Cited by 723Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

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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

Rivera, Enrique J., Goldin, Alison, Fulmer, Noah, Tavares, Rose, Wands, Jack R., de la Monte, Suzanne M.·2005·Journal of Alzheimer s Disease

DOI 10.3233/jad-2005-8304

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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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Background
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Background
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Background
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BackgroundInfluential
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BackgroundInfluential
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Background
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Altered temporal lobe white matter lipid ion profiles in an experimental model of sporadic Alzheimer's disease
Tong, M., Leão, R. A. C., Vimbela, G. V., Yalcin, E. B., Kay, J., Krotow, A., & de la Monte, S. M. (2017) · Molecular and Cellular Neuroscience · doi:10.1016/j.mcn.2017.04.010 · Cited by 17
“…levels, and insulin/IGF-1 signaling through phosphoinositol-3-kinase (PI3K)-Akt pathways that regulate cell survival, energy metabolism, neuronal plasticity and WM integrity (de la Monte and Tong, 2014; de la Monte and Wands, 2008; Rivera et al., 2005; Steen et al., 2005; Talbot et al., 2012).”
Insulin Inhibits Aβ42 Aggregation and Prevents Aβ42-Induced Membrane Disruption
Long, K., Williams, T., & Urbanc, B. (2019) · Biochemistry · doi:10.1021/acs.biochem.9b00696 · Cited by 17
Uncovering the intricacies of IGF-1 in Alzheimer’s disease: new insights from regulation to therapeutic targeting
Kaur, N., & Aran, K. R. (2025) · Inflammopharmacology · doi:10.1007/s10787-025-01641-0 · Cited by 17
“The dysregulation of the IGF-1 signaling pathway plays a crucial role in AD pathogenesis (Rivera et al. 2005).”
Extending Arms of Insulin Resistance from Diabetes to Alzheimer’s Disease: Identification of Potential Therapeutic Targets
Gupta, S. N., Singhal, N. K., Ganesh, S., & Sandhir, R. (2018) · CNS & Neurological Disorders - Drug Targets · doi:10.2174/1871527317666181114163515 · Cited by 16
iabetic Encephalopathy Affecting Mitochondria and Axonal Transport Proteins
Eslami, M. (2020) · Basic and Clinical Neuroscience Journal · doi:10.32598/bcn.11.6.1657.1 · Cited by 16
“Introduction iabetic encephalopathy and or type 3 Diabetes Mellitus (T3DM) is the chronic complication of Diabetes Mellitus (DM) (Steen et al., 2005; Rivera et al., 2005; de la Monte & Wands, 2008; Leszek, Trypka; & Tarasov, 2017).”
BackgroundInfluential
O-GlcNAcylation of Amyloid-β Protein Precursor by Insulin Signaling Reduces Amyloid-β Production
Kwon, O.-H., Cho, Y. Y., Kim, T., & Chung, S. (2019) · Journal of Alzheimer s Disease · doi:10.3233/jad-190060 · Cited by 16
“Thelevelsofbraininsulin,insulin receptor,insulinreceptorsubstrate1,phosphorylated insulinreceptor,anditsactivityaredecreased[25,26, 85,86].”
Insulin and insulin-like growth factor prevent brain atrophy and cognitive impairment in diabetic rats
Ishii, D., & Šerbed�ija, P. (2012) · Indian Journal of Endocrinology and Metabolism · doi:10.4103/2230-8210.105578 · Cited by 16
“[108] Serum IGF-I levels are reduced in patients with LOAD as well[109,110] and progressive stages of LOAD are associated with greater decline in mRNA levels of brain insulin, IGF, IR, and IGF-I receptor in postmortem frontal lobe.[111] Thus, diminished levels of insulin and IGFs in brain may contribute to the pathoge…”
Background
Diabetes of the Brain: Computational Approaches and Interventional Strategies
Narasimhan, K., Meenakumari, G., Gauthaman, K., Kamal, M. A., Abuzenadeh, A. M., Al-Qahtani, M., & Kanagasabai, R. (2014) · CNS & Neurological Disorders - Drug Targets · doi:10.2174/18715273113126660156 · Cited by 16
“Aberrant insulin metabolism caused by insulin resistance is one of the major causative factors leading to AD [20, 31-35] and this is discussed in the later section in this review.”
