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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“Additionally, postmortem investigations have revealed a decreased expression of cerebral IGF-I receptor in brains with different Braak stage severities of AD (Rivera et al., 2005).”
Background
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Background
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Background
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“…increased phosphorylation of the microtubule-associated protein tau by loss of sensitivity towards insulin and IGF-I (Carro and Torres-Aleman 2004; Rivera et al. 2005; Schubert et al. 2004), suggesting that impaired brain insulin/IGF signaling leads to aberrant tau hyperphosphorylation (Bhat and…”
BackgroundInfluential
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“Alzheimer's disease has also been associated with decreased insulin concentrations, abnormal insulin receptor function, and density in the brain (Frölich, BlumDegen, Riederer, &Hoyer, 1999; Rivera et al., 2005; Steen et al., 2005).”
Background
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“Subsequently, Rivera and colleagues demonstrated that alterations in insulin and IGF-I signaling promote brain deﬁciencies in acetylcholine biosynthesis [411].”
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Background
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“This is supported by a body of evidence such as decreased level of insulin and its receptor in the brain, de-sensitization of insulin receptor, and decreased levels and impaired functions of downstream components of the insulin signaling pathway in the AD brain (12 – 15).”
Background
Alzheimer disease and cognitive impairment associated with diabetes mellitus type 2: associations and a hypothesis
Domínguez, R. O., Pagano, M. A., Marschoff, E., González, S., Repetto, M. G., & Serra, J. A. (2014) · Neurología (English Edition) · doi:10.1016/j.nrleng.2014.10.001 · Cited by 37
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Background
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“Correction of insulin levels in AD subjects has also been correlated with improved cognition [31, 32].”
Background
Zebrafish models of diabetes-related CNS pathogenesis
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“However, recent work by De La Monte and colleagues has supported that insulin produced in the brain plays a central role in insulin signaling in the central nervous system [23,67,68].”
Background
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“Meanwhile, Rivera EJ reported that the expression level of IGF-2 was also reduced in AD brains (Rivera et al., 2005).”
Background
Loss of insulin‐like growth factor‐1 signaling in astrocytes disrupts glutamate handling
Prabhu, D., Khan, S. M., Blackburn, K., Marshall, J. P. S., & Ashpole, N. M. (2019) · Journal of Neurochemistry · doi:10.1111/jnc.14879 · Cited by 33
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“As mice age, they show reduced expression of genes in the IGF-1 pathway in various tissues((89)) and develop resistance to IGF-1.((90,91)) Moreover, aging humans show attenuation of the somatotropic axis as GH and IGF-1 serum levels are reduced with increasing age.”
Background
Coexistences of insulin signaling-related proteins and choline acetyltransferase in neurons
Wang, H., Wang, R., Zhao, Z., Ji, Z., Xu, S., Hölscher, C., & Sheng, S. (2008) · Brain Research · doi:10.1016/j.brainres.2008.10.046 · Cited by 33
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“Furthermore, it has been demonstrated that brain ChAT activity levels are significantly lowered in AD patients and that these reductions correlate with disease severity [24].”
Background
Differential Contributions of Alcohol and the Nicotine-Derived Nitrosamine Ketone (NNK) to Insulin and Insulin-Like Growth Factor Resistance in the Adolescent Rat Brain
Tong, M., Yu, R., Deochand, C., & de la Monte, S. M. (2015) · Alcohol and Alcoholism · doi:10.1093/alcalc/agv101 · Cited by 32
“This concept has further relevance with respect to Alzheimer’s disease, which also is associated with impairments in brain insulin/IGF signaling (Hoyer, 1994; Rivera et al., 2005; Steen et al., 2005; Tong et al., 2009a), yet the risk of dementia is increased by smoking (Durazzo et al., 2014).”
