Hammond, Pamela I

Abstract Background Whether diabetes and adipokine‐driven inflammation explain the association of obesity to cognitive impairment is unknown. Methods Structural equation models estimated the total effects of waist circumference on cognitive outcomes among African American participants cross‐sectionally (index exam) and longitudinally. Total effects were deconstructed into direct pathways of waist circumference to cognitive impairment and indirect mediation pathways through leptin, soluble tumor necrosis factor receptor 2 (sTNFR2), and diabetes. Waist circumference, leptin, and sTNFR2 were standardized. Cognitive impairment was defined as MMSE <21 or a z‐score < −1.5 standard deviation (SD). Incident cognitive impairment was defined among those without cognitive impairment at the index exam as follow‐up MMSE<21, z‐ score < −1.5, MMSE decline >1 point/year, or z‐score decline of >0.1 SD/year. Results Among 1008 participants (70% women, mean age 62.9 years, 14.5% with obesity, 26% with diabetes), 132 (13%) had baseline cognitive impairment. Each SD higher waist circumference was associated with higher odds of cognitive impairment, odds ratio (OR) = 1.63; (95% confidence interval: 1.17, 2.24), with mediating pathways explaining 65% of the total effect (58% from diabetes; 7% from inflammation). At follow‐up (mean 6.8 years), 106 of 535 (19.8%) had developed cognitive impairment. Each SD higher waist circumference was associated with higher odds of developing cognitive impairment (OR = 1.87; 95%CI: 1.18, 2.74); the direct effect of waist circumference explained 37% of the total effect and mediating pathways explained 63% (61% from diabetes; 2% from inflammation), although individual pathways were not statistically supported in the smaller sample. Conclusion Diabetes, and to a lesser degree, adiposity‐driven inflammation, appear to explain a substantial proportion of abdominal adiposity relationships with cognitive impairment. The impact of preventing and treating obesity on cognitive outcomes merits study.