We often think that cognitive changes, such as loss of memory in Alzheimer’s disease, are the earliest changes in dementia. But is that the case?
In fact, there is a whole cascade of other disease processes occurring in the brain before memory symptoms emerge, which has implications for how we will diagnose and treat dementia in the future. Let’s find out more.
Memory symptoms are regarded by most people as the factor determining whether someone has Alzheimer’s disease. For example, most people would consider seeing their GP/family doctor, if their memory has changed and likewise doctors would consider someone to have the early stages of Alzheimer’s disease when they report significant changes to their memory and everyday functioning. It might come, therefore, as a surprise, that memory symptoms emerge only quite late in the disease-specific (scientific speak: pathophysiological) processes causing Alzheimer’s disease.
Why is that the case?
One key aspect to understand is that Alzheimer’s disease is now considered by many scientists as ‘a disease of middle age, presenting at old age’. This means that the disease-specific processes for Alzheimer’s disease might start years or even decades before symptoms come to the fore. Years? Decades? I hear you whisper at the screen and indeed, even for many scientists, this concept is rather new as until a few years ago, it was assumed that the onset of the disease and the onset of the symptoms were quite close together. It might be a scary prospect to consider that some of us might have already the beginnings of the disease-specific processes of dementia in our brains, even though we are only middle-aged. However, there is also a positive side to this long duration between the disease onset and symptom onset. For one, we can potentially identify Alzheimer’s disease much earlier to change our ‘disease trajectory’. This also means that we have a much larger prevention and treatment window/opportunity. For example, for many diseases, the treatment window is very brief, such as in many cancers. However, since Alzheimer’s disease can take years or decades before leading to symptoms, we have years, if not decades, to prevent or treat the disease and potentially change its trajectory or even completely avoid its onset.
What are then the earliest changes in Alzheimer’s disease, before memory symptoms emerge?
All dementias, with the exception of vascular dementia, are caused by the accumulation of proteins. It is the same for Alzheimer’s disease where two proteins (amyloid and tau) accumulate inside and outside of the nerve cells. Once the levels of amyloid and tau become very high, they become toxic to the nerve cells and the nerve cells start dying. If sufficient nerve cells die, the brain cannot work normally, which causes specific cognitive symptoms, such as memory loss. It has been known for quite a long time by scientists that it is the levels of amyloid and tau we should worry about if we want to detect the disease as early as possible. However, until very recently it has been very difficult to measure amyloid and tau levels in people’s brains when they are alive – measuring them at post-mortem is by contrast fairly straightforward and has been done since Alois Alzheimer’s times. But obviously, it is no good use to detect amyloid and tau levels in the brain of people who are already passed on, since any treatment is then meaningless.
For the living, scientists developed instead ‘theoretical’ models for Alzheimer’s disease, which modelled how the different elements, proteins, brain changes, cognition etc ‘theoretically’ develop over time for the disease to emerge. I draft below a graph of one of the most commonly accepted theoretical models of the emergence of Alzheimer’s disease to illustrate better the cascade of the disease-specific processes which lead to memory symptoms. However, please note again that this is only a theory at the moment and data is only recently emerging to confirm or refute this disease development for Alzheimer’s disease. On top of that other external factors, such as lifestyle and the environment might influence the trajectories of the model and the trajectories of the factors might also differ across individuals. Just bear that in mind when looking at the graph.
Let’s go now through this graph. We can see the x-axis (the horizontal line) shows the progression of the disease from healthy/’presymptomatic’ all the way to Alzheimer’s disease. With the term presymptomatic we mean people who have the first disease changes for Alzheimer’s disease in their brain but have not yet developed symptoms, hence they are referred to as presymptomatic (pre from the Latin preposition ‘prae’ = ‘before’). The y-axis (the vertical line) shows us how the level of disease changes with lower values showing ‘healthy’ levels and higher levels showing ‘unhealthy’ levels. The exact threshold where healthy changes to unhealthy for these variables is still a matter of debate and we just have to accept for now that at some point the factors change from healthy to unhealthy. Finally, the dashed lines show potential transition points from Healthy/’Presymptomatic’ to Mild Cognitive Impairment to Alzheimer’s disease. The dashed lines are merely to give an indication when someone is likely to receive a diagnosis of Mild Cognitive Impairment or Alzheimer’s disease. But again, this might differ between individuals, as some might report their symptoms earlier than later and similarly, doctors might diagnosis someone earlier or later.
We are ready now to explore this graph in more detail.
In the graph, we can see five lines, each one a key factor in the development of Alzheimer’s disease and its eventual diagnosis. Two of the lines (black and blue) refer to the proteins accumulating in the Alzheimer’s disease process, amyloid and tau (the higher the line, the higher the levels of amyloid and tau). The orange line refers to the brain structure, meaning how affected the brain cells are by the disease process caused by the proteins. We know already that the more amyloid and tau accumulate the more the brain and particular nerve cells become affected since a large concentration of proteins are toxic to the nerve cells and the nerve cells eventually die. If this nerve cell death happens on a large scale we see changes to the brain structure, as the large nerve cell loss causes the brain to shrink (the brain shrinkage is called atrophy by clinicians – coming from the Ancient Greek word ‘atrophia’ = ‘wasting away’). The changes to brain structure in the graph mean therefore an increased level of nerve cell death which we will see as atrophy on brain imaging scans. Next, the green line is the typical memory symptoms we see in Alzheimer’s disease when people have problems recalling recent events or cannot remember where they placed things. The higher line the more memory problems. Finally, the grey line represents how the everyday functioning of people is affected by the disease, again the higher the line the more everyday functioning is affected.
