Insulin resistance in Alzheimer's disease

Abstract

The links between systemic insulin resistance (IR), brain-specific IR, and Alzheimer's disease (AD) have been an extremely productive area of current research. This review will cover the fundamentals and pathways leading to IR, its connection to AD via cellular mechanisms, the most prominent methods and models used to examine it, an introduction to the role of extracellular vesicles (EVs) as a source of biomarkers for IR and AD, and an overview of modern clinical studies on the subject. To provide additional context, we also present a novel analysis of the spatial correlation of gene expression in the brain with the aid of Allen Human Brain Atlas data. Ultimately, examining the relation between IR and AD can be seen as a means of advancing the understanding of both disease states, with IR being a promising target for therapeutic strategies in AD treatment. In conclusion, we highlight the therapeutic potential of targeting brain IR in AD and the main strategies to pursue this goal.

Figure 1

Heat map of the Pearson correlation r between a selection of probes associated with IR y-axis (top) and AD (x-axis). Heat maps highlight the relation between AD-related and IR-related gene expression levels. Squares with higher r-values (green to yellow) indicate genes that are co-expressed; squares with lower r-values (blue to dark blue) indicate genes with little to no spatial overlap.

Figure 2

AHBA sampling locations with expression values superimposed on 3D representations of the six human brain specimens as z-scores (red indicates positive, green indicates negative). The top row is GSK-3B (probe: CUST_14455_PI416261804) and the bottom row is IRS-1 (probe: A_24_P225679). Image credit: Allen Brain Atlas.