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Background: Observational evidence suggests higher educational attainment is protective for Alzheimer’s disease (AD). It is unclear whether this association is causal or confounded by demographic and socioeconomic characteristics. We examined the causal effect of educational attainment on AD using two-sample Mendelian Randomization (MR).

Methods: Effect estimates were extracted for 63 single nucleotide polymorphisms (SNPs) associated with years of schooling from the largest genome-wide association study (GWAS) of educational attainment (N=293,723) and the GWAS of AD conducted by the International Genomics of Alzheimer’s Project (n=17,008 AD cases, 37,154 controls). SNP-exposure and SNP-outcome coefficients were combined using inverse variance weighted regression, providing an estimate of the causal effect of each standard deviation (SD) increase in years of schooling on AD. We performed sensitivity analyses to examine the robustness of the causal effect estimates to the various assumptions of MR, and conducted simulation analyses to examine potential survival bias.

Results: With each SD increase in years of schooling (3.6 years), the odds of AD were, on average, reduced by 37% (odds ratio= 0.63, 95% confidence interval [CI]: 0.48 to 0.83, p<0.001). Causal effect estimates were consistent under various MR assumptions, and when using different sets of SNPs for educational attainment, lending confidence to the magnitude and direction of the effect. There was no evidence of survival bias in our study.

Conclusions: Our findings support a causal role of educational attainment on AD, whereby an additional three and a half years of schooling reduces the odds of AD by more than one third.

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