Table 2—Correlations between clinical variables, plasma cortisol, and cognition Cortisol MR lnTMT FACES Demographic variables Age Female sex Current smoking Alcohol intake (drinks/week) Anxiety and depressive symptoms HADS anxiety HADS depression Diabetes and metabolic variables Duration of diabetes (years) Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) Total cholesterol (mmol/l) A1C (%) BMI Myocardial infarction Angina ABI Cerebrovascular disease *P 0.05; †P 0.001; ‡P 0.01. 0.066* 0.003 0.021 0.037 0.010 0.044 0.036 0.047 0.005 0.152† 0.034 0.088‡ 0.009 0.027 0.048 0.011 0.171† 0.137† 0.023 0.172† 0.146† 0.154† 0.008 0.019 0.073* 0.018 0.005 0.053 0.060 0.096‡ 0.064 0.060 LNS 0.151† 0.035 0.081* 0.145† 0.137† 0.131† 0.071* 0.041 0.037 0.047 0.033 0.007 0.039 0.066* 0.021 0.082* VFT 0.074* 0.009 0.054 0.145† 0.131† 0.119† 0.069* 0.040 0.016 0.022 0.066* 0.054 0.026 0.014 0.010 0.062 DST 0.202† 0.181† 0.035 0.038 0.083* 0.187† 0.140† 0.011 0.027 0.056 0.038 0.028 0.146† 0.157† 0.075* 0.135† 0.185† 0.053 0.015 0.028 0.121† 0.179† 0.112‡ 0.049 0.001 0.019 0.005 0.001 0.086* 0.099‡ 0.026 0.110* 0.136† 0.191† 0.034 0.029 0.018 0.066* 0.109‡ 0.026 0.032 0.048 0.021 0.016 0.111‡ 0.081* 0.0 0.066* Reynolds and Associates LM 0.100‡ 0.111‡ 0.026 0.052 0.056 0.107‡ 0.033 0.009 0.043 0.012 0.012 0.029 0.030 0.060 0.022 0.067* g 0.225† 0.059 0.014 0.134† 0.147† 0.208† 0.111‡ 0.039 0.032 0.051 0.029 0.034 0.118† 0.141† 0.049 0.142† in Fig. 1 and in online appendix Table 1 (available at http://care.diabetesjournals. org/cgi/content/full/dc09-1796/DC1). CONCLUSIONS — Evidence from both animal and human studies supports the premise that high cortisol levels have an adverse effect on cognitive decline, but only a few small studies have suggested that this may occur in people with diabe- tes (1,18). In this large study of elderly men and women with type 2 diabetes, we found that higher fasting morning cortisol levels were not related to current cogni- tive ability but were associated with esti- mated cognitive change, that is, with some tests of current cognitive function- ing after adjustment for estimated prior cognitive ability. Speciﬁcally, higher cor- tisol levels were associated with signiﬁ- cantly lower general cognitive ability (g) and with signiﬁcantly poorer scores on LNS (working memory) and DST (pro- cessing speed) and with trends for poorer cognitive function in other domains, in- cluding mental ﬂexibility, nonverbal memory, immediate and delayed mem- ory, and general cognitive ability. We found signiﬁcant associations of higher cortisol levels with two cognitive domains, including working memory and poorer processing speed. The latter is the ﬁrst cognitive domain to show a decline with ageing, shows large declines, and is an early predictor of dementia (20). The smaller published studies in the literature have reported only an association be- tween cortisol and verbal declarative memory in younger subjects with diabe- tes (aged 60 years) (1,18). Our subjects were older, which may explain the differ- ent ﬁndings. In addition, as our subjects were extensively phenotyped, it was pos- sible to adjust for several potential con- founding factors inﬂuencing cognitive performance. Indeed, the relationships between cortisol and estimated cognitive change were independent of current met- Table 3—Multivariate associations between cortisol and late-life cognition and estimated cognitive change* Unadjusted § P Model 1 Sex and age P Model 2 MHVS P Model 3 Other covariates† P Model 4 Interactions‡ P MR 0.04 0.28 0.03 0.46 0.04 0.18 0.05 0.08 NSI LNS 0.06 0.07 0.05 0.13 0.07 0.04 0.07 0.02 0.44 0.002 VFT 0.04 0.27 0.04 0.21 0.03 0.36 0.02 0.51 NSI DST 0.06 0.07 0.05 0.13 0.07 0.03 0.06 0.04 NSI lnTMT 0.05 0.13 0.04 0.24 0.05 0.09 0.05 0.12 NSI FACES 0.05 0.13 0.05 0.08 0.06 0.09 0.06 0.07 NSI LM 0.04 0.20 0.05 0.16 0.04 0.27 0.05 0.13 NSI g 0.05 0.20 0.03 0.37 0.05 0.09 0.05 0.06 0.30 0.015 *Cognitive test scores adjusted for MHVS. †Other covariates HADS score, duration of diabetes, A1C, total cholesterol, BMI, hypertension, smoking, alcohol intake, myocardial infarction, angina, stroke, ABI, and level of education. ‡Interactions between plasma cortisol and covariates were tested for all models. Signiﬁcant interactions were included in the LNS model (cortisol by ABI: 0.572, P 0.002; cortisol by alcohol intake: 0.436, P 0.001) and the g model (cortisol by ABI: 0.331, P 0.038). §Standardized . NSI, no signiﬁcant interactions. care.diabetesjournals.org DIABETES CARE, VOLUME 33, NUMBER 4, APRIL 2010 717