Brain Insulin Resistance and Deficiency as Therapeutic Targets in Alzheimer’s Disease
Alzheimer’s disease [AD] is the most common cause of dementia in North America. Despite 30+ years of intense 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 evidence 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 energy 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 hyperphosphorylation, amyloid-beta accumulation, and impaired energy metabolism are reviewed. In addition, we discuss current 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 require more efficient, accurate and integrative diagnostic tools that utilize clinical, neuroimaging, biochemical, and molecular 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 decades, the prevalence rates of sporadic AD have become epidemic . 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 , embracement of additional tools such as neuroimaging and standardized biomarker panels could facilitate early detection of disease . Characteristic neuropathological hallmarks of AD include: neuronal loss, abundant accumulations of abnormal, hyperphosphorylated 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. For nearly three decades, the dominant trends have been to interpret selected AD-associated abnormalities, namely the hyper-phosphorylation of tau and deposition of AβPP-Aβ as causal rather than consequential to the neurodegeneration cascade. This approach posed significant limitations on the scope of investigation and the goals with respect to designing new treatments; ergo, success has been either modest or disappointing. On the other hand, due to collected contributions of a number of researchers, the field has recently become more receptive to alternative concepts, opening the doors to exciting new avenues of investigation and therapeutic strategies.
Growing evidence supports the concept that AD fundamentally represents a metabolic disease in which brain glucose utilization and energy production are impaired [4–8]. Metabolic abnormalities have been linked to brain insulin and insulin-like growth factor (IGF) resistance with disruption of signaling pathways that regulate neuronal survival, energy production, gene expression, and plasticity . On a cellular basis, inhibition of insulin/IGF signaling contributes to AD-type neurodegeneration by increasing: 1) the activity of kinases that aberrantly phosphorylate tau; 2) expression of AβPP and accumulation of AβPP-Aβ; 3) levels of oxidative and endoplasmic reticulum (ER) stress; 4) the generation of reactive oxygen and reactive nitrogen species that damage proteins, RNA, DNA, and lipids; 5) mitochondrial dysfunction; and 6) activation of pro-inflammatory and pro-death cascades. On a functional basis, insulin/IGF resistance causes down-regulation of target genes that are needed for cholinergic homeostasis, and it compromises systems that mediate neuronal plasticity, memory, and cognition.
The gold standard for definitively diagnosing AD is to perform a postmortem examination of the brain, with the objective of demonstrating beyond-normal aging associated densities of neurofibrillary tangles, neuritic plaques, and AβPP-Aβ deposits in corticolimbic structures, bearing in mind that neurodegeneration frequently involves multiple other cortical regions as well. The common thread among these characteristic lesions is that they harbor insoluble aggregates of abnormally phosphorylated and ubiquitinated tau, and neurotoxic AβPP-Aβ in the form of oligomers, fibrillar aggregates, or extracellular plaques. Secreted AβPP-Aβ oligomers have been demonstrated to be neurotoxic and to inhibit hippocampal long-term potentiation, i.e. synaptic plasticity .
Ultimately, to improve our capacity for diagnosis and treatment, we should be able to connect the development and progression of neuropathological lesions with the molecular, biochemical, physiological, neuro-imaging, and clinical abnormalities that correlate with AD. Therefore, gaining a better understanding of the pathophysiology of these lesions could improve our current diagnostic and treatment approaches to AD. One way to begin the process in earnest is to acknowledge that the rigid employment of standardized criteria for diagnosing AD, in fact, restricts our ability to fully comprehend the underlying disease process. For example, in addition to the characteristic lesions noted above, AD is associated with loss of neurons, fibers, and synapses, disruption of the cortical-laminar architecture, gliosis, proliferation of dystrophic neurites, and neuro-inflammatory responses, including microglial cell activation. For unclear reasons, these abnormalities are not systematically quantified, and consequently, they are not routinely incorporated into the AD diagnostic equation. At the same time, many basic cellular, molecular, biochemical, and structural abnormalities in AD overlap with those in other neurodegenerative diseases such as dementia with Lewy bodies, fronto-temporal dementias, and multiple systems atrophy, indicating that one or two biomarkers might not be sufficient to consistently and accurately diagnose AD.
