Insulin Resistance as a Link between Amyloid-Beta and Tau Pathologies in Alzheimer's Disease

Abstract

Current hypotheses and theories regarding the pathogenesis of Alzheimer's disease (AD) heavily implicate brain insulin resistance (IR) as a key factor. Despite the many well-validated metrics for systemic IR, the absence of biomarkers for brain-specific IR represents a translational gap that has hindered its study in living humans. In our lab, we have been working to develop biomarkers that reflect the common mechanisms of brain IR and AD that may be used to follow their engagement by experimental treatments. We present two promising biomarkers for brain IR in AD: insulin cascade mediators probed in extracellular vesicles (EVs) enriched for neuronal origin, and two-dimensional magnetic resonance spectroscopy (MRS) measures of brain glucose. As further evidence for a fundamental link between brain IR and AD, we provide a novel analysis demonstrating the close spatial correlation between brain expression of genes implicated in IR (using Allen Human Brain Atlas data) and tau and beta-amyloid pathologies. We proceed to propose the bold hypotheses that baseline differences in the metabolic reliance on glycolysis, and the expression of glucose transporters (GLUT) and insulin signaling genes determine the vulnerability of different brain regions to Tau and/or Amyloid beta (Aβ) pathology, and that IR is a critical link between these two pathologies that define AD. Lastly, we provide an overview of ongoing clinical trials that target IR as an angle to treat AD, and suggest how biomarkers may be used to evaluate treatment efficacy and target engagement.

Keywords: Alzheimer’s disease; IRS-1; exosomes; insulin resistance; magnetic resonance spectroscopy.

Figure 1

Tau tangle (neurofibrillary tangles (NFT), upper row) and amyloid-beta plaque (neuritic plaques (NP), bottom row) values were redrawn from data originally presented in Arnold et al. (1991) and superimposed on Brodmann maps (BA 1–48) from MRIcroGL version 1.150909. NFT and NP values are double-blinded rater assessments of tangle or plaque density. Color map and bar (“jet”) is red high, blue low.

Figure 2

(A) Heatmap (“jet”: red high, blue low) of the spatial correlation between levels of expression of various genes from the Allen Human Brain Atlas and the density of tangles (NFT) or plaques (NP) from Arnold et al. (1991). Asterisks (*/**/***) represent p values of <0.05/.01/.001, respectively. (B) Map of mean IRS-1 log2 expression in the six healthy human specimens included in the Allen Human Brain Atlas. (C) Scatter plot of the mean IRS-1 log2 expression from the Allen Human Brain Atlas and the density of tangles (NFT) from Arnold et al. (1991). Each of the 40 data points corresponds to a BA for which both gene expression levels and tangle density ratings were available.

Figure 3

(A) Precuneal voxel placement for the junctional point-resolved spectroscopy (J-PRESS) acquisition is shown in red (25 × 18 × 20 mm³) within a 3D brain cutaway image (figure created in MRIcroGL version 1.150909). (B) Sample 2D J-PRESS spectral fitting from a representative 48-year-old male cognitively normal (CN) participant. (C) Scatter plot of the correlation between the Glc/Cr and fasting Glucose values in 15 healthy male participants (red squares).

Figure 4

Graphical abstract. Baseline differences in the expression of glucose transporters (GLUT) and insulin signaling genes determine the vulnerability of different brain regions to Tau and/or Aβ pathology. Extensive temporo-parietal areas of the brain show significant metabolic reliance on glycolysis, which generates lactate. High lactate is associated with high interstitial Aβ, which assembles into Aβ oligomers. These Aβ oligomers promote Ser phosphorylation of IRS-1, impeding downstream insulin signaling and leading to brain IR. A feed-forward loop is established between IR and Aβ pathology leading to progressive Aβ deposition in NP. Chronic IR promotes tau hyperphosphorylation and this effect is more pronounced in regions that show low expression of insulin signaling proteins (IRS-1, Akt, etc.) at baseline. As a result, hyperphosphorylated tau leads to the development of NFT in a different and more restricted regional pattern than Aβ. The sum of these three inter related pathologies (IR, Aβ, Tau) produces Alzheimer’s disease.