Aims 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. Materials and 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 (OR) with 95% confidence intervals (CI), and heterogeneity was assessed with the I^2 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, eight 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 = 1.01, 95% CI: 0.99-1.03) with moderate heterogeneity (I^2 = 44.16%). Similarly, our MR analysis using 511 SNPs as instrumental variables showed no significant associations in IGAP, EADB, or UKB data, consistent across sensitivity analyses. Conclusions This meta-MR and MR analysis revealed no significant causal association between T2DM and AD, indicating that T2DM may not directly influence AD risk. Further research should explore other mechanisms linking these conditions.

The authors have declared no competing interest.

S.H. is supported by the China Scholarship Council Program (No. 202208330062). The study funder was not involved in the study design, the collection, analysis, and interpretation of data, or writing of the report, and did not impose any restrictions regarding the publication of the report.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

All data produced in the present study are available upon reasonable request to the authors