The cause of Alzheimer's disease lies in brain evolution

For many decades, scientists at the University of Leipzig have been researching the causes, diagnosis and therapy of Alzheimer's disease. Now a team led by Prof. Dr. Thomas Arendt from the Paul Flechsig Institute for Brain Research in genome and transcriptome analyzes show that the genes with altered activation in Alzheimer's were subject to evolutionary biological adaptations in the recent phylogenetic past. This makes Alzheimer's a human-specific disease that can only be simulated in animal experiments to a very limited extent. The researchers recently published these results in the journal Molecular Psychiatry.

For many decades, scientists at the University of Leipzig have been researching the causes, diagnosis and therapy of Alzheimer's disease. Now a team led by Prof. Dr. Thomas Arendt from the Paul Flechsig Institute for Brain Research in genome and transcriptome analyzes show that the genes with altered activation in Alzheimer's were subject to evolutionary biological adaptations in the recent phylogenetic past. This makes Alzheimer's a human-specific disease that can only be simulated in animal experiments to a very limited extent. The researchers recently published these results in the journal Molecular Psychiatry.

In Germany there are currently around 1,2 million people with Alzheimer's disease. About 500 new cases are added every day. According to estimates by the WHO, in about 20 years the disease will be the second leading cause of death worldwide, ahead of tumor diseases. The development of preventive or therapeutic strategies is therefore one of the most important challenges facing biomedical research today. However, all attempts to develop a therapy have so far failed. “To date, well over 300 therapeutic procedures have been successfully developed and tested on animal models. None has shown therapeutic efficacy in patients,” says Prof. Dr. Thomas Arendt, Director of the Paul Flechsig Institute for Brain Research. This inability to translate from the animal model to the patient raised fundamental doubts about the previous disease concepts.

Human genome compared to that of other mammals

Together with the working group of Prof. Dr. In a first step, Peter Stadler from the Interdisciplinary Center for Bioinformatics at the University of Leipzig, Arendt and his team compared the activity of the genes of Alzheimer's patients with those of healthy people. Here they came across a pattern: certain genes were active differently in people with Alzheimer's than in healthy people. They then traced the evolutionary development of these genes and compared them to the genomes of non-human primates and others. “The gene segments of most mammals are now known and sequenced. They are stored in large databases, so we were able to understand what changes these genes have undergone during evolution," explains Prof. Dr. Thomas Arendt.

Affected brain structures and genes only changed in recent human development

The researchers were able to show that recent evolutionary adaptations of the brain are causally involved in the development of the disease. It primarily affects those brain structures that only developed late in the more recent development of mankind towards homo sapiens. At the same time, the genes whose activity is altered in the disease were subject to evolutionary biological adaptations in the recent phylogenetic past. "The reasons for these changes in the development from the great apes to humans are the result of adaptations that have optimized the performance of the human brain," says Arendt.

Majority of animal experiments highly inappropriate

Arendt was thus able to scientifically prove the concept he had been pursuing for a long time: Alzheimer's disease is a phylogenetic, i.e. a phylogenetic, disease. At the same time, it becomes clear that Alzheimer's is a human-specific disease, the mechanism of which can only be imitated to a very limited extent in animal experiments. “This insight is likely to have far-reaching consequences for future therapy development. A large part of the animal experiments, which are almost exclusively carried out on mice, are highly unsuitable because their gene structure differs significantly from that of humans,” says Prof. Arendt. Only certain aspects of the disease could continue to be tested in animal models. Future therapeutic developments would now have to concentrate more on the genomic sections and cell components that have developed in the more recent phylogenetic development of humans.

Decades of expertise in the field of Alzheimer's research

Thomas Arendt has been researching Alzheimer's disease for 40 years. In the early 1980s, he was involved in the discovery that laid the basis for the only possible treatment to date: the researchers observed that neurons in the brains of Alzheimer's patients that use the messenger substance acetylcholine to transmit signals die. The messenger substance is no longer formed, the transmission of information no longer works. A special drug can at least slow down this process. In December 2018, the University of Leipzig was able to obtain the exclusive license for one of Prof. Dr. Thomas Arendt for the early diagnosis of Alzheimer's disease was awarded to a biotechnology company in the USA. 

Original publication in Molecular Psychiatry:

“Alzheimer-related genes show accelerated evolution” DOI: https://doi.org/10.1038/s41380-020-0680-1

Source: Press release from the University of Leipzig from March 13.03.2020, XNUMX