Metabolic Signature of Insulin Resistance and Risk of Alzheimer’s Disease

Background: Substantial evidence supports the relationship between peripheral insulin resistance (IR) and the development of Alzheimer’s disease (AD)-dementia. However, the mechanisms explaining these associations are only partly understood. We aimed to identify a metabolic signature of IR associated with the progression from mild cognitive impairment (MCI) to AD-dementia. Methods: This is a case-control study on 400 MCI subjects, free of type 2 diabetes, within the ACE cohort, including individuals ATN + and ATN−. After a median of 2.1 years of follow-up, 142 subjects converted to AD-dementia. IR was assessed using the homeostasis model assessment for insulin resistance (HOMA-IR). A targeted multiplatform approach profiled over 600 plasma metabolites. Elastic net penalized linear regression with 10-fold cross-validation was employed to select those metabolites associated with HOMA-IR. The prediction ability of the signature was assessed using support vector machine and performance metrics. The metabolic signature was associated with AD-dementia risk using a multivariable Cox regression model. Using counterfactual-based mediation analysis, we investigated the mediation role of the metabolic signature between HOMA-IR and AD-dementia. The metabolic pathways in which the metabolites were involved were identified using MetaboAnalyst. Results: The metabolic signature comprised 18 metabolites correlated with HOMA-IR. After adjustments by confounders, the signature was associated with increased AD-dementia risk (HR = 1.234; 95% CI = 1.019–1.494; p < .05). The metabolic signature mediated 35% of the total effect of HOMA-IR on AD-dementia risk. Significant metabolic pathways were related to glycerophospholipid and tyrosine metabolism. Conclusions: We have identified a blood-based metabolic signature that reflects IR and may enhance our understanding of the biological mechanisms through which IR affects AD-dementia.