PMID- 35654594 OWN - NLM STAT- MEDLINE DCOM- 20220817 LR - 20230308 IS - 1526-632X (Electronic) IS - 0028-3878 (Print) IS - 0028-3878 (Linking) VI - 99 IP - 7 DP - 2022 Aug 16 TI - Genetic Variation in Targets of Antidiabetic Drugs and Alzheimer Disease Risk: A Mendelian Randomization Study. PG - e650-e659 LID - 10.1212/WNL.0000000000200771 [doi] AB - 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: 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, p = 0.0034). These results for sulfonylureas were largely unchanged in the sensitivity analysis using a genetic variant, rs757110, that has been validated to modulate the target proteins of sulfonylureas (OR = 0.35 per 1 mmol/L decrement in blood glucose, 95% CI 0.15-0.82, p = 0.016). An association between genetic variations in the glucagon-like peptide 1 (GLP-1) analogue target and a lower risk of AD was also observed (OR = 0.32 per 1 mmol/L decrement in blood glucose, 95% CI 0.13-0.79, p = 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. CI - Copyright (c) 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology. FAU - Tang, Bowen AU - Tang B AD - From the Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm (B.T., Y.W., K.J., S.H.); Department of Clinical Neuroscience, Karolinska Institutet, Stockholm (X.J.); Brain Aging and Behavior Section, National Institute on Aging (M.T.); and Longitudinal Studies Section (L.F.), National Institute on Aging. FAU - Wang, Yunzhang AU - Wang Y AD - From the Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm (B.T., Y.W., K.J., S.H.); Department of Clinical Neuroscience, Karolinska Institutet, Stockholm (X.J.); Brain Aging and Behavior Section, National Institute on Aging (M.T.); and Longitudinal Studies Section (L.F.), National Institute on Aging. FAU - Jiang, Xia AU - Jiang X AUID- ORCID: 0000-0001-5878-8986 AD - From the Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm (B.T., Y.W., K.J., S.H.); Department of Clinical Neuroscience, Karolinska Institutet, Stockholm (X.J.); Brain Aging and Behavior Section, National Institute on Aging (M.T.); and Longitudinal Studies Section (L.F.), National Institute on Aging. FAU - Thambisetty, Madhav AU - Thambisetty M AD - From the Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm (B.T., Y.W., K.J., S.H.); Department of Clinical Neuroscience, Karolinska Institutet, Stockholm (X.J.); Brain Aging and Behavior Section, National Institute on Aging (M.T.); and Longitudinal Studies Section (L.F.), National Institute on Aging. FAU - Ferrucci, Luigi AU - Ferrucci L AD - From the Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm (B.T., Y.W., K.J., S.H.); Department of Clinical Neuroscience, Karolinska Institutet, Stockholm (X.J.); Brain Aging and Behavior Section, National Institute on Aging (M.T.); and Longitudinal Studies Section (L.F.), National Institute on Aging. FAU - Johnell, Kristina AU - Johnell K AD - From the Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm (B.T., Y.W., K.J., S.H.); Department of Clinical Neuroscience, Karolinska Institutet, Stockholm (X.J.); Brain Aging and Behavior Section, National Institute on Aging (M.T.); and Longitudinal Studies Section (L.F.), National Institute on Aging. FAU - Hagg, Sara AU - Hagg S AUID- ORCID: 0000-0002-2452-1500 AD - From the Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm (B.T., Y.W., K.J., S.H.); Department of Clinical Neuroscience, Karolinska Institutet, Stockholm (X.J.); Brain Aging and Behavior Section, National Institute on Aging (M.T.); and Longitudinal Studies Section (L.F.), National Institute on Aging. sara.hagg@ki.se. LA - eng GR - MC_PC_17228/MRC_/Medical Research Council/United Kingdom GR - MC_QA137853/MRC_/Medical Research Council/United Kingdom GR - RF1 AG067996/AG/NIA NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20220602 PL - United States TA - Neurology JT - Neurology JID - 0401060 RN - 0 (Blood Glucose) RN - 0 (Hypoglycemic Agents) RN - 89750-14-1 (Glucagon-Like Peptide 1) SB - IM CIN - Neurology. 2022 Aug 16;99(7):267-268. PMID: 35654591 MH - *Alzheimer Disease/complications/drug therapy/genetics MH - Blood Glucose/metabolism MH - *Diabetes Mellitus, Type 2/blood/drug therapy/genetics MH - Drug Repositioning MH - Genome-Wide Association Study MH - Glucagon-Like Peptide 1/therapeutic use MH - Humans MH - Hypoglycemic Agents/therapeutic use MH - Mendelian Randomization Analysis MH - Polymorphism, Single Nucleotide/genetics PMC - PMC9484609 EDAT- 2022/06/03 06:00 MHDA- 2022/08/18 06:00 PMCR- 2022/08/28 CRDT- 2022/06/02 21:43 PHST- 2021/10/11 00:00 [received] PHST- 2022/04/08 00:00 [accepted] PHST- 2022/06/03 06:00 [pubmed] PHST- 2022/08/18 06:00 [medline] PHST- 2022/06/02 21:43 [entrez] PHST- 2022/08/28 00:00 [pmc-release] AID - WNL.0000000000200771 [pii] AID - WNL-2022-200755 [pii] AID - 10.1212/WNL.0000000000200771 [doi] PST - ppublish SO - Neurology. 2022 Aug 16;99(7):e650-e659. doi: 10.1212/WNL.0000000000200771. Epub 2022 Jun 2.