# Integrative analysis of causal associations between neurodegenerative diseases and colorectal cancer

## TL;DR

This study finds that genetic risks for Alzheimer's and Lewy body dementia may increase the risk of colorectal cancer, possibly through shared biological pathways.

## Contribution

The study provides novel causal evidence linking neurodegenerative diseases to colorectal cancer using genetic data and identifies potential mediating pathways.

## Key findings

- Genetically predicted Alzheimer's disease marginally increases colorectal cancer and colon cancer risk.
- Lewy body dementia shows a significant causal effect on increased colon cancer risk.
- ERBB4 signaling and lipid metabolism may mediate the link between Lewy body dementia and colon cancer.

## Abstract

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.

•Genetic vulnerabilities to AD nominally increased the risk of overall CRC and colon cancer.•Genetically predicted LBD had a significant causal effect on the increasing risk of colon cancer.•AD’s effect on colon cancer was driven by the common risk factors, while LBD’s effect was only driven by blood lipid.•ERBB4 signaling and lipid metabolism might mediate the causal association between LBD and colon cancer.

Genetic vulnerabilities to AD nominally increased the risk of overall CRC and colon cancer.

Genetically predicted LBD had a significant causal effect on the increasing risk of colon cancer.

AD’s effect on colon cancer was driven by the common risk factors, while LBD’s effect was only driven by blood lipid.

ERBB4 signaling and lipid metabolism might mediate the causal association between LBD and colon cancer.