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Insulin and insulin-like growth factor expression and function deteriorate with progression of Alzheimer’s disease: Link to brain reductions in acetylcholine
Abstract
Reduced glucose utilization and energy metabolism occur early in the course of Alzheimer's disease (AD) and correlate with impaired cognition. Glucose utilization and energy metabolism are regulated by insulin and insulin-like growth factor I (IGF-I), and correspondingly, studies have shown that cognitive impairment may be improved by glucose or insulin administration. Recently, we demonstrated significantly reduced levels of insulin and IGF-I polypeptide genes and their corresponding receptors in advanced AD relative to aged control brains. The abnormalities in gene expression were accompanied by impaired survival signaling downstream through PI3 kinase-Akt. The present work characterizes the abnormalities in insulin and IGF gene expression and receptor binding in brains with different Braak stage severities of AD. Realtime quantitative RT-PCR analysis of frontal lobe tissue demonstrated that increasing AD Braak Stage was associated with progressively reduced levels of mRNA corresponding to insulin, IGF-I, and IGF-II polypeptides and their receptors, tau, which is regulated by insulin and IGF-I, and the Hu D neuronal RNA binding protein. In contrast, progressively increased levels of amyloid beta protein precursor (AbetaPP), glial fibrillary acidic protein, and the IBA1/AIF1 microglial mRNA transcripts were detected with increasing AD Braak Stage. Impairments in growth factor and growth factor receptor expression and function were associated with increasing AD Braak stage dependent reductions in insulin, IGF-I, and IGF-II receptor binding, ATP levels, and choline acetyltransferase (ChAT) expression. Further studies demonstrated that: 1) ChAT expression increases with insulin or IGF-I stimulation; 2) ChAT is expressed in insulin and IGF-I receptor-positive cortical neurons; and 3) ChAT co-localization in insulin or IGF-I receptor-positive neurons is reduced in AD. Together, these data provide further evidence that AD represents a neuro-endocrine disorder that resembles a unique form of diabetes mellitus (? Type 3) and progresses with severity of neurodegeneration.
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“Higher Iba1 was noted in the AD frontal cortex in four studies,20, 63, 64, 68 but was the same as control in three others32, 70, 74 and lower in the white matter of the frontal lobe in one study.32”
From Markers of microglia in post-mortem brain samples from patients with Alzheimer’s disease: a systematic review (2018) · cites this paper as [64]
In the citing paper
“Brain insulin signaling declines with age (Frolich et al., 1998; , 1999; Hoyer, 1998; Rivera et al., 2005), the primary risk factor for AD.”
From The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer’s disease (2011) · cites this paper as Rivera et al., 2005
In the citing paper
“levels of brain insulin and insulin receptors (IRs) are lower in AD (Frolich et al., 1998; Rivera et al., 2005).”
From The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer’s disease (2011) · cites this paper as Rivera et al., 2005
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“A number of the findings at upstream levels of the pathway are consistent with insulin resistance as defined above, notably decreased basal activation of IRs (28); reduced insulin binding of the IR, even early in the disorder (27); increased serine phosphorylation (pS) of IRS-1 (29, 33, 37); and reduced cytosolic and/…”
BackgroundBrain insulin resistance in type 2 diabetes and Alzheimer disease: concepts and conundrums
Arnold, S. E., Arvanitakis, Z., Macauley-Rambach, S. L., Koenig, A. M., Wang, H.-Y., Ahima, R. S., Craft, S., Gandy, S., Buettner, C., Stoeckel, L. E., et al. (2018) · Nature Reviews Neurology · doi:10.1038/nrneurol.2017.185 · Cited by 1,597
Alzheimer’s disease is type 3 diabetes—Evidence reviewed
de la Monte, S. M., & Wands, J. R. (2008) · Journal of Diabetes Science and Technology · doi:10.1177/193229680800200619 · Cited by 1,158
Self-citationTrends in insulin resistance: insights into mechanisms and therapeutic strategy
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“For example, major abnormalities in AD brains include decreased mRNA and protein expression levels of insulin, insulin receptors, insulin receptor substrate 1 (IRS1) and IGF1/2, in addition to reduced protein indicators of downstream insulin signaling activity (including phosphorylated AKT (pAKT) and phosphorylated GS…”
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“These alterations are involved in the progression of AD according to Braak staging (Rivera et al., 2005).”
