Meta-analysis links mitochondrial polygenic score to alpha-synuclein seeding in LRRK2-related Parkinson's disease

This meta-analysis examines the relationship between cerebrospinal fluid alpha-synuclein seed amplification assay (aSyn SAA) levels and LRRK2-related Parkinson's disease. The analysis pooled data from cohorts in Norway and the PPMI study, involving 76 LRRK2 p.Gly2019Ser variant carriers and 714 patients with idiopathic Parkinson's disease. The primary outcome assessed the link between aSyn SAA and LRRK2-related PD, while secondary outcomes explored connections to mitochondrial genetic burden.

The study found that 80% of patients with LRRK2-PD demonstrated aSyn seeding. In contrast, only one unaffected LRRK2 p.Gly2019Ser carrier exhibited this finding. The area under the curve for this comparison was 0.97 with a confidence interval ranging from 0.92 to 1.00. Additionally, higher mitochondrial polygenic scores were associated with increased aSyn seeding, with a pooled beta of 0.38 and a p-value of 0.028.

The authors emphasize that these results describe associations and do not establish causality. Safety data, adverse events, and discontinuations were not reported. The study does not provide practice relevance or definitive clinical guidance. These findings highlight potential biomarkers but require further validation before influencing clinical management.