Genetic Variation in Targets of Antidiabetic Drugs and Alzheimer Disease Risk: A Mendelian Randomization Study

Previous studies have highlighted antidiabetic drugs as repurposing candidates for Alzheimer disease (AD), but the disease-modifying effects are still unclear.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.In the positive control analysis, genetic variation in sulfonylurea targets was associated with higher insulin secretion, a lower risk of T2DM, and an increment in body mass index, waist circumference, and hip circumference, consistent with drug mechanistic actions and previous trial evidence. In the primary analysis, genetic variation in sulfonylurea targets was associated with a lower risk of AD (odds ratio [OR] = 0.38 per 1 mmol/L decrement in blood glucose, 95% CI 0.19-0.72,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.