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J Diabetes Sci Technol. 2008 Nov; 2(6): 1101–1113.
Published online 2008 Nov. doi: 10.1177/193229680800200619
PMCID: PMC2769828
PMID: 19885299
Suzanne M. de la Monte, M.D., M.P.H.1,2,3 and Jack R. Wands, M.D.3

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reverses diabetes type 2 young adults (☑ mellitus with chronic kidney) | reverses diabetes type 2 glucagonhow to reverses diabetes type 2 for 1Department of Pathology, Rhode Island Hospital and the Warren Alpert Medical School at Brown University, Providence, Rhode Island

2Department of Clinical Neuroscience, Rhode Island Hospital and the Warren Alpert Medical School at Brown University, Providence, Rhode Island

3Department of Medicine, Rhode Island Hospital and the Warren Alpert Medical School at Brown University, Providence, Rhode Island

Find articles by Suzanne M. de la Monte

Jack R. Wands

3Department of Medicine, Rhode Island Hospital and the Warren Alpert Medical School at Brown University, Providence, Rhode Island

Find articles by Jack R. Wands
1Department of Pathology, Rhode Island Hospital and the Warren Alpert Medical School at Brown University, Providence, Rhode Island
2Department of Clinical Neuroscience, Rhode Island Hospital and the Warren Alpert Medical School at Brown University, Providence, Rhode Island
3Department of Medicine, Rhode Island Hospital and the Warren Alpert Medical School at Brown University, Providence, Rhode Island
Correspondence to: Suzanne M. de la Monte, M.D., M.P.H., Rhode Island Hospital, 55 Claverick Street, Room 419, Providence, RI 02903; e-mail address: [email protected]_etnomaled_ennazus
Funding: This research is supported by AA02666, AA02169, AA11431, AA12908, and AA16126 from the National Institutes of Health.
Copyright © 2008 Diabetes Technology Society
This article has been cited by other articles in PMC.

Abstract

Alzheimer''s disease, central nervous system, diabetes, insulin gene expression, insulin signaling

Introduction

Alzheimer''s Disease Pathogenesis

There is an ongoing debate about the degree to which T2DM and, more recently, T1DM contribute to AD pathogenesis. This concept has been fueled by the rising prevalence rates of obesity, T2DM, and AD over the past several decades. Moreover, an interrelationship among these entities is suggested by (1) increased risk of developing mild cognitive impairment (MCI), dementia, or AD in individuals with T2DM47,48 or obesity/dyslipidemic disorders;49 (2) progressive brain insulin resistance and insulin deficiency in AD;5,10,26,27 (3) cognitive impairment in experimental animal models of T2DM and/or obesity;50,51 (4) AD-type neurodegeneration and cognitive impairment in experimentally induced brain insulin resistance and insulin deficiency;29,5255 (5) improved cognitive performance in experimental models and humans with AD or MCI after treatment with insulin sensitizer agents or intranasal insulin;28,5662 and (6) shared molecular, biochemical, and mechanistic abnormalities in T2DM and AD.47,6367 The urgency of this problem is spotlighted by the estimated 24 million people in the world with dementia and the expectation that, if current trends continue,68 prevalence rates of AD are likely to double every 20 years in the future. While aging is clearly the strongest risk factor for AD, emerging data suggest that T2DM and dyslipidemic states can contribute substantially to the pathogenesis of AD either directly or as cofactors.68

Epidemiologic studies provide convincing evidence for a significant association between T2DM and MCI or dementia and furthermore suggest that T2DM is a significant risk factor for developing AD.47,6973 However, those findings are not without controversy,74 and in a longitudinal survey, investigators found that although borderline diabetics had a significantly increased risk for future development of diabetes, dementia, or AD, the risk effects were independent rather than linked.75 What this means is that insulin resistance, i.e., impaired ability to respond to insulin stimulation, can vary among target organs and be present in just one or two organs and not in others, a phenomenon that could explain the lack of complete overlap between T2DM and AD. Correspondingly, the finding that obesity (body mass index [BMI] > 30) without T2DM produces a three-fold increase in risk for subsequently developing AD whereas overweight, but nonobese, subjects (BMI 25–30) experience a two-fold increase in risk for AD76 calls into question the specific effects of obesity and T2DM versus a yet unknown associated factor in relation to AD pathogenesis.

