Disentangling the Causal Effects of Education and Participation Bias on Alzheimer Disease Using Mendelian Randomization.

Background and Objectives: People with university degrees have a lower incidence of Alzheimer disease (AD). However, the relationship between education and AD could be due to selection, collider, or ascertainment biases, such as lower familiarity with cognitive testing or the fact that those with degrees are more likely to participate in research. In this study, we use 2-sample Mendelian randomization (MR) to investigate the causal relationships between education, participation, and AD. Methods: We used genome-wide association study summary statistics for educational attainment, 3 measures of participation, AD (clinically diagnosed AD), and AD/ADRD (AD and related dementia; includes clinical diagnosis and family history). Independent genome-wide significant single-nucleotide variations (SNVs) were extracted from the exposure data sets and harmonized with the outcome SNPs. Fixed-effects inverse variance-weighted meta-analysis was the primary MR method; Cochran 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 mode. Bidirectional analyses were used to test whether AD pathology affects participation, and multivariable MR (MVMR) assessed independent exposure-outcome effects. Results: Educational 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, although the results were not robust in sensitivity analyses (ORIVW 95% CI 1.09 [1.02-1.15], p = 0.006). Participation in the mental health questionnaire 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). Discussion: Univariable 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 suggested that education remained associated with reduced AD risk after adjusting for participation and the protective effect of education may be due to other biological mechanisms, such as cognitive reserve.