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Alzheimer’s disease

“Definitely on the right track”

München, 12/18/2015

Alois Alzheimer, who first described what has become the most common form of dementia, died 100 years ago. What is known about the illness today and, above all, what can be done about it? LMU’s Christian Haass gives us a tour d’horizon.


From your old laboratory downtown, you had a direct view of the rooms in which Alois Alzheimer once worked. What role does Munich play in Alzheimer’s own story?
It was in Munich that Alzheimer first described the pathology of the illness that would later be named after him – based on his observations in the famous case of Auguste Deter. A post-mortem had been performed on the patient and his former boss in Frankfurt had sent him the brain, which he went on to study in his lab in Munich.

What exactly did he find?
Alzheimer made a very painstaking study of the tissue. He immediately noticed that many of the nerve cells were deformed – and documented the malformations in extremely precise and detailed drawings. He observed and described the tangles, the fibrils and the plaques – all of the abnormal features in the brain that modern pathologists associate with dementia.

One hundred years have passed since Alzheimer’s death. That first report was essentially an anecdotal observation. What is the significance of the condition that he discovered and described for our society today?
Alzheimer would be astounded by the incidence of the disease today. In Germany, we have more than a million patients who suffer from Alzheimer’s. It is now by far the most frequent form of dementia. The reason for this is quite simple: Life expectancy today is much higher than it was a century ago, and age is the dominant risk factor for the condition. The older you are, the greater the risk for Alzheimer’s.

In the last 15 to 20 years, Alzheimer’s disease has become the focus of a large-scale research effort. How many labs around the world are now looking for an effective treatment for the condition?
The number is certainly in the hundreds, and pharmaceutical firms have whole departments devoted to the search for therapeutic drugs. There are so many research publications that it’s become impossible to keep up with them. One has to concentrate on the papers that are well-founded and report important findings. When I began to work on Alzheimer’s in 1990, I was able to copy all the relevant papers on in the course of a morning, and by the next day I had read them all.

Nevertheless, there is nothing on the market that really works. And 2 years ago, several clinical trials of drug candidates were prematurely ended because the early results were so disappointing. On the other hand, at some important conferences held this year the outlook was more hopeful. What has changed in the meantime?
The substances that were tested in that previous round of trials included compounds that inhibit the so-called gamma-secretase. That is one of the enzymes that cuts the toxic amyloid peptide out of a larger precursor protein, and production of this amyloid is the first step in the process that leads to the full-blown disease. However, the results of those tests were quite devastating. Patients treated with these agents suffered serious side-effects, some of them life-threatening. This was no real surprise, for these side-effects were – without exception – predictable, on the basis of what was already known about the physiological functions of gamma-secretases. These enzymes are also present in the brains of healthy individuals, because they carry out essential functions. One can’t just block their activities and expect that this will have no deleterious consequences.

What about the efforts to develop a vaccine against Alzheimer‘s?
The immunological approach is based on the injection of an antibody directed against the amyloid. The antibody reaches the brain, recognizes the amyloid and binds to it, thus marking it for destruction by immune cells. The latest experiments confirm that this is a promising strategy. We have also learned a lot from the clinical studies done so far. We hadn’t realized that the disease is initiated so early, for instance. Meanwhile, it is thought that the process begins 20 or even 30 years before the first overt symptoms appear. Without the drug tests, nobody would have thought of that. Several of the ongoing trials now include patients with mild symptoms of the disease. The immune therapy is being tested on this group, and the first results are encouraging. Three independent studies have found that the level of performance in memory tests is stabilized in patients treated with the antibody, and the magnitude of the effect depends on the amount of antibody injected. One must avoid raising false hopes, but this strategy is definitely on the right track. And quite apart from that, the results provide convincing confirmation that the amyloid plays a crucial role in the development of the disease.

But this also raises a few practical problems: How does one decide who might benefit from such a vaccine, and at what age should they be immunized?
That is indeed a very big problem. In principle, as in the case of polio in years gone by, everyone should be immunized – at least everyone older than some specific age. But of course, we must be sure that any side-effects which might appear in the course of a long-term course of immunization can ruled out. The best way to treat or prevent the disease altogether would be to vaccinate before any symptoms of memory loss have appeared. But in order to identify the right time for immunization, we need reliable biomarkers, but those we now have are far from perfect.

