Alzheimer’s disease: A light at the end of the tunnel?

29. February 2016

December 2015 marked the 100th anniversary of Alzheimer’s death. Yet, there are still no convincing studies dealing with how to stop or even reverse the mental disease that was named after him. For now, at least the right therapeutic target has been found.

In 2014, “Scientific American” used the title “Why Alzheimer’s Drugs Keep Failing” to entice people to read about the state of Alzheimer’s research. Over the last 10 years, substances that deplete the characteristic plaques in the brains of dementia patients – and which should have returned them to a clear mental state – have all failed in the final stage of development.

Anxiety and frustration among patients and pharmaceutical companies

The discovery of German neurologist, Alois Alzheimer, was not taken seriously until well into the 90s. Today, we still react to each prominent Alzheimer’s patient – like Gerd Müller – with fright. The fear of obscured consciousness is so great that playboy Gunter Sachs stated that he would rather kill himself than lose his memory. “We just need to become old enough – then we get the disease”, says Christian Haass, a renowned dementia researcher from Germany. Approximately one quarter of those in their late eighties are affected by the disease.

It is becoming increasingly clear that decreasing the amount of amyloid plaques is not the answer. In some cases, these are more prevalent in healthy individuals, than patients with an altered mental state. The correlation therefore, becomes somewhat more complicated. Both Pfizer and Johnson & Johnson completely discontinued their development projects because studies with several thousand participants did not lead to any measurable slowing of mental deterioration. Roche discontinued further testing of its amyloid antibody after the presumably low dose resulted in a barely measurable effect.

A second chance for latecomers

For the past year, experts from research institutes have been cautiously optimistic that the millions invested in research will pay out in the long term – even if there are still no convincing results. Even the Eli-Lilly antibody Solanezumab failed in both initial Phase III studies, which involved more than 1000 patients. However, scientists have not immediately abandoned this substance. Both patients in early and advanced stages were subjected to the drug. Once the disease is in full swing, the plaques can neither be stopped nor reduced. A further analysis of the data seems to suggest that starting treatment earlier may help to delay the symptoms, if only just a little.

At the end of this year, the data of a large Solanezumab study involving earlier treatment will be published. With increasing length of treatment, the effect appears to be more distinct. This means that the binding of the monomeric β-amyloid fragments affects not only the symptoms but also the pathogenesis. Imaging suggests that the extent of plaque formation did not change after treatment. However, the difference in the preservation of cognitive abilities was apparent.

Hope for a compelling large-scale study

Another β-amyloid antibody against the aggregated amyloid showed promising data in the spring of last year. Roger Nitsch and his colleagues from the University of Zurich isolated the antibodies from the immune cells of elderly people who showed no signs of Alzheimer’s disease. In an initial small Phase I trial, the drug Aducanumab, which was developed by Biogen, showed promising results. A large Phase III trial will follow.

Nevertheless, the data of the last two years has not been able to convince all those who doubt the β-amyloid hypothesis. Isabella Heuser from Charité in Berlin, a participant in the Eli-Lilly study, says “I do not consider the recent results clinically relevant”. In fact, researchers still know too little about how much of the active agent reaches the brain and which dose would achieve the optimum effect.

Blocked scissors

Further research is therefore, being conducted with other target molecules that may influence the course of the disease. The tau tangles, typical of Alzheimer’s, are hyper-phosphorylated. According to a small study on human and rat brains recently published in “Nature Medicine”, the acetylation of soluble tau protein may mark the onset of the disease. In animal models, researchers inhibited acetylation and observed decreased neuronal atrophy in the region of the hippocampus.

An important yet difficult target are the secretases – enzymes that excise the Aβ monomers from the precursor protein but which are important for normal brain metabolism. Blocking these “scissors” therefore, has serious side effects. However, a substance from Merck seems to be able to counterbalance this; MK 8931 is currently being tested in Phase III trials. Last year, Christian Haas published the discovery, of a new amyloid monomer (Aŋ) and the associated special secretase. If other secretases are blocked, it could come to this outlet in the brain. This, however, does not have positive consequences: Aŋ significantly disrupts nerve function in the area of ​​the hippocampus.

Does inflammation get on the brain’s nerves?

For a long time, it was thought that an inflammatory response in Alzheimer’s disease was probably only a “by-product” of the disease. However, a recent article from the University of Southampton appears to assign this a crucial role in the progression of the disease. Microglial cells surround the plaques; these cells are responsible for defence mechanisms in the brain. The CSF-1-receptor is responsible for the proliferation of these cells. Blocking this molecule led to improved memory and orientation in transgenic Alzheimer’s mice models without actually decreasing the number of plaques.

With a new antibody against β-amyloid, an investigation by a German researcher, reveals how difficult the search for a treatment target is. Although the number of plaques was reduced, the number of abnormally hyperactive neurons in the mouse model increased. After a short time, these neurons necrotised. The most frightening thing about this: even in young mice that had not yet formed any plaques, there was evidence of necrotising neurons. Early treatment therefore does not appear to be the only recipe for success.

The fact that the number of plaques and cognitive performance are not always connected has also been shown by the “Nun Study”. The nuns consented to an autopsy after their deaths so that their mental agility could be compared with the extent of amyloid deposits. Even the extremely healthy women had an alarmingly high number of plaques.

Studying the onset of the disease

Where do things go from here? Scientists have placed great hope on databases of individuals who have apparently developed genetic protection against the disease. One out of every two hundred Icelanders has a mutation in the amyloid precursor, which instils a strong protection against the disease. Conversely, there is also a group of people with an increased genetic risk for this type of dementia. The earliest onset of illness is currently being studied in these individuals. The goal is to find an initial treatment before the onset of the first symptoms of this unnatural brain degradation.

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1 comment:

Dr Michel Loots
Dr Michel Loots

I wonder why you do not mention TaurX methylene-blue variant, which has shown some very positive results in phase III.

#1 |

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