intercept was considered to verify the presence of pleiotropic effects of the SNPs on the outcome (i.e. to verify whether the instrumental variable is associated with the outcome independently from its association with the exposure) (Bowden et al., 2015). In total we performed 17 MR tests (online Supplemental Table S2). This number is due to the fact we were not able to test AD using a genetic instrument based on genome-wide significant (GWS) loci and, since we are conducting a two-sample MR analysis, we did not test causal relationship between AC-quantity and AC-frequency because they are based on UK Biobank cohort. For the variants included in the instrumental variable, we performed LD clumping by excluding alleles that have R2 ≥ 0.01 with another variant with a smaller association P-value considering a 1Mb window. Additionally, during the harmonization of exposure and outcome data, palindromic variants with an ambiguous allele frequency (i.e. minor allele frequency close to 50%) were removed from the analysis to avoid possible issues (Bowden et al., 2015; Hartwig et al., 2016). The variants included in each genetic instrument used in the present analysis are listed in online Supplemental Table S3. For each exposure, two instrumental variables were built
