Introduction: It is unknown if risk loci, identified by genome-wide association studies of late-onset Alzheimer's disease (LOAD), are linked to common molecular mechanisms through epistatic effects. Methods: We performed genome-wide interaction studies of five risk variants for LOAD followed by enrichment analyses to find if there are pathways that simultaneously interact with more than one variant. This novel approach was applied to four independent cohorts (5393 cases and 3746 controls). Results: We found enrichment of epistasis in gonadotropin-releasing hormone signaling with risk single-nucleotide polymorphisms in APOE and MS4A6A (P value = 3.7 x 10(-5), P value = 5.6 x 10(-6)); vascular smooth muscle contraction pathway was also enriched in epistasis with these loci (P value = 9.6 x 10(-5), P value = 2.4 x 10(-7)). MS4A6A risk variant also interacted with dilated cardiomyopathy pathway (P value = 3.1 x 10(-7)). Discussion: In addition to APOE, MS4A6A polymorphisms should be considered in hormone trials targeting gonadotropins. Interactions of risk variants with neurovascular pathways may also be important in LOAD pathology. (C) 2016 the Alzheimer's Association. Published by Elsevier Inc. All rights reserved.