A team of Cambridge researchers led by UK DRI Group Leader Prof Sir David Klenerman has shown that the accumulation of toxic brain proteins in the mid-late stages of Alzheimer’s, is driven by local replication of the proteins rather than by their spreading between brain regions. The important findings suggest that the disease mechanisms that should be therapeutically targeted may differ at each stage of the disease.
Alzheimer’s disease is the most common cause of dementia and is characterised by the accumulation of misfolded toxic proteins in the brain. One of these proteins, Tau, has been shown to spread across the brain as the disease develops, forming toxic ‘seeds’ which then replicate in previously unaffected regions. This accumulation of toxic Tau is associated with increasing cognitive symptoms such as problems with memory and language. Slowing or stopping the spreading of the Tau protein has been viewed as an exciting avenue for new treatments, but it’s not been clear whether this is an important driving mechanism at all stages of the disease.
Published today in the scientific journal Science Advances, the research team showed, using a mathematical model to analyse patient data, that the number of Tau seeds in the brain doubles approximately every five years. Using multiple independent data sets the model predicts that this local replication of Tau seeds is more important for controlling the overall levels of the toxic protein than spreading between brain regions, in the mid and late stages of Alzheimer’s disease. Therefore, it is a promising target for therapies, as targeting this process is expected to slow down the overall progression of disease significantly.
“The thinking had been that Alzheimer’s develops in a way that’s similar to many cancers: the aggregates form in one region and then spread through the brain,” said Dr Georg Meisl from Cambridge’s Yusuf Hamied Department of Chemistry, the paper’s first author. “But instead, we found that when Alzheimer’s starts there are already aggregates in multiple regions of the brain, and so trying to stop the spread between regions will do little to slow the disease.”
This is the first time that human data has been used to track which processes control the development of Alzheimer’s disease over time. It was made possible in part by the chemical kinetics approach developed at Cambridge over the last decade which allows the processes of aggregation and spread in the brain to be modelled, as well as advances in PET scanning and improvements in the sensitivity of other brain measurements.
