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. 2015 Jan 26;2(3):215–230. doi: 10.1002/acn3.161

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© 2015 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc on behalf of American Neurological Association.

This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

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KL-VS heterozygosity is associated with enhanced executive function in two independent cohorts and meta-analysis of healthy older adults, independent of age. KL-VS heterozygotes showed higher composite executive Z-scores than noncarriers in (A) Cohort 1, (B) Cohort 2, and (C) meta-analysis. Data are means ± SEM and were analyzed by a linear model adjusting for age, education, sex, APOE ε4 carrier status and (in C) center. *P < 0.05, **P < 0.01, ***P < 0.001 versus noncarrier (two-tailed). (D–F) KL-VS heterozygosity-associated enhancements in executive function were observed across all ages in (D) Cohort 1 (two-tailed P = 2.06 × 10⁻³), (E) Cohort 2 (P = 0.04), and (F) meta-analysis (P = 4.71 × 10⁻⁴). (G) In meta-analysis, right dorsolateral prefrontal cortex (rDLPFC) volume was positively correlated with composite executive Z-scores in both KL-VS heterozygotes and noncarriers (P = 0.003). (H) Mediation analysis of KL-VS heterozygosity and rDLPFC volume as predictors of executive function in Cohorts 1 and 2. Bivariate (black shaded arrows, middle and bottom) and multivariate (purple outlined arrows, top) analyses of direct and indirect effects of KL-VS heterozygosity and rDLPFC volume demonstrated that each were significant predictors of executive function, indicating that KL-VS-associated enhancement in executive function was partially mediated by rDLPFC volume. Estimated effects (beta, in bold) of genotype and/or volume as predictors of cognition, along with the standard error (in parentheses), are provided for each analysis. **P < 0.01 (two-tailed).