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Updated: Jun 5, 2025
Application of Granger Causality Analysis of the Directed Functional Connection in Alzheimer's Disease and Mild Cognitive Impairment
Published on: August 7, 2017
Causal relationships between Alzheimer's disease and metabolic dysfunction associated with fatty liver disease:
Lei Liu1, Ming Zhou1, Yuanyuan Zhang1
1Department of Transfusion, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230001, China.
Introduction/Objectives:
Several observational investigations have observed the possible links between Alzheimer's disease (AD) and metabolic dysfunction associated with fatty liver disease (MAFLD), yet the underlying causal relationships remain undetermined. This study aimed to systemically infer the causal associations between AD and MAFLD by employing a bidirectional network two-sample Mendelian randomization (MR) analysis.
Methods:
Genome-wide significant (P < 5 × 10- 8) genetic variants associated with AD and MAFLD were selected as instrumental variables (IVs) from the consortium of FinnGen, MRC-IEU, UK biobank, and genome-wide association studies (GWAS), respectively. The study sample sizes range from 55,134 to 423,738 for AD and from 218,792 to 778,614 for MAFLD. In the forward analysis, AD was set as the exposure factor, and MAFLD was employed as the disease outcome. Causal relationships between AD and MAFLD were evaluated using inverse-variance weighted (IVW), MR Egger regression, the weighted median, and weighted mode. Additionally, the reverse MR analysis was conducted to infer causality between MAFLD and AD. Sensitivity analyses were performed to assess the robustness of causal estimates.
Results:
In the forward MR analysis, the genetically determined family history of AD was associated with a lower risk of MAFLD (mother's history: ORdiscovery=0.08, 95%CI: 0.03, 0.22, P = 7.91 × 10- 7; ORreplicate=0.83, 95%CI: 0.74, 0.94, P = 3.68 × 10- 3; father's history: ORdiscovery=0.01, 95%CI: 0.01, 0.08, P = 5.48 × 10- 5; ORreplicate=0.79, 95%CI: 0.68, 0.93, P = 4.07 × 10- 3; family history: ORdiscovery=0.84, 95%CI: 0.77, 0.91, P = 6.30 × 10- 5; ORreplicate=0.15, 95%CI: 0.05, 0.41, P = 2.51 × 10- 4) in the primary MAFLD cohort. Consistent findings were observed in an independent MAFLD cohort (all P < 0.05). However, the reverse MR analysis suggested that genetic susceptibility to MAFLD had no causal effects on developing AD.
Conclusion:
Our study demonstrates a causal association between a family history of AD and a lower risk of MAFLD. It suggests that individuals with a history of AD may benefit from tailored metabolic assessments to better understand their risk of MAFLD, and inform the development of preventive strategies targeting high-risk populations.
Insights
A family history of Alzheimer's disease (AD) is causally linked to a reduced risk of metabolic dysfunction associated with fatty liver disease (MAFLD). This suggests targeted metabolic screening for individuals with a family history of AD to manage MAFLD risk.
Area of Science:
- Neuroscience and Metabolic Health
- Genetic Epidemiology
- Causal Inference
Background:
- Observational studies suggest a link between Alzheimer's disease (AD) and metabolic dysfunction associated with fatty liver disease (MAFLD).
- The causal relationship between AD and MAFLD remains unclear, necessitating further investigation.
Purpose of the Study:
- To investigate the potential causal associations between Alzheimer's disease (AD) and metabolic dysfunction associated with fatty liver disease (MAFLD).
- To employ a bidirectional Mendelian randomization (MR) analysis to infer causality.
Main Methods:
- Utilized genome-wide association study (GWAS) data for AD and MAFLD from large consortia (FinnGen, MRC-IEU, UK Biobank).
- Employed two-sample Mendelian randomization (MR) analysis, including forward (AD as exposure, MAFLD as outcome) and reverse (MAFLD as exposure, AD as outcome) analyses.
- Applied various statistical methods (IVW, MR Egger, weighted median, weighted mode) and sensitivity analyses to ensure robustness.
Main Results:
- Forward MR analysis revealed a significant causal association between a genetically determined family history of AD and a lower risk of MAFLD.
- Consistent protective effects were observed in both discovery and replicate MAFLD cohorts.
- Reverse MR analysis indicated no significant causal effect of genetic susceptibility to MAFLD on the development of AD.
Conclusions:
- This study establishes a causal link where a family history of AD is associated with a reduced risk of MAFLD.
- Suggests that individuals with a family history of AD may benefit from proactive metabolic assessments.
- Highlights the need for tailored preventive strategies for MAFLD in at-risk populations.
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