The Age at Onset of LRRK2 p.Gly2019Ser Parkinson's Disease Across Ancestries and Countries of Origin

Objectives: The objective of this study was to elucidate differences in the cumulative incidence of Leucine-rich repeat kinase 2 (LRRK2) p.Gly2019Ser-related Parkinson's disease (PD; LRRK2-PD) between ancestries and countries. Methods: We included 922 unrelated p.Gly2019Ser variant carriers (affected = 762 and unaffected = 160) from the Global Parkinson's Genetics Program (GP2) in addition to cohorts recruited from the Israeli Ashkenazi Jewish and Tunisian Arab-Berber population. Cox proportional hazard models were applied to examine differences in cumulative incidence across ancestry groups and countries. All analyses were adjusted for biological sex and were exploratory. Results: The median age at onset (AAO) of LRRK2-PD was 5 years younger in the North African (hazard ratio [HR] = 1.48, 95% confidence interval [CI] = 1.18-1.86, p = 7.0 × 10-4) compared with the European ancestry group. In contrast, the median AAO was 5 years older in the Ashkenazi Jewish (HR = 0.61, 95% CI = 0.50-0.75, p = 4.0 × 10-6) compared with the European ancestry group. Additionally, patients from Israel (HR = 1.59, 95% CI = 1.30-1.39, p = 4.0 × 10-6) and Tunisia (HR = 2.57, 95% CI: 2.16-3.06, P < 2.0 × 10-16) had a median 5-year and 10-year younger AAO compared with patients from the United States, respectively. Last, when focusing only on individuals with an Ashkenazi Jewish background, patients from Israel still had a younger AAO than those from the United States (HR = 1.82, 95% CI = 1.48-2.24, p = 1.5 × 10-8). Analogously, assessing only patients from the United States, the Ashkenazi Jewish ancestry group still had an older AAO than the European ancestry group (HR = 0.51, 95% CI = 0.39-0.67, p = 1.3 × 10-6). Interpretation: Our results provide evidence that a person's genetic ancestry and country of origin are associated with the AAO of LRRK2-PD. This highlights the potential impact of both genetic and environmental factors on LRRK2-PD AAO. ANN NEUROL 2026;99:1394-1404.