No Evidence That Appendix Removal Influences Parkinson’s Disease Development: Meta-Analysis

The research stems from Braak’s hypothesis, which proposes that Parkinson’s disease may begin in the gastrointestinal tract. According to this theory, misfolded α-synuclein proteins, believed to be key in PD pathogenesis, could travel retrogradely through the vagus nerve to the brain, initiating the neurodegenerative process. The appendix, rich in α-synuclein, has therefore been suspected as a potential starting point for the disease. However, this new analysis casts doubt on that theory.

To investigate the potential relationship, the authors performed a systematic review and meta-analysis of studies retrieved from PubMed and Embase databases up to September 10, 2024. It included only high-quality observational studies that scored at least seven on the Newcastle-Ottawa Scale. The pooled data were analyzed using a random-effects model through Review Manager 5.4, with additional subgroup and sensitivity analyses to assess the robustness of the findings.

The study revealed the following findings:

• The study found no statistically significant association between appendectomy and the risk of developing Parkinson’s disease.
• The pooled relative risk was 1.01, indicating neither an increased nor decreased risk.
• Subgroup analyses, including those considering the duration of follow-up, consistently showed similar results.
• Sensitivity analyses confirmed the robustness of the primary findings.
• This updated meta-analysis included more studies than previous reviews from 2019 and 2020.
• The study expanded demographic representation by including data from an Asian population, which had been underrepresented earlier.
• The analysis applied stricter inclusion criteria, thereby enhancing the reliability and strength of the evidence.

The findings also add nuance to the debate surrounding Braak’s hypothesis. While the hypothesis suggests that α-synuclein from the appendix may contribute to PD progression, the current results indicate that surgical removal of the appendix does not alter the risk of developing the disease. Thus, while the gastrointestinal tract may still be involved in PD's early stages, the appendix specifically may not play a decisive role.

Despite its strengths, the study does acknowledge some limitations. Most of the included studies were from high-income Western countries, which may affect the generalizability of the results. Furthermore, variations in how appendectomy and PD were defined and diagnosed across studies, along with inconsistent adjustment for confounders, may have introduced methodological variability.

"The current body of evidence does not support appendectomy as a protective or risk-enhancing factor for Parkinson’s disease. These findings contribute to a growing body of literature that questions the appendix’s role in PD pathogenesis and underscore the need for further research to unravel the complex mechanisms underlying the disease," the authors concluded.

Reference:

Chin, H. L., Tsang, Y. S., & Shi, H. (2025). Appendectomy and risk of Parkinson’s disease: A systematic review and meta-analysis. Frontiers in Neurology, 16, 1619236. https://doi.org/10.3389/fneur.2025.1619236