Mechanistically, the increased risk of dementia in T2DM and obesity could be linked to chronic hyperglycemia, peripheral insulin resistance, oxidative stress, accumulation of advanced glycation end products, increased production of pro-inflammatory cytokines, and/orcerebral microvascular disease.73 The potential role of cerebral microvascular disease as a complicating, initiating, or accelerating component of AD has been recognized for years.77 However, a magnetic resonance imaging study demonstrated that older adults with T2DM have a moderately increased risk for developing lacunes and hippocampal atrophy and that the severity of those lesions increases with the duration and progression of T2DM.78 Another study showed that T2DM and impaired fasting glucose occur significantly more frequently in AD than in non-AD controls.79 However, since diffuse and neuritic plaques were similarly abundant in T2DM and control brains, and since neurofibrillary tangles, one of the hallmarks and correlates of dementia in AD, were not increased in T2DM,79 the results suggest that T2DM can enhance progression but may not be sufficient to cause AD. Therefore, what remains unclear is the net contribution of T2DM or obesity to the pathogenesis of AD-type neurodegeneration. To address this question, we utilized an established experimental model of chronic high-fat diet (HFD) feeding of C57BL/6 mice to examine the degree to which obesity/T2DM was sufficient to produce histopathological, molecular, and/or biochemical brain abnormalities of AD-type neurodegeneration, i.e., T3DM.

reverses diabetes type 2 limits (⭐️ occurs when) | reverses diabetes type 2 treatshow to reverses diabetes type 2 for High-fat diet feeding for 16 weeks doubled mean body weight, caused T2DM, and marginally reduced mean brain weight.80 Those effects were associated with significantly increased levels of tau, IGF-1 receptor, IRS-1, IRS-4, ubiquitin, glial fibrillary acidic protein (GFAP), and 4-hydroxynonenal and decreased expression of β actin. Importantly, HFD feeding also caused brain insulin resistance manifested by reduced top-level (Bmax) insulin receptor binding and modestly increased brain insulin gene expression. However, HFD fed mouse brains did not exhibit AD histopathology or increases in APP-Aβ or phospho-tau, nor were there impairments in IGF signaling, which typically occurs in AD.10 In essence, although the chronic obesity with T2DM model exhibited mild brain atrophy with insulin resistance, oxidative stress, and cytoskeleton degradation, the effects were modest compared with AD5,10 and other more robust experimental models of T3DM,28,29 and most of the molecular, biochemical, and histopathological features that typify AD were not present. Therefore, T2DM and obesity may contribute to, i.e., serve as cofactors of AD but by themselves are probably not sufficient to cause AD. Moreover, the findings in the T2DM/obesity model indicate the unlikelihood that brain insulin resistance is sufficient to cause AD and that additional significant abnormalities, such as ongoing DNA damage and mitochondrial dysfunction, are required.

Alzheimer''s t-tests. Significant p-values are indicated over the bars. Note that insulin gene expression was not detected in temporal cortex.

Even before the initial study had been published, it was realized that if brain insulin/IGF resistance and insulin/IGF deficiency were causal in the pathogenesis of AD, the related abnormalities should be detectable in the early stages of disease and possibly worsen as disease progresses. The investigations were extended to examine the brains of patients with different degrees, i.e., Braak stages,86,87 of AD.10 In that study, we measured the expression of genes encoding insulin, IGF-1, IGF-2 polypeptides, and their corresponding receptors as well as tau and amyloid precursor protein (APP). In addition, we used competitive equilibrium and saturation binding assays to further characterize the degree to which growth factor-transmitted signaling was impaired in the brains with different severities of AD. Finally, the study included the measurement of steady-state levels of adenosine triphosphate and genes regulating acetylcholine homeostasis and energy metabolism.

Using the previously mentioned approaches, we demonstrated progressive AD Braak stage-dependent reductions in insulin, IGF-1, and IGF-2 receptor expression, with more pronounced deterioration in insulin and IGF-1 compared with IGF-2 receptors, and the lowest levels of gene expression in brains with AD Braak Stage 6 (Figure 2). Therefore, loss of insulin and IGF-1 receptor-bearing neurons begins early and progresses with disease such that, in the advanced stages, the deficits are severe and global. These results provided further evidence that the abnormalities in AD are not restricted to insulin signaling pathways, as they also involve IGF-1 and IGF-2 stimulated mechanisms. Analysis of growth-factor polypeptide genes also revealed AD Braak stage-dependent impairments in insulin, IGF-1, and IGF-2 polypeptide expression, corresponding with progressive trophic factor withdrawal (Figure 2). Again, the results support the hypothesis that abnormalities in insulin and IGF signaling mechanisms begin early in the course of AD and are therefore likely have an important role in its pathogenesis.