Background
Associations of polymorphisms in the candidate genes for Alzheimer’s disease BIN1, CLU, CR1 and PICALM with gestational diabetes and impaired glucose tolerance
Vacínová, G., Vejražková, D., Lukášová, P., Lischkova, O., Dvořáková, K., Rusina, R., Holmerová, I., Vaňková, H., Včelák, J., Bendlová, B., et al. (2017) · Molecular Biology Reports · doi:10.1007/s11033-017-4100-9 · Cited by 16
“AD is sometimes called “type 3 diabetes” because lower levels of insulin and IGF-I and lower expression of the receptors of these hormones have been found in the brains of AD patients compared to healthy controls [5, 6].”
Background
Proteomics Analysis of CA1 Region of the Hippocampus in Pre-, Progression and Pathological Stages in a Mouse Model of the Alzheimer’s Disease
Gürel, B., Cansev, M., Koç, C., Öcalan, B., Çakır, A., Aydın, S., Kahveci, N., Ulus, İ. H., Şahin, B., Karayel‐Basar, M., et al. (2019) · Current Alzheimer Research · doi:10.2174/1567205016666190730155926 · Cited by 16
Insulin Regulates the Activity of the High-Affinity Choline Transporter CHT
Fishwick, K. J., & Rylett, R. J. (2015) · PLoS ONE · doi:10.1371/journal.pone.0132934 · Cited by 16
“Importantly, a study of necropsy AD brains correlated increased Braak stage with decreased levels of insulin-like growth factor (IGF) signaling pathway components and decreased receptor binding affinity for insulin, IGF1 and IGF-2 [23].”
Background
Alzheimer′s disease: Unique markers for diagnosis & new treatment modalities
Aggarwal, N. T., Shah, R. C., & Bennett, D. A. (2015) · The Indian Journal of Medical Research · doi:10.4103/0971-5916.169193 · Cited by 19
Patients with Alzheimer’s Disease Have Increased Levels of Insulin-like Growth Factor-I in Serum but not in Cerebrospinal Fluid
Horváth, A., Salman, Z., Quinlan, P. S., Wallin, A., & Svensson, J. (2020) · Journal of Alzheimer s Disease · doi:10.3233/jad-190921 · Cited by 15
“In the postmortem human AD brain, IGF-I expression was reduced along with resistance to signaling through the insulin and IGF-I receptors [10, 11], which could result in lack of trophic signals with subsequent degeneration of neurons [1].”
The relationship between diabetes-related cognitive dysfunction and leukoaraiosis
Yuan, C.-L., Yi, R., Dong, Q., Yao, L., & Liu, B. (2021) · Acta Neurologica Belgica · doi:10.1007/s13760-021-01676-4 · Cited by 16
“Furthermore, low levels of insulin production and sensitivity could lead to reduced synthesis of acetylcholine, thereby inducing AD pathology in DM patients [4].”
Background
D-galactose-induced aging in rats – The effect of metformin on bioenergetics of brain, skeletal muscle and liver
Sumbalová, Z., Uličná, O., Kucharská, J., Rausová, Z., Vančová, O., Melicherčík, Ľ., Tvrdík, T., Nemec, M., & Kašparová, S. (2022) · Experimental Gerontology · doi:10.1016/j.exger.2022.111770 · Cited by 16
Adiponectin, the adiponectin paradox, and Alzheimer’s Disease: Is this association biologically plausible?
