PILRA polymorphism modifies the effect of APOE 4 and GM 17 on Alzheimer’s disease risk

PILRA (rs1859788 A > G) has been suggested to be a protective variant for Alzheimer’s disease (AD) and is an entry co-receptor for herpes simplex virus-1. We conducted a nested case–control study of 360 1:1-matched AD subjects. Interactions between the PILRA -A allele , APOE risk variants (ε3/ε4 or ε4/ε4) and GM 17 for AD risk were modelled. The associations were cross-validated using two independent whole-genome sequencing datasets. We found negative interactions between PILRA -A and GM 17 (OR 0.72, 95% CI 0.52–1.00) and between PILRA -A and APOE risk variants (OR 0.56, 95% CI 0.32–0.98) in the discovery dataset. In the replication cohort, a joint effect of PILRA and PILRA × GM 17/17 was observed for the risk of developing AD ( p .02). Here, we report a negative effect modification by PILRA on APOE and GM 17 high-risk variants for future AD risk in two independent datasets. This highlights the complex genetics of AD.