Brain insulin and IGF deficiency and resistance increase with progression of AD.10 Postmortem histopathological studies categorized the brains as having normal aging (Braak 0–1), or mild (Braak 2–3), moderate to severe (Braak 4–5), or end-stage (Braak 6) AD. We used mRNA isolated from fresh frozen frontal lobe tissue to measure insulin, IGF-1, or IGF-2 (A) polypeptide or (B) receptor gene expression by qRT-PCR. Results were normalized to 18S rRNA measured in the same samples. (C) For the competitive equilibrium binding assays, frontal lobe membrane protein extracts were incubated with [125I]-labeled insulin, IGF-1, or IGF-2 in the presence or absence of excess cold ligand. Radioactivity present in membrane protein precipitates was measured in a gamma counter. Specific binding (fmol/mg) was calculated using the GraphPad Prism 4 software. All graphs depict the mean ± standard deviation of results obtained from 9–12 cases per group. Intergroup comparisons were made using analysis of variance (ANOVA) with post hoc Tukey–Kramer significance tests. Significant p-values are indicated over the bars. Note axis break in Panel B.

The eventual paucity of local growth-factor gene expression could substantially impair growth-factor signaling and produce a state of growth-factor withdrawal, which is a well-established mechanism of neuronal death. Therefore, to complement the molecular data, we performed competitive equilibrium and saturation binding assays to determine if reduced levels of growth factor receptor expression were associated with and perhaps mediated by impaired ligand-receptor binding as occurs with insulin/IGF resistance. Those investigations demonstrated progressive declines in equilibrium (Figure 2) and top-level binding (Bmax) to the insulin, IGF-1, and IGF-2 receptors but either unchanged or increased binding affinity, suggesting that impaired insulin/IGF actions in AD brains were mediated by decreased polypeptide and receptor gene expression due to cell loss.

Through a series of in vitro and in vivo experiments performed by several groups, including our own, we have been able to draw the conclusion that neuronal and oligodendroglial cell survival and function are integrally related to the integrity of insulin and IGF signaling mechanisms in the brain.10,28,29,31,33,88,89 Similarly, impairments in insulin/IGF signaling lead to deficits in energy metabolism with attendant increased oxidative stress, mitochondrial dysfunction, proinflammatory cytokine activation, and APP expression.4,10,28,89 Correspondingly, the reduced expression of neuronal and oligodendroglial specific genes and the increased expression of astrocytic and microglial inflammatory genes in AD were attributed to progressive brain insulin/IGF deficiency and resistance. Although this point requires the generation of experimental models to demonstrate proof of principle, the finding that microglial, astrocytic, and APP mRNA levels are all increased in the early stages of neurodegeneration supports the inflammatory hypothesis of AD.6 Previous studies demonstrated that microglial activation promotes APP-Aβ accumulation9092 and that APP gene expression and cleavage increase with oxidative stress.93 Therefore, the mechanism we the 1 last update 31 May 2020 propose is that impaired insulin/ IGF signaling leads to increased oxidative stress and mitochondrial dysfunction,32,94,95 which induces APP gene expression and cleavage.93 The attendant APP-Aβ accumulations cause local neurotoxicity9698 and further increase in oxidative stress-induced APP expression and APP-Aβ deposition.Through a series of in vitro and in vivo experiments performed by several groups, including our own, we have been able to draw the conclusion that neuronal and oligodendroglial cell survival and function are integrally related to the integrity of insulin and IGF signaling mechanisms in the brain.10,28,29,31,33,88,89 Similarly, impairments in insulin/IGF signaling lead to deficits in energy metabolism with attendant increased oxidative stress, mitochondrial dysfunction, proinflammatory cytokine activation, and APP expression.4,10,28,89 Correspondingly, the reduced expression of neuronal and oligodendroglial specific genes and the increased expression of astrocytic and microglial inflammatory genes in AD were attributed to progressive brain insulin/IGF deficiency and resistance. Although this point requires the generation of experimental models to demonstrate proof of principle, the finding that microglial, astrocytic, and APP mRNA levels are all increased in the early stages of neurodegeneration supports the inflammatory hypothesis of AD.6 Previous studies demonstrated that microglial activation promotes APP-Aβ accumulation9092 and that APP gene expression and cleavage increase with oxidative stress.93 Therefore, the mechanism we propose is that impaired insulin/ IGF signaling leads to increased oxidative stress and mitochondrial dysfunction,32,94,95 which induces APP gene expression and cleavage.93 The attendant APP-Aβ accumulations cause local neurotoxicity9698 and further increase in oxidative stress-induced APP expression and APP-Aβ deposition.

