OBJECTIVE To determine whether intraindividual variability in fasting glucose (FG) below the threshold of diabetes is associated with cognitive function in middle adulthood beyond increasing FG. RESEARCH DESIGN AND METHODS We studied 3,307 CARDIA (Coronary Artery Risk Development in Young Adults) Study participants (age range 18-30 years and enrolled in 1985-1986) at baseline and calculated two measures of long-term glucose variability: the coefficient of variation about the mean FG (CV-FG) and the absolute difference between successive FG measurements (average real variability [ARV-FG]) before the onset of diabetes over 25 and 30 years of follow-up. Cognitive function was assessed at years 25 (2010-2011) and 30 (2015-2016) with the Digit Symbol Substitution Test (DSST), Rey-Auditory Verbal Learning Test (RAVLT), Stroop Test, Montreal Cognitive Assessment, and category and letter fluency tests. We estimated the association between glucose variability and cognitive function test score with adjustment for clinical and behavioral risk factors, mean FG level, change in FG level, and diabetes development, medication use, and duration. RESULTS After multivariable adjustment, 1-SD increment of CV-FG was associated with worse cognitive scores at year 25: DSST, standardized regression coefficient 20.95 (95% CI 21.54, 20.36); RAVLT, 20.14 (95% CI 20.27, 20.02); and Stroop Test, 0.49 (95% CI 0.04, 0.94). Findings were similar between CV-FG with each cognitive test score at year 30 and when we used an alternative measure of variability (ARV-FG) that captures variability in successive FG values. CONCLUSIONS Higher intraindividual FG variability during young adulthood below the threshold of diabetes was associated with worse processing speed, memory, and language fluency in midlife independent of FG levels.
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Acknowledgments. The authors thank the other investigators, the staff, and the participants of the CARDIA Study for their valuable contributions. Funding. M.P.B. was supported by the National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health under Award Number T32-HL-069771 to conduct the current work. The CARDIA Study is conducted and supported by the NHLBI in collaboration with the University of Alabama at Birmingham (grants HHS-N2-68201300025C and HHS-N2-68201300026C), Northwestern University (grant HHS-N2-68201300027C), the University of Minnesota (grant HHS-N2-68201300028C), the Kaiser Foundation Research Institute (grant HHS-N2-68201300029C), and the Johns Hopkins University School of Medicine (grant HHS-N2-68200900041C). The CARDIA Study is also partially supported by the Intramural Research Program of the National Institute on Aging (NIA) and an intra-agency agreement between NIA and NHLBI (grant AG-0005). Duality of Interest. No potential conflicts of interest relevant to this article were reported. Author Contributions. M.P.B. conceptualized the study and designed the analysis plan; helped with the acquisition, analysis, or interpretation of the data; performed all statistical analyses; contributed to the discussion; drafted the manuscript; and provided critical revision of the manuscript for important intellectual content. M.R.C.,L.J.L.,J.P.R.,K.Y.,andY.Y.providedcritical revision of the manuscript for important intellectual content and contributed to the discussion. D.R.J., P.J.S., R.V.S., and S.S. helped with the acquisition, analysis, or interpretation of the data; contributed to the discussion; and provided critical revision of the manuscript for important intellectual content. N.B.A. helped with the acquisition, analysis, or interpretation of the data; conceptualized the study; designed the analysis plan; provided supervision to M.P.B.; contributed to the discussion; and provided critical revision of the manuscript for important intellectual content. M.P.B. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.