Director of Population Health Sciences at the German Center for Neurodegenerative Diseases (DZNE), Professor of Population Health Sciences at the University of Bonn, Adjunct Professor of Epidemiology at the Harvard School of Public Health in Boston,
Breaking the Wall of Brain Degeneration. How Population Studies Can Help Prevent Neurodegenerative Diseases
It is great to be here. I will be speaking about dementia, which is the most frequent neurodegenerative disorder. But before I go into my talk, I would like you to have a look at your neighbour on left, and your neighbour on the right, and now wonder: who of us will be the one? Because that is the frequency with which in Western countries people will develop dementia throughout their lifetime: one in three will fall victim to dementia. It may be relatively late. So, the good news is actually you may have some years ahead in healthy circumstances. But, the truth is that dementia is really an increasing threat to society. This is a slide that shows you the instance rate, which is actually the risk to develop dementia within the next year. What you see here is that this risk very strongly increases with age, and given the change in demographics in our society— people living longer—of course, also the risk to develop dementia gets bigger. What are we talking about when we speak about dementia? I think most of you, given this frequency, have some idea of what it is. But, I think it is also nicely— strongly—depicted in the series of portraits that William Utermohlen painted. He is an American-born artist, who moved to Europe in the 1950s, and he became most famous because of the portraits—he always painted self portraits, but the ones that he continued to paint when he developed Alzheimer’s disease. This is a picture that he painted shortly after he was first diagnosed with Alzheimer’s disease. The paintings that he made in the years thereafter tell the story of the disease. This is the latest portrait that is known of his work. What are we talking about when we talk about dementia or Alzheimer’s disease? Actually, dementia is a syndrome; it describes all the symptoms. A typical way, or a way that people would mostly still consider, is that Alzheimer’s disease is the most frequent subtype of dementia, being responsible for almost two thirds of all the cases with dementia, with vascular dementia being the second most frequent cause. When we talk about Alzheimer’s disease, the underlying characteristics are basically typical changes in the brain that you see depicted. There on the left you see normal brain cells; on the right in this cartoon, you see how with neurodegenerative processes we see accumulation of tangles within the neurons, and the accumulation of amyloid plaques in between the neurons. These brain changes are considered pathognomonic, characteristic for Alzheimer’s disease. Until ten years ago, we could not observe these in vivo, when people were still alive. But ten years ago, people from Pittsburgh University developed the first ligand to allow the in vivo imaging of amyloid plaques in the brain with PET imaging.
What I will argue in the next couple of minutes that I have is that, although this pattern is still the predominant one, this actually is not really true if we look at that from a population perspective. Also, if we continue thinking that this is the distribution of dementia in the population at large, that we actually may be missing out on major opportunities to prevent disease. I am an epidemiologist. That means that we look at patterns, pattern recognition, in the population at large. This is a picture of participants of the Rotterdam study. It was taken in the early 1990s. These are actual participants in our study. The cohort studies that I am talking about is where you really follow thousands and thousands of people over a very prolonged period of time. The Rotterdam study started in 1990; we were preparing in 1989, and it is actually is still on going: 15,000 people in the area of Rotterdam being followed for the development of disease. Typical questions that we asked is: who of these people will develop dementia or other diseases and why—all motivated by the question: can we prevent disease? What have we learned over the years? What are the risk factors for Alzheimer’s disease, for dementia? Well, that is a lot of investigations into genetic causes, and, of course, they have been identified certain genetic mutations that will cause the disease, but these causal mutations—once you have a mutation in the gene you will actually get a disease—they are actually very rare. They run in families, mostly early onset families, but they, in total, explain less than 1% of all the cases that develop Alzheimer’s disease. There is a lot of error; there is genetic risk factors, which actually increase your risk, but are by themselves not sufficient to cause the disease.
And, like the APOE genotype—you may have heard of that in the literature or in the news—it plays a role in maybe 15 to 20% of all the cases, but still does not explain the majority of the people who develop dementia. There are a lot of other heads, all by themselves, actually contribute very little to the overall risk of developing Alzheimer’s disease, at least according to our current knowledge. Population research, and including the research in Rotterdam, we have looked a lot at other risk factors—non-genetic risk factors for Alzheimer’s disease, also because the non-genetic risk factors are potentially the modifiable ones, of course. This is a whole list of factors that have been invoked in potentially being related to the risk of dementia and Alzheimer’s disease. I will highlight some of the vascular risk factors, because that is actually work that we did a lot on in Rotterdam. Because of the set up of the study, where we have a lot of measurements on all our participants, we were able to look at the presence of subclinical vascular disease. For example, if you look here at the left, you see that we looked at plaque in the carotid arteries. We looked at calcification of the abdominal aorta, and we took all these measures, indicators, of the amount of arteriosclerosis, as we constructed a sort of total score and said, “The more vascular pathology people have, the higher the risk of Alzheimer’s disease”. We then took it further, and we also looked at brain scans. There is a lot of pathological changes in the brain. They are asymptomatic, but if you look at the population at large, most of the elderly people have these changes. On the left you see white matter lesions. Basically, more than 90% of the population have some of these changes. Lacunar infarcts in the middle: small cerebral infracts that never gave symptoms; more then 20% of the elderly population have at least one of these infarcts in their brain. And they turn out relevant, because when people have these sorts of lesions in their brain, if you compare them with people without lesions, they do worse on a lot of tests of cognitive function. If you follow them over time, they have an increased risk of not only developing cerebral vascular diseases, strokes, but they also have an increased risk of developing dementia. Actually, this was also supported from some other studies, the nun study a nice study in the U.S. in the late last century, where they followed Catholic nuns, who agreed to repeated examinations each year, and to donate their brains after that to Dr. Snowdon in the upper right corner, when their souls went to heaven. What we saw in that study is actually that if you look at these typical Alzheimer type pathology changes, these plaques and tangles—that it was actually really the amount of coexisting vascular pathology that determined the severity of the dementia syndrome that people had.
