Genetic evaluation of dementia with Lewy bodies implicates distinct disease subgroups
Authors: Kaivola Karri , Shah Zalak , Chia Ruth ,   International LBD Genomics Consortium, Black Sandra E , Gan-Or Ziv , Keith Julia , Masellis Mario , Rogaeva Ekaterina , Brice Alexis , Lesage Suzanne , Xiromerisiou Georgia , Calvo Andrea , Canosa Antonio , Chio Adriano , Logroscino Giancarlo , Mora Gabriele , Krüger Reijko , May Patrick , Alcolea Daniel , Clarimon Jordi , Fortea Juan , Gonzalez-Aramburu Isabel , Infante Jon , Lage Carmen , Lleó Alberto , Pastor Pau , Sanchez-Juan Pascual , Brett Francesca , Aarsland Dag , Al-Sarraj Safa , Attems Johannes , Gentleman Steve , Hardy John A , Hodges Angela K , Love Seth , McKeith Ian G , Morris Christopher M , Morris Huw R , Palmer Laura , Pickering-Brown Stuart , Ryten Mina , Thomas Alan J , Troakes Claire , Albert Marilyn S , Barrett Matthew J , Beach Thomas G , Bekris Lynn M , Bennett David A , Boeve Bradley F , Dalgard Clifton L , Dawson Ted M , Dickson Dennis W , Faber Kelley , Ferman Tanis , Ferrucci Luigi , Flanagan Margaret E , Foroud Tatiana M , Ghetti Bernardino , Gibbs J Raphael , Goate Alison , Goldstein David S , Graff-Radford Neill R , Kaufmann Horacio , Kukull Walter A , Leverenz James B , Mao Qinwen , Masliah Eliezer , Monuki Edwin , Newell Kathy L , Palma Jose Alberto , Pletnikova Olga , Renton Alan E , Resnick Susan M , Rosenthal Liana S , Ross Owen A , Scherzer Clemens R , Serrano Geidy E , Shakkottai Vikram G , Sidransky Ellen , Tanaka Toshiko , Topol Eric , Torkamani Ali , Troncoso Juan C , Woltjer Randy , Wszolek Zbigniew K , Scholz Sonja W , Scholz Sonja W 
Published: October 2021

AbstractThe APOE locus is strongly associated with risk for developing Alzheimer’s disease and dementia with Lewy bodies. In particular, the role of the APOE ε4 allele as a putative driver of α-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 ε4 (P = 5.65 × 10−8, OR = 3.21, 95% CI = 2.11–4.88), but not with dementia with Lewy bodies with APOE ε4 (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 ε4 against the 2928 neurologically healthy controls.Our examination found that APOE ε4 was associated with dementia with Lewy bodies + Alzheimer’s disease (P = 1.29 × 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 ε4 is an independent driver of α-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.