Now, we know what the lines represent we can see that there is a cascade of events happening before people develop memory symptoms and receive a diagnosis. First off, it is amyloid which is hypothesised to increase in people’s brains and this process is thought to take from a year to several decades, so the slope of the curve in the graph can clearly change. We can also see that amyloid levels are already very high before the next protein (tau) starts accumulating significantly in the brain. There are several theories around that it is the higher levels of amyloid which are required for tau to accumulate in Alzheimer’s disease, however, the jury is still out on this theory and the interaction of amyloid and tau is complicated. The next line (orange – the brain structure changes) is starting only once both proteins (amyloid and tau) are widely distributed in the brain. This would make sense since we need significant amounts of amyloid and tau to have accumulated to become toxic to the nerve cells and they start dying causing the atrophy visible on brain scans. Shortly after the brain changes emerge, memory problems become noticeable. Again, this makes sense since the intact nerve cells are required for our memory to functioning normally, however, once a lot of nerve cells start dying our memory cannot function anymore and we develop memory symptoms. It is usually at this stage that we report our memory symptoms to our doctor who would if we meet all the diagnostic criteria, give us a diagnosis of Mild Cognitive Impairment. Finally, once the memory symptoms become worse, it will affect our everyday functioning and other cognitive symptoms might also emerge, which will then lead to a diagnosis of Alzheimer’s disease by our doctor.
I hope this theoretical graph makes it clear that there is a defined cascade for most people developing Alzheimer’s disease. Scientific data has backed this model up to a large degree by showing indeed that it is the protein levels of amyloid and tau which rise first before we see brain changes and subsequent memory and everyday changes. To answer our initial question, the memory symptoms are actually emerging only quite late in the disease process leading to Alzheimer’s disease. This is quite sobering news for many people since the emergence of the memory symptoms – on which a diagnosis is made – means that the disease has taken already a significant hold of the brain. It also explains why many treatments at this stage have not such a big effect anymore, as the damage in the brain is already done.
Why not detect people then in the earlier/presymptomatic stages of the disease, so that we can treat Alzheimer’s disease better?
Indeed, this has been a large focus of the research community over the last decade. First of all, researchers started looking at other cognitive processes which might occur earlier. For example, there are strong suggestions that spatial orientation changes occur much earlier than memory symptoms in Alzheimer’s disease, as the spatial orientation brain regions are earlier affected by the diseases processes than the brain regions involved in memory. Similarly, there has been a focus on identifying the brain structure changes earlier via brain imaging techniques. Over the last few years, more sophisticated structural brain imaging techniques have been developed, which can detect more subtle brain structure changes than before, allowing potentially for an earlier diagnosis of Alzheimer’s disease.
However, the holy grail for ‘presymptomatic’ Alzheimer’s disease diagnosis has been for many years to detect the amyloid and tau changes in the brain, as they occur first in the cascade of disease process events. This seems quite a simple thing to do, but on a scientific level, it is in fact very hard to detect the protein changes in people early enough. It took until 2004-2005 when the first brain imaging scans became available for amyloid and it took another 10 years to have brain imaging scans for tau. I recommend reading my article on brain imaging in dementia (https://dementiascience.org/2020/12/07/how-does-brain-imaging-help-with-dementia-diagnostics/) to gain a deeper insight into how those brain scans work. Still, these amyloid and tau brain scans are only used to date for research and not clinical diagnostics. Nevertheless, the advent of these brain scans revealed that indeed amyloid and tau levels in the brain increase a long time before the brain structure, memory and everyday functions change. Amyloid and tau scanning is therefore used now across many research studies to investigate in more detail when these changes occur and how much of an individual difference there is between people when developing the disease.
For the advancement of our research understanding of which changes occur first the new brain imaging techniques have been a blessing, however, it is not clear how much they will impact dementia diagnosis in the future. In particular, amyloid and tau brain imaging is fairly expensive and only done at highly specialised university hospitals, making it less economically feasible as well as accessible to the majority of the population. But there is light at the horizon, as new blood tests have been in the meantime developed, which in the very near future will be available for the diagnosis of Alzheimer’s disease. Specifically, the blood tests measure amyloid and tau levels and can be administered by the GP/family doctor or even a nurse. Alzheimer specific blood test will become a true game-changer in the future and will likely change our perception of memory changes as the first symptom of Alzheimer’s disease. If you are interested in more details on how these blood tests work, please read my related blog entry (https://dementiascience.org/2020/12/14/blood-tests-for-alzheimers-disease-are-they-becoming-a-reality/).
Where does this leave us now?
There is now an interesting discrepancy emerging that memory symptoms are still considered to be the key diagnostic criteria for Alzheimer’s disease. But we know now that the amyloid and tau changes might allow to ‘shift the goalpost’ to diagnose people years before they develop memory symptoms. At the moment, there is, therefore, a large gap between the onset of the disease processes (accumulation of amyloid and tau) and the onset of memory symptoms, which only the advent of the new blood tests will bridge. It is therefore very likely that in the future, Alzheimer’s disease diagnostics will shift from memory symptoms as the key factor for a diagnosis to amyloid and tau levels measured via a blood test. This will allow to detect dementia much earlier and potentially slow down the disease development if not stop it completely with existing and future treatments.
Does this mean that memory impairment will become irrelevant in the future?
A good question. It is likely that memory symptoms will be become less relevant for Alzheimer’s disease diagnosis but will still be very important for the disease care and management. For example, one needs to measure memory changes to see if the disease is not spreading further or how much the memory changes might affect the everyday functioning of people. Memory changes will become, therefore, more likely a ‘functional outcome measure’, meaning that it will be an important measure to determine whether treatments work and how much the disease affects peoples’ everyday lives.
Something to think about.
