FMNL2 interacts with cerebrovascular risk factors to alter Alzheimer's disease risk
Raghavan, N.; Sariya, S.; Lee, A.; Gao, Y.; Reyes-Dumeyer, D.; De Jager, P.; Bennett, D.; Menon, V.; Lantigua, R.; Kukull, W.; Brickman, A.; Manly, J. J.; Gutierrez, J.; Vardarajan, B. N.; Tosto, G.; Mayeux, R.
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INTRODUCTIONLate-onset Alzheimers disease (AD) frequently co-occurs with cerebrovascular disease. We hypothesized that interactions between genes and cerebrovascular risk factors (CVRFs) contribute to AD risk. METHODSParticipants 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. RESULTSAt 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. DISCUSSIONFMNL2 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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