Abstract
The We and others have previously shown that polygenic risk score analysis (PRS)
has considerable predictive utility for identifying those at high risk of developing
Alzheimer’s disease (AD) with an area under the curve (AUC) of >0.8. However, by
far the greatest determinant of this risk is the apolipoprotein E locus with the E4
allele alone giving an AUC of ∼0.68 and the inclusion of the protective E2 allele
increasing this to ∼0.69 in a clinical cohort. An important question is to determine
how good PRS is at predicting risk in those who do not carry the E4 allele (E3
homozygotes, E3E2 and E2E2) and in those who carry neither the E4 or E2 allele (i.e.
E3 homozygotes). Previous studies have shown that PRS remains a significant
predictor of AD risk in clinical cohorts after controlling for APOE ε4 carrier
status. In this study we assess the accuracy of PRS prediction in a cohort of
pathologically confirmed AD cases and controls. The exclusion of APOE4 carriers has
surprisingly little effect on the PRS prediction accuracy (AUC ∼0.83 [95% CI:
0.80-0.86]), and the accuracy remained higher than that in clinical cohorts with
APOE included as a predictor. From a practical perspective this suggests that PRS
analysis will have predictive utility even in E4 negative individuals and may be
useful in clinical trial design.
