Cognitive decline with ageing is highly variable, with some individuals showing minimal change, and others developing dementias. Clinically significant cognitive impairment is among the most important unmet medical needs worldwide: currently there are virtually no generally accepted effective prevention strategies or treatments.
Ageing is associated with multiple changes in hormone levels and target tissue sensitivity. There is a rapidly growing evidence base exploring the associations among these parameters and variations in the trajectories of cognitive decline with ageing. For example, elevated circulating glucocorticoids with ageing, likely occurring as a result of impaired feedback regulation of the hypothalamicpituitaryadrenal axis, have been linked with cognitive decline in many studies. Higher activity of the intracellular glucocorticoid-amplifying enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), which increases local action of glucocorticoids, has also recently been implicated in cognitive decline in animal and human studies. There are few interventional studies in animals or humans which have examined glucocorticoid antagonism (e.g. receptor antagonists, 11β-HSD1 inhibitors), but these have provided some promising results. Type II diabetes mellitus is a major risk factor for cognitive decline; improved prevention and treatment of will likely have positive impacts on cognition as well as other outcomes. Including adequate cognitive outcomes measures in trials of anti-diabetes drugs in older patients would help to clarify which treatments are most effective. Many hormones show mean reductions in levels with ageing, e.g. DHEA, gonadal steroids, melatonin and GH. Some studies have linked these declines with cognitive impairment; however, inteventional studies in animals have not yet yielded clear conclusions and there is a paucity of clinical trials.
In summary, many relationships among variations in hormones and cognitive decline have been demonstrated. These provide multiple potential therapeutic targets. Definitive interventional trials are currently lacking but hold high promise for the development of new treatments.