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Background <p>Patients 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.</p> Methods <p>The 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.</p> Results <p>In the time-to-event analysis, rs429358 (<i>APOE</i> ε4) was found to be significantly associated with reduced patients' survival time across all three cohorts (<i>P</i> &lt; 1.6 × 10<sup>−8</sup>). Concurrently, we observed that both dementia symptoms (<i>P</i> &lt; 5.6 × 10<sup>−42</sup>, hazard ratio &gt; 2) and the rs429358 (<i>APOE</i> ε4) (<i>P</i> &lt; 2.4 × 10<sup>−5</sup>, hazard ratio &gt; 1.2) were significant risk factors for the survival time of PD patients in the same multivariate survival analysis with Cox proportional hazards regression across all three cohorts. More importantly, we also constructed PD model using SH-SY5Y cells to validate the screened genetic variant and noticed that expressing <i>APOE</i> ε4 allele (rs429358) significantly reduced cell activity exclusively under the pathological state of PD. This was accompanied by impaired mitochondrial function, increased DNA damage, and activation of ER stress primarily through the PERK signaling pathway.</p> Conclusions <p>In summary, we found that rs429358 (<i>APOE</i> ε4) may influence the survival time of patients with PD not only through its association with dementia but also independently.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月14日

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  • Zheng Wang,
  • Lu Li,
  • Qian Xu,
  • Hongxu Pan,
  • Yijing Wang,
  • Qin Long,
  • Yuanfeng Huang,
  • Yinghong Dai,
  • Shiyu Zhang,
  • Qiao Zhou,
  • Guihu Zhao,
  • Bin Li,
  • Beisha Tang,
  • Jian Qiu,
  • Jinchen Li

摘要

Background

Patients 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.

Methods

The 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.

Results

In 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 × 10−8). Concurrently, we observed that both dementia symptoms (P < 5.6 × 10−42, hazard ratio > 2) and the rs429358 (APOE ε4) (P < 2.4 × 10−5, hazard ratio > 1.2) were significant risk factors for the survival time of PD patients in the same multivariate survival analysis with Cox proportional hazards regression across all three cohorts. More importantly, we also constructed PD model using SH-SY5Y cells to validate the screened genetic variant and noticed that expressing APOE ε4 allele (rs429358) significantly reduced cell activity exclusively under the pathological state of PD. This was accompanied by impaired mitochondrial function, increased DNA damage, and activation of ER stress primarily through the PERK signaling pathway.

Conclusions

In 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.