Dezonne, R. S., Pereira, C. M., Martins, C. J. D. M., de Abreu, V. G., & Francischetti, E. A. (2022) · Metabolic Brain Disease · doi:10.1007/s11011-022-01064-8 · Cited by 16
A State-of-Art Review of the Vicious Circle of Sleep Disorders, Diabetes and Neurodegeneration Involving Metabolism and Microbiota Alterations
Versace, S., Pellitteri, G., Sperotto, R., Tartaglia, S., Porto, A. D., Catena, C., Gigli, G. L., Cavarape, A., & Valente, M. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241310615 · Cited by 17
“Evidence of common characteristics between age-related dementia and insulin resistance and diabetes lead to the definition of AD as the “type-3 diabetes” [30].”
Background
Everolimus: A potential therapeutic agent targeting PI3K/Akt pathway in brain insulin system dysfunction and associated neurobehavioral deficits
Bansal, S., Agrawal, M., Mahendiratta, S., Kumar, S., Arora, S., Joshi, R., Prajapat, M., Sarma, P., Prakash, A., Chopra, K., et al. (2021) · Fundamental and Clinical Pharmacology · doi:10.1111/fcp.12677 · Cited by 15
Geroprotective interventions in the 3xTg mouse model of Alzheimer’s disease
Sonsalla, M. M., & Lamming, D. W. (2023) · GeroScience · doi:10.1007/s11357-023-00782-w · Cited by 17
Neurotherapeutic effects of quercetin-loaded nanoparticles and Biochanin-A extracted from Trifolium alexandrinum on PI3K/Akt/GSK-3β signaling in the cerebral cortex of male diabetic rats
Newairy, A. A., Hamaad, F. A., Wahby, M. M., Ghoneum, M. H., & Abdou, H. M. (2024) · PLoS ONE · doi:10.1371/journal.pone.0301355 · Cited by 14
“It is well-known that cognitive function is regulated by various neurotransmitters including ACh, DA and 5-HT. ACh is oxidized by AChE whereas DA and 5-HT are metabolized by MAO [33].”
Unraveling the relationship among insulin resistance, IGF-1, and amyloid-beta 1–40: Is the definition of type 3 diabetes applicable in the cardiovascular field?
Fluca, A. L., Pani, B., Janjusevic, M., Zwas, D. R., Abraham, Y., Calligaris, M., Beltrami, A. P., Corgosinho, F. C., Marketou, M. E., D’Errico, S., et al. (2024) · Life Sciences · doi:10.1016/j.lfs.2024.122911 · Cited by 15
Diversity of Microglia-Derived Molecules with Neurotrophic Properties That Support Neurons in the Central Nervous System and Other Tissues
Wiens, K. R., Wasti, N., Ulloa, O. O., & Klegeris, A. (2024) · Molecules · doi:10.3390/molecules29235525 · Cited by 16
Neuropathology of type 2 diabetes: a short review on insulin-related mechanisms
Guerrero‐Berroa, E., Schmeidler, J., & Beeri, M. S. (2014) · European Neuropsychopharmacology · doi:10.1016/j.euroneuro.2014.01.019 · Cited by 14
The Effect of Dual-Task Testing on Balance and Gait Performance in Adults with Type 1 or Type 2 Diabetes Mellitus: A Systematic Review
Omaña, H., Madou, E., Montero‐Odasso, M., Payne, M. W. C., Viana, R., & Hunter, S. W. (2020) · Current Diabetes Reviews · doi:10.2174/1573399816999201001203652 · Cited by 14
Is the Brain Undernourished in Alzheimer’s Disease?
Aquilani, R., Costa, A. C., Maestri, R., Ramusino, M. C., Perini, G., Boselli, M., Iadarola, P., Buonocore, D., Verri, M., Dossena, M., et al. (2022) · Nutrients · doi:10.3390/nu14091872 · Cited by 15
“A puzzling problem might be the coexistence of insulin resistance/hyperinsulinemia with reduced insulin receptor density in brain structures (by up to 80% in severe AD) [74,75].”
Background
Role of Biliverdin Reductase A in the Regulation of Insulin Signaling in Metabolic and Neurodegenerative Diseases: An Update
Cimini, F. A., Marzia Perluigi, A., Barchetta, I., Cavallo, M. G., & Barone, E. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23105574 · Cited by 17
Neural Stem Cells in the Diabetic Brain
Bachor, T. P., & Suburo, Á. M. (2012) · Stem Cells International · doi:10.1155/2012/820790 · Cited by 14
“Study of autopsy material has shown that increasing AD severity associates with progressively reduced levels of mRNAs for insulin, IGF-I, and IGF-II polypeptides and their receptors [126].”
