Level of research

• The first changes in the brain appear 20 years before the appearance of symptoms.
• Naturally occurring clumps of protein damage the nerve cells in the brain and lead to inflammatory reactions.
• In the end nerve cells in the brain die, causing certain areas in the brain to shrink and to become typically forgetful.
• Currently, only the symptoms but not the causes of Alzheimer’s disease can be treated.
• New drugs that fight the causes are currently being developed.
• However, all future medications can only work if they are used very early after the occurence of Alzheimer’s symptoms or even preventively.
• One of these drugs, Aducanumab, can remove one type of the protein clumps in the brain. However, it has not yet been clarified whether it can actually stop the memory loss, even if the first results are encouraging.

Alzheimer’s disease has three major changes in the brain. The brain shrinks because nerve cells die, and there are also two types of protein clumps that are typical of the disease, the so-called amyloid plaques and the bundles of tau fibrils. These changes are caused by several molecular processes in the brain that span a period of 20 to 25 years before the first symptoms of Alzheimer’s disease appear, especially forgetfulness. At the beginning of the molecular processes there is the formation of a protein fragment, which is called amyloid b or Ab and is cut out of an even larger protein by two molecular scissors (so-called secretases). Ab is formed normally in the human body and is not harmful because it is quickly eliminated by the cellular garbage disposal in the brain. As we get older, cellular garbage disposal often doesn’t work as efficiently, so the amount of Ab in the brain increases. As a result, Ab can form clumps, which in turn damage nerve cells and cause the dew protein to form clumps. As the disease develops, both clumps become larger, which leads to the formation of the amyloid plaques and the bundles of tau fibrils. The initially small clumps continue to damage the nerve cells in the brain, leading to inflammatory reactions and ultimately the death of nerve cells in the brain. If a large part of the nerve cells are damaged or dead in certain areas of the brain, symptoms of Alzheimer’s appear. The course of the disease development described here is very well documented by experimental data, including brain imaging, brain fluid examination and genetic mutations that lead to an inherited form of Alzheimer’s disease in a few people or prevent the disease completely.

Abbildung 1: Entstehung der Alzheimer Krankheit

When are there drugs to treat the causes of Alzheimer’s disease?

Currently, only the symptoms of Alzheimer’s disease, but not the causes, can be treated. In the long phase of disease development (approx. 25 years), it would be particularly sensible to stop the development of the disease preventively and thus prevent Alzheimer’s disease before the occurence of symptoms. For prevention, it is advisable to stop the formation of Ab or its clumping. This is being tested with several medications.

One approach is to use medication to block the top of the two scissors (b-secretase) and thus prevent the formation of Ab. Since these drugs fight the very first cause of Alzheimer’s disease, they are no longer effective as soon as the symptoms of Alzheimer’s disease appear, but must be used specifically for prevention. New prevention studies are planned. It is a great help here that certain brain examinations can already predict relatively well who is likely to develop Alzheimer’s disease in a few years and is therefore particularly well suited for preventive treatment.

The most advanced is the development of the so-called passive vaccination, in which antibodies against Ab are administered by infusion and ensure that Ab is efficiently removed by cellular waste disposal. One of these drugs, aducanumab, may be approved in 2020. If given to Alzheimer’s patients, this drug will not stop the disease, but will slow it down, which is a big step forward for those affected. However, this drug may be able to completely prevent the disease if it is already administered preventively. This is now being examined in clinical studies.

In order to treat Alzheimer’s disease efficiently after it has broken out, it is important to intervene later in the sequence of the individual disease steps in Figure 1. Drugs are currently being developed here that prevent or remove the dew clumps or suppress the unwanted inflammatory reactions in the brain. However, it will take several years before these drugs are approved.

The brain is a tremendously complex organ, and diseases such as Alzheimer’s and other forms of dementia, in which nerve cells are damaged and destroyed – and so far irreversibly – are correspondingly complex. At the DZNE, the most modern research methods are used to get to the bottom of complex diseases of the brain – such as Alzheimer’s or other forms of dementia. Every month since September 2020, journalist Sabine Heinrich has been asking internationally leading scientists questions about the state of research in the DZNE’s knowledge podcast. The first episode focuses on health services research. The interviewer is Prof. Dr. Wolfgang Hoffmann from the University of Greifswald.