Is Alzheimer’s disease a type 3 diabetes? A critical appraisal
Kandimalla, R., Thirumala, V., & Reddy, P. H. (2017) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2016.08.018 · Cited by 621
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“Compared with healthy controls, AD brains displayed lower insulin signaling and insulin receptors (294, 335).”
ResultHopperton, K. E., Mohammad, D., Trépanier, M. O., Giuliano, V, & Bazinet, R. P. (2018) · Molecular Psychiatry · doi:10.1038/mp.2017.246 · Cited by 567
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“In AD brain, insulin and insulin signaling are decreased when compared with healthy control subjects (Craft et al., 1998, 2003; Rivera et al., 2005; Steen et al., 2005).”
BackgroundMechanisms of Vascular Aging: New Perspectives
Ungvari, Z. I., Kaley, G., de Cabo, R., Sonntag, W. E., & Csiszár, A. (2010) · The Journals of Gerontology Series A · doi:10.1093/gerona/glq113 · Cited by 548
Hyperinsulinemia Drives Diet-Induced Obesity Independently of Brain Insulin Production
Mehran, A. E., Templeman, N. M., Brigidi, G. S., Lim, G. E., Chu, K.-Y., Hu, X., Botezelli, J. D., Asadi, A., Hoffman, B. G., Kieffer, T. J., et al. (2012) · Cell Metabolism · doi:10.1016/j.cmet.2012.10.019 · Cited by 498
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“Brain levels of insulin and binding to the insulin receptor are reduced with age [58] and are markedly reduced in the AD brain compared to the controls [59, 60].”
BackgroundIntracerebral streptozotocin model of type 3 diabetes: Relevance to sporadic Alzheimer’s disease
Lester-Coll, N., Rivera, E. J., Soscia, S. J., Doiron, K., Wands, J. R., & de la Monte, S. M. (2006) · Journal of Alzheimer s Disease · doi:10.3233/jad-2006-9102 · Cited by 467
Freiherr, J., Hallschmid, M., Frey, W. H., Brünner, Y. F., Chapman, C. D., Hölscher, C., Craft, S., Felice, F. G. D., & Benedict, C. (2013) · CNS Drugs · doi:10.1007/s40263-013-0076-8 · Cited by 477
“In line with this hypothesis, AD patients show reduced brain insulin receptor sensitivity [9, 10], hypophosphorylation of the insulin receptor and downstream second messengers such as the insulin receptor substrate-1 [10, 11] and attenuated insulin and insulin-like growth factor receptor expression [11].”
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“insulin regulation (also referred to as brain insulin resistance) induces pathological features of AD, and can be caused by attenuated expression of insulin receptors and insulin-like growth factor, reduced brain insulin receptor sensitivity, or increased serine phosphorylation of downstream insulin signaling molecule…”
Brain metabolic dysfunction at the core of Alzheimer's disease
de la Monte, S. M., & Tong, M. (2014) · Biochemical Pharmacology · doi:10.1016/j.bcp.2013.12.012 · Cited by 472
“These and other consequences help drive pro-apoptosis, pro-inflammatory, and pro-AβPP-Aβ cascades, which worsen DNA damage, mitochondrial dysfunction, oxidative stress, and ROS generation [3, 8, 18, 19, 28].”
BackgroundInfluentialBrain Insulin Resistance and Deficiency as Therapeutic Targets in Alzheimers Disease
de la Monte, S. M. (2012) · Current Alzheimer Research · doi:10.2174/156720512799015037 · Cited by 468
“A convincing argument could be made that AD, in its pure form, represents a brain form of diabetes mellitus [7, 8] since, AD is associated with progressive brain insulin resistance in the absence of T2DM, obesity, or peripheral insulin resistance [7, 8, 89, 90].”