Background
Selection of Appropriate Reference Genes for RT-qPCR Analysis in a Streptozotocin-Induced Alzheimer’s Disease Model of Cynomolgus Monkeys (Macaca fascicularis)
Park, S.-J., Kim, Y., Lee, Y., Kim, K.-M., Kim, H., Lee, S., Kim, S., Kim, S., Kim, J., Jeong, K.-J., et al. (2013) · PLoS ONE · doi:10.1371/journal.pone.0056034 · Cited by 14
“Previous studies have revealed significantly reduced expression levels of the MAPT gene and significantly increased expression levels of the APP gene in frontal cortex, hippocampus, and hypothalamus samples of human AD relative to the control [21,22].”
Background
Neuroenergetics of traumatic brain injury
Karelina, K., & Weil, Z. M. (2015) · Concussion · doi:10.2217/cnc.15.9 · Cited by 14
Effects of pulsed electromagnetic fields on learning and memory abilities of STZ-induced dementia rats
Li, Y., Zhang, Y., Wang, W., Zhang, Y., Yu, Y., Cheing, G. L. Y., & Pan, W. (2019) · Electromagnetic Biology and Medicine · doi:10.1080/15368378.2019.1591437 · Cited by 14
“Rivera et al. demonstrated significantly reduced levels of IGF-1 and IGF-2 genes and their corresponding receptors in AD brains (Rivera et al., 2005).”
Background
Growth Hormone and Insulin-Like Growth Factor I: Effects on the Brain
Laron, Z. (2009) · Elsevier eBooks · doi:10.1016/b978-008088783-8.00078-4 · Cited by 13
Unaltered Prion Pathogenesis in a Mouse Model of High-Fat Diet-Induced Insulin Resistance
Zhu, C., Schwarz, P., Abakumova, I., & Aguzzi, A. (2015) · PLoS ONE · doi:10.1371/journal.pone.0144983 · Cited by 13
Body weight variability and the risk of dementia in patients with type 2 diabetes mellitus: A nationwide cohort study in Korea
Park, K., Nam, G. E., Han, K., & Hwang, H. (2022) · Diabetes Research and Clinical Practice · doi:10.1016/j.diabres.2022.110015 · Cited by 13
Effects of distinct n-6 to n-3 polyunsaturated fatty acid ratios on insulin resistant and AD-like phenotypes in high-fat diets-fed APP/PS1 mice
Ma, X., Guo, Y., Xu, J., Wang, X., Dong, S., Gao, Y., Halm‐Lutterodt, N. V., & Yuan, L. (2022) · Food Research International · doi:10.1016/j.foodres.2022.112207 · Cited by 13
Whole-food diet worsened cognitive dysfunction in an Alzheimer's disease mouse model
Parrott, M. D., Winocur, G., Bazinet, R. P., David, W. L., & Greenwood, C. E. (2014) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2014.08.013 · Cited by 13
Neuronal insulin receptor substrate 2 (IRS2) expression is regulated by ZBP89 and SP1 binding to the IRS2 promoter
Udelhoven, M., Pasieka, M., Leeser, U., Krone, W., & Schubert, M. (2009) · Journal of Endocrinology · doi:10.1677/joe-09-0266 · Cited by 13
“…Alzheimer’s disease revealed a markedly downregulated expression of IR and IGF1R as well as of IRS2, and these changes progressed with the severity of neurodegeneration, suggesting a role of IRS2 expression in the pathogenesis of neurodegenerative diseases (Rivera et al. 2005, Steen et al. 2005).”
