观察性研究表明，神经退行性疾病与结直肠癌（CRC）之间的相关性仍存在争议。因此，本研究旨在验证这两种疾病之间的因果关系。采用孟德尔随机化（MR）分析来评估五种主要神经退行性疾病与结直肠癌之间的因果关系。进行多变量 MR (MVMR) 分析以评估神经退行性疾病对 CRC 的直接因果影响。进行共定位和通路富集分析以进一步阐明我们的结果。进行敏感性分析以评估结果的稳健性。基因预测的阿尔茨海默病 (AD) 名义上会增加 CRC 风险（OR = 1.0620，95% CI = 1.0127-1.1136，P = 0.013）。基因预测的 CRC 与神经退行性疾病没有因果关系。此外，我们证明基因预测的 AD 会略微增加结肠癌风险（OR = 1.1621，95% CI = 1.0267-1.3153，P = 0.017）。基因预测的路易体痴呆 (LBD) 对结肠癌风险增加有显着的因果影响 (IVW OR = 1.1779, 95% CI = 1.0694-1.2975, P = 0.001)。 MVMR表明AD对结肠癌的影响是由LBD、2型糖尿病、体重指数、低密度脂蛋白胆固醇、高密度脂蛋白胆固醇、甘油三酯、总胆固醇(TC)、加工肉类消费、吸烟、饮酒驱动的和教育程度，而 LBD 对结肠癌的影响仅受 TC 的影响。共定位和通路富集分析表明，LBD 和结肠癌可能共享因果变异（附近基因 APOE），并且 ERBB4 信号传导和脂质代谢可能介导 LBD 和结肠癌之间的因果关系。敏感性分析证实了我们研究结果的可靠性。我们的研究表明，AD 的遗传脆弱性名义上会增加结直肠癌和结肠癌的总体风险。基因预测的 LBD 表明患结肠癌的风险升高，可能与 ERBB4 信号传导和脂质代谢有关。© 2024 作者。

Observational studies have shown that the correlation between neurodegenerative diseases and colorectal cancer (CRC) remains controversial. Therefore, this study aimed to verify the causal association between these two diseases.Mendelian randomization (MR) analysis was used to assess the causal relationships between five major neurodegenerative diseases and CRC. Multivariable MR (MVMR) analysis was conducted to assess the direct causal effect of neurodegenerative diseases on CRC. Colocalization and pathway enrichment analyses were conducted to further elucidate our results. Sensitivity analysis was conducted to assess the robustness of the results.Genetically predicted Alzheimer's disease (AD) nominally increased CRC risk (OR = 1.0620, 95%CI = 1.0127-1.1136, P = 0.013). There was no causal effect of genetically predicted CRC on neurodegenerative diseases. Furthermore, we demonstrated that genetically predicted AD marginally increased colon cancer risk (OR = 1.1621, 95%CI = 1.0267-1.3153, P = 0.017). Genetically predicted Lewy body dementia (LBD) had a significant causal effect on the increasing risk of colon cancer (IVW OR = 1.1779, 95%CI = 1.0694-1.2975, P = 0.001). MVMR indicated that effect of AD on colon cancer was driven by LBD, type 2 diabetes, body mass index, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglyceride, total cholesterol (TC), processed meat consumption, smoking, alcohol consumption, and educational attainment, whereas the effect of LBD on colon cancer was only influenced by TC. Colocalization and pathway enrichment analysis suggested that LBD and colon cancer possibly shared causal variants (nearby gene APOE), and ERBB4 signaling and lipid metabolism may mediate the causal association between LBD and colon cancer. Sensitivity analysis confirmed the reliability of our findings.Our study demonstrated that genetic vulnerabilities to AD nominally increased the overall risk of CRC and colon cancer. Genetically predicted LBD indicated an elevated risk of colon cancer, potentially linked to ERBB4 signaling and lipid metabolism.© 2024 The Authors.