. Demonstrated brain insulin resistance in Alzheimer's disease patients is associated with IGF-1 resistance, IRS-1 dysregulation, and cognitive decline. J Clin Invest. 2012 Apr 2;122(4):1316-38. PubMed.

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  1. Type 2 diabetes has been identified as one of the risk factors for AD. Two papers analyzing insulin signaling in the brains of Alzheimer’s disease (AD) patients have been published back to back in the Journal for Clinical Investigation.

    Talbot et al. analyzed insulin signaling in the brains of non-diabetic AD patients using a novel approach of incubating brain tissue "ex vivo" with insulin or insulin-like growth factor 1 (IGF-1) to test what biochemical responses, insulin receptors (IR) phosphorylation signatures, and associated second-messenger signaling cascade profiles look like. The classic markers of insulin desensitization were analyzed using Western blot and immunohistological quantifications. They found that the hippocampus of AD patients exhibit markedly reduced responses to insulin signaling in the IR→ insulin receptor substrate 1 (IRS-1)→ PI3K signaling pathway with greatly reduced responses to IGF-1 in the IGF-1R→ IRS-2→ PI3K signaling pathway. Reduced insulin responses were maximal at the level of IRS-1, and were consistently associated with basal elevations of IRS-1 phosphorylated at serine 616 (IRS-1 pS616) and 636/639 (IRS-1 pS636/639). These phosphorylation sites signify a downregulation of insulin signaling, and are a classic profile for insulin desensitization as seen in type 2 diabetes.

    These biomarkers of brain insulin resistance increased progressively from non-AD control cases to mild cognitively impaired cases and to AD cases, independently of diabetes or ApoE4 status. Levels of IRS-1 pS616 and IRS-1 pS636/639 and their activated kinases correlated positively with those of oligomeric Aβ plaques, and negatively associated with episodic and working memory, even after adjusting for Aβ plaques, neurofibrillary tangles, and ApoE4. Brain insulin resistance thus appears to be an early and common feature of AD, a phenomenon accompanied by IGF-1 resistance and closely associated with IRS-1 dysfunction, which is potentially triggered by Aβ oligomers and yet promotes cognitive decline independent of classic AD pathology (Talbot et al., 2012).

    Previous studies in cultured neurons showed that Aβ oligomers bind to insulin receptors and induce the uptake of these receptors into the cell (De Felice et al., 2009). The current study by Talbot et al. suggests that this mechanism may be at work in the brains of AD patients and desensitizes insulin signaling at an early stage. This is of vital importance, as insulin and IGF-1 play vital roles as growth factors in the brain. A reduction of this signaling will make neurons vulnerable to stress and less able to repair, and predispose to synaptic dysfunction and cognitive impairment (Hoyer, 2004; Craft, 2007). It may be that early insulin growth factor signaling desensitization leads the way to further neurodegenerative processes, and eventually to the development of AD.

    The second paper follows in the same footsteps and demonstrates that in several in-vitro and in-vivo assays, Aβ oligomers activate the JNK/TNF-α apoptosis-inducing pathway, induce IRS-1 phosphorylation at multiple serine residues, and inhibit physiological IRS-1 tyrosine phosphorylation (pTyr) in mature cultured hippocampal neurons. Bomfim et al. found that impaired IRS-1 signaling was also present in the hippocampi of APP/PS1 mice, a model of AD. Importantly, intracerebroventricular injection of Aβ oligomers triggered hippocampal IRS-1pSer and JNK activation in Cynomolgus monkeys, verifying the results observed in rodents.

    The Aβ oligomer-induced neuronal pathologies found in vitro, including impaired axonal transport, were prevented by exposure to the GLP-1 receptor agonist exendin-4 (exenatide, Byetta), a drug that is on the market as a treatment for type 2 diabetes. In APP/PS1 mice, exendin-4 decreased levels of hippocampal IRS-1pSer, activated JNK growth factor signaling, and improved performance in memory tasks. These exciting results support previous findings of GLP-1 analogues preventing neurodegenerative processes in Alzheimer’s disease (Perry and Greig, 2004; Holscher, 2011), Parkinson’s disease (Li et al., 2009; Harkavyi and Whitton, 2010), amyotrophic lateral sclerosis (ALS) (Li et al., 2012), and stroke (Li et al., 2009). Several clinical trials are ongoing, testing either exendin-4 or liraglutide (Victoza), both drugs that are currently on the market as treatments for type 2 diabetes, in patients with AD or with Parkinson’s disease. Exendin-4 is currently tested in patients with Parkinson’s disease at University College London, U.K. (see ClinicalTrials.gov). The same drug is also tested in AD patients in a clinical trial conducted by the NIH/NIA in the US (see ClinicalTrials.gov). Two clinical trials testing liraglutide in patients with MCI/AD are being conducted at the University of Aarhus, Denmark (see ClinicalTrials.gov), and in London at the Hammersmith Hospital in the U.K.

