Alzheimer’s disease involves complex interactions between genetic, epigenetic and environmental factors that precede clinical symptoms. We recently showed that the way our genes respond to the environment is critical for cognitive function and relevant to the disease. However, the precise mechanisms are poorly understood, and to gain a better understanding will require advanced experimental modelling. Promising to this end is the use of stem cells to generate what is known as brain organoids. These are self-organizing three-dimensional tissues that consist of neurons and glia in a manner similar to the actual brain. Because such brain organoids consist of human cells and reflect aspects of human brain architecture and cellular interactions, they enable the study of disease pathogenesis in a system that is highly related to the human brain.

We have established a pipeline where we use human blood cells, taken from healthy controls and subjects with Alzheimer’s disease, that we reprogram into the necessary stem cells that allow us to generate organoids. Using these, we will assess subject-specific pathological signatures and investigate fundamental cellular disease mechanisms related to how DNA is modified, how the expression of genes is altered, and how cells change their function in connection with the disease. Our aim is to identify dysregulated genes and networks, aberrant cell populations, and ultimately therapeutic drug candidates that can be efficiently screened in brain organoids.

Brain organoids from participants of the Trønderbrain cohort generated through differentiation of human induced pluripotent stem cells (hiPSCs) show complex cytoarchitecture and great cell-type diversity.

Tuj1- immature neurons, Sox2 – neuronal progenitors, MAP2 – mature neurons, GFAP – astrocytes and DAPI – cell nuclei.