Researchers have used human data for the first time to determine the speed at which Alzheimer's disease develops. They also discovered that the process is very different from what was previously believed. These results could have significant implications for the development and testing of possible treatments.
An international team led by the University of Cambridge discovered that Alzheimer's disease does not start at a single location in the brain, but instead starts a chain reaction that leads to the death of brain cell. The disease's ability to kill cells in these areas, via the production of toxic proteins clusters, restricts how fast it progresses.
Researchers used brain samples taken from Alzheimers patients post-mortem and PET scans of living patients to monitor the aggregation tau, one the two main proteins involved in the condition.
Alzheimer's disease is caused by tau and amyloid beta, a protein that also causes brain shrinkage and cell death. This causes memory loss, personality changes, and difficulty performing daily tasks.
Researchers combined five datasets and applied them to the same mathematical modeling to find that the mechanism that controls the progression of Alzheimer's disease was the replication of aggregates within the brain. This is not the spreading of aggregates from one area to another.
These results were published in Science Advances. They open up new avenues for understanding Alzheimer's disease and other neurodegenerative diseases. Future treatments may also be possible.
Advertisement
The brain processes that lead to Alzheimer's disease have been described over many years using terms such as chain reaction and cascade. Because it is difficult to study because it can develop over many decades, a definitive diagnosis cannot be made until tissue from the brain has been examined after death.
Researchers have relied heavily on animal models for years to study the disease. The toxic protein clusters in Alzheimer's disease colonize different parts of the brain, according to mice.
It was thought that Alzheimers develops in a manner similar to other cancers. The aggregates form in one area and then spread throughout the brain. Dr Georg Meisl, from Cambridge's Yusuf Hamied Department of Chemistry was the first author of the paper. Instead, we discovered that Alzheimers begins in multiple brain regions, so it is difficult to stop its spread.
It is the first time human data have been used to track the processes that control the progression of Alzheimer's disease over time. This was possible partly thanks to the Cambridge chemical kinetics approach, which allowed the brain processes of aggregation/spread to be modelled. Also, PET scanning has made it possible and other brain measurements have improved in sensitivity.
Co-senior author Professor Tuomas Knowles from the Department of Chemistry said that this research shows how important it is to work with human data rather than imperfect animal models. It is exciting to see the advancement in this field fifteen year ago. The basic molecular mechanisms for simple systems were discovered in a test tube by our group and others. But now we are able to study the process at the molecular levels in real patients which is an important step towards developing treatments.
Researchers found that tau aggregate replication takes up to five years. Co-senior author Professor David Klenerman from the UK Dementia Research Institute, University of Cambridge, stated that neurons are remarkable at stopping aggregates from growing. However, we need to improve their abilities if we want to develop an effective treatment. It is amazing how biology evolved to prevent the aggregation and formation of proteins.
Advertisement
Researchers believe their method could be used to develop treatments for Alzheimer's disease. This disease affects approximately 44 million people around the world. It targets the most critical processes that occur in the human development of the disease. The methodology could also be used to treat other neurodegenerative diseases like Parkinson's disease.
Knowles stated that the key finding is that stopping aggregates from replicating is more effective than stopping them propagating in the stages of the disease.
Researchers are currently looking at earlier stages in the development and expansion of studies to other diseases like Frontal temporal dementia and traumatic brain injury.
This study was conducted in collaboration with researchers from the University of Cambridge, Harvard Medical School and the UK Dementia Research Institute. The Sidney Sussex College Cambridge, European Research Council Grant Number and the Royal Society, JPB foundation, Rainwater foundation all acknowledge funding.