    This shows that GLP-1 receptor agonists have great promise in treating neurodegenerative diseases such as AD. A special symposium will be held on this topic at the next Society for Neuroscience Conference in New Orleans.

    References:

    . Insulin resistance and Alzheimer's disease pathogenesis: potential mechanisms and implications for treatment. Curr Alzheimer Res. 2007 Apr;4(2):147-52. PubMed.

    . Protection of synapses against Alzheimer's-linked toxins: insulin signaling prevents the pathogenic binding of Abeta oligomers. Proc Natl Acad Sci U S A. 2009 Feb 10;106(6):1971-6. PubMed.

    . Glucagon-like peptide 1 receptor stimulation as a means of neuroprotection. Br J Pharmacol. 2010 Feb 1;159(3):495-501. PubMed.

    . Diabetes as a risk factor for Alzheimer's disease: insulin signalling impairment in the brain as an alternative model of Alzheimer's disease. Biochem Soc Trans. 2011 Aug;39(4):891-7. PubMed.

    . Glucose metabolism and insulin receptor signal transduction in Alzheimer disease. Eur J Pharmacol. 2004 Apr 19;490(1-3):115-25. PubMed.

    . Exendin-4 ameliorates motor neuron degeneration in cellular and animal models of amyotrophic lateral sclerosis. PLoS One. 2012;7(2):e32008. PubMed.

    . GLP-1 receptor stimulation preserves primary cortical and dopaminergic neurons in cellular and rodent models of stroke and Parkinsonism. Proc Natl Acad Sci U S A. 2009 Jan 27;106(4):1285-90. PubMed.

    . A new Alzheimer's disease interventive strategy: GLP-1. Curr Drug Targets. 2004 Aug;5(6):565-71. PubMed.

    . Demonstrated brain insulin resistance in Alzheimer's disease patients is associated with IGF-1 resistance, IRS-1 dysregulation, and cognitive decline. J Clin Invest. 2012 Apr 2;122(4):1316-38. PubMed.

  2. Maintaining Insulin and IGF-1 Receptor Responses in AD
    The back-to-back papers by Talbot et al. and Bomfim at al. in the Journal of Clinical Investigation emphasize the importance of neuronal insulin and insulin-like growth factor 1 (IGF-1) resistance as early pathological triggers of synaptic decline and cognitive failure in AD, and highlight the potential to normalize these functions using long-lasting glucagon-like peptide 1 receptor (GLP-1R) agonists, which are currently used to treat type 2 diabetes mellitus (T2DM).

    This admirable investigation by Konrad Talbot established experimental conditions to measure downstream responses to near physiological concentrations of insulin and IGF-1 “ex vivo” in postmortem human brain tissue from AD patients and controls via measurement of receptor activation and interaction/activation of the insulin receptor substrate 1/2 (IRS-1/2) PI3-kinase-Akt pathway. These conditions now clearly show insulin and IGF-1 resistance to be an early and progressive feature of neuronal/synaptic pathogenesis and cognitive decline in AD. Bomfim et al. highlight the potential of protection from insulin resistance in the AD brain by treatment with long-lasting GLP-1R agonists. The experimental conditions developed by Talbot et al. will now be extremely useful in interrogating these and other drug treatments that can be used to ameliorate defects in this pathway in AD. The researchers also emphasize the functional relevance of a specific brain insulin/IGF-1R resistance to cognitive failure in AD that is independent of peripheral insulin resistance in T2DM.

