Insulin Resistance, Cognitive Impairment and Neurodegeneration: Roles of Nitrosamine Exposure, Diet and Lifestyles

In Western societies, Alzheimer's disease (AD) is epidemic (de la Monte, Neusner et al. 2009). For decades, the prevailing theories about AD pathogenesis focused on the roles of hyper-phosphorylated and ubiquitinated cytoskeletal proteins in neuronal perikarya and dystrophic fibers, and increased expression and abnormal processing of amyloid-beta precursor protein (AβPP), leading to AβPP-Aβ peptide deposition in neurons, plaques, and vessels, as mediators of neuronal loss, neuritic pathology, synaptic disconnection, and loss of plasticity. Apart from aging, which is the most dominant risk factor, it has not been possible to define convincing roles for AβPP-Aβ or phospho-tau accumulations as principal driving forces of neurodegeneration that could account for all of the protean manifestations of AD, including neuro-inflammation, mitochondrial dysfunction, white matter fiber loss, and neurotransmitter deficiencies. This point is particularly relevant with respect to sporadic AD, which accounts for the vast majority of cases. However, it is entirely possible that the focal points of 30+ years of intense research on the accumulation, abnormal processing, and misfolding of essentially two proteins are somewhat misplaced since these process could be the end-result rather than the cause of the pathophysiological processes that trigger and propagate the neurodegeneration cascade. Growing evidence supports the concept that AD is actually a metabolic disease in which, neurodegeneration is mediated by impairments in brain glucose utilization and energy production that begin early in the course of disease, and worsen with its progression (Frolich, Blum-Degen et al. 1998; Hoyer 2002; Hoyer 2004; Rivera, Goldin et al. 2005; Steen, Terry et al. 2005). AD-associated reductions in glucose utilization and energy metabolism are accompanied by increased oxidative stress and neuro-inflammation, which appear to be driven by insulin and insulin-like growth factor (IGF) resistance in the brain. AD can be regarded as a brain-specific form of diabetes mellitus, i.e. Type 3 diabetes. This chapter reviews the data showing that sporadic AD in humans is associated with progressive impairments in brain insulin and IGF signaling, and contrasts the roles of peripheral insulin resistance disease states versus primary brain insulin/IGF resistance using data from both human and experimental animal studies. Epidemiological and experimental evidence supporting exposures, particularly to environmental toxins such as nitrosamines, rather than only genetic factors as causal in the pathogenesis of AD are discussed. Dietary and