Background
Regional mitochondrial DNA and cell-type changes in post-mortem brains of non-diabetic Alzheimer’s disease are not present in diabetic Alzheimer’s disease
Thubron, E. B., Rosa, H. S., Hodges, A., Sivaprasad, S., Francis, P. T., Pienaar, I. S., & Malik, A. N. (2019) · Scientific Reports · doi:10.1038/s41598-019-47783-4 · Cited by 32
Dicholine salt of succinic acid, a neuronal insulin sensitizer, ameliorates cognitive deficits in rodent models of normal aging, chronic cerebral hypoperfusion, and beta-amyloid peptide-(25–35)-induced amnesia
Storozheva, Z. I., Proshin, A. T., Sherstnev, V. V., Storozhevykh, T. P., Senilova, Y. E., Александровна, П. Н., Pinelis, V. G., Семенова, Н. А., Zakharova, E. I., & Анатольевич, П. И. (2008) · BMC Pharmacology · doi:10.1186/1471-2210-8-1 · Cited by 32
“Activity of choline acetyltransferase, a key enzyme of acetylcholine biosynthesis, is reduced in insulin receptor-positive neurons in Alzheimer's disease and expression of choline acetyltransferase is increased with insulin stimulation [54].”
Background
Reduced TNF-α and increased IGF-I levels in the serum of Alzheimer's disease patients treated with the neurotrophic agent Cerebrolysin
Alvarez, X. A., Sampedro, C., Cacabelos, R., Linares, C., Aleixandre, M., García-Fantini, M., & Moessler, H. (2009) · The International Journal of Neuropsychopharmacology · doi:10.1017/s1461145709990101 · Cited by 32
“TNF-a overexpression in AD brains, cerebrospinal fluid and serum, as well as decreased serum levels and brain gene expression of IGF-I have been found in AD patients (Alvarez et al. 2007; Del Villar & Miller, 2004; Rivera et al. 2005).”
BackgroundMethod
The Role of Insulin and Insulin-Like Growth Factor-1/FoxO-Mediated Transcription for the Pathogenesis of Obesity-Associated Dementia
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“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
Early Intranasal Insulin Therapy Halts Progression of Neurodegeneration: Progress in Alzheimer’s Disease Therapeutics
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“In addition to forwarding research on a newer and probably less costly approach to treatment, the study builds on the emerging concept that AD is fundamentally mediated by progressive brain insulin deficiency and resistance (4, 5).”
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“, 2010) with alterations in both the levels and phosphorylation state of IGF-I receptor (IGF-IR) as well as the levels and distribution of IGF-I and IGF-IR mRNA in the brain (Rivera et al., 2005; Steen et al., 2005).”
Background
Focus on the Correlations between Alzheimer’s Disease and Type 2 Diabetes
Fiore, V., Rosa, A. D., Falasca, P., Marci, M., Guastamacchia, E., Licchelli, B., Giagulli, V. A., Pergola, G. D., Poggi, A., & Triggiani, V. (2019) · Endocrine Metabolic & Immune Disorders - Drug Targets · doi:10.2174/1871530319666190311141855 · Cited by 32
“Furthermore, hyperinsulinemia increases SPs and NFT deposits, that can competitively inhibit the binding of insulin to the IR [75-76], causing further insulin resistance.”
Background
Unwinding Complexities of Diabetic Alzheimer by Potent Novel Molecules
Gupta, S., Nair, A. B., Jhawat, V., Mustaq, N., Sharma, A., Dhanawat, M., & Khan, S. A. (2020) · American Journal of Alzheimer s Disease & Other Dementias® · doi:10.1177/1533317520937542 · Cited by 33
“This secreted protein travels with insulin through the bloodstream and gets deposited in the brains of the people having type 2 diabetes mellitus which was similar to patients with Alzheimer.”