A critical goal in these investigations was to draw connections between brain insulin/IGF deficiency and resistance and the major dementia-associated structural and biochemical abnormalities in AD. In this regard, the postmortem studies demonstrated that the Braak stage-associated declines in tau mRNA paralleled the progressive reductions in insulin and IGF-1 receptor expression in AD. In addition, the studies demonstrated AD Braak stage-associated declines in choline acetyltransferase (ChAT) expression with reduced colocalization of ChAT with insulin or IGF-1 receptor immunoreactivity in cortical neurons. These results correspond with experimental data demonstrating that neuronal tau and ChAT gene expression are regulated by IGF-1 and insulin stimulation.88 Therefore, brain insulin and IGF deficiency and resistance could account for the cytoskeletal collapse, neurite retraction, synaptic disconnection, loss of neuronal plasticity, and deficiencies in acetylcholine production, all of which correlate with cognitive decline and dementia in the 1 last update 31 May 2020 AD. Altogether, the studies utilizing postmortem human brain tissue provide solid evidence that AD is associated with fundamental abnormalities in insulin/IGF signaling mechanisms that are highly correlated with development and progression of structural, molecular, and biochemical lesions that correlate with dementia. Although the abnormalities noted in AD share features in common with T1MD and T2MD, they are nonetheless distinguished by the dual presence of trophic factor deficiencies and trophic factor receptor resistance, ergo the term “type 3 diabetes.”A critical goal in these investigations was to draw connections between brain insulin/IGF deficiency and resistance and the major dementia-associated structural and biochemical abnormalities in AD. In this regard, the postmortem studies demonstrated that the Braak stage-associated declines in tau mRNA paralleled the progressive reductions in insulin and IGF-1 receptor expression in AD. In addition, the studies demonstrated AD Braak stage-associated declines in choline acetyltransferase (ChAT) expression with reduced colocalization of ChAT with insulin or IGF-1 receptor immunoreactivity in cortical neurons. These results correspond with experimental data demonstrating that neuronal tau and ChAT gene expression are regulated by IGF-1 and insulin stimulation.88 Therefore, brain insulin and IGF deficiency and resistance could account for the cytoskeletal collapse, neurite retraction, synaptic disconnection, loss of neuronal plasticity, and deficiencies in acetylcholine production, all of which correlate with cognitive decline and dementia in AD. Altogether, the studies utilizing postmortem human brain tissue provide solid evidence that AD is associated with fundamental abnormalities in insulin/IGF signaling mechanisms that are highly correlated with development and progression of structural, molecular, and biochemical lesions that correlate with dementia. Although the abnormalities noted in AD share features in common with T1MD and T2MD, they are nonetheless distinguished by the dual presence of trophic factor deficiencies and trophic factor receptor resistance, ergo the term “type 3 diabetes.”

Alzheimer''s t-tests. Significant p-values are indicated over the bar graphs.

Corresponding with the findings in AD,5 the ic-STZ-treated brains had increased levels of activated GSK-3β, phospho-tau, ubiquitin, APP and APP-Aβ and decreased levels of tau protein. These results are consistent with previous studies demonstrating that tau is regulated by insulin/IGF-1 stimulation88,118 and that tau phosphorylation and ubiquitination increase with oxidative stress and activation of GSK-3β.93 Similarly, APP mRNA increases with oxidative stress and is a feature of sporadic AD.5,10 Increased APP gene expression could account for APP-Aβ accumulation in AD and ic-STZ-treated brains. Potential sources of oxidative stress in AD and the ic-STZ model include (1) mitochondrial dysfunction;6,53,95 (2) microglial cell activation with increased cytokine release; and (3) impaired insulin/IGF signaling through PI3 kinaseAkt, leading to increased levels of GSK-3β activity.

