Many people know that Alzheimer’s disease is caused by proteins ‘going wrong’ in the brain. One of those key proteins is amyloid. But how does amyloid ‘go wrong’? And how does this potentially cause Alzheimer’s disease?
Let’s find out.
‘Proteins, glorious proteins’
Proteins are the building blocks of life. They have so many vital functions in our body that it is nearly impossible to list all those function. Since proteins are so vital for our body’s healthy functioning, it should come maybe not as a surprise that when proteins ‘go wrong’ it can create an enormous havoc in our body and in the worst cases severe disease. Such diseases, also called proteinopathies (literally meaning diseases caused by proteins) are become increasingly common when we age as protein processes are more likely to ‘go wrong’ the older we get. Many age-related disease, such as Parkinson’s disease, Huntington’s disease or Motor Neuron Disease are caused by different proteinopathies.
The other major age-related disease caused by a proteinopathy is, of course, dementia. One important thing to understand is that different dementias (Alzheimer’s disease, Frontotemporal dementia, Dementia with Lewy Bodies etc.) are caused by different proteinopathies. The only exception is vascular dementia, which, as the name gives already away, is caused by blockages or leakages to our brain’s vascular/blood vessel system. So, nearly all dementias are caused by different proteinopathies, however as always life is more complicated and different proteinopathies can overlap between different types of dementia. This fact can make the distinction between different dementias quite confusing. If you are interested to find out more about teh overlap and differences between clinical and protein classification of distinctions of dementia, I recommend reading my on this topic here.
So, nearly all dementias are caused by proteinopathies but how do these protein disease actually cause the disease? Let’s have a look at Alzheimer’s disease, the most common form of dementia, for which the role of the proteins in the development in the disease is best understood. Alzheimer’s disease is thought to be caused by two proteins (amyloid and tau). In this article I will focus on amyloid with a future article explaining the contribution of tau to Alzheimer’s disease.
Amyloid, or to be more precise the Amyloid Precursor Protein (APP), is a key protein in our brain’s healthy functioning. Specifically, the amyloid protein sits in the cell wall of our nerve cells and helps our nerve cells to grow and repair themselves. Yes, you heard that right, amyloid, one of the proteins responsible for Alzheimer’s disease, is actually good for our nerve cells before it ‘goes wrong’.
So, what happens with amyloid that it contributes to Alzheimer’s disease?
The problem starts when the amyloid precursor protein comes to the end of its lifetime and is recycled by the body. Our cells are always recycling and renewing their proteins, to keep the proteins functioning as best as possible. It is the recycling process stage for the Amyloid Precursor Protein that determines whether we will be at a higher risk of Alzheimer’s disease in the future. For the recycling process, our body uses other proteins, so called secretases, to snip the Amyloid Precursor Protein in different parts so they can be recycled. One can think of the secretases as a type of scissors which ‘snip’ the Amyloid Precursor Protein at very specific points into different parts so the body can recycle them.
Now, for the successful recycling of the Amyloid Precursor Protein, the alpha(α)-secretase does the job and ‘snips’ the Amyloid Precursor Protein at the right places so that the remaining parts can be instantly recycled. Most of the Amyloid Precursor Protein is recycled in this way (see the left side of the figure below, showing the successful recycling of the Amyloid Precursor Protein). However, for yet unknown reasons, in some instances, the Amyloid Precursor Protein is protein gets cut by two other secretases, the beta(β)- and gamma(γ)-secretases. The beta(β)- and gamma(γ)secretases cut the amyloid precursor protein at two different places, resulting in three pieces. Two of those pieces can be easily recycled but the third one – beta(β)-amyloid is not so easy to recycle by the body.
Since beta(β)-amyloid is not so easy to recycle, the nerve cells does what we do with our rubbish every week – put it outside to see if someone will pick it up. Some of the beta-amyloid is indeed removed by the body and then recycled. However, the older we get the less efficient this clearance of beta-amyloid becomes – for yet unknown reasons. This means the older we are the more beta-amyloid can be found outside the nerve cells of our brain.
This might be not a problem per se but the problem arises that beta-amyloid is quite ‘sticky’ and likes to stick togther with other beta-amyloid molecules. Once the beta-amyloid starts sticking together they form strings or sheets of beta-amyloid, so called beta-amyloid oligomers or fibrils (oligomer simply means lots of proteins; fibrils means strings of proteins). Even worse those beta-amyloid oligomers/fibrils start sticking together forming beta-amyloid plaques (plaques are random conglomerations of fibrils), which are even harder to break down as they consist of thousands of beta-amyloid molecules in a jumbled mess. It is actually those beta-amyloid plaques which Alois Alzheimer found under the microscope when he investigated the brain of people with Alzheimer’s disease in 1906/07. He described the beta-amyloid plaques as ‘millet-sized seeds’, although, of course Alzheimer did not know that these ‘millet-sized seeds’ he described were made out of beta-amyloid. It took another 70-80 years after Alzheimer’s initial description that it was discovered that those ‘millet-sized seeds’ were in fact consisting of beta-amyloid plaques.
