Fig. 2

The AD risk based on APOE and polygenic risk score (PRS) in the 36 families. Each node represents one family, with PRS plotted on the x-axis and APOE-risk on the y-axis. The effect sizes of PRS and APOE were scaled to the mean of an in-house population-based control dataset (n = 980). For interpretation of the effect sizes: 0, OR = 1; 1, OR = 2.7; and 2, OR = 7.4. The horizontal lines for APOE-risk indicate families with risk >1 (i.e., at least one APOE-ε44 carrier) and risk >2 (i.e., fully segregating with APOE-ε44). Dark colored nodes depict families with pathogenic variant (n = 8), whereas light colored nodes represent families with a variant of uncertain significance (n = 8). Families with a pathogenic variant are clustered in the lower left corner, with a minor impact of APOE and PRS. Other families in the same region, yet without monogenic defect, would be suitable candidates for further genetic evaluation. Families with a relatively high APOE burden are located in the upper part of the plot, which also includes most families with a VUS. The overall contribution of PRS seems modest (average beta = 0.05, OR = 1.05), with the highest risk observed in the family with a GRN variant (beta = 0.61, OR = 1.84)