A crucial step was to determine whether ic-STZ could cause disturbances in acetylcholine homeostasis and cognitive impairment as they occur in AD. QRT-PCR and immunohistochemistry detected reduced levels of ChAT and increased levels of AChE mRNA and protein in icSTZ-treated brains relative to control brains. Note that energy metabolism leads to production of Acetyl-CoA, which is needed to make acetylcholine. Since the ChAT gene is responsive to insulin and IGF-1 stimulation, deficits in insulin/IGF signaling and energy metabolism push in the direction of cholinergic deficiency mediated by impaired energy metabolism and decreased expression of ChAT, which are key features in AD. In addition, increased levels of AChE expression in the ic-STZ brains could result in increased degradation of acetylcholine, thereby exacerbating the acetylcholine deficits caused by reduced ChAT expression. The significance of these results is highlighted by the prominent learning and memory deficits detected in ic-STZ-treated rats.28,29

Type 3 Diabetes May Be Treatable, Preventable, or Curable with Antidiabetes Drugs

The findings that (1) pronounced insulin/IGF deficiency and resistance develop early in the course of AD; (2) insulin/IGF signaling abnormalities progress with severity of neurodegeneration;5,10 and (3) an experimental animal model with features closely mimicking the molecular, biochemical, and neuroanatomical pathologies of AD could be generated by intracerebral delivery of a drug that causes T1DM or T2DM led us to test the hypothesis that AD-type neurodegeneration and cognitive could be reduced or prevented by early treatment with insulin-sensitizer antidiabetes agents such as peroxisome proliferator-activated receptor (PPAR) agonists. Peroxisome proliferator-activated receptor agonists function at the level of the nucleus to activate insulin-responsive genes and signaling mechanisms. PPAR-α, PPAR-δ, and PPAR-γ are all expressed in adult human brains, including AD, but PPAR-δ is the most abundant of the three isoforms.6 The experimental design involved treating rats with ic-STZ, followed by a single intraperitoneal injection of saline, a PPAR-α (GW7647; 25 µg/kg), PPAR-δ (L-160,043; 2 µg/kg), or PPAR-γ (F-L-Leu; 20 µg/kg) activator (CalBiochem, Carlsbad, CA).28 The doses used were considerably lower than those routinely given to treat T2DM. The major effects of the PPAR agonist treatments were to prevent brain atrophy, preserve insulin and IGF-2 receptor bearing CNS neurons, and particularly with regard to the PPAR-δ agonist, prevent ic-STZ-induced deficits in learning and memory.28 Since the ic-STZ-mediated losses of insulin and IGF-expressing cells were not prevented by the PPAR agonist treatments, the PPAR agonists probably functioned by preserving insulin and IGF responsive (receptor-bearing) cells, including neurons and oligodendroglia. In support of this concept was finding that insulin receptor expression and binding were increased by the PPAR agonist treatments (Figure 4). Peroxisome proliferator-activated receptor agonist mediated preservation of insulin/IGF responsive neurons was associated with increased expression of ChAT, which has an important role in cognition, as cholinergic neuron deficits are a fundamental feature of AD.119122 Importantly, the PPAR-δ agonist mediated increases in insulin binding, and ChAT were associated with significant improvements in learning and spatial memory tasks as demonstrated using Morris water maze tests28 (Figure 5). These effects of the PPAR agonist treatments are consistent with the facts that ChAT expression is regulated by insulin/IGF88,118 and insulin/IGF resistance mediates cognitive impairment in AD. The PPAR-mediated increases in MAG-1 expression, corresponding to oligodendroglia, were of particular interest because previous research demonstrated that one of the earliest AD lesions was white matter atrophy and degeneration with loss of oligodendroglial cells.107 Within the context of the present discussion, white matter atrophy in AD can now be interpreted as a manifestation of CNS insulin/IGF resistance since oligodendroglia require intact insulin/IGF signaling mechanisms for survival and function, including myelin synthesis.123,124 Besides preserving insulin and IGF receptor-bearing CNS cells and signaling mechanisms germane to survival, energy metabolism, and neurotransmitter functions, the PPAR agonists rescued the ic-STZ model by lowering critical AD-associated indices of oxidative stress, including microglial and astrocyte activation, p53, nitric oxide synthase and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase gene expression, lipid peroxidation, DNA damage, APP expression, and tau phosphorylation.6,28,29,91,92,125,126

