α‐Synuclein Seeding Discriminates Between LRRK2 G2019S Variant Carriers with and Without Parkinson's Disease

BACKGROUND: Reliable biomarkers for Parkinson's disease (PD) pathology detection are essential for research. α-Synuclein (aSyn) seed amplification assay (SAA) is a validated biomarker for misfolded aSyn. OBJECTIVE: The aim was to assess the association between aSyn SAA and LRRK2-related PD (LRRK2-PD) and its link to mitochondrial genetic burden. METHODS: We included N = 76 LRRK2 p.Gly2019Ser variant carriers (N = 22 affected, N = 54 unaffected), N = 714 patients with idiopathic PD (iPD), and N = 411 controls from Norway. We analyzed cerebrospinal fluid (CSF)-based aSyn SAA in N = 10 PD patients and N = 30 unaffected LRRK2 p.Gly2019Ser carriers, alongside N = 6 controls and N = 56 iPD patients. A mitochondrial polygenic score (MGS) was derived from genotyping data, using Parkinson's Progression Markers Initiative (PPMI) as an additional cohort (iPD: N = 355, LRRK2-PD: N = 118). In patients with PD, we explored the association between mitochondrial genetic burden and aSyn SAA outcome as well as SAA kinetic measurements. RESULTS: Seeding was observed in 80% of patients with LRRK2-PD and in 1 unaffected variant carrier (AUC = 0.97, confidence interval [CI] 0.92-1.00). In an exploratory meta-analysis across 2 PD cohorts, higher MGS was associated with increased aSyn seeding (pooled β = 0.43, odds ratio [OR] = 1.54, P = 0.014). In the Norwegian cohort, assessing aSyn SAA kinetic measurements, higher MGS was associated with a higher maximum slope (β = 1.22, standard error [SE] = 0.50, P = 0.020). In PPMI, higher MGS was associated with shorter time to threshold (β = -0.34, SE = 0.13, P = 0.007) and time to maximum slope (β = -0.35, SE = 0.13, P = 0.007). CONCLUSIONS: CSF-based aSyn SAA can discriminate between LRRK2-PD and unaffected carriers. Our findings suggest an association between mitochondrial genetic burden and aSyn seeding.