pital clinics and biased toward the more severe end of the spectrum of diabetes. The main limitation of our study is its cross- sectional design. We accounted partly for this by adjusting for a vocabulary measure (MHVS), which allowed us to estimate life- time cognitive change. In addition, the use of multiple statistical tests raises the possi- bility of our signiﬁcant ﬁndings being type 1 errors. The tests we used are recognized to be sensitive and so we think this unlikely, but clearly the results need replicating in other populations. If further investigation demonstrates that the relationship between cortisol and lifetime cognitive change is causal, such that higher lifetime levels of cortisol accelerate age-related cognitive impairment, it is pos- sible that therapeutic manipulations that lower cortisol levels may help to improve cognitive function. Access of cortisol to the glucocorticoid receptor is regulated by local activity of the 11 -hydroxysteroid dehy- drogenase enzymes (11 -HSDs), which catalyze the interconversion of the active steroid cortisol and its inactive metabolite cortisone. 11 -HSD1 reactivates cortisol from inactive cortisone in many central ner- vous system and metabolic sites, increasing activation of the glucocorticoid receptor. In a small, randomized, double-blind, placebo-controlled, crossover study, ad- ministration of the 11 -HSD inhibitor, car- benoxolone, improved verbal ﬂuency after 4 weeks in 10 healthy elderly men (aged 55–75 years) and improved verbal memory after 6 weeks in 12 people with type 2 diabetes (25). Whether this short- term effect on cognitive ability could be reproduced over longer time periods, and therefore help reduce the cognitive de- cline associated with aging, is unknown. Notably, verbal ﬂuency was not related to fasting plasma cortisol in the current study. In conclusion, morning cortisol levels in elderly people with type 2 diabetes are high, with deleterious effects on cognitive function. Further investigation is re- quired to determine the direction and na- ture of this relationship, which, if causal, would support the use of therapeutic strategies to lower cortisol action (25) to ameliorate cognitive decline in individu- als with type 2 diabetes. Acknowledgments — This study was sup- ported by a grant from the Medical Research Council. Funding from the Biotechnology and Biological Sciences Research Council, Engi- neering and Physical Sciences Research Coun- care.diabetesjournals.org cil, Economic and Social Research Council, and Medical Research Council is gratefully ac- knowledged. B.M.F., J.R.S., I.J.D., and J.F.P. are members of the University of Edinburgh Centre for Cognitive Ageing and Cognitive Ep- idemiology, part of the cross council Lifelong Health and Wellbeing Initiative. 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