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

By Neha Raghavan, Sanjeev Sariya, Annie Lee, Yizhe Gao, Dolly Reyes-Dumeyer, Phil De Jager, David Bennett, Vilas Menon, Rafael Lantigua, Walter Kukull, Adam Brickman, Jennifer J Manly, Jose Gutierrez, Badri N. Vardarajan, Giuseppe Tosto, Richard Mayeux

Posted 02 Sep 2020
medRxiv DOI: 10.1101/2020.08.30.20184879

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= 7.7x10-7). A SNP within FRMD4B, rs1498837, was nominally significant (p=7.95x10-7). 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.

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