    The findings of both Talbot et al. and Bomfim et al. add further weight to previous work (Craft, 2007; Freude et al., 2009; Frolich et al., 1998; Frolich et al., 1999; Hoyer, 2004; Ma et al., 2009; Steen et al., 2005), including our own (Griffin et al., 2005; Moloney et al., 2010), which described clear defects in the components of the IGF-1R/IR/IRS-1/2-Akt-mTOR pathway in the AD brain that were strongly indicative of insulin and IGF-1 resistance in the disease. Both Talbot et al. and Bomfim et al. emphasize the aberrant and heightened phosphorylation of IRS-1 at Ser616, and also other Ser residues (636/639), to be mechanistically important in the development of insulin resistance in AD neurons, as it is in T2DM. Increased phosphorylation of IRS-1 at Ser312 and Ser616 was first identified in AD neurons by Konrad Talbot and colleagues (Talbot et al., 2006). Subsequently, two detailed studies, one from our group (Moloney et al., 2010) and that of Greg Cole (Ma et al., 2009), showed very marked increases in IRS-1 phosphorylation at Ser616 and Ser312 in neurons of AD temporal cortex, and of Ser616 in neurons of the 3xTg-AD model (Ma et al., 2009). Importantly, Talbot et al. now identify IRS-1-pSer616 as a potential early biomarker for insulin resistance in AD, as IRS-1-pSer616 is evident in patients with MCI. Of all the extensive measures they performed, increased IRS-1-pSer616 has the strongest and most negative relationship to episodic as well as working memory.

    The two papers also provide further evidence that signaling via Aβ oligomeric species (AβO) causes insulin resistance in AD (De Felice et al., 2009; Zhao et al., 2008). Greg Cole’s group initially showed that AβO-induced JNK activation could lead to phosphorylation of IRS-1 at Ser616 (Ma et al., 2009). This is now further shown in the study by Bomfim et al. They highlight TNF-α activation of JNK as being crucial in this mechanism, thus revealing strong similarities to inflammatory pathways that induce insulin resistance in T2DM. Their finding that the blocking of PKR (double stranded RNA-dependent protein kinase) and Ikβ kinase (IKK) also inhibits oligomer-induced Ser phosphorylation of IRS-1 strengthens the inflammatory connection.

    Most of the key kinases (e.g., JNK, Akt, mTOR) implicated in the sustained serine phosphorylation of IRS-1 are shown here by Talbot et al. to be highly correlated with total and oligomeric Aβ load in AD brain. Importantly, these kinases are all implicated in the hyperphosphorylation of tau as well. Sometimes, overemphasis of GSK-3β as a major tau kinase overlooks Akt and mTOR/p70S6 kinase, which also phosphorylate tau at critical residues important for detachment of the protein form microtubules, for altered tau function in neurons, and for tau fibrillogenicity (Ksiezak-Reding et al., 2003; Li et al., 2005; Pei and Hugon, 2008). Here, neither Talbot et al. nor Bomfim et al. examined the potential colocalization of pSer-IRS-1 (616/636.639/312) with phospho-tau or neurofibrillary tangles in AD. However, our previous work found a striking colocalization between IRS-1-pSer616 (and pSer312) and NFTs in AD neurons (Moloney et al., 2010). Ma et al., 2009, also found this in the AD and 3xTg-AD brain. Further exploration in this area should allow dissection and targeting of the initiating kinase signal(s) that functionally link non-responsive insulin and IGF-1 receptors to the early pathogenesis of not just Aβ, but also tau in MCI.

    The challenge to re-establish insulin responses in AD brain has been taken up with some promising studies, including the use of with nasal insulin (Craft et al., 2012) and drugs that restore insulin sensitivity in T2DM, particularly the long-lasting GLP-1R agonists (Holscher et al., 2010). The protective effect of an omega 3 fatty acid diet and of curcumin on both JNK activation and aberrantly increased levels of IRS-1-pSer616 have also been described (Ma et al., 2009). The findings of Bomfim et al. provide exciting data showing that the GLP-1 analogue exendin-4 (exenatide, Byeta) could decrease IRS-1-pS levels and activated JNK in the APP/PS1 model, and also improve behavioral measures of cognition. This offers hope that these agents could restore brain insulin and IGF-1 responsiveness to normal levels in AD brain.

