INSR and Alzheimer disease: In support of this hypothesis, AD patients have shown reduced brain insulin receptor sensitivity, hyperphosphorylation of insulin receptor and downstream second messenger such as insulin receptor substrate-1 (IRS-1) and attenuated insulin and insulin-like growth factor receptor expression (Watson and Craft, 2003; Rivera et al., 2005; Steen et al., 2005; Holscher and Li, 2010; Talbot et al., 2012; de La Monte, 2012c; Freiherr et al., 2013).