The APOE ε4 allele affects the survival of patients with Parkinson's disease independent of dementia.

backgroundPatients with Parkinson's disease (PD) tend to have a shorter life expectancy compared to the general population. While the genetic architecture significantly influences individual variability in survival among these patients with PD, the contributions of most genetic variations to this heterogeneity remain unclear.

methodsThe study included 2365 living and 1575 deceased unrelated White European PD patients from the UK Biobank, of whom 503 had PD as the primary cause of death and 423 had PD as the secondary cause of death. Consequently, a genome-wide time-to-event analysis, utilizing a saddle point approximation implementation based on the Cox proportional hazards regression model, was performed to identify variants associated with the survival time of PD patients across three distinct cohorts as follows: (I) PD as the primary cause of death, (II) PD as the primary or secondary cause of death, and (III) all-cause mortality. To investigate the impact of APOE ε4 on cell viability, SH-SY5Y cells overexpressing different APOE isoforms were treated with rotenone to model PD-related stress. Cell viability, flow cytometry, immunofluorescence, and western blotting were used to assess APOE ε4 related effects and underlying mechanisms.

resultsIn the time-to-event analysis, rs429358 (APOE ε4) was found to be significantly associated with reduced patients' survival time across all three cohorts (P < 1.6 × 10

conclusionsIn summary, we found that rs429358 (APOE ε4) may influence the survival time of patients with PD not only through its association with dementia but also independently.