Now, it is the amyloid plaques which are the real problem, as they are in essence, a sticky mess of lots of beta-amyloid molecules stuck together. A good analogy for those beta-amyloid plaques is to imagine we are cooking pasta shapes. After cooking the pasta shapes we drain them and leave them as is. This will cause the pasta shapes to stick together randomly in a big blob. This pasta blob is very similar to amyloid plaques. Now, if we ruined our pasta like this we would simply throw the ‘blob’ in the bin but that is not an option for our body with the beta-amyloid plaques. Instead, it can only recycle each beta-amyloid by itself. Now, imagine you would have to unpick your pasta ‘blob’ to get each pasta shape out to throw it in the bin or recycle it. It would takes us a long time to do it and a very tedious job to do. It is very similar for our body with beta-amyloid plaques which take a very long time to recycle and in some cases the plaques stay with us our whole life. This means that beta-amyloid plaques can be in our brains for many years if not decades as they are very hard to clear up for our body.
That’s all very interesting but what has that all to do with Alzheimer’s disease?
The relationship of beta-amyloid plaques and Alzheimer’s disease was already realised by Alois Alzheimer himself in 1906/07 but it was only in the 1990s that our knowledge of beta-amyloid allowed to establish the exact relationship between beta-amyloid plaques and Alzheimer’s disease. A key discovery in the 1990s was that people who have a genetic mutation which causes an increased production of beta-amyloid were more likely to develop Alzheimer’s disease. This led to the formulation of the ‘Amyloid Cascade Hypothesis’ which remains to this day a highly influential hypothesis and affected not only how Alzheimer’s disease was investigated but also the development of Alzheimer drug treatments.
Amyloid Cascade Hypothesis
The Amyloid Cascade Hypothesis states that higher the levels of beta-amyloid the more likely we develop Alzheimer’s disease. In other words, the higher levels or accumulation of beta-amyloid are the cause of Alzheimer’s disease. It was a groundbreaking theory which is influential even to this day but we should emphasise that it is still a ‘hypothesis’ – even though a lot of research evidence now indicates that most of the hypothesis is correct.
But what about the cascade term? Which cascade needs to be happen for Alzheimer’s disease to occur?
One cascade is the actual accumulation of beta-amyloid and there is still a lot of discussion and research happening to find out how much beta-amyloid needs to accumulate for someone to develop Alzheimer’s disease. There is also other research investigating whether all aspects of beta-amyloid are detrimental and increase our risk for Alzheimer’s disease. The other key aspect to understand is how the accumulation of beta-amyloid actually leads to Alzheimer’s disease in the long-term. Below a graph which tries to illustrate how the Alzheimer’ scientific community currently sees the disease developing. Note this is a theoretical graph and there is still a lot of research ongoing to determine in real life as to how quickly the curves emerge after each other and which slopes they have. It also means that for different people with Alzheimer’s disease these curves might look quite different, but for illustration purposes it gives a good overview of how the disease is ‘supposed’ to develop.
Let’s have a look now at the graph in more detail. On the x-axis (the horizontal line at the bottom of the graph) we can see the different stages of Alzheimer’s disease, starting from healthy to Mild Cognitive Impairment (MCI) to Alzheimer’s disease. On the y-axis (the vertical line at the left side of the graph) we can see that it indicates the amount of change from healthy to unhealthy, in essence the higher the curves the more unhealthy that protein, structure or symptom is. The two dashed lines gives indications when most people, and again this is only a theoretical graph, would get a diagnosis of Mild Cognitive Impairment or Alzheimer’s disease. We are ready now to talk about the actual curves.
In black, right at the beginning we can see the hypothesised curve for amyloid, well it actually refers to amount of beta-amyloid plaques outside of the nerve cells. From the black line, we can see that beta-amyloid levels rise in healthy or ‘presymptomatic’ (since they show no symptoms yet) people for quite some time without affecting their brain structure, memory or everyday functioning. The next line (blue) gives us the levels of tau, the other critical proteins responsible for Alzheimer’s disease. We can see that levels of tau increase, similar to amyloid over time. Only when there are already quite high levels of amyloid and tau in the brain, changes to the brain structure can be seen. With brain structure we mean here brain scans, such as MRI, which can measure atrophy – the nerve cells loss caused by the high levels of amyloid and tau (here an article on atrophy if you want to find out more). In essence, the higher levels of beta-amyloid and tau become toxic to our brain cells and the brain cells start dying. It is is this dying of the brain cells which eventually causes the symptoms to emerge.