Hints that AD could represent a metabolic disease emerged from studies showing that the early stages of AD were marked by deficits cerebral glucose utilization [10–15], and that as the disease progressed, metabolic and physiological abnormalities worsened [16, 17]. Subsequently, AD was shown to be associated with brain insulin resistance and insulin deficiency, with significant abnormalities in the expression of genes and activation of kinases that are regulated by insulin and insulin-like growth factor (IGF) signaling [4–8]. Moreover, it was shown that in AD, progressive declines in cerebral glucose utilization, and deficits in insulin signaling and insulin-responsive gene expression worsen with severity of disease. In particular, insulin/IGF regulated genes, including choline acetyltransferase, tau, and glyceraldehyde-3-phosphate dehydrogenase (GAPDH), which mediate cholinergic/cognitive, neuronal cytoskeletal, and metabolic functions, are suppressed in AD . Insulin resistance mediated impairments in energy metabolism lead to oxidative stress, generation of reactive oxygen species (ROS), DNA damage, and mitochondrial dysfunction, all of which drive pro-apoptosis, pro-inflammatory, and pro-AβPP-Aβ cascades. Experimental animals in which brain insulin receptor expression and function were suppressed exhibited cognitive impairment and neurodegeneration with features that overlap with AD [18–22].
In AD brains, deficits in insulin/IGF signaling are due to the combined effects of insulin/IGF resistance and deficiency. Insulin/IGF resistance is manifested by reduced levels of insulin/IGF receptor binding and decreased responsiveness to insulin/IGF stimulation, while the trophic factor deficiency is associated with reduced levels of insulin polypeptide and gene expression in brain and cerebrospinal fluid [6–8, 23–25]. In essence, AD can be regarded as a form of brain diabetes that has elements of both insulin resistance and insulin deficiency. To consolidate this concept, we proposed that AD be referred to as, “Type 3 diabetes” [7, 8].
INSULIN AND INSULIN-LIKE GROWTH FACTOR ACTIONS IN THE BRAIN
In the central nervous system (CNS), insulin and IGF signaling play critical roles in regulating and maintaining cognitive function. Insulin, IGF-1 and IGF-2 polypeptide and receptor genes are expressed in neurons [26–28] and glial cells [29–32] throughout the brain, and their highest levels of expression are in structures typically targeted by neurodegenerative diseases [33, 34]. Insulin and IGFs regulate a broad range of neuronal functions throughout life, from embryonic and fetal development to adulthood. The corresponding signaling pathways are activated by insulin and IGF binding to their own receptors, resulting in phosphorylation and activation of intrinsic receptor tyrosine kinases. Subsequent interactions between the phosphorylated receptors and insulin receptor substrate (IRS) molecules promote transmission of downstream signals that inhibit apoptosis, and stimulate growth, survival, metabolism, and plasticity. Anti-apoptotic mechanisms inhibited by insulin/IGF stimulation include BAD (inhibitor of Bcl-2), Forkhead Box O (FoxO), glycogen synthase kinase 3β (GSK-3β), and nuclear factor kappa B (NF-κB). GSK-3β regulates Wnt signaling by phosphorylating β-catenin and thereby targeting it for ubiquitin/proteosome-mediated degradation. Wnt signaling mediates synaptic plasticity in the CNS. Therefore, major functions supported by the insulin/IGF signaling axis include, neuronal growth, survival, differentiation, migration, energy metabolism, gene expression, protein synthesis, cytoskeletal assembly, synapse formation, neurotransmitter function, and plasticity [26, 35–38]. Correspondingly, impaired signaling through insulin and IGF receptors has dire consequences with respect to the structural and functional integrity of the CNS.
