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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“Therefore, blood glucose abnormalities and insulin resistance affect Ach synthesis which may be related to the neurocognitive impairment seen in diabetes mellitus (Rivera et al., 2005).”
Background
Identification of IGF-1 Effects on White Adipose Tissue and Hippocampus in Alzheimer’s Disease Mice via Transcriptomic and Cellular Analysis
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Arsenic impairs insulin signaling in differentiated neuroblastoma SH-SY5Y cells
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BackgroundInfluential
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Retracted
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“…these studies, Starks et al. (43) stated that they found a positive relationship with tau measurements in apolipoprotein E (APOE) ε 4 positive individuals, but that they also did not find a direct relationship between systemic insulin resistance and CSF A β , total tau or phospho-tau levels (19).”
Background
Alzheimer’s Disease and Diabetes
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“Moreover, AD brains show decreased insulin levels, decreased activity of insulin receptors and signs of compensatory mechanisms such as increased insulin receptor density [3] indicating AD as “type 3 diabetes” [4, 5].”
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A multipronged, nutritional-based strategy for managing Alzheimer’s disease
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Background
How to Stabilize Both the Proteins and the Membranes: Diverse Effects of sHsps in Neuroprotection
Tóth, M. E., Sántha, M., Penke, B., & Vı́gh, L. (2015) · Heat shock proteins · doi:10.1007/978-3-319-16077-1_23 · Cited by 6
Effect of a Novel Polyherbal Formulation on Diabetes Induced Memory Deficits in Rats
(2015) · Clinical and Experimental Pharmacology · doi:10.4172/2161-1459.1000194 · Cited by 4
“Inappropriate activation of kinases result in inhibitory phosphorylation that affects PI3K and the MAPK insulin mediated signalling cascades, both of which are involved in the maintenance of synaptic plasticity and cell stress response [2,7,50].”
Background
Insulin Resistance and Oligodendrocyte/Microvascular Endothelial Cell Dysfunction as Mediators of White Matter Degeneration in Alzheimer’s Disease
de la Monte, S. M., & Grammas, P. (2019) · Codon Publications eBooks · doi:10.15586/alzheimersdisease.2019.ch8 · Cited by 7
“In light of the known importance of insulin and IGF signaling for maintaining a broad array of homeostatic functions in both neurons and oligodendrocytes (38–40), and strong evidence for brain insulin and IGF deficiencies and resistances beginning early in the course of AD (41, 42), it is plausible to hypothesize that…”
Background
Deletion of serine racemase reverses neuronal insulin signaling inhibition by amyloid‐β oligomers
Zhou, J., Zhang, Z., yang, Y., Liao, F., Zhou, P., Wang, Y., Zhang, H., Jiang, H., Alinejad, T., Shan, G., et al. (2022) · Journal of Neurochemistry · doi:10.1111/jnc.15664 · Cited by 5
“For example, insulin, insulin- like growth factors, and their receptors are reduced relative to levels in aged control brains (Rivera et al., 2005; Steen et al., 2005).”
Background
Common and rare variants of EGF increase the genetic risk of Alzheimer's disease as revealed by targeted sequencing of growth factors in Han Chinese
Li, X., Xu, M., Bi, R., Tan, L., Yao, Y., & Zhang, D. (2022) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2022.10.009 · Cited by 5
The identities of insulin signaling pathway are affected by overexpression of Tau and its phosphorylation form
Ma, N., Liang, Y., Yue, L., Liu, P., Xu, Y., & Zhu, C. (2022) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2022.1057281 · Cited by 6
Insulin Resistance, Cognitive Impairment and Neurodegeneration: Roles of Nitrosamine Exposure, Diet and Lifestyles
de la Monte, S., Tong, M., & Jack, R. (2011) · InTech eBooks · doi:10.5772/17682 · Cited by 5
Alzheimer's Disease: From Animal Models to the Human Syndrome
Orta‐Salazar, E., Vargas-Rodríguez, I., Castro-Chavira, S. A., Feria‐Velasco, A., & Díaz-Cintra, S. Y. (2016) · InTech eBooks · doi:10.5772/64619 · Cited by 6
“proposed that chronic deficits in insulin signaling mediate the pathogenesis of AD [96].”
