Cambridge researchers have used human data to measure the speed of different processes that lead to Alzheimer’s disease and found that it develops in a very different way than previously thought. The results could help researchers to develop new treatments.

An international research team, led by the University of Cambridge and supported by the NIHR Cambridge BRC, found that Alzheimer’s disease starts in multiple, different regions of the brain, rather than from a single point which then spreads elsewhere. How quickly the disease kills cells in these regions determines how quickly the disease progresses overall.

The researchers used post-mortem brain samples from Alzheimer’s patients, as well as brain PET scans from living patients with a range of cognitive impairment, from mild impairment through to those with late-stage Alzheimer’s disease. The researchers used the samples and scans to track how a protein called tau (one of two key proteins thought to cause the condition) formed into clumps called ‘aggregates’.

In Alzheimer’s disease, tau and another protein called amyloid-beta, build up into tangles and plaques (clumps) – aggregates – causing brain cells to die and the brain to shrink. This results in memory loss, personality changes and difficulty carrying out daily tasks. For many years, the processes within the brain which result in Alzheimer’s disease have been described using terms like ‘cascade’ and ‘chain reaction’. It is a difficult disease to study, since it develops over decades, and a definitive diagnosis can only be given following examination of samples of brain tissue after death.

However, by combining five different datasets and applying them to the same mathematical model, the researchers observed that the speed at which aggregates multiply in individual regions of the brain determines the progression of Alzheimer’s disease, rather than aggregates spreading from one region to another.

“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.”

The results, reported in the journal Science Advances, open up new ways of understanding the progress of Alzheimer’s and other neurodegenerative diseases, and new ways that future treatments might be developed.

This is the first time that human data has been used to understand the development of Alzheimer’s disease over time. It was made possible in part by approaches developed in Cambridge over the last decade, which allowed the modelling of protein aggregation and spread in the brain, as well as advances in PET scanning and improvements in the sensitivity of other brain measurements.

“This research shows the value of working with human data instead of imperfect animal models,” said co-senior author Professor Tuomas Knowles, also from the Department of Chemistry. “It’s exciting to see the progress in this field – fifteen years ago, the basic molecular mechanisms were determined for simple systems in a test tube by us and others; but now we’re able to study this process at the molecular level in real patients, which is an important step to one day developing treatments.”

The researchers found that tau aggregates multiply slower than expected – taking up to five years. “Neurons are surprisingly good at stopping aggregates from forming, but we need to find ways to make them even better if we’re going to develop an effective treatment,” said co-senior author Professor Sir David Klenerman, from the UK Dementia Research Institute at the University of Cambridge. “It’s fascinating how biology has evolved to stop the aggregation of proteins.

“The work allows us to determine the rate limiting molecular step in the development and spread of tau aggregate through the brain and hence should be targeted for an effective therapy for Alzheimer’s disease. In future it also might allow the effectiveness of a potential treatment to be measured by analysing the changes in PET signal over time using the model we have developed,” Professor Sir David Klenerman added.

The researchers say their research could be used to help the development of treatments for Alzheimer’s disease, which affects an estimated 44 million people worldwide, by targeting the most important processes that occur when humans develop the disease. It could also be applied to other neurodegenerative diseases, such as Parkinson’s disease.  

“The key discovery is that stopping the replication of aggregates rather than their propagation is going to be more effective at the stages of the disease that we studied,” said Knowles.

The researchers are now planning to look earlier in the development of the disease, and extend the studies to other diseases such as Frontal temporal dementia, traumatic brain injury and progressive supranuclear palsy where tau aggregates are also formed during disease.

The study is a collaboration between researchers at the UK Dementia Research Institute, the University of Cambridge and Harvard Medical School. Funding is acknowledged from Sidney Sussex College Cambridge, the European Research Council, the Royal Society, JPB Foundation, the Rainwater Foundation, the NIH, and the NIHR Cambridge Biomedical Research Centre, which supports the Cambridge Brain Bank.

To read the full paper:

Georg Meisl et al.
‘In vivo rate-determining steps of tau seed accumulation in Alzheimer’s disease.’ Science Advances (2021).
DOI: 10.1126/sciadv.abh1448