IMPAIRED INSULIN/IGF SIGNALING AND TAU PATHOLOGY IN AD
The major neuronal cytoskeletal lesions that correlate with severity of dementia in AD, including neurofibrillary tangles and dystrophic neurites, contain aggregated and ubiquitinated insoluble fibrillar tau. In other words, tau accumulation and pathology are the most significant structural correlates of dementia in AD [39, 40]. In AD, tau, a microtubule-associated protein, gets hyperphosphorylated due to inappropriate activation of several proline-directed kinases, including GSK-3β. As a result, tau protein misfolds and self-aggregates into insoluble fibrillar structures [paired helical filaments and straight filaments] that form neurofibrillary tangles, dystrophic neurites, and neuropil threads . Intra-neuronal accumulations of fibrillar tau disrupt neuronal cytoskeletal networks and axonal transport, leading to synaptic disconnection and progressive neurodegeneration . Besides fibrillar tau, pre-fibrillar tau can aggregate, forming soluble tau oligomers or insoluble granular tau, which contribute to neurodegeneration by causing synaptic disconnection and neuronal death . The eventual ubiquitination of hyper-phosphorylated tau , combined with dysfunction of the ubiquitin-proteasome system , cause further accumulation of insoluble fibrillar tau, oxidative stress, and ROS generation, which together promote neuronal apoptosis, mitochondrial dysfunction, and necrosis in AD .
Growing evidence suggests that many of the aforementioned cellular aspects of AD neurodegeneration may be caused by brain insulin/IGF resistance [7, 8] which, as in other brain insulin-resistance states, results in inhibition of downstream pro-growth and pro-survival signaling pathways (Fig. 11) [46–49]. Tau gene expression and phosphorylation are regulated by insulin and IGF stimulation [50, 51]. In AD, brain insulin and IGF resistance result in decreased signaling through phosphoinositol-3-kinase (PI3K), Akt [50,51], and Wnt/β-catenin , and increased activation of glycogen synthase kinase 3β (GSK-3β) [53–57]. GSK-3β over-activation is partly responsible for the hyper-phosphorylation of tau, which leads to tau misfolding and fibril aggregation . In addition, tau hyper-phosphorylation in AD is mediated by increased activation of cyclin-dependent kinase 5 (cdk-5) and c-Abl kinases [59, 60], and inhibition of protein phosphatases 1 and 2A [41, 60, 61]. Besides hyper-phosphorylation, tau pathology in AD is mediated by impaired tau gene expression due to reduced insulin and IGF signaling . Consequences include, failure to generate sufficient quantities of normal soluble tau protein, vis-a-vis accumulation of hyper-phosphorylated insoluble fibillar tau, and attendant exacerbation of cytoskeletal collapse, neurite retraction, and synaptic disconnection.
INSULIN/IGF RESISTANCE AND AMYLOID-BETA (AΒ) NEUROTOXICITY
AD is associated with dysregulated expression and processing of amyloid precursor protein (AβPP), resulting in the accumulation of AβPP-Aβ (Aβ) oligomeric fibrils or insoluble larger aggregated fibrils (plaques) that are neurotoxic (Fig. 22). Pathophysiologically, increased AβPP gene expression, together with altered proteolysis, result in accumulation of 40 or 42 amino acid length Aβ peptides that can aggregate. In familial forms of AD, mutations in the AβPP, presenilin 1 (PS1), and PS2 genes, or inheritance of the Apoliprotein E ε4 (ApoE- ε4) allele, are responsible for increased synthesis and deposition of Aβ peptides in the brain. However, in sporadic AD, which accounts for 90% or more of the cases, the causes of Aβ accumulation and toxicity are still under intense investigation. Over the past few years, interest in the role of impaired insulin/IGF signaling as either the cause or consequence of dysregulated AβPP-Aβ expression and protein processing has grown.
