FMNL2 interacts with cerebrovascular risk factors to alter Alzheimer’s disease risk

INTRODUCTION Late-onset Alzheimer’s disease (AD) frequently co-occurs with cerebrovascular disease. We hypothesized that interactions between genes and cerebrovascular risk factors (CVRFs) contribute to AD risk. METHODS Participants age 65 years or older from five multi-ethnic cohorts (N=14,669) were included in genome-wide association meta-analyses for AD including an interaction factor for a CVRF score created from body mass index, hypertension, heart disease, and diabetes. Significant gene level results were substantiated using neuropathological and gene expression data. RESULTS At the gene-level, FMNL2 interacted with the CVRF score to significantly modify AD risk (p= 7.7×10 -7 ). A SNP within FRMD4B , rs1498837, was nominally significant (p=7.95×10 -7 ). Increased FMNL2 expression was significantly associated with brain infarcts and AD. DISCUSSION FMNL2 is highly expressed in the brain and has been associated with ischemic stroke and failures in endosomal trafficking, a major pathway in AD pathology. The results highlight an interaction between FMNL2 and CVRFs on AD susceptibility.