Genetic evaluation of dementia with Lewy bodies implicates distinct disease subgroups

The APOE locus is strongly associated with risk for developing Alzheimer's disease and dementia with Lewy bodies. In particular, the role of the APOE epsilon 4 allele as a putative driver of alpha-synuclein pathology is a topic of intense debate. Here, we performed a comprehensive evaluation in 2466 dementia with Lewy bodies cases versus 2928 neurologically healthy, aged controls. Using an APOE-stratified genome-wide association study approach, we found that GBA is associated with risk for dementia with Lewy bodies in patients without APOE epsilon 4 (P = 6.58 x 10(-9), OR = 3.41, 95% CI = 2.25-5.17), but not with dementia with Lewy bodies with APOE epsilon 4 (P = 0.034, OR = 1.87, 95%, 95% CI = 1.05-3.37). We then divided 495 neuropathologically examined dementia with Lewy bodies cases into three groups based on the extent of concomitant Alzheimer's disease co-pathology: pure dementia with Lewy bodies (n = 88), dementia with Lewy bodies with intermediate Alzheimer's disease co-pathology (n = 66) and dementia with Lewy bodies with high Alzheimer's disease co-pathology (n = 341). In each group, we tested the association of the APOE epsilon 4 against the 2928 neurologically healthy controls. Our examination found that APOE epsilon 4 was associated with dementia with Lewy bodies + Alzheimer's disease (P = 1.29 x 10(-32), OR = 4.25, 95% CI = 3.35-5.39) and dementia with Lewy bodies + intermediate Alzheimer's disease (P = 0.0011, OR = 2.31, 95% CI = 1.40-3.83), but not with pure dementia with Lewy bodies (P = 0.31, OR = 0.75, 95% CI = 0.43-1.30). In conclusion, although deep clinical data were not available for these samples, our findings do not support the notion that APOE epsilon 4 is an independent driver of alpha-synuclein pathology in pure dementia with Lewy bodies, but rather implicate GBA as the main risk gene for the pure dementia with Lewy bodies subgroup.