BackgroundInfluential
Tobacco Smoke Exposure Impairs Brain Insulin/IGF Signaling: Potential Co-Factor Role in Neurodegeneration
Deochand, C., Tong, M., Agarwal, A., Cadenas, E., & de la Monte, S. M. (2016) · Journal of Alzheimer s Disease · doi:10.3233/jad-150664 · Cited by 30
“accumulation are early abnormalities in AD [34], the”
Shared Molecular Mechanisms among Alzheimer’s Disease, Neurovascular Unit Dysfunction and Vascular Risk Factors: A Narrative Review
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Background
GLP-1 Analogs, SGLT-2, and DPP-4 Inhibitors: A Triad of Hope for Alzheimer’s Disease Therapy
Złotek, M., Kurowska, A., Herbet, M., & Piątkowska‐Chmiel, I. (2023) · Biomedicines · doi:10.3390/biomedicines11113035 · Cited by 30
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Growth factor treatment to overcome Alzheimer's dysfunctional signaling
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“Indeed, AD patients show reduced brain insulin receptor sensitivity (Rivera et al., 2005; Talbot et al., 2012), hypophosphorylation of the insulin receptor and downstream second messengers such as IRS-1 (Steen et al.”
Background
Dementia, stroke and migraine — Some common pathological mechanisms
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Association between exenatide use and incidence of Alzheimer's disease
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Potential Roles of Glucagon-Like Peptide-1 and Its Analogues in Dementia Targeting Impaired Insulin Secretion and Neurodegeneration
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“Compared to age-matched controls, patients with memory impairment had lower CSF insulin, impaired insulin-like signal transduction, insufficient brain insulin and insulin-like growth factor I expression and function, 44 and impaired glucose metabolism.”
IGF-1 promotes β-amyloid production by a secretase-independent mechanism
Araki, W., Kume, H., Oda, A., Tamaoka, A., & Kametani, F. (2009) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2009.01.044 · Cited by 29
Retardation of fetal dendritic development induced by gestational hyperglycemia is associated with brain insulin/IGF‐I signals
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“Generally, insulin regulates glucose metabolism, whereas IGF-I exhibits the features of trophic factors (Cole and Frautschy, 2007; Rivera et al., 2005).”
Background
When aging-onset diabetes is coming across with Alzheimer disease: Comparable pathogenesis and therapy
Tang, J., Pei, Y., & Zhou, G. (2013) · Experimental Gerontology · doi:10.1016/j.exger.2013.04.013 · Cited by 28
“In recent years, it has been accepted that AD is also a degenerative metabolic disease where the brain glucose uptake and utilization are impaired (Rivera et al., 2005).”
Altered expression of insulin‐degrading enzyme and regulator of calcineurin in the rat intracerebral streptozotocin model and human apolipoprotein E‐ε4–associated Alzheimer's disease
Delikkaya, B., Moriel, N., Tong, M., Gallucci, G. M., & de la Monte, S. M. (2019) · Alzheimer s & Dementia Diagnosis Assessment & Disease Monitoring · doi:10.1016/j.dadm.2019.03.004 · Cited by 29
“The progressive declines in brain expression of genes and proteins required for insulin signaling as well as evidence for increased insulin resistance with severity of AD led to the concept that AD is a form of brain diabetes mellitus, that is, type 3 diabetes [6,7].”
BackgroundInfluential
Acteoside‐improved streptozotocin‐induced learning and memory impairment by upregulating hippocampal insulin, glucose transport, and energy metabolism
Chen, J., Gao, L., Zhang, Y., Su, Y., Kong, Z., Wang, D., & Yan, M. (2020) · Phytotherapy Research · doi:10.1002/ptr.6811 · Cited by 28
“In the current study, the expression and functionality of insulin and its receptor were found to be depleted significantly in the ICV-STZ model, which might be the outcome of reduced acetylcholine level in the brain (Rivera et al., 2005).”
Background
Islet amyloid polypeptide & amyloid beta peptide roles in Alzheimer’s disease: two triggers, one disease
Menezes, R., Martins, I. C., Ferreira, S., & Raimundo, A. (2020) · Neural Regeneration Research · doi:10.4103/1673-5374.300323 · Cited by 29
“For instance, a brain that lost the ability to respond to glucose, insulin and/ or insulin-like growth factor (IGF), can easily suffer neuronal loss (Rivera et al., 2005).”