BackgroundInfluentialThe Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer’s disease
Ferreira, S. T., & Klein, W. L. (2011) · Neurobiology of Learning and Memory · doi:10.1016/j.nlm.2011.08.003 · Cited by 442
Mitochondria and Cardiovascular Aging
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Alzheimer’s disease: insights into pathology, molecular mechanisms, and therapy
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Altered Insulin Signaling in Alzheimer’s Disease Brain – Special Emphasis on PI3K-Akt Pathway
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Insulin resistance and Alzheimer's disease
De La Monte, S. M. (2009) · BMB Reports · doi:10.5483/bmbrep.2009.42.8.475 · Cited by 392
“In addition, inhibition of insulin/IGF-1 signaling blocks the Wnt pathway (24), which negatively regulates GSK-3β via a PI3K/Akt-independent mechanism.”
BackgroundInfluential(Pre)diabetes, brain aging, and cognition
Roriz‐Filho, J. S., Roriz, T. M. D. S., Rosset, I., Camozzato, A. L., dos Santos, A. C., Chaves, M. L. F., Moriguti, J. C., & Roriz‐Cruz, M. (2008) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2008.12.003 · Cited by 397
Diabetes mellitus and Alzheimer's disease: shared pathology and treatment?
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Metabolic-cognitive syndrome: A cross-talk between metabolic syndrome and Alzheimer's disease
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“Recent findings show that insulin signaling may play an important role in the activities of cholinergic neurons through insulin-related proteins colocalized with ChAT (50).”
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“correlated with reduced expression of choline acetyltransferase, which is needed to generate acetylcholine [31, 99, 100].”
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“Recently, we demonstrated that ChAT gene expression was regulated by insulin and IGF-1 stimulation, and that in AD as well as in the ic-STZ model, impaired insulin and IGF-1 signaling mechanisms correlate with deficits in acetylcholine production [3].”
InfluentialInsulin in Central Nervous System: More than Just a Peripheral Hormone
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“This can be supported by the reports on age- and AD-related decrease in insulin mRNA and protein levels [11, 282, 283], IR or IGF-1R expression [11, 40, 219, 284], IRS-1 and IRS-2 levels [11], markers of Tyr kinase activity (namely, active IRS-1, PI3K, and ERK1/2) [40, 175], or a reduced association of Shc with Grb2 […”
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Type 3 diabetes is sporadic Alzheimer׳s disease: Mini-review
de la Monte, S. M. (2014) · European Neuropsychopharmacology · doi:10.1016/j.euroneuro.2014.06.008 · Cited by 324
“Over the past several years, this field of research has greatly expanded due to growing information about the causes and consequences of brain insulin resistance and deficiency in relation to cognitive impairment (Craft, 2005a, 2006, 2007; de la Monte et al., 2006; Lester-Coll et al., 2006; Rivera et al., 2005; Steen…”
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Querfurth, H., & Lee, H.-K. (2021) · Molecular Neurodegeneration · doi:10.1186/s13024-021-00428-5 · Cited by 288
“The evidence points to a combination of insulin deficiency [129], attenuated insulin receptor expression [130] and insulin resistance [131, 132].”
BackgroundThe Therapeutic Potential of Metformin in Neurodegenerative Diseases
Rotermund, C., Machetanz, G., & Fitzgerald, J. C. (2018) · Frontiers in Endocrinology · doi:10.3389/fendo.2018.00400 · Cited by 316
Astrocytes as Key Regulators of Brain Energy Metabolism: New Therapeutic Perspectives
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“Brain insulin resistance is also believed to contribute to metabolic dysfunctions in AD (Rivera et al., 2005).”
BackgroundThe Mechanisms of Action of Curcumin in Alzheimer’s Disease
Tang, M., & Taghibiglou, C. (2017) · Journal of Alzheimer s Disease · doi:10.3233/jad-170188 · Cited by 317
“Postmortem studies on AD patients has shown that brain tissues exhibited decreased insulin receptor binding [83], lower levels of activated insulin receptor [84], and increased inhibitory phosphorylation of IRS-1 [82].”
