Type 2 diabetes (T2D) is commonly co-morbid with Alzheimer's disease (AD). However, it remains unclear whether T2D itself or the antidiabetic drug metformin contributes to the progression of AD.

This study aimed to investigate the overall and independent effects of T2D and metformin use on the risk of AD.

Summary genome-wide association study datasets were utilized for the Mendelian randomization (MR) and multivariable MR (MVMR) analyses, including ones for T2D (N = 455,017), metformin (N = 456,276), and AD (N = 453,733). Additionally, using the proportional imbalance method, we analyzed AD-related adverse drug events in the FDA Adverse Event Reporting System (FAERS) database (covering Q1 2004 to Q2 2024).

Our two-sample MR analysis indicated that T2D is not associated with the risk of AD (OR: 1.03, CI: 0.99–1.08, P = 0.128). However, while not statistically significant, genetic signature for metformin exposure demonstrated a trend toward an increased risk of AD (OR: 1.05, CI: 1.00–1.09, P = 0.053). Interestingly, in MVMR analysis, which evaluates independent effects of T2D and metformin exposure on T2D, we found a robust association of T2D with a decrease in the risk of AD (OR: 0.82, CI: 0.68–0.98, P = 0.031), while the use of metformin was associated with a higher risk of AD (OR: 1.26, CI: 1.06–1.50, P = 9.45E-3). In the FAERS database, a total of 228,283 metformin-related adverse event reports from 67,742 cases were found. For metformin as the target drug and AD as the target adverse event, signal analysis reported 29 cases of AD (ROR: 0.83, 95 % CI: 0.58–1.19, P = 0.3126).

Our study reveals the opposite independent causal effects of T2D and metformin exposure on AD. These findings highlight the importance of assessing AD risk when prescribing metformin to patients with T2D.