Educational attainment, structural brain reserve, and Alzheimer’s disease: a Mendelian randomization analysis

Abstract

Higher 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.

Psychological Distress and Meniere's Disease: A Bidirectional Two‐Sample Mendelian Randomization Study

“…We identified 75 SNPs that are strongly related to the neuroticism sum score (SUM) (F statistics: average 41.41, range 29.81-138.44). Similarly, representative SNPs were obtained for the 13 subclusters of neuroticism using the same method (24 SNPs for often feel "fed-up" [FED-UP], 25 ). They were all then included in the MR, which showed that the SUM is a cause of the onset of MD (OR = 1.682, 95% CI: 1.072-2.638, P = 0.024).…”

“…The IVW method assumes that all included SNPs meet the IVs assumptions; the weighted median method assumes that only 50% of the included SNPs meet the IV assumption 24 ; and MR-Egger assumes that IVs will affect the outcome through confounding factors in addition to their effect on the exposure, which will result in weaker statistical power. 20 As IVW is currently the most widely accepted method used to determine causation relationships between exposure and outcome, 25,26 we also used IVW as our primary analytical method. For each method, we calculated the odds ratios (OR), 95% confidence intervals (CI), and P values.…”