Unraveling the Controversy: The Causal Link Between Osteoarthritis and Alzheimer's Disease

Abstract

Objectives

Research on osteoarthritis (OA) and Alzheimer's disease (AD) is currently highly controversial, and the upstream and downstream relationships between them remain unclear. This study aimed to assess the association between OA and AD using Mendelian randomization (MR).

Method

Summary data from genome-wide association studies (GWAS) were obtained for OA and AD. Single nucleotide polymorphisms (SNPs) were selected as instrumental variables (IVs), and significant (p < 5.0 × 10⁻⁸) and independent (r² < 0.001) SNPs were extracted for two-sample MR analyses. Inverse variance weighting (IVW) was used to assess these causal relationships, and meta-analysis was used to combine MR results from multiple IVWs. Confounders were assessed by multivariate Mendelian randomization (MVMR). Results were reported as odds ratios (OR). Heterogeneity was then tested using Cochran's Q test, multiplicity was tested using the MR-Egger intercept and MR-PRESSO, and sensitivity analyses were performed using the leave-one-out sensitivity test.

Results

The MR results showed a positive causal effect of AD and OA (IVW OR = 19.89, 95% CI = 2.90–136.57, p = 0.002; OR = 1.28, 95% CI = 1.11–1.47, p = 0.017; OR = 1.27, 95% CI = 1.11–1.46, p = 0.017) and no significance of the reverse MR results (p > 0.05). Meta-analysis of the MR results confirmed this finding and was significant in all population subgroups (OR = 1.29, 95% CI = 1.18–1.40). The findings were maintained after controlling confounders using MVMR (OR = 6.75, 95% CI = 1.50–30.44, p = 0.013). These analyses were confirmed to be reliable and stable by sensitivity testing.

Conclusions

Our study found a positive causal effect of OA and AD, which was confirmed by the highest levels of evidence-based medicine. It may provide meaningful evidence for the current controversy.