Disentangling the causal effects of education and participation bias on Alzheimer's disease using Mendelian Randomization

IntroductionPeople with university degrees have a lower incidence of Alzheimers Disease (AD). However, the relationship between education and AD could be due to selection, collider, and ascertainment biases, such as lower familiarity with cognitive testing or the fact that those with degrees are more likely to participate in research. Here, we use two-sample Mendelian randomization (MR) to investigate the causal relationships between education, participation, and AD. MethodWe used genome-wide association study (GWAS) summary statistics for educational attainment, three different measures of participation, AD (clinically diagnosed AD), and AD/ADRD (clinical diagnosis and family history of AD and related dementias). Independent genome-wide significant single nucleotide polymorphisms (SNPs) were extracted from the exposure summary statistics and harmonized with the outcome SNPs. Fixed-effects inverse variance weighted meta-analysis was the primary MR method; Cochrans Q statistic and MR Egger intercept were used to test for heterogeneity and pleiotropy, and Radial-MR was used to identify outliers. Sensitivity analyses included MR Egger, Weighted Median, and Weighted mode. Bidirectional analyses were used to test if AD pathology affects participation and multivariable MR (MVMR) assessed independent exposure-outcome effects. ResultsEducational attainment reduced the risk of AD (ORIVW 95% CI= 0.70 [0.63, 0.79], p = 8e-10), and the results were robust based on sensitivity analyses. However, education increased the risk of AD/ADRD, though the results were not robust to sensitivity analyses (ORIVW 95% CI= 1.09 [1.02, 1.15], p = 0.006). Participation in MHQ reduced the odds of AD (ORIVW 95% CI= 0.325 [0.128, 0.326], p = 0.01). When adjusting for participation in MVMR, education remained associated with a reduced risk of AD (ORIVW 95% CI= 0.76 [0.62, 0.92], p = 0.006). ConclusionUnivariate MR analyses indicated that education and participation reduced the risk of AD. However, MR also suggested that education increased the risk of AD/ADRD, highlighting the inconsistencies between clinical and proxy diagnoses of AD, as proxy-AD may be affected by selection, collider, or ascertainment bias. MVMR indicated that participation is unlikely to explain the effect of education on AD identified in MR, and the protective effect of educational attainment may be due to other biological mechanisms, such as cognitive reserve.