‘CAA is a condition in which the protein amyloid-beta accumulates in the walls of small blood vessels in the brain,’ Wermer explains. ‘As a result, these vessels become fragile and can leak or rupture. It is an important cause of brain haemorrhages in older people and can also contribute to memory problems and dementia.’ The disease is common: an estimated quarter of people aged 65 and over already show some degree of CAA-related changes in brain tissue. CAA is also frequently observed in people with Alzheimer’s disease.
Until now, it was thought that CAA arises because the brain’s clearance system becomes less efficient with age. Amyloid-beta, a protein normally produced by the brain itsel, is then not adequately removed and begins to clump together. In Alzheimer’s disease this mainly occurs in brain tissue, whereas in CAA a variant of amyloid-beta accumulates in blood vessels.
The patient had a remarkable medical history: as a child she had undergone surgery for a benign brain tumour. Wermer discovered that several young CAA patients in her care had a similar history. They developed CAA twenty to thirty years after their operation. ‘How could that be?’ Wermer wondered.
The answer began to emerge at a conference, where a young patient was discussed who had received donor dura mater during brain surgery. In the 1970s and 1980s, a material called Lyodura, made from the dura mater of deceased human donors, was used for this purpose. It later became clear that, in rare cases, this material could transmit the prion disease Creutzfeldt-Jakob disease. Prions are abnormally folded proteins that can ‘induce’ other proteins to misfold as well.
This led Wermer to a new hypothesis: could amyloid-beta sometimes spread in a similar way? In other words, could a minute amount of abnormal protein from a donor trigger a process in a recipient that only leads to disease decades later?
This research question became even more relevant following Scandinavian studies showing that people who had received a blood transfusion from a donor with recurrent brain haemorrhages later had a higher risk of brain haemorrhage themselves. Because CAA is often accompanied by multiple brain haemorrhages, Wermer began to ask whether amyloid-beta might also be transmissible via blood.
With a Vici grant of €1.5 million from the Dutch Research Council, Wermer will now investigate this systematically. Her research will examine whether amyloid-beta can indeed be present in the bloodstream and reach the brain, and whether people with CAA are more likely to have received a blood transfusion in the past. She will also analyse, at the molecular level, what the protein looks like when it potentially spreads and explore why some individuals are genetically more susceptible to accumulation in the vessel wall than others.
The potential impact of this research is considerable. Each year, tens of thousands of people in the Netherlands receive a blood transfusion. If CAA were indeed transmissible through blood, this could have implications for screening, donation procedures and safety measures surrounding blood and organ donation.
At the same time, the research offers hope. There is currently no treatment that can halt CAA. By gaining a better understanding of how amyloid-beta behaves, how it accumulates and how it may influence other proteins, new therapies could be developed to slow down or prevent this process.
The Vici grant enables researchers to develop an innovative research line over the next five years and further expand their research group. Vici is one of the largest personal scientific awards in the Netherlands and is aimed at senior researchers. The funding instrument allows them to pursue research of their own choosing, thereby giving innovative scientific research a strong impulse.
Wermer is Head of the Department of Neurology at the UMCG and previously received both Veni and Vidi grants for her research into stroke.
