The Role of Cortisol in CNS Disease –11β-HSD1 Inhibition as a Potential New Therapeutic Strategy for Alzheimer’s Disease and Major Depressive Disorder

Cortisol is primarily synthesized by the adrenal glands, but also within specific tissues via a distinct enzymatic pathway. 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) catalyses the synthesis of cortisol within cells to create local higher cortisol environments in those organs where it is highly expressed such as the liver and brain. An extensive preclinical and clinical literature suggests that chronically, excess cortisol is detrimental. Since 11β-HSD1 expression rises with ageing, contributes to cognitive and affective disorders, and is strongly associated with Alzheimer’s disease, 11β-HSD1 inhibitors may plausibly treat cognitive and functional decline in Alzheimer’s disease and improve depression. Two inhibitors (ABT-384 and emestedastat) were studied in 12-week trials in patients with clinically diagnosed, unconfirmed Alzheimer’s disease (AD) and showed no overall benefits as a cognitive enhancer. When a subgroup with elevated blood pTau181 was later evaluated in the emestedastat trial, a slowing in progression was observed. A trial of emestedastat treatment has also reported anti-depressant activity. Thus, 11β-HSD1 inhibition appears to be a viable therapeutic mechanism. A pivotal, confirmatory trial of emestedastat treatment in 247 patients with mild-moderate AD is due to report topline results in November this year.