Background
The relationship between polyneuropathy and cognitive functions in type 2 Diabetes Mellitus patients
Timer, S. M. (2018) · SiSli Etfal Hastanesi Tip Bulteni / The Medical Bulletin of Sisli Hospital · doi:10.14744/semb.2018.37929 · Cited by 5
Traumatic brain injury as a precursor to neurodegenerative diseases: Mechanisms linking TBI to Alzheimer’s disease
Bamel, K., Panwar, A., Kumar, M., Kumar, S., Sharma, V., & Sharma, A. K. (2025) · Brain Disorders · doi:10.1016/j.dscb.2025.100232 · Cited by 5
Influence of metabolic stress and metformin on synaptic protein profile in SH‐SY5Y‐derived neurons
Yang, A. J. T., Mohammad, A., Finch, M. S., Tsiani, E., Spencer, G. E., Necakov, A., & MacPherson, R. E. K. (2023) · Physiological Reports · doi:10.14814/phy2.15852 · Cited by 3
“Early reports examining post-mortem AD brains, describe impaired insulin binding (Rivera et al., 2005), reduced insulin receptor content (Steen et al., 2005), and increased inhibitory phosphorylation of various serine sites of IRS-1 (Moloney et al., 2010).”
Background
Plasma Insulin Predicts Early Amyloid-β Pathology Changes in Alzheimer’s Disease
Chen, Y., Initiative, A. D. N., Wang, Z.-B., Liu, X., & Mao, Z. (2024) · Journal of Alzheimer s Disease · doi:10.3233/jad-240289 · Cited by 4
“Autopsy studies have shown that reduced insulin and IR in AD brains are associated with neuropathology [17], particularly in the hippocampus and cerebellar cortex, which is inversely correlated with cognitive function [18].”
Potential role of tanycyte-derived neurogenesis in Alzheimer’s disease
Qi, G., Tang, H., Hu, J., Kang, S., & Qin, S. (2024) · Neural Regeneration Research · doi:10.4103/nrr.nrr-d-23-01865 · Cited by 7
The Associations Between Serum Insulin-like Growth Factor-I, Brain White Matter Volumes, and Cognition in Mild Cognitive Impairment and Alzheimer’s Disease
Horváth, A., Quinlan, P. S., Eckerström, C., Åberg, N. D., Wallin, A., & Svensson, J. (2024) · Journal of Alzheimer s Disease · doi:10.3233/jad-231026 · Cited by 4
“IGF-I in the brain is derived from passage from the circulation across the blood-brain barrier (BBB) [2] or by local IGF-I production [3].”
Background
Role of stereotaxically injected IgG from db/db mice in the phosphorylation of the microtubule-associated protein tau in hippocampus
Shuai, H., Zhang, J., Zhang, J., Xie, J., Zhang, M., Ma, J., Zhang, L., & Wang, X. (2012) · Brain Research · doi:10.1016/j.brainres.2012.08.049 · Cited by 4
Type 2 Diabetes, Obesity, and Risk for Dementia: Recent Insights into Brain Insulin Resistance and Hypometabolism
Hugenschmidt, C. E. (2016) · Current Behavioral Neuroscience Reports · doi:10.1007/s40473-016-0093-2 · Cited by 4
Neurocognitive impairment in patients with comorbid diabetes mellitus and depression
Padilla, V. L., Rustad, J. K., Harvey, P. D., Wasserman, B., Ziemer, D. C., & Musselman, D. L. (2017) · Personalized Medicine in Psychiatry · doi:10.1016/j.pmip.2016.12.004 · Cited by 4
A transient insulin system dysfunction in newborn rat brain followed by neonatal intracerebroventricular administration of streptozotocin could be accompanied by a labile cognitive impairment
Abbasi, Z., Rassouli, F. B., Seno, M. M. G., & Fereidoni, M. (2017) · Neuroscience Research · doi:10.1016/j.neures.2017.10.003 · Cited by 4
Insulin-Like Growth Factor-II and Ischemic Stroke—A Prospective Observational Study
Åberg, D., Åberg, N. D., Jood, K., Redfors, P., Blomstrand, C., Isgaard, J., Jern, C., & Svensson, J. (2021) · Life · doi:10.3390/life11060499 · Cited by 4
“IGF-I and IGF-II are mainly produced in the liver [3], but there is also production in other tissues including the CNS, most prominently in neurons [4,5].”
Background
Low Serum Insulin-like Growth Factor-I Is Associated with Decline in Hippocampal Volume in Stable Mild Cognitive Impairment but not in Alzheimer’s Disease
Horváth, A., Quinlan, P. S., Eckerström, C., Åberg, N. D., Wallin, A., & Svensson, J. (2022) · Journal of Alzheimer s Disease · doi:10.3233/jad-220292 · Cited by 4
“In the postmortem human brain free from neurological diseases, the distribution of IGF-IRs was greater in the hippocampus compared with other brain regions [51].”