    What appears to go wrong in AD neurons is that systems, including IGF-1R and IR signaling, lose their “off switch,” which is exemplified by the extremely heightened kinase activation that typifies AD neurons. This kinase overdrive is dangerous, as it appears to feed back to completely turn off normal signals, for example, those of insulin and IGF-1, both of which have important function in memory/plasticity. Most evidence points to AβO being the instigator and propagator of this abnormal kinase activation. However, there is often an interplay/competition between these systems, where, for example, IR tyrosine kinase activation can inhibit AβO binding to neurons (De Felice et al., 2009). Therefore, therapies should aim to normalize the insulin and IGF-1 signaling system so that it can respond appropriately to insulin/IGF-1, turn itself on and off correctly, and negate/deter the Aβ-induced kinase overdrive. In line with this, appropriate but not overactivation of the IGF-1R/IR pathway is strongly linked to healthy longevity and proteostasis, including that for Aβ (Cohen and Dillin, 2008; Cohen et al., 2009). GLP-1 analogues are very worthy of attention as AD treatments that attempt to restore this insulin/IGF-1 sensitivity. They also have significant anti-inflammatory properties (Kim et al., 2009; McClean et al., 2011), can reduce Aβ (McClean et al., 2011; Perry et al., 2003), and improve measures of learning and memory in animal models (Abbas et al., 2009; During et al., 2003; Greenberg and Jin, 2006). Thus, the outcome of ongoing clinical trials of these agents in AD and also Parkinson’s disease is awaited with interest.

    References:

    . Impairment of synaptic plasticity and memory formation in GLP-1 receptor KO mice: Interaction between type 2 diabetes and Alzheimer's disease. Behav Brain Res. 2009 Dec 14;205(1):265-71. PubMed.

    . The insulin paradox: aging, proteotoxicity and neurodegeneration. Nat Rev Neurosci. 2008 Oct;9(10):759-67. PubMed.

    . Reduced IGF-1 signaling delays age-associated proteotoxicity in mice. Cell. 2009 Dec 11;139(6):1157-69. PubMed.

    . Insulin resistance and Alzheimer's disease pathogenesis: potential mechanisms and implications for treatment. Curr Alzheimer Res. 2007 Apr;4(2):147-52. PubMed.

    . Intranasal insulin therapy for Alzheimer disease and amnestic mild cognitive impairment: a pilot clinical trial. Arch Neurol. 2012 Jan;69(1):29-38. PubMed.

    . Protection of synapses against Alzheimer's-linked toxins: insulin signaling prevents the pathogenic binding of Abeta oligomers. Proc Natl Acad Sci U S A. 2009 Feb 10;106(6):1971-6. PubMed.

    . Glucagon-like peptide-1 receptor is involved in learning and neuroprotection. Nat Med. 2003 Sep;9(9):1173-9. PubMed.

    . Brain insulin and insulin receptors in aging and sporadic Alzheimer's disease. J Neural Transm. 1998;105(4-5):423-38. PubMed.

    . A disturbance in the neuronal insulin receptor signal transduction in sporadic Alzheimer's disease. Ann N Y Acad Sci. 1999;893:290-3. PubMed.

    . Neurodegeneration and neurogenesis: focus on Alzheimer's disease. Curr Alzheimer Res. 2006 Feb;3(1):25-8. PubMed.

    . The role of IGF-1 receptor and insulin receptor signaling for the pathogenesis of Alzheimer's disease: from model organisms to human disease. Curr Alzheimer Res. 2009 Jun;6(3):213-23. PubMed.

    . Activation of Akt/PKB, increased phosphorylation of Akt substrates and loss and altered distribution of Akt and PTEN are features of Alzheimer's disease pathology. J Neurochem. 2005 Apr;93(1):105-17. PubMed.

    . The role of GLP-1 in neuronal activity and neurodegeneration. Vitam Horm. 2010;84:331-54. PubMed.

    . Glucose metabolism and insulin receptor signal transduction in Alzheimer disease. Eur J Pharmacol. 2004 Apr 19;490(1-3):115-25. PubMed.

    . Exendin-4 protects dopaminergic neurons by inhibition of microglial activation and matrix metalloproteinase-3 expression in an animal model of Parkinson's disease. J Endocrinol. 2009 Sep;202(3):431-9. PubMed.

    . Akt/PKB kinase phosphorylates separately Thr212 and Ser214 of tau protein in vitro. Biochim Biophys Acta. 2003 Nov 20;1639(3):159-68. PubMed.

