Objective: To document differences between the evolution of self-reported symptoms and prodromal markers in LRRK2 G2019S carriers and non-carriers with and without Parkinson’s Disease (PD).

Background: Gain of function LRRK2 G2019S variants increase the risk of PD; however, the natural history of PD in LRRK2 G2019S carriers is not well understood due to small sample sizes and the lack of prospective data.

Method: Participants were recruited from the 23andMe, Inc. database and consented to enroll into a 42-month prospective online survey-based study to assess PD risk. Self-reported clinical motor, cognitive and autonomic features were surveyed every 6 months. Polygenic risk scores (PRS) were computed using published allele weights from 1,805 variants (Nalls et al., 2019). PRS and clinical features were compared across idiopathic PD and LRRK2 PD using linear and logistic regression.

Results: A total of 1,302 LRRK2 G2019S carriers and 109,472 non-carrier controls were enrolled. At baseline, the cohort included 188 cases of LRRK2 PD and 2,133 cases of idiopathic PD (non-carriers). Compared to idiopathic PD, the LRRK2 PD group reported an earlier age of PD diagnosis (~2 years), a longer disease duration (~1 year), were more likely to be of Ashkenazi Jewish ancestry, and were more likely to have a first degree relative diagnosed with PD. LRRK2 PD reported a similar burden of motor features, but significantly lower rates of REM sleep behavior disorder (RBD), hyposmia, and cognitive difficulties that remained significant after controlling for disease duration and education. PRS were greater in LRRK2 than idiopathic PD, and a higher PRS burden was associated with an earlier age of PD diagnosis. Over the 42 months, we observed 5 incident cases of PD in LRRK2 carriers and 56 incident cases in non-carriers. None of the LRRK2 phenoconverters reported having RBD prior to diagnosis.

Conclusion: The LRRK2 G2019S founder mutation results in a slowly progressive and predominantly motor subtype of PD. The lower rates of reported RBD and smell deficits in LRRK2 PD suggest that the current prodromal criteria for calculating PD risk should be modified to increase the precision of detecting LRRK2 PD. Additive contributions from other polygenic variants may improve progression models of PD.

References: Nalls, M. A., Blauwendraat, C., Vallerga, C. L., Heilbron, K., Bandres-Ciga, S., Chang, D., Tan, M., Kia, D. A., Noyce, A. J., Xue, A., Bras, J., Young, E., von Coelln, R., Simón-Sánchez, J., Schulte, C., Sharma, M., Krohn, L., Pihlstrøm, L., Siitonen, A., … Zhang, F. (2019). Identification of novel risk loci, causal insights, and heritable risk for Parkinson’s disease: A meta-analysis of genome-wide association studies. The Lancet Neurology, 18(12), 1091–1102. https://doi.org/10.1016/S1474-4422(19)30320-5

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MDS Abstracts - https://www.mdsabstracts.org/abstract/the-natural-history-of-parkinsons-disease-in-lrrk2-g2019s-carriers/