However, recent human and preclinical studies have provided convincing evidence that AD is a degenerative metabolic disease, which is mediated by impairments in brain insulin responsiveness, glucose utilization, and energy metabolism leading to increased oxidative stress, inflammation, and worsening of insulin resistance (Hoyer, 2002, 2004; Schubert et al., 2004; Rivera et al., 2005; Steen et al., 2005; Watson and Craft, 2006; Craft, 2007; Neumann et al., 2008; Krikorian et al., 2010; Luchsinger, 2010; Baker et al., 2011; Talbot et al., 2012; Butterfield et al., 2014a,b; de La Monte, 2014). This evidence concerns the gene INS and Alzheimer disease.