AD (fixed-effect inverse-variance weighted method: β = 0.28, P = 1.3 × 10−6; Fig. 2). Since this causal estimate was generated from a genetic instrument including suggestive variants, we confirmed this result using the MR-RAPS method: β = 0.28, P = 5.6 × 10−5. A similar effect size was also observed for the MD instrumental variable based on GWS loci (40 SNPs; fixed-effect inverse-variance weighted method: β = 0.27, P = 0.054). Results indicated that MD is associated with a 32% increase in the odds for AD risk per unit increase in the log(OR) for MD (95% CI 18–48%) and were consistent across multiple MR approaches (online Supplemental Table S5.17). As mentioned above, the MD genetic instrument did not show evidence of horizontal pleiotropic effects as demonstrated by MR-Egger regression intercept (P = 0.297, online Supplemental Table S6), confirming that the causal effect of MD on AD does not appear to be biased by horizontal pleiotropy. The heterogeneity tests indicated no evidence of heterogeneity in the MD-AD result (P > 0.13; online Supplemental Table S3). The MR-PRESSO global test (Verbanck et al., 2018) also supported the absence of horizontal pleiotropy (RSSobs = 285.6, P = 0.143). The MR-RAPS overdispersion test
