Little genomic support for Cyclophilin A-matrix metalloproteinase-9 pathway as a therapeutic target for cognitive impairment in APOE4 carriers

Mendelian randomization analysis

We used two-sample Mendelian randomization⁴ to examine (i) whether APOE4 (tagged by the C allele of single nucleotide polymorphism rs429358⁵) has a causal effect on blood-based CypA or MMP9 expression quantitative trait loci (eQTLs) and protein quantitative trait loci (pQTLs), and (ii) whether blood-based CypA and MMP9 eQTLs and pQTLs have a causal effect on the risk of Alzheimer’s disease (AD). Methods for conducting two-sample MR analyses have been published previously⁴. Briefly, two-sample MR provides an estimate of the causal effect of an exposure on an outcome, using independent samples to obtain the gene-exposure and gene-outcome associations, provided three key assumptions hold: (i) genetic variants are robustly associated with the exposure of interest (i.e. replicate in independent samples), (ii) there is no confounding of the causal effect…