Regarding a possible role of FKBP5 in the concept of ‘brain reserve’ in late life depression there are two hypothesis: first, one could assume that considering the adverse effects of a dysregulated HPA axis on the brain structure, FKBP5, as a central element of the HPA axis, might modulate the ‘brain reserve’ itself and gains its influence on depressive disorders via this pathway. This evidence concerns the gene FKBP5 and major depressive disorder.