Background
Neuroprotection by aripiprazole against β-amyloid-induced toxicity by P-CK2α activation via inhibition of GSK-3β
Park, S. Y., Shin, H. K., Lee, W. S., Bae, S. S., Kim, K., Hong, K. W., & Kim, C. D. (2017) · Oncotarget · doi:10.18632/oncotarget.22777 · Cited by 13
“Studies have been reported that IGF2 mRNA expression declines in the frontal cortex of AD patients at a relatively early stage of neuropathology [19], and that intrahippocampal injection of IGF2 in rat enhances memory function [36].”
Background
Premature hippocampus-dependent memory decline in middle-aged females of a genetic rat model of depression
Lim, P. H., Wert, S. L., Tunc‐Ozcan, E., Marr, R. A., Ferreira, A., & Redei, E. E. (2018) · Behavioural Brain Research · doi:10.1016/j.bbr.2018.02.030 · Cited by 13
The Role of Long Noncoding RNAs in Diabetic Alzheimer’s Disease
Kim, Y., & Song, J. (2018) · Journal of Clinical Medicine · doi:10.3390/jcm7110461 · Cited by 13
“Previous studies suggested that diabetes is a strong risk factor for AD [11] and diabetes-induced AD has been emerging as a major pathogenic mechanism of AD [29,30].”
Background
Timing Matters: Circadian Effects on Energy Homeostasis and Alzheimer’s Disease
Loehfelm, A., Boucsein, A., Pretz, D., & Tups, A. (2018) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2018.12.001 · Cited by 13
Lin28B regulates the fate of grafted mesenchymal stem cells and enhances their protective effects against Alzheimer's disease by upregulating IGF‐2
Wu, K., Zhang, R., Lu, Y., Wen, L., Li, Y., Duan, R., Yao, Y., & Jia, Y. (2019) · Journal of Cellular Physiology · doi:10.1002/jcp.28750 · Cited by 14
Associations of the Glycaemic Control of Diabetes with Dementia and Physical Function in Rural-Dwelling Older Chinese Adults: A Population-Based Study
Jia, Y., Liu, R., Tang, S. H., Zhang, D., Wang, Y., Cong, L., Hou, T., Ren, J., & Du, Y. (2021) · Clinical Interventions in Aging · doi:10.2147/cia.s319633 · Cited by 13
“On the other hand, the accumulation of the amyloid-beta peptide, which is the main pathologic change in AD, may induce neuronal insulin resistance,(39) and insulin is significantly reduced in advanced AD brains compared with aged control brains.(40) In addition, a person with dementia may be not able to properly parti…”
Background
Tau Loss of Function, by Deletion or Aggregation, Contributes to Peripheral Insulin Resistance
Al‐Lahham, R., & Méndez, N. (2023) · Journal of Alzheimer s Disease · doi:10.3233/jad-230392 · Cited by 13
“…considered it a type 3 diabetes, with little emphasis on the link between systemic insulin resistance and AD, despite the fact that the incidence of T2D is higher in AD patients [5, 6, 10, 16, 33–36], and that peripheral insulin resistance and diabetes are also risk factors for AD [2, 3, 37–43].”
Assessment of the therapeutic potential of hesperidin and proteomic resolution of diabetes-mediated neuronal fluctuations expediting Alzheimer’s disease
Khowal, S., Mustufa, M. M. A., Chaudhary, N. K., Naqvi, S. H., Parvez, S., Jain, S. K., & Wajid, S. (2015) · RSC Advances · doi:10.1039/c5ra01977j · Cited by 12
Impact of morphine on the expression of insulin receptor and protein levels of insulin/IGFs in rat neural stem cells
Salarinasab, S., Nourazarian, A., Nikanfar, M., Abdyazdani, N., Kazemi, M., Feizy, N., & Rahbarghazi‬, R. (2017) · Neuroscience Letters · doi:10.1016/j.neulet.2017.09.035 · Cited by 11
“The reduced function of insulin, IGFs as well as insulin receptor in Alzheimer's disease has been demonstrated by numerous studies [27,28].”
Background

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
DOI: 10.3233/jad-2005-8304
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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Insulin and insulin-like growth factor expression and function deteriorate with progression of Alzheimer’s disease: Link to brain reductions in acetylcholine

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