Mendelian randomization
The A allele of rs4291 that associated with lower cortical ACEexpression was negatively associated with SBP (effect estimate per
increase -0.28mmHg, 95% confidence interval -0.35 to -0.22). This same
variant was positively associated with AD risk (odds ratio [OR]
1.06, 95% confidence interval [CI] 1.04 to 1.08, figure 2).
However, strong associations were not identified for the other
neurodegenerative traits as outlined in figure 2 (OR for lacunar stroke
0.97 (95% CI 0.93 to 1.01); OR for Parkinson’s disease 0.99 (95% CI
0.96 to 1.03); beta estimate for cognitive function 0.01 (95% CI -0.001
to 0.01); beta estimate for white matter hyperintensity -0.02 (95% CI
-0.11 to 0.07; Supplementary Table 2). Genetically predicted SBP was not
associated with AD risk (OR 1.01, 95% confidence interval 1.0 to 1.01)
using a genome-wide instrument, suggesting that while SBP colocalizes
with cortical ACE expression at the ACE gene, reduction in
SBP more generally is not directly associated with AD risk. These
findings was consistent in sensitivity analysis (Supplementary Table 3).