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. The gene discussed is FKBP5; the disease is depressive disorder.