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

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ObjectivesThe 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.MethodsWe 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.ResultsThe 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 -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).InterpretationOur 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.

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