BACKGROUND: Mendelian Randomization (MR) studies have reported that type 2 diabetes (T2D) was not associated with Alzheimer disease (AD). We adopted a modified, mechanism-specific MR design to explore this surprising result. METHODS: Using inverse-variance weighted MR analysis, we evaluated the association between T2D and AD using data from 39 single nucleotide polymorphisms (SNPs) significantly associated with T2D in DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) and the corresponding associations of each SNP with AD risk obtained from the International Genomics of Alzheimer's Project (IGAP, n=17,008 AD cases and n=37,154 controls). We evaluated mechanism-specific genetic subscores, including β-cell function, insulin sensitivity, and adiposity, and repeated analyses in 8501 Health and Retirement Study participants for replication and model validation. RESULTS: In IGAP, the overall T2D polygenic score did not predict AD [odds ratio (OR) for the T2D polygenic score=1.01; 95% confidence interval (CI), 0.96, 1.06] but the insulin sensitivity polygenic score predicted higher AD risk (OR=1.17; 95% CI, 1.02, 1.34). In the Health and Retirement Study, polygenic scores were associated with T2D risk; the associations between insulin sensitivity genetic polygenic score and cognitive phenotypes were not statistically significant. CONCLUSIONS: Evidence from polygenic scores suggests that insulin sensitivity specifically may affect AD risk, more than T2D overall.
BACKGROUND: Mendelian Randomization (MR) studies have reported that type 2 diabetes (T2D) was not associated with Alzheimer disease (AD). We adopted a modified, mechanism-specific MR design to explore this surprising result. METHODS: Using inverse-variance weighted MR analysis, we evaluated the association between T2D and AD using data from 39 single nucleotide polymorphisms (SNPs) significantly associated with T2D in DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) and the corresponding associations of each SNP with AD risk obtained from the International Genomics of Alzheimer's Project (IGAP, n=17,008 AD cases and n=37,154 controls). We evaluated mechanism-specific genetic subscores, including β-cell function, insulin sensitivity, and adiposity, and repeated analyses in 8501 Health and Retirement Study participants for replication and model validation. RESULTS: In IGAP, the overall T2D polygenic score did not predict AD [odds ratio (OR) for the T2D polygenic score=1.01; 95% confidence interval (CI), 0.96, 1.06] but the insulin sensitivity polygenic score predicted higher AD risk (OR=1.17; 95% CI, 1.02, 1.34). In the Health and Retirement Study, polygenic scores were associated with T2D risk; the associations between insulin sensitivity genetic polygenic score and cognitive phenotypes were not statistically significant. CONCLUSIONS: Evidence from polygenic scores suggests that insulin sensitivity specifically may affect AD risk, more than T2D overall.
Authors: K M V Narayan; James P Boyle; Theodore J Thompson; Edward W Gregg; David F Williamson Journal: Diabetes Care Date: 2007-03-19 Impact factor: 19.112
Authors: A Nunomura; G Perry; G Aliev; K Hirai; A Takeda; E K Balraj; P K Jones; H Ghanbari; T Wataya; S Shimohama; S Chiba; C S Atwood; R B Petersen; M A Smith Journal: J Neuropathol Exp Neurol Date: 2001-08 Impact factor: 3.685
Authors: Jessica R Marden; Elizabeth R Mayeda; Eric J Tchetgen Tchetgen; Ichiro Kawachi; M Maria Glymour Journal: Alzheimer Dis Assoc Disord Date: 2017 Jan-Mar Impact factor: 2.703
Authors: Rebecca Carnegie; Jie Zheng; Hannah M Sallis; Hannah J Jones; Kaitlin H Wade; Jonathan Evans; Stan Zammit; Marcus R Munafò; Richard M Martin Journal: Lancet Psychiatry Date: 2019-11-20 Impact factor: 27.083