The concept that Aβ toxicity causes insulin resistance, and the opposing argument that brain insulin resistance with attendant oxidative stress and neuro-inflammation promotes Aβ accumulation and toxicity are both supported by experimental data. For example, studies have established that insulin stimulation accelerates trafficking of Aβ from the trans-Golgi network, where it is generated, to the plasma membrane, and that insulin stimulates Aβ extracellular secretion  and inhibits its intracellular accumulation and degradation by insulin-degrading enzyme [64, 65]. Although it remains uncertain as to whether these physiological actions of insulin on AβPP processing contribute to Aβ burden, what is apparent is that impaired insulin signaling can disrupt both the processing of AβPP and clearance of Aβ . The accumulation of Aβ exacerbates the problem because Aβ disrupts insulin signaling by competing with insulin, or reducing the affinity of insulin binding to its own receptor [67, 68]. In addition, AβPP oligomers inhibit neuronal transmission of insulin-stimulated signals by desensitizing and reducing the surface expression of insulin receptors. Furthermore, intracellular AβPP-Aβ directly interferes with PI3 kinase activation of Akt, which leads to impaired survival signaling, increased activation of GSK-3β, and hyper-phosphorylation of tau. Hyper-phosphorylated tau is prone to misfold, aggregate, and become ubiquitinated, leading to the formation of dementia-associated paired-helical filament-containing neuronal cytoskeletal lesions. Since IGF-1 or IGF-2 suppression of GSK-3β activity  reduces the neurotoxic effects of AβPP [70–73], the neuro-protective properties of these and related trophic factors could be exploited for therapeutic purposes in AD.
INSULIN/IGF RESISTANCE, OXIDATIVE STRESS, AND METABOLIC DYSFUNCTION IN AD
Insulin and IGF signaling pathways regulate glucose utilization, metabolism, and ATP synthesis needed for cellular homeostasis and dynamic modulation of a broad range of functions (Tables 1,1, ,22). Deficits in cerebral glucose utilization and energy metabolism occur very early in the course of AD, such that they are detectable either prior to, or coincident with the initial stages of cognitive dysfunction [25, 74, 75]. These findings lend strong support the concept that impairments in insulin signaling have important roles in the pathogenesis of AD . Glucose uptake and utilization in brain are dependent upon glucose transport. Glucose transporter 4 (GLUT4) is abundantly expressed along with insulin receptors, in medial temporal lobe structures, which notably are major targets of AD neurodegeneration. Insulin stimulates GLUT4 gene expression and protein trafficking from the cytosol to the plasma membrane to modulate glucose uptake and utilization. Therefore, insulin stimulation of GLUT4 is critical to the regulation of neuronal metabolism and the generation of energy needed for memory and cognition. Although postmortem brain studies have not detected significant reductions in GLUT4 expression in AD , the well-documented deficits in brain glucose utilization and energy metabolism vis-a-vis brain insulin/IGF resistance could instead be mediated by impairments in GLUT4 trafficking between the cytosol and plasma membrane.
|Impairment||Adverse Effect||Role in Alzheimer’s Disease|
|GLUT4 function||Reduced glucose uptake and utilization||Energy deficits; compromised homeostatic functions, disruption of neuronal cytoskeleton, synaptic disconnection|
|Insulin receptor function||Decreased signaling through IRS, PI3K-Akt||Reduced neuronal and oligodendroglial survival, neuronal plasticity, myelin maintenance|
|Increased activation of GSK-3β and phosphatases that negatively regulate insulin signaling||Increased tau phosphorylation, oxidative stress, neuro-inflammation, pro-apoptosis signaling
Decreased Wnt signaling
|Reduced insulin-responsive gene expression||Reduced choline acetyltransferase expression –> deficits in acetylcholine
Decreased GAPDH expression, further impairment of glucose metabolism
|Insulin receptor function or hyper-insulinemia||Endothelial cell injury, intimal thickening, and vessel wall fibrosis||Microvascular disease and cerebral hypoperfusion|
|Mitochondrial function||Increased oxidative stress, ROS, RNS||DNA damage, lipid peroxidation, energy deficits, cell death, increased AβPP expression, Aβ42 deposition and fibrillarization|
|Myelin maintenance||Myelin breakdown, increased generation of ceramides and other toxic sphingolipids; lipid peroxidation; ROS||Increased neuro-inflammation, oxidative stress, pro-apoptosis signaling, further insulin resistance
White matter atrophy due to fiber and myelin loss
|Insulin/IGF availability||Trophic factor withdrawal||Death or impaired function of insulin/IGF dependent neurons and glial cells|
|Hyperglycemia||Accumulation of advanced glycation end-products||Disrupts removal of Aβ42|
Abbreviations: GLUT4=glucose transporter 4; IRS= insulin receptor substrate; PI3K= phosphoinositol-3- kinase; GSK-3β = glycogen synthase kinase 3β; GAPDH=glyceraldehyde-3-phosphate dehydrogenase; ROS=reactive oxygen species; RNS=reactive nitrogen species; AβPP= amyloid-β – precursor protein; Aβ 42=amyloid beta peptide-42 amino acids 1-42 cleavage product; IGF=insulin-like growth factor.
