Assessment of APOE in atypical parkinsonism syndromes

Atypical parkinsonism syndromes are a heterogeneous group of neurodegenerative disorders that include corticobasal degeneration (CBD), Lewy body dementia (LBD), multiple system atrophy (MSA), and progressive supranuclear palsy (PSP). The APOE epsilon 4 allele is a well-established risk factor for Alzheimer's disease; however, the role of APOE in atypical parkinsonism syndromes remains controversial. To examine the associations of APOE epsilon 4 and epsilon 2 alleles with risk of developing these syndromes, a total of 991 pathologically-confirmed atypical parkinsonism cases were genotyped using the Illumina NeuroChip array. We also performed genotyping and logistic regression analyses to examine APOE frequency and associated risk in patients with Alzheimer's disease (n = 571) and Parkinson's disease (n = 348). APOE genotypes were compared to those from neurologically healthy controls (n = 591). We demonstrate that APOE epsilon 4 and epsilon 2 carriers have a significantly increased and decreased risk, respectively, of developing Alzheimer's disease (epsilon 4: OR: 4.13, 95% CI: 3.23-5.26, p = 3.67 x 10(-30); epsilon 2: OR: 0.21, 95% CI: 0.13-0.34; p = 5.39 x 10(-10)) and LBD (epsilon 4: OR: 2.94, 95% CI: 2.34-3.71, p = 6.60 x 10(-20); epsilon 2: OR = OR: 0.39, 95% CI: 0.26-0.59; p = 6.88 x 10(-6)). No significant associations with risk for CBD, MSA, or PSP were observed. We also show that APOE epsilon 4 decreases survival in a dose-dependent manner in Alzheimer's disease and LBD. Taken together, this study does not provide evidence to implicate a role of APOE in the neuropathogenesis of CBD, MSA, or PSP. However, we confirm association of the APOE epsilon 4 allele with increased risk for LBD, and importantly demonstrate that APOE epsilon 2 reduces risk of this disease.