Causal effect of Insulin Resistance on Small Vessel Stroke and Alzheimer's Disease: A Mendelian Randomization Analysis

Abstract

Background The causal effect of insulin resistance on small vessel stroke and Alzheimer Disease was controversial in previous studies. Methods We selected 12 single-nucleotide polymorphisms (SNPs) associated with body mass index (BMI)-adjusted fasting insulin levels and 5 SNPs associated with gold standard measures of insulin resistance as instrumental variables in Mendelian randomization (MR) analyses. Summary statistical data of SNP-small vessel stroke and of SNP-AD associations were derived from the Multi-ancestry Genome-Wide Association Study of Stroke Consortium and Psychiatric Genomics Consortium-Alzheimer’s Disease Workgroup data of individuals of European ancestry. Two-sample MR estimates were conducted with inverse-variance-weighted, robust inverse-variance-weighted, simple median, weighted median, weighted mode-based estimator, and MR pleiotropy residual sum and outlier methods. Results Genetically predicted higher insulin resistance had a higher odds ratio (OR) of small vessel stroke (OR 1.23; 95% confidence interval [CI] 1.05–1.44; P = 0.01 using BMI-adjusted fasting insulin; OR 1.25; 95% CI 1.07–1.46; P = 0.006 using gold standard measure of insulin resistance) and AD (OR 1.13; 95% CI 1.04–1.23; P = 0.004 using BMI-adjusted fasting insulin; OR 1.02; 95% CI 1.00-1.03; P = 0.03 using gold standard measures of insulin resistance) using the inverse-variance-weighted method. No evidence of pleiotropy was found using MR-Egger regression. Conclusion Our findings provide genetic support for a causal effect of insulin resistance on small vessel stroke and AD. Further investigation on the involved mechanisms is needed.

Genetically proxied lean mass and risk of Alzheimer’s disease: mendelian randomisation study

“…Several mendelian randomisation analyses have identified the effects of cardiometabolic risk factors on the risk of Alzheimer’s disease, which could be further investigated as potential mediators of the effect of lean mass on Alzheimer’s disease in future analyses. Alternative potential pathways include insulin resistance 41 and blood pressure 42 (although with mixed results 43 44 ). However, our analysis with coronary artery disease as a risk factor suggests that the burden of atherosclerotic disease is unlikely to be a relevant mediator.…”