How is the disease process initiated?
It definitely starts with the production of the amyloid peptide, which is cleaved from the precursor protein by two enzymes, the beta- and the gamma-secretases, which act like scissors. This is a perfectly normal physiological process, and goes on all the time. The amyloid molecules have a tendency to form aggregates, which give rise to long fibrils that subsequently form the basis of the plaques. Obviously, the young brain manages to get rid of these insoluble deposits. But as one gets older, the more difficult that task becomes.

So which of these forms is toxic to the nerve cell? The amyloid, the intermediate forms, the plaques?
This is an issue that is still the subject of controversial discussion among researchers. I believe the answer is: All of them together. But even that is not everything. The amyloid fibrils provoke the destruction of so-called tau proteins, which are part of the cell’s internal transport system. As a result, the railway network in the cell disintegrates, and fragments of the tracks clump together, causing the nerve cell’s transport infrastructure to collapse. Significantly, the first nerve cells that die are those with the longest projecting fibers, the so-called axons. I am now convinced that the amyloid only provides the initial impulse that sets off the avalanche, the cascade of reactions that lead to the death of the nerve cell. This is another reason why it is important that any therapy directed against the amyloid should begin early on.

You recently discovered another fragment that is cleaved from the same precursor as the conventional amyloid peptide. How could this have escaped detection for so long?
That’s a very good question! This new processing pathway is used significantly more often than the one that leads to the beta-amyloid. I found the first indications that there was a second pathway in operation in 1991. But I didn’t follow these up because my boss at the time told me to concentrate on the processing of the beta-amyloid. But then a member of my own group, Dr. Michael Willem, “rediscovered” the other pathway.

So what does this resurrected eta-amyloid do?
It regulates the activity and functional plasticity of neurons. The beta-amyloid, whose amino acid sequence partially overlaps with that of the eta form, promotes neuronal hyperactivity, which causes chaos in the brain, so to speak. The eta-amyloid does precisely the opposite. It brings neuronal activity to a virtual standstill, which is just as bad. But the real problem is that the concentration of eta-amyloid rises significantly when the beta-secretase is inhibited. – And inhibition of the beta-secretase is one of the approaches that is now undergoing clinical trials! So this effect on the eta-amyloid deserves a very hard look in the context of the drug tests – quite apart from the fact that the beta-secretase interacts with at least 30 or 40 other protein substrates. We know nothing at all about what most of those proteins do. Their functions are certainly affected by agents that inhibit the secretase, and that may well have catastrophic consequences.

But your work is no longer focused exclusively on the mechanisms of Alzheimer’s alone. Your research strategy has become much broader. Why?
A whole series of neurodegenerative diseases has been defined, and one of the crucial questions is whether or not they share some common underlying features at the mechanistic level. If so, it might be possible to treat them all in similar or related ways. For example, inflammation processes are a common feature of all these conditions. Two-and-a-half years ago a gene was identified, mutations in which are known to play an important role not only in the pathogenesis of Alzheimer’s, but also in that of other neurodegenerative disorders, such as Parkinson’s, frontotemporal dementia (FTD), FTD-like syndrome and amyotrophic lateral sclerosis (ALS). This gene is expressed only in microglia, the cells that act as the brain’s waste-disposal squad, which are also prominent in inflammation processes. We have shown that the mutation negatively affects the phagocytic function of the microglia. This means that these immune cells are less capable than non-mutant microglia of engulfing and digesting plaques and dead cells. But such cell debris must be disposed of, because it induces inflammation. So this is probably the common mechanism – and it might be possible to mitigate its effects if one could find a way to enhance the activity of this gene. Another argument in favor of such a strategy is that the gene is active only in the microglia in the brain, and nowhere else. So an intervention that targeted the product of this gene should have no side-effects on neuronal metabolism.


Prof. Dr. Christian Haass holds the Chair of Metabolic Biochemistry at LMU, is Spokesperson for the Munich-based branch of the German Center for Neurodegenerative Diseases (DZNE) and Coordinator of SyNergy (the Munich Cluster für Systems Neurology), a Cluster of Excellence.