Biomarkers of brain insulin resistance and neuroimaging correlates in early Alzheimer's disease

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Insulin resistance (IR) and type 2 diabetes are risk factors for Alzheimer's disease (AD). Exosomes are endosome-derived vesicles containing macromolecules reflecting their cellular source. Using a methodology for enriching blood exosomes for neuronal origin, we recently identified differentially phosphorylated forms of Insulin Receptor Substrate-1 (IRS-1), as in vivo biomarkers of brain-specific IR in AD (Kapogiannis et al., FASEB J, 2014). Here, we assess their cognitive, functional connectivity, and brain structure correlates in AD. In 26 patients with early AD (Global CDR 0.5 or 1), we isolated blood exosomes and enriched for neuronal origin by immunoabsorption with anti-L1CAM antibody. We measured concentrations of total IRS-1, total phosphorylated tyrosine (pY-), and phosphorylated Ser312 (pS312-) IRS-1. T1-weighted MPRAGE images were acquired and gray matter (GM) images were segmented using the VBM8 toolbox; voxel-based morphometry analysis against exosomal biomarkers was conducted in SPM8. The Allen Human Brain Atlas was used to create a GM mask of IRS-1 gene microarray expression values, which was used for Biological Parametric Mapping. Independent component analysis (ICA) with the GIFT toolbox was used to derive ventral, anterior and posterior default mode networks (DMNs) from resting EPI images (Fig.2A). Associations between DMNs and exosomal biomarkers were examined with the MANCOVAN toolbox. Higher pY-IRS-1 predicted worse global cognition, and immediate and delayed verbal memory. Higher pY-IRS-1 and pS312-IRS-1 were associated with less GM in lateral and medial temporal cortex, precuneus and medial prefrontal DMN nodes, before and after adjusting for IRS-1 expression (Fig.1). Higher pS312-IRS-1 was associated with lower low- to medium-frequency spectral power of anterior DMN (Fig.2.B.C.). Higher pY-IRS-1 was associated with higher low-frequency spectral power of anterior DMN, higher medium- to high-frequency spectral power of posterior and ventral DMN, and spatially restricted posterior DMN (Fig.2.D.E.F.G).