Trial of CORT108297 to Attenuate the Effects of Acute Stress in the Allocortex (CORT-X)

CORT-X will examine if mitigation of stress-mediated pathogenesis of Alzheimer's disease (AD) is a feasible target for intervention in individuals at risk for this disease. This single-site (Baltimore, Maryland) phase II clinical trial is a 2-week, randomized, placebo-controlled crossover study of the effects of the selective glucocorticoid receptor antagonist, CORT108297, on cognitive test performance in 26 individuals with mild cognitive impairment (MCI) due to AD and in 26 cognitively normal individuals with an increased risk for AD due to family history, genetics, and/or subjective memory complaints. All subjects will participate in a brief stressor (public speaking and mental arithmetic) and provide saliva samples so investigators can measure stress hormone response. Then, following 2 weeks of treatment with placebo or CORT108297, in counterbalanced order, participants will complete cognitive tests assessing memory and executive function. All study participants will receive CORT108297 and placebo over the course of this 10-week trial that requires 6 in-person study visits. The primary aims will compare the effects of CORT108297 to placebo on cognitive test performance in individuals with MCI due to AD and in individuals at risk for AD, and describe the side effects of CORT108297 in study participants. Secondary aims will identify subject characteristics that predict positive response to study drug.