Intranasal Insulin Improves Memory in Humans: Superiority of Insulin Aspart
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“…disorder with strikingly reduced CNS expression of genes encoding insulin, IGF-I and IGF-II, as well as the insulin and IGF-I receptors (Rivera et al, 2005), our finding of improved memory performance after intranasal intake of insulin and its analogs may be of significance for the…”
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“76 Insulin was found to modulate A β protein precursor expression and processing both in vivo and in vitro.”
Aberrant insulin signaling in Alzheimer's disease: current knowledge
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“AD etiology appears to be linked to a multitude of mechanisms that have not been yet completely elucidated.”
BackgroundInfluentialThe role of type 2 diabetes in neurodegeneration
Verdile, G., Fuller, S. J., & Martins, R. N. (2015) · Neurobiology of Disease · doi:10.1016/j.nbd.2015.04.008 · Cited by 290
de la Monte, S. M. (2012) · Drugs · doi:10.2165/11597760-000000000-00000 · Cited by 265
“Growing evidence supports the concept that AD is a degenerative metabolic disease in which brain glucose uptake and utilization are impaired.([6-10])”
BackgroundInfluentialDiabetes mellitus and cognitive impairments
Saedi, E., Gheini, M. R., Faiz, F., & Arami, M. A. (2016) · World Journal of Diabetes · doi:10.4239/wjd.v7.i17.412 · Cited by 279
Insulin Resistance and Oxidative Stress in the Brain: What’s New?
Maciejczyk, M., Żebrowska, E., & Chabowski, A. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20040874 · Cited by 293
“Deficits in insulin/IGF receptor binding were also noted in the cerebrospinal fluid (CSF) of AD patients [58,70,74].”
BackgroundDiabetes and Alzheimer’s disease crosstalk
Baglietto‐Vargas, D., Shi, J. J., Yaeger, D. M., Ager, R. R., & LaFerla, F. M. (2016) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2016.03.005 · Cited by 263
The relationship between Alzheimer's disease and diabetes: Type 3 diabetes?
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Mechanisms Underlying Caloric Restriction and Lifespan Regulation
Ungvari, Z. I., Parrado‐Fernández, C., Csiszár, A., & de Cabo, R. (2008) · Circulation Research · doi:10.1161/circresaha.107.168369 · Cited by 243
Insulin Dysfunction InducesIn VivoTau Hyperphosphorylation through Distinct Mechanisms
Planel, E., Tatebayashi, Y., Miyasaka, T., Liu, L., Wang, L., Herman, M., Yu, W. H., Luchsinger, J. A., Wadzinski, B. E., Duff, K., et al. (2007) · Journal of Neuroscience · doi:10.1523/jneurosci.3949-07.2007 · Cited by 242
“, 1999), decreased brain insulin and insulin-like growth factor I expression and function (Rivera et al., 2005), and reduced glucose metabolism (Mosconi, 2005).”
BackgroundMechanisms of mitochondrial dysfunction and energy deficiency in Alzheimer’s disease
Atamna, H., & Frey, W. H. (2007) · Mitochondrion · doi:10.1016/j.mito.2007.06.001 · Cited by 278
“Reported decreases in the levels of both insulin and IGF-I in the brains of AD patients (Rivera et al., 2005) likely contribute to the energy hypometabolism and cognitive impairment found in AD.”
BackgroundMcNay, E. C., & Recknagel, A. K. (2011) · Neurobiology of Learning and Memory · doi:10.1016/j.nlm.2011.08.005 · Cited by 233
“example in brains taken from patients with Alzheimer’s disease (Rivera et al., 2005; Steen et al., 2005).”
Insulin, cognition, and dementia
Cholerton, B., Baker, L. D., & Craft, S. (2013) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2013.08.008 · Cited by 243
“(Frolich et al., 1998; Hoyer, 2002) Subsequently, reduced insulin and insulin-like growth factor 1 message was shown to correlate with increasing Alzheimer pathology and cholinergic deficit (Rivera et al., 2005).”
BackgroundInsulin Resistance and Diabetes Mellitus in Alzheimer’s Disease
Burillo, J., Marqués, P., Jiménez, B., González-Blanco, C., Benito, M., & Guillén, C. (2021) · Cells · doi:10.3390/cells10051236 · Cited by 246
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“In addition, there is an increasing evidence to support a link between pathogenesis of AD and functional disturbances of brain IR signaling (Frölich et al., 1998, 1999; Rivera et al., 2005; Huang et al., 2010b).”
