My research focuses on understanding how stress impacts brain ageing and cognitive function in health and disease. The goal is to uncover mechanisms in the brain that could reveal potential targets for the treatment of cognitive impairment associated with ageing and stress-related disorders.

Cognitive impairment in the absence of neuropathology occurs in a substantial segment of the elderly population. The mechanisms that underlie mild cognitive impairment (MCI), which may precede dementia, are not fully understood. Risk factors include age, genetics and other health conditions such as diabetes, obesity, and depression. One environmental factor linked to MCI of particular interest is increased exposure to stress glucocorticoid hormones over the lifespan.

We discovered that 11beta-HSD1, an enzyme that locally generates active glucocorticoids within specific target tissues including in the brain, directly contributes to age-related cognitive decline. Among our key findings, a deficiency of 11beta-HSD1 in a transgenic mouse model protects against impaired memory in old age; and pharmacological inhibition of the enzyme reverses the age-related memory deficits. This highlights 11beta-HSD1 as a novel therapeutic target for cognitive enhancement. For the translation of our preclinical work to humans, Prof. Scott Webster developed the CNS-active 11beta-HSD1 inhibitor Xanamem currently in clinical trials for early Alzheimer’s disease and major depressive disorder (Actinogen Medical).