We need brain cells for our brain to function normally but once the brain cells get affected by the rising levels of amyloid and tau they cannot function anymore properly and start dying. Once brain cells start dying on a large scale it becomes increasingly harder to compensate for the function of those brain cells. The symptoms we observe are therefore the failure or dysfunction of the brain cells affected by the high levels of amyloid and tau. For Alzheimer’s disease, we know that memory specific regions become first affected and brain cells in those memory brain regions start dying. In turn this causes people to start having memory symptoms (shown in the green line) and finally those symptoms can also affect our everyday functioning (grey line).
We can see now that amyloid and tau start to accumulating a very long time before we actually see changes to the brain structure and even longer before we see symptoms appear. It also means that once people report memory problems to their doctor, they often have a lot of proteins in their brains and brain cells have started dying. This realisation has led to a push to develop markers for amyloid and tau levels before memory symptoms appear. For many years measuring amyloid and tau levels in the brain was only possible via an unpleasant and expensive lumbar puncture but more recently blood tests have been developed to detect amyloid and tau levels in people (please see my article on this here). The scientific and clinical communities are very excited by the new blood tests as they will transform the diagnostics of Alzheimer’s disease in the future. With the new blood tests we don’t have to wait anymore for memory symptoms to appear before making a diagnosis. Instead, we can detect the rising levels of amyloid and tau a long time before brain structures get affected by the proteins levels and symptoms start emerging. In essesn, we can detect whether someone is at higher risk for Alzheimer’s disease without having memory symptoms.
So, what, you might say. There is still no treatment or cure for Alzheimer’s disease. Why should I get an even earlier diagnosis?
Disease risk reduction/prevention
In fact, it makes a big difference to get an earlier diagnosis. The earlier we can detect abnormal levels of amyloid and tau, the earlier we can try to reduce those amyloid and tau levels. In turn, we can potentially delay or amerliorate the onset or progression of the disease. Indeed, we already know that lifestyle changes or existing medication can potentially reduce our risk for dementia by up to 40%, if, and it’s a big if, we detect the disease early enough. So far, we mostly detected the disease only when symptoms have emerged and hence we know that amyloid and tau levels are already very high in the brain and brain cells have likely died. But if we can detect those amyloid and tau levels much earlier we are really in for a fighting chance to change our future risk for Alzheimer’s diseas.
The other key aspect for early amyloid detection is that new pharmaceutical drugs are targeting to reduce beta-amyloid in the brain. There has been recently a new drug certified in the US (Aduhelm), which is targeting exactly the reduction of beta-amyloid. The irony is that Aduhelm is to date only licensed to be prescribed for people who have a diagnosis of Alzheimer’s disease and hence memory and everyday function symptoms. We now know that at this stage, the levels of of amyloid are already very high in the brain and, therefore, removing beta-aymloid will have a limited effect on people’s symptoms. This is in fact exactly what has been found for Aduhelm and created some controversy. Please read my related article here, if you are interested in the story behind Aduhelm.
Still, for the future the new blood tests will be a game changer and will allow people to take beta-aymloid reducing drugs long before they develop memory symptoms. This will make a big difference to their future risk of Alzheimer’s disease but even without these new drugs earlier diagnosis is a good thing as we can change our risk for the disease or even delay the onset of the Alzheimer’s disease.
Taken together, beta-amyloid is a key protein in the development of Alzheimer’s disease. Beta-amyloid is formed when the Amyloid Precursor Protein is dimantled and recycled. For yet unknown reasons, proteins cutting the Amyloid Precursor Protein, so-called secretases, sometimes cut the protein into different parts, one of which is beta-amyloid. Beta-amyloid is difficult to recycle for the body and hence is ejected from the nerve cell where it can accumulate for many years if not decades and starts sticking together with other beta-amyloid molecules forming beta-amyloid oligomers/fibrils and plaques. The more those plaques accumulate outside nerve and other brain cells the more toxic those plaques become to the nerve and brain cells, which eventually die. These increasing levels of beta-amyloid lead to a cascade of changes in the brain. Along with another protein (tau), they start affecting nerve cells which die and cause the typical symptoms and everyday functions in the brain.
It is key now to detect those changes in beta-amyloid earlier so that we can reduce beta-amyloid levels in our brains which in turn will reduce our future risk for Alzheimer’s disease. Amyloid is, therefore, a key protein for the development of Alzheimer’s disease and knowing how it ‘goes wrong’ is is critical to understand our risk for the disease.