BackgroundInsulin-like growth factor-1 and risk of Alzheimer dementia and brain atrophy
Westwood, A. J., Beiser, A., DeCarli, C. S., Harris, T. B., Chen, T. C., He, X., Roubenoff, R., Pikula, A., Au, R., Braverman, L. E., et al. (2014) · Neurology · doi:10.1212/wnl.0000000000000382 · Cited by 228
“neurodegeneration that develops in the later stages of AD or from an acquired IGF-1 resistance secondary to alterations in the IGF-1 signaling pathway.(21,23) To our knowledge, there have been no prior studies relating IGF-1 to total brain volumes on MRI in healthy persons.”
BackgroundAMP‐activated protein kinase: a potential player in Alzheimer’s disease
Salminen, A., Kaarniranta, K., Haapasalo, A., Soininen, H. S., & Hiltunen, M. O. (2011) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2011.07331.x · Cited by 224
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“Moreover, brain IGF-1 mRNA levels are diminished in late AD, whereas IGF-1 serum levels are increased in early stages of disease, suggesting that IGF-1 resistance plays a role in the pathogenesis of AD (14, 41).”
BackgroundClaxton, A., Baker, L. D., Wilkinson, C. W., Trittschuh, E. H., Chapman, D., Watson, G. S., Cholerton, B., Plymate, S. R., Arbuckle, M., & Craft, S. (2013) · Journal of Alzheimer’s Disease · doi:10.3233/jad-122308 · Cited by 215
“[5–7].”
Insulin-resistant brain state: The culprit in sporadic Alzheimer's disease?
Correia, S. C., Santos, R. X., Perry, G., Zhu, X., Moreira, P. I., & Smith, M. A. (2011) · Ageing Research Reviews · doi:10.1016/j.arr.2011.01.001 · Cited by 212
Neuronal Apoptosis in Neurodegeneration
Okouchi, M., Ekshyyan, O. Y., Maracine, M., & Aw, T. Y. (2007) · Antioxidants and Redox Signaling · doi:10.1089/ars.2007.1511 · Cited by 222
“For instance, decreases in insulin, IGF, and their receptors have been documented in the hippocampus in diabetic encephalopathy and AD patients (203, 309).”
Modifiable Risk Factors for Alzheimer’s Disease
Edwards III, G. A., Gamez, N., Escobedo Jr., G., Calderon, O., & Moreno-Gonzalez, I. (2019) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2019.00146 · Cited by 253
Yarchoan, M. M., Toledo, J. B., Lee, E. B., Arvanitakis, Z., Kazi, H., Han, L.-Y., Louneva, N., Lee, V. M. ‐., Kim, S. F., Trojanowski, J. Q., et al. (2014) · Acta Neuropathologica · doi:10.1007/s00401-014-1328-5 · Cited by 215
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Bharadwaj, P., Wijesekara, N., Liyanapathirana, M., Newsholme, P., Ittner, L. M., Fraser, P. E., & Verdile, G. (2017) · Journal of Alzheimer s Disease · doi:10.3233/jad-161192 · Cited by 209
Molecular links between Alzheimer’s disease and diabetes mellitus
Yang, Y., & Song, W. (2013) · Neuroscience · doi:10.1016/j.neuroscience.2013.07.009 · Cited by 211
The Aging Heart: Figure 1.Preprint
Chiao, Y. A., & Rabinovitch, P. S. (2015) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a025148 · Cited by 204
“…IGF-1 treatment of aged rats protects against mitochondrial oxidative stress (Puche et al. 2008), and other studies suggest that interventions that increase circulating IGF-1 levels exert cardiovascular protective effects in aging (Rivera et al. 2005; Groban et al. 2006; Lopez-Lopez et al. 2007).”
BackgroundChanges in insulin and insulin signaling in Alzheimer’s disease: cause or consequence?
