The Effect of LRRK2 and GBA1 Mutations on Survival in Early- and Late-Onset Parkinson's Disease.

BACKGROUND: Mutations in the glucocerebrosidase 1 (GBA1) and leucine-rich repeat kinase 2 (LRRK2) genes are associated with Parkinson's disease (PD) phenotype. OBJECTIVE: To asses the contribution of genetic status to long-term survival of patients with PD. METHODS: A total of 2039 PD patients with Ashkenazi ancestry were genotyped for mutations in the GBA1 and LRRK2 genes between 2005 and 2025 at Tel-Aviv Medical Center. National death registries were studied to identify date of death. The primary endpoint was defined as overall survival. Regression analysis was performed to assess the risk for each group. Separate analysis comparing early-onset PD (EOPD, age of onset <50) to late-onset PD (LOPD) was also conducted. RESULTS: Mortality hazard ratios (HRs) were increased for GBA1-PD (1.52; 95% confidence interval [CI]: 1.27-1.81) and reduced for LRRK2-PD (0.76; 95% CI: 0.59-0.96) compared to idiopathic PD (iPD). Median survival for all groups was lower than expected, ranging from 18 to 20 years from onset. Women were associated with lower mortality HR = 0.69 (95% CI: 0.60-0.79). EOPD patients had increased overall disease duration compared to LOPD, with lower survival and age at death (67.8 ± 9.3 vs. 80.2 ± 7.3), consistent across genetic subgroups. CONCLUSIONS: PD is associated with reduced longevity compared to population norms. LRRK2-PD has reduced mortality, and GBA1-PD has increased mortality compared to iPD. EOPD is associated with longer disease duration and lower overall life expectancy compared to patients with LOPD. These findings can assist in discussing prognosis with patients and demonstrate the need for research directed at these subgroups to identify factors and interventions to help personalize patient care. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.