Investigation of the genetic aetiology of Lewy body diseases with and without dementia

• DOI: 10.1093/braincomms/fcae190
• Publication Date: 2024-05-31T22:03:58Z
• Authors: Lesley Yue Wu; Raquel Real; Alejandro Martine...; Ruth Chia; Michael A Lawton; Maryam Shoai; Catherine Bresner; Cornelis Blauwend...; Andrew B Singleton; Mina Ryten; ; Yevgeniya Abramzon; Sarah Ahmed; Camille Alba; Marilyn S Albert; Dagmar Bacikova; Matthew J Barrett; Thomas G Beach; David A Bennett; Lilah M Besser; Eileen H Bigio; Bradley F Boeve; Ryan C Bohannan; Chad A Caraway; Jose-Alberto Palma; Ruth Chia; Clifton L Dalgard; Dennis Dickson; Jinhui Ding; Kelley Faber; Tanis Ferman; Luigi Ferrucci; Margaret E Flanagan; Tatiana M Foroud; Bernardino Ghetti; J Raphael Gibbs; Alison Goate; David Goldstein; Neill R Graff-Rad...; Heng-Chen Hu; Daniel Hupalo; Scott M Kaiser; Horacio Kaufmann; Ronald C Kim; Gregory Klein; Walter Kukull; Amanda Kuzma; James Leverenz; Grisel Lopez; Qinwen Mao; Elisa Martinez-Mc...; Eliezer Masliah; Ed Monuki; Kathy L Newell; Lucy Norcliffe-Ka...; Matthew Perkins; Olga Pletnikova; Alan E Renton; Susan M Resnick; Owen A Ross; Marya S Sabir; Clemens R Scherzer; Sonja W Scholz; Geidy Serrano; Vikram Shakkotai; Ellen Sidransky; Andrew B Singleton; Toshiko Tanaka; Nahid Tayebi; Bryan J Traynor; Juan C Troncoso; Coralie Viollet; Ronald L Walton; Randy Woltjer; Zbigniew K Wszolek; Sandra E Black; Ziv Gan-Or; Julia Keith; Mario Masellis; Ekaterina Rogaeva; Dag Aarsland; Safa Al-Sarraj; Johannes Attems; Raffaele Ferrari; Steve Gentleman; John A Hardy; Angela K Hodges; Seth Love; Ian McKeith; Christopher M Morris; Huw R Morris; Laura Palmer; Stuart Pickering-...; Regina H Reynolds; Mina Ryten; Alan J Thomas; Bension S Tilley; Claire Troakes; Francesca Brett; Alexis Brice; Charles Duyckaerts; Suzanne Lesage; Maura Brunetti; Andrea Calvo; Antonio Canosa; Adriano Chiò; Gianluca Floris; Giancarlo Logroscino; Chiara Zecca; Jordi Clarimon; Monica Diez-Fairen; Juan Fortea; Isabel González-A...; Jon Infante; Carmen Lage; Alberto Lleó; Pau Pastor; Laura Porcel-Molina; Eloy Rodríguez-Ro...; Pascual Sanchez-Juan; Rejko Krüger; Patrick May; Georgia Xiromerisiou; Sonja W Scholz; Bryan J Traynor; Nigel M Williams; Michele T M Hu; Yoav Ben-Shlomo; Donald G Grosset; John Hardy; Huw R Morris
• Keywords: Aging; Lewy Body Dementia; Biological Psychology; Clinical Sciences; 610; Neurodegenerative; Genome-wide association studies; Article; Clinical Research; 616; Genetics; Acquired Cognitive Impairment; Psychology; 2.1 Biological and endogenous factors; Alzheimer's Disease Related Dementias (ADRD); Parkinson's Disease; Biomedical and Clinical Sciences; Prevention; Human Genome; Neurosciences; Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD); Lewy body diseases; International Lewy Body Dementia Genomics Consortium; Brain Disorders; Neurological; genome-wide association studies; Dementia; Original Article; APOE; dementia

Abstract 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.