Stanley, M., Macauley, S. L., & Holtzman, D. M. (2016) · The Journal of Experimental Medicine · doi:10.1084/jem.20160493 · Cited by 201
“…<65 y/o and AD patients -mRNA: in hippocampus and hypothalamus -mRNA: progressive reduction with Braak stage Brain IR (total) ↓ Frölich et al., 1998; Rivera et al., 2005; Steen et al., 2005 -Comparing controls <65 y/o and AD patients -mRNA and protein -mRNA: progressive reduction with Braak…”
InfluentialChallenges for Alzheimer's Disease Therapy: Insights from Novel Mechanisms Beyond Memory Defects
Frozza, R. L., Lourenco, M. V., & Felice, F. G. D. (2018) · Frontiers in Neuroscience · doi:10.3389/fnins.2018.00037 · Cited by 213
“AD brains exhibit lower levels of insulin and reduced insulin receptor (IR) expression and sensitivity (Rivera et al., 2005; Steen et al., 2005; Talbot et al., 2012).”
BackgroundCorreia, S. C., Santos, R. X., Carvalho, C., Cardoso, S., Candeias, E., Santos, M. S., Oliveira, C. R., & Moreira, P. I. (2012) · Brain Research · doi:10.1016/j.brainres.2011.12.063 · Cited by 202
Rojas-Gutierrez, E., Muñoz‐Arenas, G., Treviño, S., Espinosa, B., Chávez, R., Rojas, K., Flores, G., Díaz, A., & Guevara, J. (2017) · Synapse · doi:10.1002/syn.21990 · Cited by 205
“Deficient insulin signaling begins early and progresses with the development of the disease (De la Monte & Wands, 2008; Rivera et al., 2005).”
BackgroundKe, Y. D., Delerue, F., Gladbach, A., Götz, J., & Ittner, L. M. (2009) · PLoS ONE · doi:10.1371/journal.pone.0007917 · Cited by 189
“glucose metabolism have also been found in AD [14–16].”
BackgroundBrain mitochondrial dysfunction as a link between Alzheimer's disease and diabetes
Moreira, P. I., Santos, M. S., Seiça, R. M. F., & Oliveira, C. R. (2007) · Journal of the Neurological Sciences · doi:10.1016/j.jns.2007.01.017 · Cited by 190
“In addition, the same research group demonstrated that insulin and insulin-like growth factor expression and function deteriorate with progression of AD being these effects linked to brain reductions in acetylcholine [32].”
BackgroundThe role of insulin and neurotrophic factor signaling in brain aging and Alzheimer’s Disease
Cole, G. M., & Frautschy, S. A. (2006) · Experimental Gerontology · doi:10.1016/j.exger.2006.08.009 · Cited by 193
Neural stem cell therapy for neurodegenerative disorders: The role of neurotrophic support
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Clinical development of curcumin in neurodegenerative disease
Hu, S., Maiti, P., Ma, Q., Zuo, X., Jones, M. R., Cole, G. M., & Frautschy, S. A. (2015) · Expert Review of Neurotherapeutics · doi:10.1586/14737175.2015.1044981 · Cited by 179
“In AD subjects, there are deficits in glucose metabolism [72] corresponding to reductions in insulin signaling [73,74].”
Type 2 diabetes as a risk factor for cognitive impairment: current insights
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“39 The critical pathological mechanism in AD is an accumulation of A β .”
Impaired insulin signalling and allostatic load in Alzheimer disease
Felice, F. G. D., Gonçalves, R. A., & Ferreira, S. T. (2022) · Nature reviews. Neuroscience · doi:10.1038/s41583-022-00558-9 · Cited by 183
Intranasal Insulin for Alzheimer’s Disease
Hallschmid, M. (2021) · CNS Drugs · doi:10.1007/s40263-020-00781-x · Cited by 188
Diagnostic, Prognostic, and Mechanistic Biomarkers of Diabetes Mellitus-Associated Cognitive Decline
Ehtewish, H., Arredouani, A., & El‐Agnaf, O. M. A. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23116144 · Cited by 189
“This observation suggests that insulin may play a significant role in cognition by regulating cerebrocortical activity and brain metabolism and, most likely, by controlling the production of the neurotransmitter acetylcholine [88,89].”