This is also depicted in this slide, which is maybe a bit more complicated at first. What we here see is a population study, also from the U.S, where they followed a lot of people and also looked at the pathological changes in the brain after people died. They knew the condition when they died, whether they were demented, yes or no. What is interesting here, if you look at the upper row, that is the people who died with dementia. Then you see that people who had pure Alzheimer disease pathology in the brain was only 30%--not the 60 or 70% that you would predict on the basis of that we say two thirds of everybody has Alzheimer’s disease. Most of the people who died with dementia actually had mixed pathology, as you see in the total in the right. Then compare it with the lower panel, the people who died without dementia. Of these people, also one third approximately fulfilled criteria of Alzheimer’s disease, pure Alzheimer’s disease. So this pure Alzheimer’s disease pathology actually did not tell apart the people who died with or without dementia. What really told them apart was this huge group of people with mixed dementias. I think this has two important complications. One: most of the dementia in the general population is not pure Alzheimer’s disease, but it is really the result of a lot of different pathologies. But also, if you look at the lower line, the presence of Alzheimer’s disease pathology in itself is not sufficient to give clinical symptoms. Actually, there are a lot of people who somehow have the reserve, or the resilience, to still perform normally, even though they have extensive pathology. Maybe pathology is not that abnormal. Maybe it is not this Alzheimer-type pathology that causes the disease symptoms. So, if we then look at this first graph that I showed you before, I think this is a very naïve picture of what is actually going on. At a very early age, yes, there we do see—and I don’t have the time to show you those results—that Alzheimer type pathology really tells the people apart who have the dementia: yes or no. There is pure pathology. This pure pathology is the basis for our disease models. It is actually also the basis for our development of most of the therapies now for Alzheimer’s disease.
But, the majority of the patients are on the right side, right? There is multi-causal disease; there is complex disease. There is a huge overlap with normality. Maybe this is also why many of these Alzheimer therapies fail. We see one failed trial after the other, but it may be because we are targeting the wrong pathology. So what is our picture now of dementia, and what would be the next steps? Here you see how we now think that most of the neurodegenerative dementias develop. Over a prolonged period, there is a period where people still function normally, and then there is a gradual decline, and then people have the full-blown dementia syndrome. Most of our research thus far focuses on the end of the curve, right, to develop therapies for people who already have the symptoms. Actually, also, much of the population research focused on finding causes for the clinical onset of dementia. But, the real culprits probably have to be looked for much earlier in life. They may even start before life. Likely, most of the dementing disorders that we see are accumulation of multiple causes over the life course that finally end up in these clinical syndromes. This is, I think, the challenge for the future. We have to look much earlier in life, over the life course, and find the risk factors. They are not only the risk factors; the risk factors are potentially modifiable, but, of course, also the markers: how can we identify people that may benefit from interventions? Very briefly—I don’t have the time—this is what brought me to Germany, because actually there we are building a new study to precisely do so. That may be a good topic for another talk another time. Just to go to my take-home messages: What I would like to tell you today is that I think that the concept of dementia has become Alzheimerized. But, if we look at the population at level, it is a syndrome—much more than a single disease. Vascular and lifestyle factors contribute to the dementia risk, and this offers opportunities for prevention. We have to focus also on the protective factor: reserve, resilience—a little bit of patience. Given that Alzheimer’s disease is multifactorial, our interventions probably will not be huge, but they may be little steps toward a good end. (Pantomime enters the stage and offers her a rose). Aaaah... that is really nice: food for thought. Two thoughts and then I will accept your flower. First, there is no heroism in prevention, and I think this is really one of the biggest challenges if we think of prevention. The second, I think that we should consider, in the case of neurodegeneration that maybe we do not want to break that wall; maybe we just want to push it a little bit away. With that I end my talk... (Pantomime gives her a small silver box) and I am glad to accept ... a brain.