Statistical analysis
We conducted colocalization analysis of genetic associations forACE gene expression in brain cortex tissue and AD liability within +/-20kb of the ACE gene using coloc,8 a Bayesian method for colocalization. We also assessed for three-way colocalization with SBP using the HyPrColoc method9(Hypothesis Prioritisation for multi-trait Colocalization), to investigate whereby AD risk, cortical ACE expression and blood pressure share a common causal variant. The single-nucleotide polymorphism (SNP) with the greatest posterior probability from colocalization analysis of cortical ACE expression and AD risk represents the genetic proxy most likely to simulate the effect of cerebral cortex ACE modulation on AD risk. We then employ a MR paradigm to explore whether this variant is associated with other neurodegenerative traits. Finally, the effect of SBP on AD risk was explored in an MR analysis using an instrument comprising of genetic variants from across the genome. Full details are given in Supplementary Methods.