specific illness or substance, the body can easily reproduce them if exposed again. This is why previously having an illness or receiving a vaccination can provide increased immunity. Substances that cause us to produce antibodies are called antigens, and can include proteins, foreign cells and bacteria.

This laboratory study developed a potential method to screen for the immune response to various diseases using slides covered in special synthetic chemicals, which would show the presence of antibodies consistent with specific diseases. The technique was then tested to determine whether it could find a difference in the antibodies produced by people with Alzheimer’s disease and by healthy control subjects. Usually, diagnosis of Alzheimer’s disease requires a series of cognitive tests and the exclusion of other causes through brain imaging. It can only be confirmed by looking at changes in the brain after death.

To find antibodies that may be relevant to diseases, researchers currently use libraries of antigens. By passing blood over these, they can detect whether an individual has relevant antibodies as these will bind to the appropriate antigen. However, when screening for new antibodies that may be produced in a particular disease, this approach is not especially useful as the antigens being screened for are selected based on the likelihood that they play a role in the disease. Additionally, some proteins involved in different diseases are normally produced by the body, meaning the body would not have produced any antibodies against them. However, if normal proteins undergo changes to become the “disease form” of the protein, this may trigger an immune response.

To search for antibodies, the researchers used unnatural synthetic molecules called “peptoids”. These peptoids can form shapes that cannot be made by normal unmodified proteins but may mimic some aspects of the shape of disease proteins, allowing them to bind to antibodies specifically created in response to certain diseases.

What did the research involve?

The researchers made 4,608 synthetic peptoids of varying shapes and fixed their position on microscope slides. They then took blood from a mouse that had been treated with chemicals to make it develop symptoms resembling multiple sclerosis (MS). MS affects the nervous system, in which an immune response is thought to contribute to the disease’s progression.

The blood was passed over the microscope slide so that the antibodies in the blood could bind to the peptoids. The researchers then used a secondary antibody, which would bind to any mouse antibodies that had bound to the various peptoids on the slide. The secondary antibody was fluorescent so it could be visually detected.

The researchers used this initial experiment to optimise the concentration of blood and to find some peptoids that had bound antibodies. They then used the slides to compare blood from the mice with MS to blood from normal, control mice. If there were areas on the slide where bonding had occurred using MS mouse blood but not control mouse blood, it might indicate antibodies that were specifically produced in response to the MS-like condition.

The researchers then continued their experiments in humans, looking at whether they could see a difference between blood samples from people with Alzheimer’s disease and those of healthy elderly people. They took stored blood samples from six people with Alzheimer’s disease (three of whom had had their Alzheimer’s confirmed following autopsy) and six age-matched, healthy controls. The researchers passed the blood samples over a slide containing 15,000 peptoids. To make sure that any result was specific for Alzheimer’s disease, they also analysed six samples from people with Parkinson’s disease.

After using the screening technique to initially to find peptoids that bound antibodies from people with Alzheimer’s but not controls, the researchers repeated the test in an additional 16 Alzheimer’s samples, 14 controls and six people with lupus (an immune disease).

What were the basic results?

In the mouse model of MS, the researchers found that an antibody binding to three peptoids, which they named AMogP1-3, could differentiate between healthy mice and mice with MS-like symptoms. They were able to determine that the antibody that bound to the AMogP1-3 peptoids was the antibody that bound to a protein called Mog. Injection with the Mog protein had been used to cause MS symptoms in the mice. This was a proof of concept that use of an unnatural molecule could confirm the presence of an antibody that recognises a disease-triggering protein.

For the Alzheimer’s screening, the researchers chose three spots on the slide which had the greatest fluorescent signal (indicating that lots of antibodies had bound). These sites contained three peptoids that distinguished the people with Alzheimer’s from the controls. The researchers named the peptoids AD peptoids (ADP) 1-3. At least three times as many antibodies had bound in the Alzheimer’s samples compared to the control samples.

In the larger sample of Alzheimer’s and controls, the researchers found that the sensitivity (percentage of Alzheimer’s samples correctly identified as having Alzheimer’s) was 93.7% and the specificity (percentage of control samples correctly identified as control samples) was between 93.7% and 100% for each of the peptoids.

They found that ADP1 and ADP3 bound to the same antibody, while ADP2 bound to a different antibody.

How did the researchers interpret the results?

The researchers said that their new approach did not require them to identify a specific antigen to screen for antibodies that are raised in disease. Rather, by using a large collection of unnatural molecules, some of which may happen to have the right shape to bind to an antibody, they were able to carry out a high level of screening in samples of people with disease compared to controls.

They said that for Alzheimer’s samples, their “preliminary study is promising as it represents a high level of diagnostic sensitivity and specificity, at least within the relatively limited range of samples analyzed”. However, they pointed out that “more work will be required before it is clear whether the peptoids ADP1-3 will be useful for the clinical diagnosis of Alzheimer’s disease”.

Conclusion

This research has applied a novel approach to antibody screening, using slides coated with thousands of synthetic molecules to screen blood samples for antibodies associated with specific diseases. This well-conducted preliminary research may potentially provide a new method to screen for the presence antibodies that may be characteristic of a disease, and may also aid diagnostics.

When tested in a small number of blood samples from people with Alzheimer’s disease and healthy controls, the researchers’ method could clearly discriminate between the two groups and found higher levels of two antibodies in the Alzheimer’s samples compared to the controls.

While this interesting work could theoretically screen for a range of conditions, the researchers rightly highlight the preliminary nature of their study and emphasise that more work is needed before this could be a diagnostic test for Alzheimer’s or any other disease. In particular, they say:

  • There is now the need for analysis of samples from a larger number of patients from a more diverse population.
  • The samples came from people who had a confirmed diagnosis of Alzheimer’s disease. It is important to test samples from patients who have milder cognitive impairment that subsequently progresses to Alzheimer’s disease to see whether it is possible to use this test for early detection of Alzheimer’s disease.
  • While the test can identify the presence of antibodies consistent with a particular disease, it cannot identify which antigens the antibody is designed to neutralise. Therefore, the technique cannot determine which proteins may cause or contribute to the development of a disease.

Overall, this is promising research that may lead to a blood test for Alzheimer’s and other diseases, although it is still at an early stage. To progress, the technique will need further validation in much larger groups of people.

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