# Association between diabetes mellitus and risk of Alzheimer’s disease: a meta-analysis and systematic review

## TL;DR

This study finds that diabetes increases the risk of Alzheimer's disease, but results vary when adjusting for genetic factors.

## Contribution

A meta-analysis showing diabetes as an independent risk factor for Alzheimer's disease, with insights on APOE ϵ4 mutation adjustment.

## Key findings

- Diabetes mellitus is significantly associated with increased Alzheimer’s disease risk (HR = 1.36).
- The association remains consistent in both Asian and non-Asian populations.
- Adjusting for APOE ϵ4 mutations removes the statistical significance of the diabetes-Alzheimer’s link.

## Abstract

Diabetes mellitus (DM) is hypothesized to increase the risk of Alzheimer’s disease (AD). However, existing studies have yielded conflicting results, with some demonstrating a significant association between DM and AD risk while others have not. Therefore, this meta-analysis aimed to systematically evaluate the association between DM and AD risk.

Comprehensive searches were conducted in PubMed, Web of Science, and Embase databases to identify cohort or case–control studies investigating the association between DM and AD risk. All eligible studies published before October 2025 were included. The Newcastle–Ottawa Scale (NOS) was used to assess the risk of bias. Hazard ratio (HR) and 95% confidence interval (CI) were pooled as the effect size for meta-analysis. Heterogeneity among studies was evaluated using Cochran’s Q test and I2 statistics. Statistical analyses were performed with RevMan 5.3 software.

A total of 11 studies involving 3,393,545 participants were included. A meta-analysis revealed that DM was significantly associated with an increased risk of AD (HR = 1.36, 95% CI (1.19, 1.55), P < 0.00001). A subgroup analysis showed that DM increased the risk of AD regardless of sample size (<100,000: HR = 1.33, 95% CI (1.11–1.59), P = 0.002; >100,000: HR = 1.39, 95% CI (1.13–1.71), P = 0.002). The consistency in P-values may be coincidental, and the results should be interpreted in conjunction with the high heterogeneity across studies. This association was consistent in both Asian (HR = 1.45, 95% CI: 1.20–1.76, P < 0.00001) and non-Asian populations (HR = 1.29, 95% CI: 1.13–1.48, P < 0.00001). After adjusting for APOE ϵ4 mutations, there was no statistically significant difference in the risk association between DM and AD (HR = 1.07, 95% CI (0.97–1.19), P = 0.177), whereas without adjustment for APOE ϵ4 mutation, DM was associated with an increased AD risk (HR = 1.42, 95% CI (1.23–1.64), P < 0.00001).

This meta-analysis provides compelling evidence that DM is an independent risk factor for AD, offering important implications for clinical practice and future research. However, due to the methodological limitations of this study, the results should be interpreted with caution. Large-scale, high-quality prospective cohort studies are needed to fully investigate the relationship between DM and AD risk.

https://www.crd.york.ac.uk/prospero/, identifier CRD420251159844.