Epigenetic Evidence That C9orf72 Promoter Hypermethylation Is Protective: A Blinded Replication (P5.168)

Objective: Background: expansions in FTLD/ALS have been associated with variable rates of decline, but the biological mechanism for this heterogeneity is unknown. Recent epigenetic evidence suggests that C9orf72 promoter hypermethylation provides a protective benefit of FTLD/ALS, including longer survival, reduced pathological burden, and reduced grey matter atrophy. However, these findings have been established in a single research center and not replicated in an independent sample. Methods: promoter methylation was measured blind to clinical details in the peripheral DNA of 27 symptomatic ALS (N=8) and FTLD (N=19) patients with a C9orf72 expansion. Survival was measured from time of disease onset to either the date of death or, if still living, the current disease duration. A permutation-based linear regression evaluated whether methylation status (hypermethylatedu003e10[percnt]; hypomethylatedu003c10[percnt]) was related to Results: promoter methylation (M=15.44[percnt]; SD=15.01) and survival (M=7.15 years; SD=4.49) has a wide range in FTLD/ALS patients. Regression analysis revealed a significant protective benefit of C9orf72 promoter methylation with survival (p=0.029) in the FTLD cohort: hypermethylation yields a 3.80 year increase in survival. The combined FTLD/ALS analysis conferred a similar pattern, though only approaching significance (p=0.080): hypermethylation yields a 2.58 year increase in Conclusions: study provides an independent replication of the protective benefit of C9orf72 promoter methylation and a biological mechanism for clinical heterogeneity in FTLD/ALS. A diminished ALS effect may be confounded by reduced survival associated with motor neuron disease. We suggest that epigenetic modification of C9orf72 provides a candidate mechanism for therapeutic treatment of FTLD/ALS.Study Support: This work was supported by funding to ForeFront, a collaborative research group dedicated to the study of frontotemporal dementia and motor neurone disease, NHMRC (#1037746,#APP1022684,#1079679), ARC Centre of Excellence in Cognition and its Disorders Memory Node (#CE110001021), NIH (AG043503,AG017586), Doris Duke Charitable Foundation, u0026 Dana Foundation. Disclosure: Dr. McMillan has nothing to disclose. Dr. Devenney has nothing to disclose. Dr. Liu has nothing to disclose. Dr. Piguet has nothing to disclose. Dr. Bartley has nothing to disclose. Dr. Hodges has nothing to disclose. Dr. Halliday has nothing to disclose. Dr. Lee has nothing to disclose.