Figure 7: AD risk factors cause loss of gene-expression control.Our central hypothesis is that the various AD risk factors eventually lead to aberrant gene-expression and loss of transcriptional control. This is based on the assumption that proper gene-expression is a core feature of cellular homeostasis and that changes occurring at various compartments of the cell (e.g. at the synapse) will eventually signal to the nucleus and cause gene-expression changes. In the case of FMN2 we provide for example evidence that chronically low levels of FMN2 disturb synaptic actin dynamics and thereby affect ERK1/2-dependent gene-expression programs. Thus, even if an AD risk factor may play no direct role in gene-expression it may eventually contribute to a loss of transcriptional plasticity. We therefore suggest that targeting pathological gene-expression could be a suitable therapeutic approach, especially for multifactorial diseases such as AD, where it is nearly impossible to determine all of the genetic and environmental factors that eventually contribute to clinical phenotypes. 