Brain Insulin Resistance and Deficiency as Therapeutic Targets in Alzheimers Disease

Abstract

Alzheimer's disease [AD] is the most common cause of dementia in North America. Despite 30+ years of in-tense investigation, the field lacks consensus regarding the etiology and pathogenesis of sporadic AD, and therefore we still do not know the best strategies for treating and preventing this debilitating and costly disease. However, growing evi-dence supports the concept that AD is fundamentally a metabolic disease with substantial and progressive derangements in brain glucose utilization and responsiveness to insulin and insulin-like growth factor [IGF] stimulation. Moreover, AD is now recognized to be heterogeneous in nature, and not solely the end-product of aberrantly processed, misfolded, and aggregated oligomeric amyloid-beta peptides and hyperphosphorylated tau. Other factors, including impairments in en-ergy metabolism, increased oxidative stress, inflammation, insulin and IGF resistance, and insulin/IGF deficiency in the brain should be incorporated into all equations used to develop diagnostic and therapeutic approaches to AD. Herein, the contributions of impaired insulin and IGF signaling to AD-associated neuronal loss, synaptic disconnection, tau hyper-phosphorylation, amyloid-beta accumulation, and impaired energy metabolism are reviewed. In addition, we discuss cur-rent therapeutic strategies and suggest additional approaches based on the hypothesis that AD is principally a metabolic disease similar to diabetes mellitus. Ultimately, our ability to effectively detect, monitor, treat, and prevent AD will re-quire more efficient, accurate and integrative diagnostic tools that utilize clinical, neuroimaging, biochemical, and mo-lecular biomarker data. Finally, it is imperative that future therapeutic strategies for AD abandon the concept of uni-modal therapy in favor of multi-modal treatments that target distinct impairments at different levels within the brain insulin/IGF signaling cascades. ALZHEIMER'S DISEASE AND BRAIN GLUCOSE METABOLISM Alzheimer's disease [AD] is the most common cause of dementia in North America, and over the past several dec-ades, the prevalence rates of sporadic AD have become epi-demic [1]. Although the clinical diagnosis of AD is based on criteria set by the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association (NINCDS/ ADRDA) and DSM-IV criteria [2], embracement of addi-tional tools such as neuroimaging and standardized bio-marker panels could facilitate early detection of disease [3]. Characteristic neuropathological hallmarks of AD include: neuronal loss, abundant accumulations of abnormal, hyper-phosphorylated cytoskeletal proteins in neuronal perikarya and dystrophic fibers, and increased expression and abnor-mal processing of amyloid-beta precursor protein (APP), leading to APP-A peptide deposition in neurons, plaques, and vessels. For nearly three decades, the dominant trends have been to interpret selected AD-associated abnormalities, namely the hyper-phosphorylation of tau and deposition of