|Neurodegenerative Disease Process||Mechanism of impairing brain insulin signaling||Consequences in relation to brain insulin signaling|
|Aβ42 toxicity||Competes with insulin and reduces affinity of insulin binding to its receptor
AβPP oligomers desensitize and reduce surface expression of insulin receptors
Interferes with PI3K activation of Akt
|Disrupts insulin signaling
Impairs insulin stimulated neuronal survival and plasticity
Increases GSK-3β activation and tau hyperphosphorylation
|Microvascular disease||Cerebral hypoperfusion, hypoxic-ischemic injury||Exacerbates insulin resistance;|
|Oxidative stress||DNA damage, lipid peroxidation, fibrillarization of oligomeric tau and Aβ42||Increases neuro-inflammation and pro-inflammatory cytokine inhibition of insulin signaling
Toxic lipids impair signaling through PI3K-Akt
|Transition metal ion accumulations||Mitochondrial dysfunction, oxidative stress, tau and AβPP oligomer fibrillarization||Impairs glucose uptake and utilization, inhibits insulin signaling|
|Hyperphosphorylated-ubiquitinated tau||Increases oxidative stress, promotes neuro-inflammation||Enhances insulin resistance|
Abbreviations: PI3K= phosphoinositol-3- kinase; GSK-3β = glycogen synthase kinase 3β; AβPP= amyloid-β – precursor protein; Aβ 42=amyloid beta peptide-42 amino acids 1-42 cleavage product
Deficiencies in energy metabolism tipped by inhibition of insulin/IGF signaling increase oxidative stress, mitochondrial dysfunction, and pro-inflammatory cytokine activation [19, 48, 76]. Oxidative stress leads to increased generation and accumulation of reactive oxygen (ROS) and reactive nitrogen species (RNS) that attack subcellular components and organelles. The resulting chemical modifications, including adducts formed with DNA, RNA, lipids, and proteins, compromise the structural and functional integrity of neurons. Consequences include, loss of cell membrane functions, disruption of the neuronal cytoskeleton with dystrophy and synaptic disconnection, deficits in neurotransmitter function and neuronal plasticity, and perturbation of signal transduction and enzymatic pathways required for energy metabolism, homeostasis, and neuronal survival.
Mitochondrial dysfunction exacerbates electron transport chain function, reducing ATP generation and increasing ROS production. Pro-inflammatory cytokine activation is mediated by neuro-inflammatory responses in microglia and astrocytes. Neuro-inflammation increases oxidative stress, organelle dysfunction, and pro-apoptosis signaling. Moreover, stresses caused by inhibition of insulin/IGF signaling stimulate AβPP gene expression  and aberrant AβPP cleavage, with attendant increased AβPP-Aβ deposition and toxic fibril formation in the brain [73, 78–82]. Persistence of oxidative stress leads to constitutive activation of kinases e.g. GSK-3β, that promote aberrant hyper-phosphorylation of tau. Therefore, in AD, oxidative stress and impairments in energy metabolism stemming from brain insulin/IGF resistance quite likely contribute to neuronal loss, AβPP toxicity, tau cytoskeletal pathology, and neuro-inflammation [7, 26, 83]. The degree to which these abnormalities can be effectively targeted for therapy in AD is actively under investigation.
