Amyloid: the trigger of a lethal cascade leading to nerve cell death

In Alzheimer's patients, clumps of amyloid form in the brain long before the first symptoms appear. They play a central role in the development of the disease.

The clumps are one of the most striking phenomena in the brains of Alzheimer's patients: they consist of a protein called beta amyloid (amyloid for short) and are deposited between the nerve cells. Experts refer to these clumps as plaques, which disrupt signal transmission between nerve cells and ultimately initiate a cascade that is fatal for nerve cells. Amyloid plaques therefore play a central role in Alzheimer's disease - and also offer an important starting point for future therapies.

Amyloid is produced by all humans - from birth. With increasing age, its concentration in the brain increases; this is also a normal development. In the healthy brain, amyloid is decomposed without any problems. In Alzheimer's disease, however, this decomposition process is disturbed and the clumps form. Amyloid alone, however, cannot cause the disease. In the brains of all Alzheimer's patients, there is another deposit in nerve cells - tau accumulations. For a long time, there were two conflicting camps in science - the proponents of the Amyloid hypothesis and the proponents of the Tau hypothesis. The proponents saw one of these proteins as the trigger of Alzheimer's dementia. In the meantime, however, the opposition between the hypotheses has been largely resolved: it has been shown that amyloid is at the head of a cascade, which then triggers the accumulation of tau, which in turn triggers nerve cell death and, consequently, memory loss. 

The amyloid plaques form at a very early stage. In some cases, it takes decades from the first clumps until patients feel the first Alzheimer's symptoms and complain of memory problems for the first time. The malicious aspect of this is that by this time the disease has progressed so far that it is often too late for effective treatment. Those who come to the memory clinic for the first time because of their Alzheimer's disease usually already have massive amyloid plaques everywhere in their brains.

Many researchers working on an Alzheimer's drug are therefore targeting the amyloid. Their reasoning: If the clumping can be prevented at an early stage, it could potentially prevent the disease. The starting point is the amyloid cascade: amyloid triggers a whole series of subsequent effects at the molecular level. If plaque formation is prevented, this cascade could be interrupted, is the assumption of the scientists.

In recent years, promising approaches have repeatedly failed, and numerous drug trials had to be discontinued. Most recently, however, an active substance called lecanemab has achieved great success in Alzheimer's treatment in a clinical trial. This antibody recognizes plaques in the brain and thus initiates their degradation by immune cells. Antibodies such as lecanemab succeed in removing up to 70 percent of the plaques from the brain. Over 18 months of treatment, this therapy reduced memory loss by 34 percent. At the same time, tau accumulation decreased and nerve cell death was also reduced. This ultimately proved the amyloid hypothesis in humans. Anti-amyloid therapy interrupts the cascade and slows memory loss. For patients, this is a promising success, but it also has its limitations: For example, a prerequisite for its effectiveness is that patients are treated at a very early stage - at a moment when they themselves often hardly notice any memory loss. Many patients at a more advanced stage still have no drug available.

Another important question in connection with amyloid is therefore how plaques can be detected at an early stage. Today, researchers can use amyloid PET for this purpose - however, this positron emission tomography, an imaging technique, is an extremely complex and expensive procedure, which is why it cannot be used on a widespread basis. One solution could be so-called blood biomarkers, such as those recently discovered at the DZNE: These are an indicator that can be determined in a blood sample. If certain substances are present in the blood in a certain concentration, this indicates the clumping of amyloid beta in the brain. In addition, a reduction of amyloid in the blood indicates the beginning of a deposition process in the brain. As the amyloid clumps together and is deposited in the plaques, there is no longer enough free amyloid to be removed into the blood. This test is very reliable and can be used at very early stages, when PET is not sensitive enough.

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