Evaluating the Causal Association Between Type 2 Diabetes and Alzheimer’s Disease: A Two-Sample Mendelian Randomization Study
<b>Background/Objectives</b>: 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 clarif...
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2025-04-01
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| author | Si Han Tom Lelieveldt Miriam Sturkenboom Geert Jan Biessels Fariba Ahmadizar |
| author_facet | Si Han Tom Lelieveldt Miriam Sturkenboom Geert Jan Biessels Fariba Ahmadizar |
| author_sort | Si Han |
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| description | <b>Background/Objectives</b>: 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. <b>Methods</b>: 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 I<sup>2</sup> 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. <b>Results</b>: 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 (I<sup>2</sup> = 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. <b>Conclusions</b>: 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. |
| format | Article |
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| language | English |
| publishDate | 2025-04-01 |
| publisher | MDPI AG |
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| series | Biomedicines |
| spelling | doaj-art-38f894c2db32401d95f3ed6e15d5c36f2025-08-20T01:56:29ZengMDPI AGBiomedicines2227-90592025-04-01135109510.3390/biomedicines13051095Evaluating the Causal Association Between Type 2 Diabetes and Alzheimer’s Disease: A Two-Sample Mendelian Randomization StudySi Han0Tom Lelieveldt1Miriam Sturkenboom2Geert Jan Biessels3Fariba Ahmadizar4Department of Data Science and Biostatistics, Julius Global Health, University Medical Center Utrecht, 3584 CX Utrecht, The NetherlandsDepartment of Biomedical Science, University College Utrecht, Utrecht University, 3508 TC Utrecht, The NetherlandsDepartment of Data Science and Biostatistics, Julius Global Health, University Medical Center Utrecht, 3584 CX Utrecht, The NetherlandsDepartment of Neurology, Brain Center, University Medical Center Utrecht, 3584 CX Utrecht, The NetherlandsDepartment of Data Science and Biostatistics, Julius Global Health, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands<b>Background/Objectives</b>: 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. <b>Methods</b>: 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 I<sup>2</sup> 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. <b>Results</b>: 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 (I<sup>2</sup> = 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. <b>Conclusions</b>: 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.https://www.mdpi.com/2227-9059/13/5/1095type 2 diabetesAlzheimer’s diseaseMendelian randomization |
| spellingShingle | Si Han Tom Lelieveldt Miriam Sturkenboom Geert Jan Biessels Fariba Ahmadizar Evaluating the Causal Association Between Type 2 Diabetes and Alzheimer’s Disease: A Two-Sample Mendelian Randomization Study Biomedicines type 2 diabetes Alzheimer’s disease Mendelian randomization |
| title | Evaluating the Causal Association Between Type 2 Diabetes and Alzheimer’s Disease: A Two-Sample Mendelian Randomization Study |
| title_full | Evaluating the Causal Association Between Type 2 Diabetes and Alzheimer’s Disease: A Two-Sample Mendelian Randomization Study |
| title_fullStr | Evaluating the Causal Association Between Type 2 Diabetes and Alzheimer’s Disease: A Two-Sample Mendelian Randomization Study |
| title_full_unstemmed | Evaluating the Causal Association Between Type 2 Diabetes and Alzheimer’s Disease: A Two-Sample Mendelian Randomization Study |
| title_short | Evaluating the Causal Association Between Type 2 Diabetes and Alzheimer’s Disease: A Two-Sample Mendelian Randomization Study |
| title_sort | evaluating the causal association between type 2 diabetes and alzheimer s disease a two sample mendelian randomization study |
| topic | type 2 diabetes Alzheimer’s disease Mendelian randomization |
| url | https://www.mdpi.com/2227-9059/13/5/1095 |
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