Insulin Resistance and Metabolic Failure Underlie Alzheimer Disease

Alzheimer disease (AD) is the most common cause of dementia in North America. Despite 30+ years of intensive research, gaps remain in our understanding of AD pathogenesis and approaches to treatment. However, the recent rapid shift to a paradigm that focuses on the roles of metabolic dysfunction and insulin and insulin-like growth factor (IGF) resistance as causal agents of cognitive impairment and neurodegeneration holds promise. The overarching hypothesis, that AD is a brain diabetes (type 3), accounts for the impairments in neuronal survival, myelin maintenance, energy metabolism, synaptic integrity, and plasticity, and the well-recognized neuropathological processes including, tau hyper-phosphorylation, amyloid-beta (APP -A ) accumulation, oxidative and endoplasmic reticulum stress, and cerebral microvascular disease. Herein, we discuss the roles of aging, lifestyle choices, peripheral insulin resistance diseases, including obesity, type 2 diabetes mellitus, nonalcoholic fatty liver disease, and metabolic syndrome, nitrosamine exposures, and familial/genetic factors as mediators of brain diabetes, cognitive impairment, and neurodegeneration. The data suggest that neurodegeneration can be initiated and propagated by the buildup of agents consequential to peripheral insulin resistance, i.e. toxic lipids (ceramides), and predicts that toxic ceramides generated in liver or visceral fat, cross the blood-brain barrier and cause brain insulin resistance, stress, and inflammation. This extrinsic mechanism of neurodegeneration accounts for the strikingly concurrent and overlapping increases in prevalence of all insulin resistance diseases. Yet, there is evidence that AD/type 3 diabetes occurs as the dominant or only manifestation of insulin resistance. The predicted intrinsic pathway of neurodegeneration is nearly identical to the extrinsic pathway, except its underlying basis is direct toxic/metabolic injury to the brain, or familial AD-associated mutations and gene variants that accelerate the trajectory to brain insulin resistance with aging. Finally, we propose that progressive cognitive impairment and neurodegeneration in AD are effectuated by a positive feedback mal-signaling cascade, whereby declining function of insulin/IGF networks dysregulate lipid metabolism and increase local levels of toxic ceramides. Toxic ceramides promote inflammation, endoplasmic reticulum and oxidative stress, and mitochondrial dysfunction, all of which exacerbate brain insulin/IGF resistance. Over time and with aging, adducts accumulate in DNA, RNA, protein, and lipids, causing continuous multi-modal molecular failure, leading to disruption of cytoskeletal function, A PP-A secretion, synaptic plasticity, cell survival mechanisms, and myelin maintenance. Once established, the reverberating loop must be targeted using multipronged approaches to disrupt spiraling progression of the AD neurodegeneration cascade. Metabolic Syndrome and Neurological Disorders, First Edition. Edited by Tahira Farooqui and Akhlaq A. Farooqui. C © 2013 John Wiley & Sons, Inc. Published 2013 by John Wiley & Sons, Inc. 1 CO PY RI GH TE D M AT ER IA L BLBS136-c01 BLBS136-Farooqui Printer: Yet to Come September 3, 2013 7:14 246mm×189mm 2 METABOLIC SYNDROME AND NEUROLOGICAL DISORDERS