Educational attainment, structural brain reserve, and Alzheimer’s disease: a Mendelian randomization analysis
Authors: Seyedsalehi Aida , Warrier Varun , Bethlehem Richard A. I. , Perry Benjamin I. , Burgess Stephen , Murray Graham K. 
Published: March 2022

AbstractHigher educational attainment is observationally associated with lower risk of Alzheimer’s disease. However, the biological mechanisms underpinning this association remain unclear. The protective effect of education on Alzheimer’s disease may be mediated via increased brain reserve. We used two-sample Mendelian randomization to explore putative causal relationships between educational attainment, structural brain reserve as proxied by MRI phenotypes, and Alzheimer’s disease.Summary statistics were obtained from genome-wide association studies of educational attainment (n=1,131,881), late-onset Alzheimer’s disease (35,274 cases, 59,163 controls), and 15 measures of grey or white matter macro- or micro-structure derived from structural or diffusion MRI (nmax=33,211). We conducted univariable Mendelian randomization analyses to investigate bidirectional associations between (i) educational attainment and Alzheimer’s disease, (ii) educational attainment and imaging-derived phenotypes, (iii) imaging-derived phenotypes and Alzheimer’s disease. Multivariable Mendelian randomization was used to assess whether brain structure phenotypes mediated the protective effect of education on Alzheimer’s disease risk.Genetically-proxied educational attainment was inversely associated with Alzheimer’s disease (odds ratio per standard deviation increase in genetically-predicted years of schooling = 0.70, 95% confidence interval [CI]: 0.60, 0.80). There was also evidence for positive associations between genetically-predicted educational attainment and four cortical macro-structure metrics (surface area: β=0.30, 95% CI: 0.20, 0.40; volume: β=0.29, 95% CI: 0.20, 0.37; intrinsic curvature: β=0.18, 95% CI: 0.11, 0.25; local gyrification index: β=0.21, 95% CI: 0.11, 0.31), as well as inverse associations with cortical intracellular volume fraction (β=-0.09, 95% CI: − 0.15, −0.03) and white matter hyperintensities volume (β=-0.14, 95% CI: −0.23, −0.05).Genetically-proxied levels of three cortical macro-structure metrics were positively associated with years of education (surface area: β=0.13, 95% CI: 0.10, 0.16; volume: β=0.15, 95% CI: 0.11, 0.19; intrinsic curvature: β=0.12, 95% CI: 0.04, 0.19). We found no evidence of associations between genetically-predicted imaging-derived phenotypes and Alzheimer’s disease. The inverse association of genetically-predicted education with Alzheimer’s disease did not attenuate after adjusting for imaging-derived phenotypes in multivariable analyses.Our results provide support for a protective causal effect of educational attainment on Alzheimer’s disease risk, as well as bi-directional causal associations between education and several brain macro- and micro-structure metrics. However, we did not find evidence that these structural markers affect risk of Alzheimer’s disease. The protective effect of education on Alzheimer’s disease may be mediated via other measures of brain reserve not included in the present study, or by alternative mechanisms.