Genetic Variation in Targets of Antidiabetic Drugs and Alzheimer Disease Risk

Abstract

BACKGROUND AND OBJECTIVES: Previous studies have highlighted antidiabetic drugs as repurposing candidates for Alzheimer disease (AD), but the disease-modifying effects are still unclear. METHODS: A 2-sample mendelian randomization study design was applied to examine the association between genetic variation in the targets of 4 antidiabetic drug classes and AD risk. Genetic summary statistics for blood glucose were analyzed using UK Biobank data of 326,885 participants, whereas summary statistics for AD were retrieved from previous genome-wide association studies comprising 24,087 clinically diagnosed AD cases and 55,058 controls. Positive control analysis on type 2 diabetes mellitus (T2DM), insulin secretion, insulin resistance, and obesity-related traits was conducted to validate the selection of instrumental variables. RESULTS: = 0.014). However, this result should be interpreted with caution because the positive control analyses for GLP-1 analogues did not comply with a weight-loss effect as shown in previous clinical trials. Results regarding other drug classes were inconclusive. DISCUSSION: Genetic variation in sulfonylurea targets was associated with a lower risk of AD, and future studies are warranted to clarify the underlying mechanistic pathways between sulfonylureas and AD.