BackgroundBarone, E., Domenico, F. D., Marzia Perluigi, A., & Butterfield, D. A. (2021) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2021.09.006 · Cited by 182
de la Monte, S. M., Longato, L., Tong, M., & Wands, J. R. (2009) · PubMed · Cited by 167
Gene-environment interactions in Alzheimer's disease: A potential path to precision medicine
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“…on the role of insulin in AD pathology, De la Monte proposed that AD could be referred as ‘Type-3Diabetes’ as it has composite features of both Type 1 diabetes (insulin deficiency) and Type 2 diabetes (insulin resistance) (de la Monte, 2014; Hoyer, 2004; Rivera et al., 2005; Talbot et al., 2012).”
BackgroundInsulin resistance and pathological brain ageing
Cholerton, B., Baker, L. D., & Craft, S. (2011) · Diabetic Medicine · doi:10.1111/j.1464-5491.2011.03464.x · Cited by 164
Werner, H., & LeRoith, D. (2014) · European Neuropsychopharmacology · doi:10.1016/j.euroneuro.2014.01.020 · Cited by 167
“Decreases were also seen in downstream mediator transcripts and the extent of these reductions were in correlation with the severity of the disease (Rivera et al., 2005).”
BackgroundWang, X., Zheng, W. H., Xie, J., Wang, T., Wang, S., Teng, W., & Wang, Z. (2010) · Molecular Neurodegeneration · doi:10.1186/1750-1326-5-46 · Cited by 161
“Discussion The accumulating evidence that a lower expression of insulin and insulin receptors occurs in the brain of AD suggests a role of impaired insulin signaling pathway in the pathogenesis of AD [27,28].”
BackgroundMetabolic syndrome and the role of dietary lifestyles in Alzheimer’s disease
Pasinetti, G. M., & Eberstein, J. A. (2008) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2008.05454.x · Cited by 160
“In contrast, Steen et al. (2005) and Rivera et al. (2005) observed that AD is associated with significantly reduced IR content and IR activity in the brain.”
BackgroundInsulin and Alzheimer's Disease: Untangling the Web
Craft, S., Cholerton, B., & Baker, L. D. (2012) · Journal of Alzheimer s Disease · doi:10.3233/jad-2012-129042 · Cited by 161
“This initial finding has been confirmed and extended by other investigators, who have demonstrated reduced CSF insulin in patients with AD and mild cognitive impairment (MCI) [18, 19], and reduced insulin and IGF-I signaling with increasing AD pathology and cholinergic deficit [20].”
Shared links between type 2 diabetes mellitus and Alzheimer's disease: A review
Mittal, K., & Katare, D. P. (2016) · Diabetes & Metabolic Syndrome Clinical Research & Reviews · doi:10.1016/j.dsx.2016.01.021 · Cited by 161
Diet Intervention and Cerebrospinal Fluid Biomarkers in Amnestic Mild Cognitive Impairment
Bayer-Carter, J. L., Green, P. S., Montine, T. J., VanFossen, B. T., Baker, L. D., Watson, G. S., Bonner, L. M., Callaghan, M., Leverenz, J. B., Walter, B. K., et al. (2011) · Archives of Neurology · doi:10.1001/archneurol.2011.125 · Cited by 160
“Evidence of a tipping point in CSF A 42 concentration that corresponds with initiation of brain A deposition is seen in studies of transgenic mice.34-36 Conclusive evidence of a tipping point model of CSF A 42 in humans is limited by the lack of longitudinal data spanning the continuum from healthy young adult age thr…”
InfluentialDevi, L., Alldred, M. J., Ginsberg, S. D., & Ohno, M. (2012) · PLoS ONE · doi:10.1371/journal.pone.0032792 · Cited by 159
“[6–9].”