Treatment with PPAR agonists restores brain insulin receptor binding in ic-STZ-treated rats.28 Long Evans rat pups were treated with 50 mg/kg ic-STZ or vehicle and sacrificed 30 days later to examine brains for insulin and IGF polypeptide and receptor gene expression and insulin and IGF receptor binding. Temporal lobe membrane protein extracts were used in competitive equilibrium binding assays to measure specific binding to the (A) insulin, (B) IGF-1, or (C) IGF-2 receptors as described in Figure 2. Graphs depict the mean ± standard error of the mean of results. Data were analyzed using ANOVA with the Tukey–Kramer post hoc significance test. Significant p-values are shown within each panel.

Peroxisome proliferator-activated receptor-δ agonist treatment preserves visual-spatial learning and memory in ic-STZ-treated rats.28 Long Evans rat pups were treated with 50 mg/kg ic-STZ or vehicle, followed by a single intraperitoneal injection of a PPAR-α (GW7647; 25 µg/kg), PPAR-δ (L-160,043; 2 µg/kg), or PPAR-γ (F-L-Leu; 20 µg/kg) agonist (n = 8 rats per group). Four weeks later, the rats were subjected to Morris water maze testing, in which the latency required to locate the hidden platform was measured for 3 independent trials on 4 consecutive days. Area under the curve (AUC) was computed for the 3 daily trials. Graphs depict the mean AUC ± standard error of the mean for latency (seconds) in each group. Data were analyzed using ANOVA with the Tukey–Kramer post hoc significance test. Performance in the control and ic-STZ + PPAR-δ groups were similar, and on Days 2, 3, and 4, their mean latencies required to locate the hidden platform were significantly shorter than in the other 3 groups.

Conclusions

Altogether, the results from these studies provide strong evidence in support of the hypothesis that AD represents a form of diabetes mellitus that selectively afflicts the brain. Positive data stemmed from (1) direct analysis of postmortem human brains with documented AD; (2) an experimental animal model in which brain diabetes with cognitive impairment and molecular and pathological features that mimic AD was produced by intracerebral administration of a drug that is commonly used to produce T1DM or T2DM; and (3) a study showing that PPAR agonists, which are used to treat T2DM, prevent many of the AD-associated neurodegenerative effects of ic-STZ. The data are supported by abundant in vitro experiments that demonstrated essentially the same or similar effects of STZ or oxidative stress treatments of neuronal cells. The human and experimental animal model studies also showed that CNS impairments in insulin/IGF signaling mechanisms can occur in the absence of T1DM or T2DM. Finally, we demonstrated that although obesity with T2DM causes brain insulin resistance with some features of AD-type neurodegeneration, the effects are relatively modest, not associated with significant histopathological lesions, and lack most of the critical abnormalities that typify AD. Therefore, T2DM was deemed not sufficient to cause AD, although it could possibly serve as a cofactor in its pathogenesis or progression. Altogether, the data provide strong evidence that AD is intrinsically a neuroendocrine disease caused by selective impairments in insulin and IGF signaling mechanisms, including deficiencies in local insulin and IGF production. At the same time, it is essential to recognize that T2DM and T3DM are not solely the end results of insulin/IGF resistance and/or deficiency, because these syndromes are unequivocally accompanied by significant activation of inflammatory mediators, oxidative stress, DNA damage, and mitochondrial dysfunction, which contribute to the degenerative cascade by exacerbating insulin/ IGF resistance. Referring to AD as T3DM is justified, because the fundamental molecular and biochemical abnormalities overlap with T1DM and T2DM rather than mimic the effects of either one. Some of the most relevant data supporting this concept have emerged from clinical studies demonstrating cognitive improvement and/or stabilization of cognitive impairment in subjects with early AD following treatment with intranasal insulin or a PPAR agonist.58,60,127130

Abbreviations

AChEacetylcholinesterase
ADAlzheimer''s disease: epidemiology, genetics, and beyond. Neurosci Bull. 2008;24(2):105–109. [PMC free article] [PubMed] [Google Scholar]
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