Analysis of C9orf72 Intermediate Alleles in a Retrospective Cohort of Neurological Patients: Risk Factors for Alzheimer's Disease?

BACKGROUND

C9orf72 hexanucleotide GGGGCC (G4C2) large repeat expansions within the first intron of the gene are a major cause of familial frontotemporal dementia, but also of apparently sporadic cases. Alleles with > 30 repeats are often considered pathogenic, but the repeat length threshold is still undefined. It is also unclear if C9orf72 intermediate alleles (9-30 repeats) have clinically significant effects.

OBJECTIVES

We correlated the presence of C9orf72 intermediate alleles with clinical diagnoses in a perspective cohort referred to a secondary memory clinic.

METHODS

All samples were genotyped with AmplideXPCR/CE C9ORF72 Kit (Asuragen, Inc), an optimized C9orf72 PCR amplification reagent.

RESULTS

We showed that in patients with Alzheimer's disease (AD) the frequency of the intermediate repeat alleles was significantly increased versus controls (34/54, 63%AD versus 16/39, 41%CTRLs, *p = 0.01, OR 2.91 CI 95%1.230-6.077), whereas no significant differences (p > 0.05) were observed when comparing all other dementias with non-demented individuals.

CONCLUSION

Our findings suggest that C9orf72 intermediate repeat units may represent a genetic risk factor, contributing to the occurrence of AD. Nevertheless, further longitudinal studies, including larger cohort of subjects with intermediate alleles with long-term follow-up, would be needed to confirm these results.