A role for ATXN1, ATXN2 and HTT intermediate repeats in frontotemporal dementia and Alzheimer's disease

We analyzed the frequency of intermediate alleles (IAs) in the ATXN1, ATXN2 and HTT genes in several neurodegenerative diseases. The study included 1,126 Alzheimer disease (AD), 440 frontotemporal dementia (FTD) and 610 Parkinson's disease (PD) patients. In all cohorts, we genotyped ATXN1 and ATXN2 CAG repeats. Additionally, in the FTD cohort we determined the number of HTT CAG-repeats. The frequency of HTT IAs was higher in FTD patients (6.9%) vs controls (2.9%) and in the C9orf72 expansion non carriers (7.2%) vs. controls (2.9%), although the difference was non-significant after correction for multiple testing. Compared to controls, progressive non-fluent aphasia (PNFA) groups showed a significantly higher frequency of HTT IAs ( 13.6% vs 2.9% controls). For the ATXN2 gene, we observed an IAs increased frequency in AD cases (AD 4.1% vs controls 1.8%) and in the behavioural FTD (bvFTD) group (4.8% vs 1.8%). For the ATXN1 gene we found a significant increase of IAs in PNFA patients (18.6%) vs controls (6.7%). In conclusion, our work suggests that the HTT and ATXN1 IAS may contribute to PNFA pathogenesis and point to a link between ATXN2 IAS and AD.