Tackling tau, scientists find local spread is how Alzheimer’s progresses

Researchers have shed light on how one of the hallmark Alzheimer’s proteins, tau, spreads throughout the human brain during disease, and what limits this spread at various disease stages.

Scientists at the University of Cambridge used a mixture of chemical, mathematical and biological techniques to track the protein’s progress across different brain regions.

They published their findings today (Friday 29 October) in the scientific journal, Science Advances.

In Alzheimer’s disease, a protein called tau starts to behave out of character. Abnormal changes in the protein causes tau to stick together and form damaging tangles inside nerve cells.

Tau proteins can also grow and create more copies (called replication), as well as spreading from cell to cell across the brain.

This happens in a predictable way, but it is unclear how the proteins spread and exactly what effect this has on the brain.

Now, Prof Sir David Klenerman at the University of Cambridge led a team of researchers including Alzheimer’s Research UK’s Chief Scientific Officer, Prof James Rowe, to shed more light on this process.

The scientists wanted to understand whether the replication or the spreading of tau is the most damaging factor.

Their findings suggest that in mid-late stage Alzheimer’s, it appears to be local replication of tau that drives the most build-up, rather than spreading of the protein between brain regions.

The discovery suggests that new treatments against tau could be most effective if designed to stop this replication of tau inside the brain.

They also found that this spread occurs in the human brain a lot slower than other models of disease that researchers would commonly use to study the disease such as test tube experiments and studies using mice.

Dr Sara Imarisio, Head of Research at Alzheimer’s Research UK, said: “Tau is a protein that forms tangles inside brain nerve cells during Alzheimer’s but exactly how the protein spreads throughout the human brain during the disease has so far eluded scientists. Alzheimer’s disease is the leading cause of dementia, a devastating condition that affects the lives of nearly one million people in the UK. “In this work, scientists have used a multi-angled approach to shed more light on the mechanisms by which tau contributes to the progression of Alzheimer’s disease. This study highlights that the replication of tau is the limiting factor in the progression of mid-to-late stages of Alzheimer’s disease rather than the spread of tau between brain regions. The findings could help scientists focus in on the most effective way to target potential new treatments for Alzheimer’s disease. “This thorough research study highlights the advantage of bringing together different disciplines and datasets to advance our understanding of Alzheimer’s disease, including postmortem brain tissue and PET brain imaging. “Tau is a culprit protein in a number of different dementias, and it would make sense to explore how this protein spreads in diseases like frontotemporal dementia. Hopefully this study and others like it will help focus the development of future treatments that target tau, so any future treatments have a better chance of slowing the disease processes themselves and have benefit for people with dementia.”

The collaborative team included researchers at the UK Dementia Research Institute, co-founded by Alzheimer’s Research UK.

The team used a mixture of methods, including brain tissue from 29 individuals at different stages of disease and PET imaging of tau in the brain taken two years apart.

The team combined the information from five different datasets and applied them to the same mathematical model

Science Advances: In vivo rate-determining steps of tau seed accumulation in Alzheimer’s