BackgroundInfluential
Retracted Article: The interaction between insulin resistance and Alzheimer’s disease: a review article
Albar, N. Y., Hassaballa, H., Shikh, H., Albar, Y., Ibrahim, A. S., Mousa, A. H., Alshanberi, A. M., Elgebaly, A. S., & Bahbah, E. I. (2024) · Postgraduate Medicine · doi:10.1080/00325481.2024.2360887 · Cited by 4
“The disease has also been linked to diminished neurotransmitter levels like acetylcholine, norepinephrine, and dopamine [9,10].”
Background
Retracted
Nutrition and Dementia
Coppedè, F., Bosco, P., Fuso, A., & Troen, A. M. (2012) · Current Gerontology and Geriatrics Research · doi:10.1155/2012/926082 · Cited by 5
“The expression of the IR and the IGF-1R was reduced in brains of AD patients [84, 85], whereas increased IGF-1 serum levels were detected [85, 86].”
Background
Preliminary use of insulin-like growth factor-I as a biomarker for sorting high-dose donepezil responders among Japanese patients with Alzheimer's disease
Yamagata, B., Watanabe, T., Tomioka, H., Kobayashi, H., Nakano, Y., & Mimura, M. (2010) · Regulatory Peptides · doi:10.1016/j.regpep.2010.04.010 · Cited by 4
Association between insulin and executive functioning in alcohol dependence: a pilot study
Han, C., Bae, H., Won, S.-D., Lim, J., & Kim, D. (2015) · Neuropsychiatric Disease and Treatment · doi:10.2147/ndt.s92029 · Cited by 4
“In particular, patients with Alzheimer’s disease often experience insulin resistance and severe neurodegeneration in conjunction with declining insulin level.(31) However, when brain insulin levels increase, cognitive functions improve.”
Background
Metabolic Syndrome as a Risk Factor for Alzheimer Disease
Farooqui, A. A. (2013) · Springer eBooks · doi:10.1007/978-1-4614-7318-3_8 · Cited by 5
Caloric Restriction and Cardiovascular Disease
Csiszár, A., de Cabo, R., & Ungvari, Z. I. (2010) · Springer eBooks · doi:10.1007/978-90-481-8556-6_15 · Cited by 4
Cardiac Aging
Dai, D., Chiao, Y. A., Wessells, R. J., Bodmer, R., Szeto, H. H., & Rabinovitch, P. S. (2015) · Elsevier eBooks · doi:10.1016/b978-0-12-411596-5.00017-4 · Cited by 4
Exercise and its beneficial impacts on mood disorders and neurodegeneration: a novel mechanistic perspective of the exosomes involvement
Wang, J., Fan, S., & Wang, J. (2025) · Molecular and Cellular Biochemistry · doi:10.1007/s11010-025-05357-1 · Cited by 3
Phytochemicals in Life Style Associated Human Diseases
Verma, H., Gangwar, P., Yadav, A., Yadav, B., Rao, R., Kumari, S., Kaur, S., Dhiman, M., & Mantha, A. K. (2025) · Advances in Science, Technology & Innovation/Advances in science, technology & innovation · doi:10.1007/978-3-031-80973-6_19 · Cited by 3
Oral–Gut Microbiota Crosstalk and Epigenetic Targets in Metabolic and Neuropsychiatric Diseases
Mostafavi, S., Nohesara, S., Pirani, A., Abdolmaleky, H. M., & Thiagalingam, S. (2025) · Nutrients · doi:10.3390/nu17213367 · Cited by 5
The impact of insulin resistance on cognitive impairment and cerebrospinal fluid biomarkers in Alzheimer's disease
Giuffrè, G. M., Scalese, A., QUARANTA, D., Donnarumma, F., Vita, M. G., Carrozza, C., Rossini, P. M., Calabresi, P., & Marra, C. (2026) · Neurobiology of Disease · doi:10.1016/j.nbd.2026.107352 · Cited by 3
Brain insulin resistance as a driver of proteinopathy in neurodegeneration: from cell-type-specific mechanisms to targeted therapeutics
Xiang, M., Cao, S.-Y., Sun, X.-H., Hu, J.-W., Lv, M., Li, J., & Li, W. (2026) · Translational Neurodegeneration · doi:10.1186/s40035-026-00573-1 · Cited by 3
“Cortical pyramidal neurons show progressive impairment of insulin signaling, correlating with Braak stage in postmortem AD brains, suggesting that BIR may propagate along neuroanatomical pathways in parallel with proteinopathy spread [49].”
