The goal of this study was to further explore potential mechanisms through which diabetogenic dietary conditions that result in promotion of insulin resistance (IR), a feature of non-insulin dependant diabetes mellitus (type-2 diabetes), may influence Alzheimer's disease (AD). Using genome-wide array technology, we found that connective tissue growth factor (CTGF), a gene product described previously for its involvement in diabetic fibrosis, is elevated in brain tissue in an established mouse model of diet-induced IR. With this evidence we continued to explore the regulation of CTGF in postmortem AD brain tissue and found that CTGF expression correlated with the progression of AD clinical dementia and amyloid neuritic plaque (NP) neuropathology, but not neurofibrillary tangle (NFT) deposition. Consistent with this evidence, we also found that exposure of Tg2576 mice (a model AD-type amyloid neuropathology) to a diabetogenic diet that promotes IR results in a ~2-fold elevation in CTGF steady-state levels in the brain, coincident with a commensurate promotion of AD-type amyloid plaque burden. Finally, using in vitro cellular models of amyloid precursor protein (APP)-processing and Abeta generation/clearance, we confirmed that human recombinant (hr)CTGF may increase Abeta1-40 and Abeta1-42 peptide steady-state levels, possibly through a mechanism that involves gamma-secretase activation and decreased insulin-degrading enzyme (IDE) steady-state levels in a MAP kinase (MAPK)/ phosphatidylinositol 3-kinase (PI-3K)/protein kinase-B (AKT)1-dependent manner. The findings in this study tentatively suggest that increased CTGF expression in the brain might be a novel biological predicative factor of AD clinical progression and neuropathology in response to dietary regimens promoting IR conditions.