A blood test for Alzheimer’s disease has been the ‘holy grail’ for dementia diagnostics for many years, if not decades. Not only would a simple blood test confirm a diagnosis much quicker but it would also allow better and earlier treatment of Alzheimer’s disease. However, only recently these blood tests coming into reality.

Why did it take so long to develop blood tests for Alzheimer’s disease and how do they work?

Let’s find out.

Alzheimer’s disease is thought to be caused by two proteins accumulating in the brain – amyloid and tau. To be a bit more specific, it is not amyloid and tau themselves causing the disease, as both have important functions in the nerve cells of the brain. Instead, it is specific forms of amyloid and tau which seem to cause the disease. I deliberately say ‘seem’ as the exact mechanism of how they cause the disease is still not fully understood.

What are these ‘specific forms’ of amyloid and tau?

They are beta-amyloid and phosophorylated tau.

Beta-amyloid

Beta-amyloid is a waste product of amyloid when amyloid gets dismantled/recycled in the nerve cell. After the dismantling of amyloid, the beta-amyloid part of amyloid gets ejected from the nerve cell and waits to be transported off by the corticospinal fluid to be recycled by the body. This is a fairly normal process happening in our brain. However, if too much beta-amyloid accumulates outside of our nerve cells, it tends to become ‘sticky’ and starts sticking together with other beta-amyloid molecules. Once the beta-amyloid molecules start sticking together they form beta-amyloid sheets – imagine those beta-amyloid sheets like lasagne sheets. Those beta-amyloid ‘lasagne sheets’ start sticking together lengthwise with each other forming so-called amyloid fibrils.

Fibrils (from Latin for fibre) are nothing else than short fibres of beta-amyloid ‘lasagne sheets’. If there are a lot of beta-amyloid fibrils around, they form beta-amyloid plaques. Plaques are a jumbled mess of beta-amyloid fibrils and are the real culprit – along with beta-amyloid fibrils – for Alzheimer’s disease. It is very difficult for the brain to break down or recycle those beta-amyloid fibrils and plaques and once they form they might stay with us for years. The key issue is that the more beta-amyloid fibrils and plaques we have in our brain the higher our chance of developing Alzheimer’s disease – again the exact mechanism why that is the case is still being investigated.

How do we measure such beta-amyloid fibrils/plaques?

There are three ways to measure such beta-amyloid fibrils/plaques. They are 1) amyloid-PET, 2) corticospinal fluid and 3) blood plasma. For the amyloid-PET, there are molecules, so-called ligands, which attach themselves to the beta-amyloid fibrils/plaques in our brain and make them visible on a PET scan (see my blog entry on brain imaging in dementia for more details). The measurement for beta-amyloid in corticospinal fluid and blood plasma is in fact very similar, as it relies on antibodies.

What are antibodies and how do they work?

Antibodies are nothing else than molecules which are designed to attach themselves to other specific molecules. People might be aware of antibodies which are used for vaccines, by activating the immune system. However, for Alzheimer’s disease diagnostics we have to think more of antibodies as molecules which highlight beta-amyloid and phosphorylated tau in either the corticospinal fluid or blood plasma. To measure the levels of beta-amyloid in someone we ‘simply’ need to get a sample of their corticospinal fluid or blood and then add beta-amyloid antibodies to it in a laboratory. The number of antibodies attaching itself to the sample gives us then an approximation of the levels of beta-amyloid a person has in their brain.

Sounds pretty simple, doesn’t it? So, why is this not already widely used for dementia diagnostics?

In fact, such beta-amyloid antibodies exist already for several years and are used for corticospinal fluid samples. However, getting a sample of corticospinal fluid from people is a complex procedure as it requires people to undergo a lumbar puncture. During a lumbar puncture, a long needle is inserted between the vertebrae of our back to extract the corticospinal fluid. Because it is quite an invasive procedure, lumbar punctures are usually only done in a hospital by a qualified doctor. The procedure is also not very pleasant for the person undergoing it, which in addition to the significant costs, make it not a feasible diagnostic option for most people.

