Introduction: Growing evidence suggests a connection between insulin resistance and apolipoprotein E (APOE) genotype in Alzheimer's disease (AD) pathogenesis, but the mechanisms are unclear. We examined effects of insulin resistance and APOE genotype on blood-brain barrier (BBB) integrity in AD. Methods: BBB integrity was measured in 196 biologically-confirmed non-diabetic patients with AD evaluating CSF/serum albumin ratio, kappa and lambda free light chains (FLCs). Insulin resistance was assessed using triglyceride-glucose index (TyG). The impact of TyG on BBB integrity, and its interaction with APOE genotypes, was analyzed using multivariate models. Results: Sixty-four percent of patients with AD showed altered TyG, with the 21.8% classified as high TyG. TyG subgroups were associated with BBB abnormalities, with similar AD clinical and biomarkers profile. A significant interaction between TyG and APOE ε4/ε4 genotype on BBB permeability was found in multivariate analyses. Discussion: Insulin resistance is a common feature in non-diabetic AD and correlates with altered BBB permeability, interacting synergistically with APOE genotype. Highlights: Insulin resistance and apolipoprotein E (APOE) genotype are well-recognized risk factors for Alzheimer's disease (AD). Insulin resistance shows high prevalence in patients with AD. Insulin resistance is related to damage in blood-brain barrier (BBB) integrity. The association between the triglyceride-glucose (TyG) index and BBB permeability varies in relation to APOE genotype; patients with the APOE ε4/ε4 displayed higher BBB permeability.
