Opposite causal effects of type 2 diabetes and metformin on Alzheimer's disease.

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The Journal of Prevention of Alzheimer's Disease Pub Date : 2025-03-09 DOI:10.1016/j.tjpad.2025.100129

Dongming Liu, Hongbao Cao, Ancha Baranova, Chenxin Xu, Fuquan Zhang

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Abstract

Background: 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.

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

Methods: 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).

Results: 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).

Conclusions: 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.

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2型糖尿病和二甲双胍对阿尔茨海默病的相反因果效应。

背景：2型糖尿病（T2D）通常与阿尔茨海默病（AD）共病。然而，目前尚不清楚是T2D本身还是抗糖尿病药物二甲双胍导致了AD的进展。目的：本研究旨在探讨T2D和二甲双胍使用对AD风险的整体和独立影响。方法：利用全基因组关联研究汇总数据集进行孟德尔随机化（MR）和多变量MR （MVMR）分析，包括T2D （N = 455,017）、二甲双胍（N = 456,276）和AD （N = 453,733）。此外，使用比例不平衡法，我们分析了FDA不良事件报告系统（FAERS）数据库（涵盖2004年第一季度至2024年第二季度）中与ad相关的药物不良事件。结果：我们的双样本MR分析显示，T2D与AD的风险无关（OR: 1.03, CI: 0.99-1.08, P = 0.128）。然而，尽管没有统计学意义，二甲双胍暴露的遗传特征显示出AD风险增加的趋势（OR: 1.05, CI: 1.00-1.09, P = 0.053）。有趣的是，在评估T2D和二甲双胍暴露对T2D的独立影响的MVMR分析中，我们发现T2D与AD风险降低有很强的相关性（OR: 0.82, CI: 0.68-0.98, P = 0.031），而使用二甲双胍与AD风险升高相关（OR: 1.26, CI: 1.06-1.50, P = 9.45E-3）。在FAERS数据库中，从67,742例病例中共发现228,283例二甲双胍相关不良事件报告。以二甲双胍为靶药物，以AD为靶不良事件，信号分析报告AD 29例（ROR: 0.83, 95% CI: 0.58 ~ 1.19, P = 0.3126）。结论：我们的研究揭示了T2D和二甲双胍暴露对AD的相反的独立因果效应。这些发现强调了在给T2D患者开二甲双胍处方时评估AD风险的重要性。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

The Journal of Prevention of Alzheimer's Disease Medicine-Psychiatry and Mental Health

CiteScore

9.20

自引率

0.00%

发文量

期刊介绍： The JPAD Journal of Prevention of Alzheimer’Disease will publish reviews, original research articles and short reports to improve our knowledge in the field of Alzheimer prevention including: neurosciences, biomarkers, imaging, epidemiology, public health, physical cognitive exercise, nutrition, risk and protective factors, drug development, trials design, and heath economic outcomes.JPAD will publish also the meeting abstracts from Clinical Trial on Alzheimer Disease (CTAD) and will be distributed both in paper and online version worldwide.We hope that JPAD with your contribution will play a role in the development of Alzheimer prevention.