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

Individuals must meet criteria for mild cognitive impairment due to Alzheimer's disease according to National Institute on Aging (NIA)/Alzheimer's Association recommendations OR be cognitively normal based on clinical and cognitive assessment in the Enrollment Visit and have at least one of the following risk factors for AD:

• Known to have at least 1 apolipoprotein E (APOE) ε4 allele;

• Subjective cognitive concerns with a T score < 40 on the Multifactorial Memory Questionnaire Satisfaction Scale;

• A first-degree relative with dementia.

Inclusion Criteria for all subjects:

• At least 55 years of age;

• Body mass index >17 and <30;

• Post-menopausal (if female)

• Non-smoker;

• Availability of a study partner who has frequent contact with the subject (10+ hours/week in person and by telephone), and is able to provide an independent evaluation of functioning;

• Native English speaker;

• Good general health with no disease expected to interfere with the study;

• Willing and able to participate for the duration of the study.

Exclusion Criteria for all subjects:

• Participation in a therapeutic clinical trial at any time during the study;

• Abnormal corrected QT interval using Bazett's formula (QTcB; defined as > 450 ms for men and > 470 ms for women) as determined on ECG;

• Any significant neurologic disease other than suspected incipient Alzheimer's disease, such as Parkinson's disease, multi-infarct dementia, Huntington's disease, normal pressure hydrocephalus, brain tumor, progressive supranuclear palsy, seizure disorder, subdural hematoma, multiple sclerosis, or history of significant head trauma followed by persistent neurologic deficits or known structural brain abnormalities, including lacunes in critical memory structures including the hippocampus and parahippocampal cortex;

• Major depression, bipolar disorder within the past 1 year;

• History of alcohol or drug dependence;

• Any significant systemic illness or unstable medical condition, which could lead to difficulty complying with the protocol;

• General surgery within the last 3 months;

• Sensory impairment (poor vision or hearing) significant enough to interfere with ability to provide valid cognitive test data;

• Treatment within the last six months with antidepressants, neuroleptics, sedative hypnotics, or glucocorticoids;

• Treatment within the last six months with medications metabolized by the CYP2C9 or CYP2C19 enzymes, most notably clopidogrel and proton pump inhibitors;

• Concurrent use of a CYP3A inhibitor, including grapefruit juice, and St. John's Wort;

• Exceptions to these guidelines may be considered on a case-by-case basis at the discretion of the PI.