MECHANISMS OF BRAIN INSULIN/IGF RESISTANCE IN NEURODEGENERATION [FIG. [FIG.33]
Although aging is clearly the dominant risk factor for AD, growing evidence suggests that peripheral insulin resistance with obesity, T2DM, metabolic syndrome (dyslipidemic states), and non-alcoholic steatohepatitis (NASH) mediate brain insulin/IGF resistance, and thereby contribute to the pathogenesis of mild cognitive impairment (MCI), dementia, and AD [5, 6, 25, 26, 50, 51, 84–87]. However, only within the past several years has this field greatly expanded due to input from both human and experimental animal studies that produced new information about the causes and consequences of brain insulin resistance and deficiency in relation to cognitive impairment [7, 8, 22, 83, 88–90]. Concerns over the role of peripheral insulin resistance as a mediator of cognitive impairment and sporadic AD have been ratcheted up by globalization of the obesity epidemic [1, 84]. In order to develop logical and novel approaches for treating and preventing neurodegeneration based on the brain insulin resistance hypothesis, three main questions must be addressed: 1) Do T2DM and other peripheral insulin resistance states cause neurodegeneration, including AD? 2) Do T2DM and other peripheral insulin resistance disease states principally serve as co-factors in the pathogenesis of cognitive impairment and neurodegeneration? or 3) Do T2DM and AD fundamentally represent the same disease processes occurring in different target organs and tissues? These questions are addressed below.
Contributions of Obesity and T2DM to Cognitive Impairment and Neurodegeneration
Epidemiologic studies demonstrated that individuals with glucose intolerance, deficits in insulin secretion, or T2DM have a significantly increased risk for developing mild cognitive impairment (MCI) or AD-type dementia. Longitudinal studies provided further evidence that T2DM [91, 92] and obesity/dyslipidemic disorders  were correlated with later development of MCI, dementia, or AD [91, 94–99]. However, one study showed that obesity itself, with or without superimposed T2DM, increased the risk for MCI, AD, or other forms of neurodegeneration , suggesting that systemic factors related to obesity, other than T2DM, can promote neurodegeneration. On the other hand, although a relatively high percentage of individuals with MCI or dementia have T2DM, peripheral insulin resistance, or obesity, the vast majority of patients with AD do not have these diseases. To gain a better understanding of the contributions of T2DM and obesity to neurodegeneration, attention must be given to postmortem human and experimental animal studies.
In general, the arguments made in favor of the concept that T2DM or obesity causes AD are not founded; however, the concept that peripheral insulin resistance disease states contribute to cognitive impairment and AD pathogenesis or progression does have a sound basis. Against a causal role are the findings that, postmortem human brain studies demonstrated no significant increase in AD diagnosis among diabetics , and similarly abundant densities of senile plaques and rates of neurofibrillary tangle pathology were observed in subjects with T2DM compared with normal aged controls, although peripheral insulin resistance was more common in AD than with normal aging . Since neurofibrillary tangles and dystrophic neurites are hallmarks of AD and correlate with severity of dementia, the abovementioned findings in human postmortem studies indicate that T2DM alone is not sufficient to cause AD. On the other hand, in experimental mouse and rat models, chronic high fat diet (HFD) feeding and diet induced obesity (DIO) with associated T2DM, do cause cognitive impairment with deficits in spatial learning and memory [103, 104]. Moreover, experimental obesity with T2DM causes mild brain atrophy with brain insulin resistance, neuro-inflammation, oxidative stress, and deficits in cholinergic function [105, 106]. An important qualifier about these studies is that the associated brain abnormalities were typically modest in severity, and they were devoid of the most important structural lesions that characterize AD, i.e. neurofibrillary tangles. Therefore, observations both in humans and experimental models suggest that while obesity or T2DM can be associated with cognitive impairment, mild brain atrophy, and a number of AD-type biochemical and molecular abnormalities in brain, including insulin resistance and oxidative stress, they do not cause significant AD pathology. Instead, the findings suggest that T2DM, obesity, and probably other peripheral/systemic insulin resistance states serve as co-factors contributing to the pathogenesis or progression of neurodegeneration. The significance of these results is that therapeutic strategies designed to treat T2DM, obesity, and systemic insulin resistance could help slow the progress or reduce the severity of AD, but they will not likely prevent it altogether. Correspondingly, a number of studies have already demonstrated that treatment with hypoglycemic or insulin sensitizer agents can be protective in reducing the incidence and severity of AD brain pathology .