    . Levels of mTOR and its downstream targets 4E-BP1, eEF2, and eEF2 kinase in relationships with tau in Alzheimer's disease brain. FEBS J. 2005 Aug;272(16):4211-20. PubMed.

    . Beta-amyloid oligomers induce phosphorylation of tau and inactivation of insulin receptor substrate via c-Jun N-terminal kinase signaling: suppression by omega-3 fatty acids and curcumin. J Neurosci. 2009 Jul 15;29(28):9078-89. PubMed.

    . The diabetes drug liraglutide prevents degenerative processes in a mouse model of Alzheimer's disease. J Neurosci. 2011 Apr 27;31(17):6587-94. PubMed.

    . Defects in IGF-1 receptor, insulin receptor and IRS-1/2 in Alzheimer's disease indicate possible resistance to IGF-1 and insulin signalling. Neurobiol Aging. 2010 Feb;31(2) PubMed.

    . mTOR-dependent signalling in Alzheimer's disease. J Cell Mol Med. 2008 Dec;12(6B):2525-32. PubMed.

    . Glucagon-like peptide-1 decreases endogenous amyloid-beta peptide (Abeta) levels and protects hippocampal neurons from death induced by Abeta and iron. J Neurosci Res. 2003 Jun 1;72(5):603-12. PubMed.

    . Impaired insulin and insulin-like growth factor expression and signaling mechanisms in Alzheimer's disease--is this type 3 diabetes?. J Alzheimers Dis. 2005 Feb;7(1):63-80. PubMed.

    . Expression of pIRS-1 (S312 and S616) is elevated in MCI and AD and correlates with cognitive impairment and neurofibrillary pathology. (2006): Alzheimer Dement 2. [Suppl 3] A54.

    . Amyloid beta oligomers induce impairment of neuronal insulin receptors. FASEB J. 2008 Jan;22(1):246-60. PubMed.

  3. Insulin Receptor Substrates Enter Center Stage in Alzheimer’s Disease
    Type 2 diabetes, as well as obesity in midlife, have been identified as risk factors for AD. Both conditions are linked to peripheral insulin resistance. Several reports during the last decade suggested that brains from AD patients are insulin- and IGF-1-resistant, leading to the proposal that AD might be a brain-type diabetes or diabetes type 3 (Steen et al., 2005). Early work indicated that Aβ decreases insulin receptor (IR) tyrosine kinase activity by binding to the IR (Xie et al., 2002). If there have been any doubts that insulin/IGF-1 signaling is disturbed in AD, these papers by Talbot et al. and Bomfim et al. clearly demonstrate central insulin resistance as part of AD pathogenesis. Furthermore, both papers highlight the role of insulin receptor substrates and their phosphorylation patterns in this pathology. The insulin receptor substrates (IRSs) mediate the intracellular signaling of the IR and IGF-1R. In particular, both investigators described increased IRS-1 phosphorylation at serine 616 (IRS-1 pS616) and 636/639 (IRS-1 pS636/639) in AD brains. Phosphorylation at these sites desensitizes insulin signaling and is known to decrease insulin sensitivity in peripheral tissues. Similar observations in AD brains have been published previously (Moloney et al., 2010). Thus, at least three independent investigations suggest that desensitizing insulin receptor (IR) and/or IGF-1R signaling via serine phosphorylation of IRS-1 is a common feature of AD pathology.

    The IRS family integrates not only signals from the insulin and IGF-1 receptor, but also from nutrients and cytokines. Accordingly, Talbot et al. and Bomfim et al. investigated serine kinases downstream of the insulin/IGF-1 signaling cascade and serine kinases activated by cytokines. Their findings suggest a model where insulin/IGF-1 signaling can be turned down by two different mechanisms: 1) activation of IR/IGF-1R downstream serine kinases (e.g., mTOR, Akt, ERK, and GSK-3β) that desensitize the pathway; and/or 2) cytokine activated kinases (e.g., JNK or IKK) that impair IRS-1 signalling via serine phosphorylation. Interestingly, IRS-1 pS616 and IRS-1 pS636/639 phosphorylation correlated positively with oligomeric Aβ in AD brains, and is negatively associated with episodic and working memory. Therefore, reducing oligomeric Aβ possibly restores insulin sensitivity (as suggested by Bomfim et al.). Taken together, disturbed insulin and IGF-1 signaling, on the level of IRS-1, are an early feature of AD pathology.