PKC and Insulin Pathways in Memory Storage: Targets for Synaptogenesis, Anti-apoptosis, and the Treatment of AD
Sun, M., Nelson, T. J., & Alkon, D. L. (2010) · Research and perspectives in Alzheimer's disease · doi:10.1007/978-3-642-04300-0_10 · Cited by 3
Diabetic Ketoacidosis Induces Tau Hyperphosphorylation in Rat Brain
Basurto‐Islas, G., Tung, Y. C., Dai, C., Iqbal, K., & Gong, C. (2024) · Journal of Alzheimer s Disease Reports · doi:10.3233/adr-240040 · Cited by 3
ApoE2 affects insulin signaling in the hippocampus and spatial cognition of aged mice in a sex-dependent manner
Wang, Y., Liu, H., Ye, Y., Fang, W., Lin, A., Dai, X., Ye, Q., Chen, X., & Zhang, J. (2025) · Cell Communication and Signaling · doi:10.1186/s12964-025-02093-3 · Cited by 4
“Notably, Aβ competes with insulin for binding to the insulin receptor (IR), significantly decreasing the binding efficiency of insulin to IR [20].”
Alterations in cerebral perfusion and substrate metabolism in type 2 diabetes: interactions with APOE-ε4
Schain, M., Johansson, E., Laitinen, I., Löwenmark, A. F., Lubberink, M., Gummesson, A., Danfors, T., Nuutila, P., ESTERLINE, R. L., Johansson, L., et al. (2025) · Diabetologia · doi:10.1007/s00125-025-06405-7 · Cited by 4
“It also functions as a precursor for acetylcholine, a neurotransmitter hypothesised to be involved in the association between type 2 diabetes and Alzheimer’s disease [17].”
Cerebrospinal fluid soluble insulin receptor levels in Alzheimer's disease
Thomas, P., Leclerc, M., Evitts, K. M., Brown, C., Miller, W., Hanson, A. J., Banks, W. A., Gibbons, L. E., Domoto‐Reilly, K., Jayadev, S., et al. (2024) · Alzheimer s & Dementia Diagnosis Assessment & Disease Monitoring · doi:10.1002/dad2.12603 · Cited by 2
Mini Review: the non-neuronal cardiac cholinergic system in type-2 diabetes mellitus
Saw, E. L., Fronius, M., Katare, R., & Kakinuma, Y. (2024) · Frontiers in Cardiovascular Medicine · doi:10.3389/fcvm.2024.1425534 · Cited by 3
Primate-specific 82-kDa choline acetyltransferase attenuates progression of Alzheimer’s disease-like pathology in the APPNL-G-F knock-in mouse model
AlQot, H. E., & Rylett, R. J. (2024) · Scientific Reports · doi:10.1038/s41598-024-78751-2 · Cited by 5
“AD 31,32 .”
A Neonatal Mild Defect in Brain Insulin Signaling Predisposes a Subclinical Model of Sporadic Alzheimer's to Develop the Disease
Abbasi, Z., Seno, M. M. G., & Fereidoni, M. (2021) · Journal of Molecular Neuroscience · doi:10.1007/s12031-021-01797-8 · Cited by 3
Neurochemical Aspects of Neurodegenerative Diseases
Farooqui, A. A. (2010) · Springer eBooks · doi:10.1007/978-1-4419-6652-0_8 · Cited by 3
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Ghareeb, D. A., Mohamed, S. K., & El-Sayed, M. (2013) · Journal of Biomedical Science and Engineering · doi:10.4236/jbise.2013.67093 · Cited by 5
“with an ACh decrease in the brain [131].”
Background
Insulin Resistance: A Bridge between T2DM and Alzheimer’s Disease
Giacomazza, D., & Carlo, M. D. (2013) · Journal of Diabetes & Metabolism · doi:10.4172/2155-6156.1000263 · Cited by 3
“On the basis of the large number of observations, since the first years of the XXI century, T2DM has been identified as a risk factor for Alzheimer’s disease (AD) [12-17].”
Background
Is there a role fordiet in cognitive rehabilitation?
Parrott, M. D., & Greenwood, C. E. (2008) · Cambridge University Press eBooks · doi:10.1017/cbo9781316529898.020 · Cited by 3
Role of Hypertension and Hyperlipidemia in the Pathogenesis of Dementia
Kaira, M., Walia, V., & Garg, M. (2022) · Springer eBooks · doi:10.1007/978-981-16-7606-2_10 · Cited by 3

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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