Causal effect of insulin resistance on small vessel stroke and Alzheimer's disease: A Mendelian randomization analysis

The causal effect of insulin resistance on small vessel stroke and Alzheimer's disease (AD) was controversial in previous studies. We therefore applied Mendelian randomization (MR) analyses to identify the causal effect of insulin resistance on small vessel stroke and AD.We selected 12 single-nucleotide polymorphisms (SNPs) associated with fasting insulin levels and five SNPs associated with "gold standard" measures of insulin resistance as instrumental variables in MR analyses. Summary statistical data on SNP-small vessel stroke and on SNP-AD associations were derived from studies by the Multi-ancestry Genome-Wide Association Study of Stroke consortium (MEGASTROKE) and the Psychiatric Genomics Consortium-Alzheimer Disease Workgroup (PGC-ALZ) in 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 (MR-PRESSO) methods.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 fasting insulin; OR 1.25, 95% CI 1.07-1.46, p = 0.006 using gold standard measures of insulin resistance) and AD (OR 1.13, 95% CI 1.04-1.23, p = 0.004 using 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.Our findings provide genetic support for a potential causal effect of insulin resistance on small vessel stroke and AD.