First, the observational analyses adjusted for APOE ε4 status, and there is evidence that APOE ε4 status modifies proteomic signatures in AD.154 Second, effect estimates based on MR assume a lifelong exposure to altered protein levels from birth.155 In contrast, observational analyses are based on the human proteome measured at a single time point in adult life. Here, APOE is linked to Alzheimer disease.