Genome-wide association studies identify novel loci in rapidly progressive Alzheimer's disease

INTRODUCTION: Recent data suggest that distinct prion-like amyloid beta and tau strains are associated with rapidly progressive Alzheimer's disease (rpAD). The role of genetic factors in rpAD is largely unknown.METHODS: Previously known AD risk loci were examined in rpAD cases. Genomewide association studies (GWAS) were performed to identify variants that influence rpAD. RESULTS: We identified 115 pathology-confirmed rpAD cases and 193 clinical rpAD cases, 80% and 69% were of non-Hispanic European ancestry. Compared to the clinical cohort, pathology-confirmed rpAD had higher frequencies of apolipoprotein E (APOE) epsilon 4 and rare missense variants in AD risk genes. A novel genome-wide significant locus (P < 5x10(-8)) was observed for clinical rpAD on chromosome 21 (rs2832546); 102 loci showed suggestive associations with pathology-confirmed rpAD (P < 1x10(-5)).DISCUSSION: rpAD constitutes an extreme subtype of AD with distinct features. GWAS found previously known and novel loci associated with rpAD.