    Intriguingly, basal levels of Akt and ERK phosphorylation were increased in AD brains (Talbot et al.), indicating that the IRS-1 serine phosphorylation observed in AD does not decrease basal downstream IR/IGF-1R signaling. In fact, IRS-1 dysfunction only became apparent when tissue was stimulated with insulin or IGF-1, suggesting that blocking IR/IGF-1R signaling on the level of the IRS proteins could have a protective effect. In line with this interpretation, recent data from model organisms have shown that insulin and IGF-1 resistance protect neurons from proteotoxicity and decrease Aβ load (Cohn et al., 2006; Cohn et al., 2009; Freude et al., 2009; Stöhr et al., 2011). In particular, decreased IGF-1 signaling led to Aβ hyper-aggregation, representing a mechanism of detoxification of oligomeric Aβ. Moreover, complete inactivation of the IR or the IGF-1R reduces Aβ generation at least in rodent models of AD (Freude et al., 2009; Stöhr et al., 2011). Hence, the data of Talbot and colleagues might suggest that serine phosphorylation of IRS-1 protects neurons from (potentially harmful) overstimulation of signaling. Thus, IR/IGF-1 resistance in AD brains might be a compensatory phenomenon in order to protect the brain from Aβ production and proteotoxicity via increased IR/IGF-1R signaling. The correlation between insulin resistance and memory impairment might just reflect the correlation between oligomeric Aβ and cognitive deficits. However, central insulin resistance is not only present in AD, but even more pronounced in human type 2 diabetes in the absence of AD. Since most diabetic patients never develop AD, it is unlikely that insulin resistance is “the” major pathogenic factor in AD (Liu et al., 2011).

    There have been promising studies using intranasal insulin (Craft et al., 2012) or peripheral IGF-1 applications (Carro et al., 2002) in humans and rodents. These formulations might not directly act on neurons but possibly regulate the export of Aβ monomers or oligomers from the brain to the blood or CSF, since IR/IGF-1R signaling has been shown to regulate Aβ export from the brain (Carro et al., 2002; Carro et al., 2006). In this case, increased neuronal insulin signaling in AD brains in response to insulin or IGF-1 treatment would not be directly induced via the stimulation of insulin receptors, but secondary due to a decrease of Aβ oligomers, which block insulin signaling. Alternatively, chronic insulin or IGF-1 treatment might eventually lead to decreased neuronal insulin or IGF-1 signaling as it has been described in vitro (Kim et al., 2011), and, in turn, insulin-induced insulin resistance would reduce Aβ production and toxicity.

    A further promising therapeutic approach might be GLP-1 analogues. These drugs reduce inflammation, improve learning and memory, and reduce Aβ load, at least in rodents. Possibly secondary to decreased inflammation and Aβ burden, these drugs restore IR signaling as elegantly demonstrated by Bomfim et al. and Christian Hölscher’s group (McClean et al., 2012). However, the interplay between the different pathological hallmarks (e.g., tau, β amyloid, neuritic dystrophy) and IRS-mediated signals needs further attention and investigation to evaluate this pathway as a therapeutic target for AD.

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    . The diabetes drug liraglutide prevents degenerative processes in a mouse model of Alzheimer's disease. J Neurosci. 2011 Apr 27;31(17):6587-94. PubMed.

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    . Opposing activities protect against age-onset proteotoxicity. Science. 2006 Sep 15;313(5793):1604-10. PubMed.

    . Reduced IGF-1 signaling delays age-associated proteotoxicity in mice. Cell. 2009 Dec 11;139(6):1157-69. PubMed.

    . Neuronal IGF-1 resistance reduces Abeta accumulation and protects against premature death in a model of Alzheimer's disease. FASEB J. 2009 Oct;23(10):3315-24. PubMed.

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    . Defects in IGF-1 receptor, insulin receptor and IRS-1/2 in Alzheimer's disease indicate possible resistance to IGF-1 and insulin signalling. Neurobiol Aging. 2010 Feb;31(2) PubMed.

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    . Intranasal insulin therapy for Alzheimer disease and amnestic mild cognitive impairment: a pilot clinical trial. Arch Neurol. 2012 Jan;69(1):29-38. PubMed.

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