Metabolic signature of insulin resistance and risk of Alzheimer’s disease
Laia Gutierrez-Tordera, Laura Panisello, Pablo García-Gonzalez, Agustín Ruiz, José Luis Cantero, Melina Rojas-Criollo, Muhammad Mursil, Mercedes Atienza, Nil Novau-Ferré, Javier Mateu-Fabregat, Hamza Mostafa, Domènec Puig, Jaume Folch, Hatem Rashwan, Marta Marquié, Mercè Boada, Christopher Papandreou, Mònica BullóAbstract
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 follow-up, 142 subjects converted to AD-dementia. IR was assessed using the HOMA-IR. A targeted multi-platform 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<0.05). 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.