In the case of APP, endothelial dysfunction was implicated as a contributing factor for frailty in C57BL6 backgrounds [63,64], and it is possible that more general reactions of the CNS to disease (e.g., neuroinflammatory responses), rather than the effects of particular protein fibril conformation, might underlie a negative synergism with a C57BL6 background. The gene discussed is APP; the disease is endothelial dysfunction.