α‐Synuclein Seeding Discriminates Between
LRRK2 G2019S
Variant Carriers with and Without Parkinson's Disease
Theresa Lüth, Carolin Gabbert, Teresa Kleinz, Christoph Much, Björn‐Hergen Laabs, Sebastian Sendel, Inke R. König, Amke Caliebe, Matthew Farrer, Brian Fiske, Cornelis Blauwendraat, Christine Klein, Joanne Trinh, Abstract
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. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.