Harmful tau protein spreads through networks. Author provided
Alzheimer’s disease is a devastating brain illness that affects an estimated 47m people worldwide. It is the most common cause of dementia in the Western world. Despite this, there are currently no treatments that are effective in curing Alzheimer’s disease or preventing its relentless progression.
Alzheimer’s disease is caused by the build-up of two abnormal proteins, beta-amyloid and tau. Tau is particularly important because it causes neurons and their connections to die, preventing brain regions from communicating with each other normally. In the majority of cases, tau pathology first appears in the memory centres of the brain, known as the entorhinal cortex and hippocampal formation. This has been shown to occur many years before patients have any symptoms of disease.
Over time, tau begins to appear in increasing quantities throughout the brain. This causes the characteristic progression of symptoms in Alzheimer’s diseases, where initial memory loss is followed by more widespread changes in thinking and behaviour that lead to a loss of independence. How this occurs has been controversial.
In our study, published in Brain, we provide the first evidence from humans that tau spreads between connected neurons. This is an important step, because stopping this spread at an early stage might prevent or freeze the symptoms of Alzheimer’s disease.
This idea, called “transneuronal spread”, has been proposed before and is supported by studies in mice. If abnormal tau is injected into a healthy mouse brain, it quickly spreads and causes the mice to manifest dementia symptoms. However, it had not previously been shown that this same process occurs in humans. The evidence from mouse studies was controversial, as the amount of tau injected was relatively high, and disease progression occurred much more rapidly than it does in humans.
Artist’s impression of tau spreading between connected neurons. Author provided
In our study, we combined two advanced brain imaging techniques. The first, positron emission tomography (PET), allows us to scan the brain for the presence of specific molecules. With this, we were able to directly observe the abnormal tau in living patients, to see exactly how much of it was present in each part of the brain.
The second, functional magnetic resonance imaging (fMRI), measures blood flow in the brain in real time. This allowed us to observe the activity produced by brain regions communicating with each other. For the first time, by scanning the same people with both methods, we were able to directly relate the connections of the brain to the distribution of abnormal tau in living humans with Alzheimer’s disease.
We used a mathematical technique called “graph analysis” to analyse brain connectivity. This technique involved splitting the brain up into 598 regions of equal size. We then treated the connectivity between regions like a social network, assessing factors such as the number of contacts a brain region had, how many “friendship” groups it took part in, and how many of a brain region’s contacts were also contacts of each other.