Investigation of the genetic aetiology of Lewy body diseases with and without dementia
Authors: Wu Lesley Yue , Real Raquel , Martinez-Carrasco Alejandro , Chia Ruth , Lawton Michael A , Shoai Maryam , Bresner Catherine , Blauwendraat Cornelis , Singleton Andrew B , Ryten Mina ,   International Lewy Body Dementia Genomics Consortium, Abramzon Yevgeniya , Ahmed Sarah , Alba Camille , Albert Marilyn S , Bacikova Dagmar , Barrett Matthew J , Beach Thomas G , Bennett David A , Besser Lilah M , Bigio Eileen H , Boeve Bradley F , Bohannan Ryan C , Caraway Chad A , Palma Jose-Alberto , Chia Ruth , Dalgard Clifton L , Dickson Dennis , Ding Jinhui , Faber Kelley , Ferman Tanis , Ferrucci Luigi , Flanagan Margaret E , Foroud Tatiana M , Ghetti Bernardino , Gibbs J Raphael , Goate Alison , Goldstein David , Graff-Radford Neill R , Hu Heng-Chen , Hupalo Daniel , Kaiser Scott M , Kaufmann Horacio , Kim Ronald C , Klein Gregory , Kukull Walter , Kuzma Amanda , Leverenz James , Lopez Grisel , Mao Qinwen , Martinez-McGrath Elisa , Masliah Eliezer , Monuki Ed , Newell Kathy L , Norcliffe-Kaufmann Lucy , Perkins Matthew , Pletnikova Olga , Renton Alan E , Resnick Susan M , Ross Owen A , Sabir Marya S , Scherzer Clemens R , Scholz Sonja W , Serrano Geidy , Shakkotai Vikram , Sidransky Ellen , Singleton Andrew B , Tanaka Toshiko , Tayebi Nahid , Traynor Bryan J , Troncoso Juan C , Viollet Coralie , Walton Ronald L , Woltjer Randy , Wszolek Zbigniew K , Black Sandra E , Gan-Or Ziv , Keith Julia , Masellis Mario , Rogaeva Ekaterina , Aarsland Dag , Al-Sarraj Safa , Attems Johannes , Ferrari Raffaele , Gentleman Steve , Hardy John A , Hodges Angela K , Love Seth , McKeith Ian , Morris Christopher M , Morris Huw R , Palmer Laura , Pickering-Brown Stuart , Reynolds Regina H , Ryten Mina , Thomas Alan J , Tilley Bension S , Troakes Claire , Brett Francesca , Brice Alexis , Duyckaerts Charles , Lesage Suzanne , Brunetti Maura , Calvo Andrea , Canosa Antonio , Chiò Adriano , Floris Gianluca , Logroscino Giancarlo , Zecca Chiara , Clarimon Jordi , Diez-Fairen Monica , Fortea Juan , González-Aramburu Isabel , Infante Jon , Lage Carmen , Lleó Alberto , Pastor Pau , Porcel-Molina Laura , Rodríguez-Rodríguez Eloy , Sanchez-Juan Pascual , Krüger Rejko , May Patrick , Xiromerisiou Georgia , Scholz Sonja W , Traynor Bryan J , Williams Nigel M , Hu Michele T M , Ben-Shlomo Yoav , Grosset Donald G , Hardy John , Morris Huw R 
Published: May 2024

Up to 80% of Parkinson's disease patients develop dementia, but time to dementia varies widely from motor symptom onset. Dementia with Lewy bodies presents with clinical features similar to Parkinson’s disease dementia, but cognitive impairment precedes or coincides with motor onset. It remains controversial whether dementia with Lewy bodies and Parkinson's disease dementia are distinct conditions or represent part of a disease spectrum. The biological mechanisms underlying disease heterogeneity, in particular the development of dementia, remain poorly understood, but will likely be the key to understanding disease pathways and, ultimately, therapy development. Previous genome-wide association studies in Parkinson's disease and dementia with Lewy bodies/Parkinson's disease dementia have identified risk loci differentiating patients from controls. We collated data for 7804 patients of European ancestry from Tracking Parkinson’s, The Oxford Discovery Cohort, and Accelerating Medicine Partnership—Parkinson's Disease Initiative. We conducted a discrete phenotype genome-wide association study comparing Lewy body diseases with and without dementia to decode disease heterogeneity by investigating the genetic drivers of dementia in Lewy body diseases. We found that risk allele rs429358 tagging APOEe4 increases the odds of developing dementia, and that rs7668531 near the MMRN1 and SNCA-AS1 genes and an intronic variant rs17442721 tagging LRRK2 G2019S on chromosome 12 are protective against dementia. These results should be validated in autopsy-confirmed cases in future studies.