Onderzoek naar microglia-fenotypen bij de ziekte van Alzheimer vanuit een multi-omics perspectief

Alzheimer's disease is the most common cause of dementia, yet treatments that truly slow it down are still limited. One reason is that Alzheimer's develops over many years and affects many processes in the brain. Alongside neurons, the brain's immune system is deeply involved - especially microglia, the immune cells that act as the brain's cleaners and first responders. Microglia patrol the brain, remove waste, and react to damage. In Alzheimer's, they gather around amyloid-β plaques and can be helpful (clearing debris and protecting tissue) or harmful (staying switched on too long and causing inflammation). Many genetic risk factors for Alzheimer's affect genes that are particularly active in microglia, making them important for understanding disease and finding new treatment targets. However, microglia are very sensitive to their surroundings: they can behave differently depending on the experimental model used and on a person's genetics. Another open question is why women are diagnosed with Alzheimer's more often than men. Longer lifespan plays a part, but biology may also matter, including differences linked to sex chromosomes. This thesis studies human microglia using several model systems and types of data, with a focus on proteins (the molecules that do most of the work in cells) as well as genes. First, we map a "core" set of microglial proteins by comparing human and mouse microglia across different commonly used settings, showing which features are consistent and which change with the model - information that matters when translating results to human disease. Next, we use human microglia made from stem cells that are genetically matched except for their sex chromosomes (XX, XY, or XO) and transplant them into mouse brains with amyloid plaques. This lets us separate "sex" from "sex chromosomes" and shows that the number of X chromosomes inside microglia strongly shifts their behaviour, pushing cells toward more immune activity and changes in fat and energy-related pathways. We then test how well these patterns hold up in real human diversity, using microglia from 31 different donors studied together, where we find similar sex-linked patterns across backgrounds and a broadly similar microglial response to amyloid in both sexes. Finally, we introduce a continuous "X-Factor" (X-FAC) scale that captures meaningful differences between individuals beyond simple female/male labels. Together, these results offer resources and practical tools for understanding how experimental models, genetics, and sex chromosomes shape human microglia in Alzheimer's disease.