Limited Alzheimer-type neurodegeneration in experimental obesity and type 2 diabetes mellitus
Moroz, N., Tong, M., Longato, L., Xu, H., & de la Monte, S. M. (2008) · Journal of Alzheimer s Disease · doi:10.3233/jad-2008-15103 · Cited by 151
“…A β PP gene expression; 4) pro-inflammatory cytokine activation; 5) impairments in IGF-I and IGF-II receptor binding; 6) reduced expression of IGF-I and IGF-II polypeptide and receptor genes;and 7) impairments in acetylcholine homeostasis [14,32,50,56] were not present in ourmod-el of obesity/T2DM.”
InfluentialSanders, L. M. J., Hortobágyi, T., Karssemeijer, E. G. A., Van der Zee, E. A., Scherder, E. J. A., & van Heuvelen, M. J. G. (2020) · Alzheimer's Research & Therapy · doi:10.1186/s13195-020-00597-3 · Cited by 154
“Although lower levels in these neurobiological factors could leave more room for improvement, it is also possible that the neurobiological system is less responsive in PwD [103, 104].”
BackgroundLyn‐Cook, L. E., Lawton, M., Tong, M., Silbermann, E., Longato, L., Jiao, P., Mark, P., Wands, J. R., Xu, H., & de la Monte, S. M. (2009) · Journal of Alzheimer s Disease · doi:10.3233/jad-2009-0984 · Cited by 154
“Since AD shares many biochemical, molecular, and signal transduction abnormalities in common with T2DM and NASH, but the relevant pathology is fundamentally confined to the CNS in the vast majority of cases, we suggested that AD be regarded as “Type 3 diabetes” [10,11].”
Insulin‐like growth factor 2 reverses memory and synaptic deficits in APP transgenic mice
Pascual‐Lucas, M., da Silva, S. V., Scala, M. D., García, C., González‐Aseguinolaza, G., Mulle, C., Alberini, C. M., Cuadrado‐Tejedor, M., & García‐Osta, A. (2014) · EMBO Molecular Medicine · doi:10.15252/emmm.201404228 · Cited by 147
“In line with previous findings (Rivera et al , 2005), we observed that IGF2 protein levels decline in the hippocampus of the AD brain; this led us to test the hypothesis that IGF2 is a potential treatment for AD in preclinical models.”
Metabolic Syndrome as a Risk Factor for Alzheimer’s Disease: A Focus on Insulin Resistance
Ezkurdia, A., Ramírez, M. J., & Solas, M. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24054354 · Cited by 160
Metadata
- Authors
- Rivera, E. J., Goldin, A., Fulmer, N., Tavares, R., Wands, J. R., & de la Monte, S. M.
- Affiliations
- Brown University (US)
- Departments of Pathology and Medicine, Rhode Island Hospital and Brown Medical School, Providence, RI, USA
- ORCID
- Wands, Jack R.
- Venue
- Journal of Alzheimer s Disease
- Publisher
- SAGE Publications
- Published
- 2005-12-05
- Volume
- 8
- Issue
- 3
- Pages
- 247-268
- ISSN
- 1387-2877 (ISSN-L)
- 1875-8908
- OpenAlex
- W1718410121
- Cited by
- 723
- References
- 71
- Citations by year
- 2026: 16 · 2025: 24 · 2024: 32 · 2023: 35 · 2022: 56 · 2021: 45 · 2020: 43 · 2019: 52 · 2018: 46 · 2017: 29 · 2016: 43 · 2015: 44 · 2014: 51 · 2013: 42 · 2012: 43
- FWCI
- 8.79
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Alzheimer s Disease (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute on Alcohol Abuse and Alcoholism (AA12458, AA-02666, AA11931)
- National Institute on Aging (P50 AG05128, P50AG005128)
- National Center for Research Resources (P20RR 15578, P20RR015578)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- Alzheimer's disease, insulin
- MeSH terms
- Acetylcholine, Aged, Aged, 80 and over, Aging, Alzheimer Disease, Apolipoproteins E, Brain, Choline O-Acetyltransferase, Cognition Disorders, Female, Genotype, Glucose, Humans, Insulin, Insulin Resistance, Insulin-Like Growth Factor I, Male, RNA, Messenger, Gene Expression, Amyloid beta-Protein Precursor, tau Proteins, DNA Primers, Disease Progression, Reverse Transcriptase Polymerase Chain Reaction
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