Evaluating the Causal Association Between Type 2 Diabetes and Alzheimer's Disease: A Two-Sample Mendelian Randomization Study

Abstract

Background/Objectives: Type 2 diabetes mellitus (T2DM) and Alzheimer's disease (AD) are significant global health issues. Epidemiological studies suggest T2DM increases AD risk, though confounding factors and reverse causality complicate this association. This study aims to clarify the causal relationship between T2DM and AD through a systematic review and meta-analysis of Mendelian randomization (MR) studies and a new two-sample MR analysis. Methods: A literature search across major databases was conducted through May 2024 to identify MR studies linking T2DM and AD. Fixed/random-effect models provided pooled odds ratios (ORs) with 95% confidence intervals (CIs), and heterogeneity was assessed with the I² statistic. For our MR analysis, we pooled genetic variants from selected studies and analyzed AD outcomes using IGAP, EADB, and UKB databases. Multiple MR methods, including inverse variance weighted (IVW) and pleiotropy-robust approaches, were applied for validation. Results: Of 271 articles, 8 MR studies were included (sample sizes: 68,905 to 788,989), all from European ancestry. Our meta-analysis found no significant causal link between T2DM and AD (OR = 1.02, 95% CI: 1.00-1.04) with moderate heterogeneity (I² = 31.3%). Similarly, our MR analysis using 512 SNPs as instrumental variables showed no significant associations in IGAP, EADB, or UKB data, which is consistent across sensitivity analyses. Conclusions: This meta-MR and MR analysis revealed no significant causal association between T2DM and AD, indicating that genetic predisposition to T2DM does not appear to causally influence AD risk, though modifiable clinical or environmental aspects of T2DM may still contribute to neurodegenerative processes. Further research should explore other mechanisms linking these conditions.

Keywords: Alzheimer’s disease; Mendelian randomization; type 2 diabetes.

Figure 1

Conceptual framework of Mendelian Randomization analysis assessing the causal effect of type 2 diabetes mellitus on Alzheimer’s disease. T2DM, type 2 diabetes mellitus. Green arrows indicate the assumed causal pathway. Blue arrows show potential confounding paths. Dashed arrows with red crosses represent violations of MR assumptions.

Figure 2

PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) flow diagram for systematic review and meta-analysis of association between type 2 diabetes and Alzheimer’s disease. T2DM, type 2 diabetes mellitus; AD, Alzheimer’s disease; MR, mendelian randomization; IVW, inverse variance weighting.

Figure 3

The pooled results of the Mendelian Randomization analysis between type 2 diabetes mellitus and Alzheimer’s disease (based on fixed effect model with heterogeneity I² = 31.3%). * The p-values were not reported in the original studies. To enable inclusion in the meta-analysis, p-values were calculated based on the reported odds ratio and 95% confidence intervals. The calculation process can be found in Supplementary Material S2. SNP, single nucleotide polymorphism; OR, odds ratio; CI, confidence interval.

Figure 4

(a–c) The causal association between type 2 diabetes mellitus and Alzheimer’s disease—MR analysis using the IGAP, EADB, and the UKB datasets. SNP, single nucleotide polymorphism; OR, odds ratio; CI, confidence interval; IGAP, The International Genomics of Alzheimer’s Project; EADB, European Alzheimer & Dementia Biobank consortium; UKB, UK Biobank.

Figure 4

(a–c) The causal association between type 2 diabetes mellitus and Alzheimer’s disease—MR analysis using the IGAP, EADB, and the UKB datasets. SNP, single nucleotide polymorphism; OR, odds ratio; CI, confidence interval; IGAP, The International Genomics of Alzheimer’s Project; EADB, European Alzheimer & Dementia Biobank consortium; UKB, UK Biobank.

Figure 5

Heatmap of inverse variance weighted odds ratios representing estimated causal effect of type 2 diabetes on Alzheimer’s disease across varying linkage disequilibrium (LD) clumping thresholds (x-axis, R² = 0.001 to 0.8) in different data sources (y-axis). IGAP, The International Genomics of Alzheimer’s Project; EADB, European Alzheimer & Dementia Biobank consortium; UKB, UK Biobank. Note: Odds ratios consistently close to 1 across all LD clumping thresholds suggest no evidence for causal effect of type 2 diabetes on risk of Alzheimer’s disease.