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Abstract Higher educational attainment (EA) 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 EA, structural brain reserve as proxied by MRI phenotypes, and Alzheimer’s disease. Summary statistics were obtained from genome-wide association studies of EA (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) EA and Alzheimer’s disease, (ii) EA 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 effect of education on Alzheimer’s disease risk. Genetically-proxied EA was inversely associated with Alzheimer’s disease (odds ratio per standard deviation [SD] increase in genetically-predicted years of schooling (YOS) = 0.70, 95% confidence interval [CI] 0.60, 0.80). There were positive associations between genetically-predicted EA and four cortical metrics (SD units change in imaging phenotype per one SD increase in genetically-predicted YOS: surface area 0.30 [95% CI 0.20, 0.40]; volume 0.29 [95% CI 0.20, 0.37]; intrinsic curvature 0.18 [95% CI 0.11, 0.25]; local gyrification index 0.21 [95% CI 0.11, 0.31]), and inverse associations with cortical intracellular volume fraction (-0.09 [95% CI -0.15, -0.03]) and white matter hyperintensities volume (-0.14 [95% CI -0.23, -0.05]). Genetically-proxied levels of surface area, cortical volume and intrinsic curvature were positively associated with EA (SD units change in YOS per one SD increase in respective genetically-predicted imaging phenotype: 0.13 [95% CI 0.10, 0.16]; 0.15 [95% CI 0.11, 0.19]; 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 EA 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 potential bidirectional causal relationships between education and brain macro- and micro-structure. 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.

Original publication




Journal article




Oxford University Press (OUP)

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