Association of Statin use with Parkinson's Disease Progression in a Prospective Cohort Study and Multi-omics Analyses.

BACKGROUND: While more than 30% of patients with Parkinson’s disease (PD) are prescribed statins, the impact of statin use on the progression of PD remains incompletely elucidated. We aimed to comprehensively investigate the impact of statin use on PD progression. We analyzed longitudinal data from the Parkinson’s Progression Markers Initiative (PPMI) to examine associations between statin use and clinical manifestations and cerebrospinal fluid (CSF) biomarkers. Mendelian randomization and Bayesian colocalization analyses were employed to assess genetic relationships between HMGCR inhibition (a proxy for statins) and PD phenotypes. Multi-omics analyses utilized postmortem substantia nigra RNA-seq data and CSF proteomics from living patients to explore potential mechanisms. In the PPMI cohort, statin use was associated with a faster cognitive decline among PD patients during longitudinal follow-up, ​​which was partially mediated by reduced CSF Aβ42. Genetic analyses indicated detrimental effects of HMGCR inhibition on cognitive function, dyskinesia, and restless legs syndrome in PD. In addition, RNA-seq analysis of substantia nigra suggested that HMGCR expression gradually decreases with PD progression, showing significant reductions in moderate and advanced stages. Finally, CSF proteomics revealed that statin use was associated with 238 upregulated and 203 downregulated proteins in PD, among which 28 proteins were linked to cognitive decline and significantly enriched in pathways related to substantia nigra development and PD. Our study suggests that statins may accelerate cognitive decline in PD patients through mechanisms potentially involving reduced CSF Aβ42 levels, inhibition of HMGCR in the substantia nigra, and disruption of PD-related protein pathways.