Despite these shortcomings, corticospinal fluid antibody testing has been proven to be extremely precise and sensitive to pick up the earliest changes of Alzheimer’s disease, even long before people develop memory and spatial disorientation symptoms. But it is not a very practical solution for confirming the dementia diagnosis in every person.

Why not use blood plasma for beta-aymloid testing?

Good question. Blood tests are routinely done all over the world and can be administered by family doctors and nurses even in the community. However, the problem until 2-3 years ago was that it was not possible to measure beta-amyloid reliably in the blood. The main reason why it was not possible was that the concentration of beta-amyloid in the blood is much lower than in corticospinal fluid. That makes sense, as corticospinal fluid surrounds the brain and spinal cord directly, therefore, having more beta-amyloid fibrils, whereas much fewer of those fibrils are getting into the blood. It required new technology to amplify the beta-amyloid in the blood sufficiently to measure it reliably in people.

Since this new technology emerged it is possible to measure beta-amyloid reliably in the blood, the whole field has undergone a revolution with several research groups developing new antibodies and tests for Alzheimer’s disease. We are now at a stage, where several of these tests are ready to be approved as diagnostic tools for clinics. It is an incredibly exciting time, as it will allow using a simple blood sample to confirm a diagnosis of Alzheimer’s disease.

What about the other protein – tau? Don’t we need confirmation of both amyloid and tau for a definite diagnosis of Alzheimer’s disease?

Correct. Let’s have a look at tau now.

Phosphorylated tau

Phosphorylated tau is the other ‘culprit’ for Alzheimer’s disease. Similar to amyloid, tau is a very important protein in the nerve cells, not only providing structure to the nerve cells but also helping to transport nutrients through the nerve cell. The key change to tau for the development of Alzheimer’s disease is that it becomes ‘phosphorylated’.

What does phosphorylation mean?

Phosphorylation means that too much phosphate (a molecule common in the body) attaches itself to tau. Normal tau needs some phosphate to work correctly, but if too much phosphate is around, it cannot work properly anymore. The exact reasons why too much phosphate attaches itself to tau are still being investigated.

Once tau is phosphorylated it becomes, similar to amyloid, ‘sticky’ and starts glueing itself to other phosphorylated tau molecules, forming tau fibrils. Imagine again those fibrils as lasagne sheets glued lengthwise together, but now consisting of tau. Similar to beta-amyloid, the more tau fibrils we have in our brain, the higher risk we have of developing Alzheimer’s disease, so it is important to measure the levels of tau in the brain if possible.

How do we measure phosphorylated tau fibrils?

Similar to beta-amyloid, we can measure phosphorylated tau fibrils with 1) tau-PET, 2) corticospinal fluid and 3) blood plasma. There exist now PET ligands for tau, which are still fairly experimental and mostly used for research studies and clinical trials.

By contrast, antibodies for tau have been around for much longer and have been routinely used for corticospinal fluid for many years. Raised tau levels can be reliably measured with corticospinal fluid, but again the constraint is that not everyone has access or is eligible for a lumbar puncture. The blood plasma antibodies for tau have only been developed very recently – in the last 18 months or so and are still undergoing significant validation, testing and safety checks. However, the initial results from those studies show great promise, making it very likely that they will be available in the near future for dementia diagnostics, along with amyloid blood antibodies.

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Summary

There is a quiet revolution happening at the moment in dementia research with blood tests very soon available for the diagnosis of dementia. In particular, amyloid blood test are currently undergoing certification by independent medical bodies to be approved for clinical diagnostics. For tau blood tests we have to wait a little bit longer until they have been further tested and validated. However, there are exciting times ahead for dementia diagnosis, as blood tests will allow the better establishment of a definite diagnosis of dementia, as well as which type of dementia.

So what? Why does this matter?

The reason it matters is that we can treat people much more specifically for their type of dementia. This tailoring of treatment will allow getting people with dementia the best possible care. In the future, these blood tests might be also available for screening people in the population to see if they are at increased risk for dementia (For now the blood tests will be only approved for confirmation of diagnosis). The potential future screening of dementia via blood tests might allow detecting dementia disease changes much earlier, long before people develop symptoms, which in turn will allow to treat or even prevent the disease before any symptoms occur.

Exciting times!

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