Unlike monogenic causal gene defects as in the Huntingtin gene or monolithic risk factors like APOE4 haplotype for Alzheimer’s disease, the discriminative ability of PRSs for cancer or CVD is compromised by the environmental factors that come into play, and the imperfect measurement of the full genetic signal that would include structural variants and potentially gene–gene interactions. This evidence concerns the gene APOE and early-onset autosomal dominant Alzheimer disease.