Genetic evaluation of dementia with Lewy bodies implicates distinct disease subgroups
Por:
Kaivola, K, Shah, Z, Chia, R, Scholz, SW, Alcolea, D., Clarimón, J., Fortea, J., Lleó, A., Int LBD Genomics Consortium
Publicada:
3 jun 2022
Ahead of Print:
1 abr 2022
Resumen:
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.
Filiaciones:
Kaivola, K:
Univ Hosp, Dept Neurol, Helsinki, Finland
Univ Hosp, Translat Immunol Program, Helsinki, Finland
Univ Helsinki, Helsinki, Finland
NINDS, Neurodegenerat Dis Res Unit, 35 Convent Dr,Room 1B-205, Bethesda, MD 20892 USA
Shah, Z:
NINDS, Neurodegenerat Dis Res Unit, 35 Convent Dr,Room 1B-205, Bethesda, MD 20892 USA
Chia, R:
NIA, Lab Neurogenet, Bethesda, MD 20892 USA
Scholz, SW:
NINDS, Neurodegenerat Dis Res Unit, 35 Convent Dr,Room 1B-205, Bethesda, MD 20892 USA
Johns Hopkins Univ, Dept Neurol, Sch Med, Baltimore, MD 21287 USA
Alcolea, D.:
Institut d’Investigació Biomèdica Sant Pau (IIB SANT PAU), Sant Quintí 77-79, 08041 Barcelona, Spain
Clarimón, J.:
Institut d’Investigació Biomèdica Sant Pau (IIB SANT PAU), Sant Quintí 77-79, 08041 Barcelona, Spain
Fortea, J.:
Institut d’Investigació Biomèdica Sant Pau (IIB SANT PAU), Sant Quintí 77-79, 08041 Barcelona, Spain
Lleó, A.:
Institut d’Investigació Biomèdica Sant Pau (IIB SANT PAU), Sant Quintí 77-79, 08041 Barcelona, Spain
Green Published, hybrid
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