We, therefore, conducted a mediation analysis to determine the degree to which Aβ mediated the effect of PRS2 (being the most significant non-APOE-PRS predicting CSF P-tau181) on CSF P-tau181 levels, a well-studied biomarker for altered metabolism of soluble tau in AD.28 As a result, the association between PRS2 and levels of CSF P-tau181 was mediated in part (37%) by Aβ positivity (Figure 4; eTable 11). This evidence concerns the gene APOE and Alzheimer disease.