Association of cardiovascular disease management drugs with Lewy body dementia: a case–control study
Authors: Scholz Sonja W , Moroz Brian E , Saez-Atienzar Sara , Chia Ruth , Cahoon Elizabeth K , Dalgard Clifton L ,   The American Genome Center, Dalgard Clifton L , Adeleye Adelani , Soltis Anthony R , Alba Camille , Viollet Coralie , Bacikova Dagmar , Hupalo Daniel N , Sukumar Gauthaman , Pollard Harvey B , Wilkerson Matthew D , Martinez Elisa McGrath ,   International Lewy Body Dementia 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 , Ferman Tanis , Ferrucci Luigi , Flanagan Margaret E , Foroud Tatiana M , Ghetti Bernardino , Gibbs J Raphael , Goate Alison , Goldstein David S , Graff-Radford Neill R , Kantarci Kejal , Kaufmann Horacio , Kukull Walter A , Leverenz James B , Mao Qinwen , Masliah Eliezer , Monuki Edwin , Newell Kathy L , Palma Jose-Alberto , Perkins Matthew , 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 , Traynor Bryan J , Troncoso Juan C , Woltjer Randy , Wszolek Zbigniew K , Scholz Sonja W , Freedman Daryl Michal , Pfeiffer Ruth M 
Published: December 2023

Abstract
Lewy body dementia is the second most common neurodegenerative dementia after Alzheimer’s disease. Disease-modifying therapies for this disabling neuropsychiatric condition are critically needed. To identify drugs associated with the risk of developing Lewy body dementia, we performed a population-based case–control study of 148 170 US Medicare participants diagnosed with Lewy body dementia between 1 January 2008 and 31 December 2014 and of 1 253 043 frequency-matched controls. We estimated odds ratios and 95% confidence intervals for the association of Lewy body dementia risk with 1017 prescription drugs overall and separately for the three major racial groups (Black, Hispanic and White Americans). We identified significantly reduced Lewy body dementia risk associated with drugs used to treat cardiovascular diseases (anti-hypertensives: odds ratio = 0.72, 95% confidence interval = 0.70–0.74, P-value = 0; cholesterol-lowering agents: odds ratio = 0.85, 95% confidence interval = 0.83–0.87, P-value = 0; anti-diabetics: odds ratio = 0.83, 95% confidence interval = 0.62–0.72, P-value = 0). Notably, anti-diabetic medications were associated with a larger risk reduction among Black Lewy body dementia patients compared with other racial groups (Black: odds ratio = 0.67, 95% confidence interval = 0.62–0.72, P-value = 0; Hispanic: odds ratio = 0.86, 95% = 0.80–0.92, P-value = 5.16 × 10−5; White: odds ratio = 0.85, 95% confidence interval = 0.82–0.88, P-value = 0). To independently confirm the epidemiological findings, we looked for evidence of genetic overlap between Lewy body dementia and cardiovascular traits using whole-genome sequence data generated for 2591 Lewy body dementia patients and 4027 controls. Bivariate mixed modelling identified shared genetic risk between Lewy body dementia and low-density lipoprotein cholesterol levels, Type 2 diabetes and hypertension. By combining epidemiological and genomic data, we demonstrated that drugs treating cardiovascular diseases are associated with reduced Lewy body dementia risk, and these associations varied across racial groups. Future randomized clinical trials need to confirm our findings, but our data suggest that assiduous management of cardiovascular diseases may be beneficial in this understudied form of dementia.