21 September was World Alzheimer's Day. In that same week news was announced about blood tests for Alzheimer's that would be available within the next one or two years. “I have two things to say about that”, says Ingrid Philippens, a researcher of neurodegenerative disorders (Parkinson's and Alzheimer's).
Before discussing the latest developments, we should have a brief look at the bigger picture. What is the status of Alzheimer's research in 2018? What do we know, and what don't we know yet?
How brain cells disappear
“Researchers have been studying Alzheimer's and trying to discover the cause for years”, says Ingrid. “Despite all the research, we still don't know what causes this disease. Some people point to so-called amyloid deposits: abnormal protein clusters which form ‘plaques’ in the brain. Although Alzheimer's patients have these plaques, not everyone with plaques develops Alzheimer's. In other words, plaques are a precondition for Alzheimer's but don't necessarily lead to Alzheimer's.”
Alongside the formation of amyloid plaques, so-called neurofibrillary tangles are often regarded as the cause of the degeneration of nerve cells in the brain, followed by Alzheimer's symptoms. “The plaques develop outside the cells and activate the tangles, which occur inside the cell. These tangles prevent good communication within the brain, meaning that information can no longer get through. This could certainly be a reason why everything starts to go wrong. Ultimately, cognitive decline is linked with the disappearance of brain cells. The amyloid plaques come first, then tangles develop and brain cells degenerate – we know the order in which these things happen, but we're still not exactly sure how they happen.”
The accelerating effect of inflammation
The hypothesis of the BPRC is that ‘inflammation’ plays a role in the disease. “By inflammation, we don't mean wounds or the like, but internal inflammation which activates the immune system. In marmosets, we activated inflammation in the presence of these plaques. This showed that an inflammation in combination with plaques accelerates the disease process. This is also evident in people who have suffered a brain injury, for example after a blow to the head (boxers, for example). As such a blow leads to internal inflammation, these people run a greater risk of developing Alzheimer's.”
According to Ingrid, anti-inflammatory drugs can have some preventive benefits. “People with rheumatoid arthritis take anti-inflammatory drugs on a daily basis. It has become apparent that people who take anti-inflammatory drugs every day have a lower risk of developing Alzheimer's – provided that they started taking those drugs at a relatively young age, before they had the chance to develop Alzheimer's. If you only start taking anti-inflammatory drugs once the process has already started, it's too late. It won't work at that stage. So even though preventive action is possible, we don’t exactly know when and how to intervene.”
It's never just Alzheimer's
Ingrid is keen to make an important point about the many things that have been written and said about Alzheimer's. “People never solely develop Alzheimer's. They often develop this disease later in life with a long medical history behind them, including all kinds of medical conditions. Plenty of illnesses that people have had in the past or that they still suffer from can play a role. For example, it has been demonstrated that diabetes increases the risk of developing Alzheimer's. But we often talk about Alzheimer's on the basis of the symptoms and the clinical picture at the end.”
According to Ingrid, the causes of the disease may be completely different for all these patients. “Nonetheless, we lump everything together under the heading of Alzheimer's and try to find a single treatment to help all the patients in this very diverse group. We don’t realise that a group of ten patients might require ten different treatments. As a result, clinical trials with human subjects constantly fail. The treatment helps some people but not others, and it isn't clear why. Consequently, these drugs are not entering the market, even though they could have been useful for a small population of these patients.”
Not all patients are the same
According to Ingrid, the scientific world can make an important step forward by improving the diagnostic tools, to be able to distinguish between different kinds of patients. “It's difficult though to perform studies with small groups, as you need large populations to establish whether a drug actually helps. As you are dealing with a slow progressive disorder, it takes a very long time before any improvements become visible. Current treatment only focuses on ways to suppress the symptoms, and in particular on preserving cognitive functions. There's nothing else we can do; as there is still no treatment for Alzheimer's, people can't be cured. Unfortunately.”
So what about the news of the blood tests which should be available within the next one to two years, enabling the early detection of Alzheimer's? “Let's imagine that we can actually do so, then what? We still won't have cured anyone: we'll just know that a person has Alzheimer's. That knowledge would be very useful if we had a treatment, but we don't.” The second point Ingrid wants to make is related to the wide variety of medical factors underlying the illness. “That test might be suitable for only 2% of Alzheimer's patients. The danger is that you might think you don't have Alzheimer's, but you could still have a different form of the disease. So the test could be misleading. The reality is that we still know very little. That may be unpleasant, but it's the truth. That's why research is still very much needed.”
Complex illness
BPRC uses animal models to contribute to this research. “We need these in order to establish how mechanisms work, allowing us to find a better target for treatment, for a new drug. You can't just use cells in a Petri dish, because Alzheimer's is a highly complex disease which involves many different areas of the brain and major interactions within the body as well. Even the gut flora plays a role. This is not something you can isolate in a cell culture. You need an intact body and for ethical reasons, we can't use people for this.”
Based on the abovementioned hypothesis that inflammation plays a role in the disease process, it turns out that marmosets (and probably also rhesus monkeys) naturally display this plaque progression as they get older. “The older monkeys also start to develop the same amyloid plaques. This is very interesting for treatments which focus on preventing amyloid progression. We tried to accelerate the progress of the disease by adding inflammatory factors, otherwise you have to wait a very long time. Another thing is that the progress of the disease varies greatly in humans. People who develop Alzheimer's earlier in life have probably already suffered from inflammation. We also induce the same mechanism in animal models. This allows us to examine the brain for various different factors which may play a role in Alzheimer’s. That is our role in this research.”