The present study sought to determine whether glucocorticoids modulate the hallmark neuropathological features of AD and, if so, the underlying mechanism. To this end the authors investigated the pathological consequences of stress-level glucocorticoid administration on Abeta formation and tau biology using both in vitro and in vivo approaches. Here the authors report the novel findings that levels of the beta-secretase enzyme [beta-APP cleaving enzyme (BACE)] and its substrate APP are selectively increased after glucocorticoid administration, resulting in increased production of Abeta peptides. Notably, administering glucocorticoids to the triple transgenic (3Tg-AD) mice, which develop both Abeta and tau pathologies in an age-dependent manner, exacerbated the formation of both lesions. The present findings highlight a mechanism by which stress affects AD neuropathology and suggest that stress management or pharmacological reduction of glucocorticoids warrant additional consideration in the regimen of AD therapies.