The relationship between Alzheimer's disease and intracerebral hemorrhage based on Mendelian randomization

Abstract

Background

Traditional epidemiologic studies suggest that Alzheimer's disease (AD) may be associated with intracerebral hemorrhage (ICH).

Objective

To explore whether there is a causal relationship between AD and ICH and the underlying mechanisms involved.

Methods

Mendelian randomization (MR) approach was used to explore causal relationships. The genetic instrumental variables of the candidate genetic instrumental variable AD were obtained from genome-wide association studies. The inverse variance weighted method was the primary method for MR analysis and meta-analysis. The obtained single nucleotide polymorphisms were analyzed for corresponding genes for subsequent pathway enrichment and protein-protein interaction analysis.

Results

For the single AD dataset, our MR analysis of the AD datasets versus the ICH datasets revealed a genetically predicted causal relationship between AD and ICH (OR 5.947, 95%CI 1.165–30.356, p_IVW= 0.032). In addition, the MR-Egger method and MR-PRESSO method revealed no horizontal pleiotropic effect of AD on the risk of ICH. Meta-analysis of each dataset using IVW revealed a final calculated OR of 1.08 (95%CI 1.02–1.15, p = 0.01). Subsequent pathway enrichment analysis revealed that the corresponding genes were involved mainly in the metabolic process of amyloid-β (Aβ) and negatively regulated Aβ formation. In the PPI network analysis, proteins such as ApoE, SROL1, CLU, ABCA7, and AβPP were found to be closely related and located in the key position of the center.

Conclusions

We verified the causal relationship between AD and ICH via MR, and identified the possible pathological mechanisms involved. We also discovered that Aβ plays an important role in this process.

Graphical abstract

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