In Alzheimer’s disease, harmful protein build-ups develop in the brain, damaging brain cells. The brain’s immune cells, attempt to clean up these protein clumps, but in people with Alzheimer’s disease this process often fails.
'The APOE-ε4 gene variant increases the risk of Alzheimer’s and is associated with abnormal immune responses,' Van Olst explains. 'That’s why I want to investigate how this gene variant affects the functioning of immune cells in the brain.'
'The brain’s immune cells, called microglia, have a wide range of tasks,' says Van Olst. 'They are spider-shaped cells that constantly scan their surroundings for threats. You can think of them as the cleaners and guards of the brain. They clear away harmful waste, remove dead cells, defend against viruses and bacteria, and maintain the connections between brain cells. In short: they make sure everything is in order.'
In Alzheimer’s disease, proteins such as amyloid-beta and tau accumulate in the brain. These clumps can damage brain cells and need to be removed. Microglia try to do that job, but in Alzheimer’s disease, they become overstressed and overactive. Instead of protecting the brain, they may release inflammatory substances or even attack healthy cells. When this happens, their energy is drained, and they stop working on their maintaining tasks.
'We don’t fully understand yet why microglia malfunction in Alzheimer’s,' says Van Olst. 'But we do know that genetic predisposition plays an important role. One of the strongest genetic risk factors for Alzheimer’s is the APOE-ε4 variant. However, how this variant leads to abnormal immune responses is still unclear.'
With her Veni grant, Van Olst focuses on epigenetics: the system that determines whether genes are switched on or off, without changing the DNA itself. 'Think of DNA as a cookbook,' Van Olst explains. 'It contains all the recipes (genes) your body might need. But not every cell uses every recipe. A muscle cell, for instance, uses different instructions than a brain or immune cell. Epigenetics decides which recipes are used – it's like the head chef choosing which dishes to prepare.' These decisions are controlled by switches on the DNA. Factors like age, environment, diet, stress and disease can affect these switches and potentially change how microglia behave.
Van Olst wants to find out whether altered activity of these switches could explain why microglia behave differently in people who carry the APOE-ε4 gene variant and whether that contributes to their higher risk of Alzheimer’s disease. 'Ultimately, I want to understand why microglia stop working properly in Alzheimer’s patients who carry this risk gene.'
Her research could lead to the development of new treatments or the improvement of existing ones. 'We know that people with the APOE-ε4 variant often respond less well to current Alzheimer’s therapies. That may be due to differences in immune responses. If we understand how these immune cells function differently in APOE-ε4 carriers, we can look for ways to fix that in the future.'