Role of aspartyl-(asparaginyl)-β-hydroxylase mediated notch signaling in cerebellar development and function
Silbermann, E., Moskal, P., Bowling, N., Tong, M., & de la Monte, S. M. (2010) · Behavioral and Brain Functions · doi:10.1186/1744-9081-6-68 · Cited by 28
“In previous studies, we used this approach to characterize cell loss and cell type shifts associated with disease states [30,35,36].”
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“tylcholine esterase did not change (Rivera et al., 2005).”
Thyroid hormone improves insulin signaling and reduces the activation of neurodegenerative pathway in the hippocampus of diabetic adult male rats
Prieto-Almeida, F., Panveloski-Costa, A. C., Crunfli, F., Teixeira, S. D. S., Nunes, M. T., & Torrão, A. D. S. (2017) · Life Sciences · doi:10.1016/j.lfs.2017.11.013 · Cited by 27
Intranasal Insulin: a Treatment Strategy for Addiction
Kashyap, B., Hanson, L. R., & Frey, W. H. (2020) · Neurotherapeutics · doi:10.1007/s13311-019-00822-4 · Cited by 27
“Systems with impaired insulin signaling pathways have demonstrated inhibition of acetylcholine biosynthesis and subsequently have incurred debilitating effects on neuronal plasticity [173, 174].”
Background
Gold nanoparticle-enhanced X-ray microtomography of the rodent reveals region-specific cerebrospinal fluid circulation in the brain
Pan, S., Yang, P. H., DeFreitas, D., Ramagiri, S., Bayguinov, P. O., Hacker, C. D., Snyder, A. Z., Wilborn, J., Huang, H., Koller, G. M., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-36083-1 · Cited by 26
Malignant Brain Aging: The Formidable Link Between Dysregulated Signaling Through Mechanistic Target of Rapamycin Pathways and Alzheimer’s Disease (Type 3 Diabetes)
de la Monte, S. M. (2023) · Journal of Alzheimer s Disease · doi:10.3233/jad-230555 · Cited by 28
“…is associated with signiﬁcant impairments in brain glucose utilization [153, 167, 168], energy metabolism, trophic factor expression and responsiveness, and signal transduction networks stemming from the insulin and IGF-1 receptors and extending downstream through PI3K-Akt pathways [154, 162, 169].”
Influential
Different Approaches, One Target: Understanding Cellular Mechanisms of Parkinson's and Alzheimer's Diseases
Torrão, A. D. S., Café-Mendes, C. C., Real, C. C., Hernandes, M. S., Ferreira, A. F. B., Santos, T. O., Chaves-Kirsten, G. P., Mazucanti, C. H., Ferro, E. S., Scavone, C., et al. (2012) · Brazilian Journal of Psychiatry · doi:10.1016/j.rbp.2012.08.004 · Cited by 27
Insulin and IGF-I prevent brain atrophy and DNA loss in diabetes
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“Postmortem LOAD brains reveal a progressive decline in insulin and IR, as well as IGF and IGF-I receptor, mRNA levels (Rivera et al., 2005).”
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The Ames dwarf mutation attenuates Alzheimer's disease phenotype of APP/PS1 mice
Puig, K. L., Kulas, J. A., Franklin, W. F., Rakoczy, S. G., Taglialatela, G., Brown‐Borg, H. M., & Combs, C. K. (2016) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2015.12.021 · Cited by 31
Cognitive impairment in patients with type 2 diabetes mellitus: prevalence, pathogenetic mechanisms, the effect of antidiabetic drugs
Ostroumova, O. D., Surkova, E. V., Chikh, E. V., Rebrova, E. V., & Borisov, M. S. (2018) · Diabetes Mellitus · doi:10.14341/dm9660 · Cited by 29
Low serum insulin-like growth factor-I (IGF-I) level is associated with increased risk of vascular dementia
Quinlan, P. S., Horváth, A., Nordlund, A., Wallin, A., & Svensson, J. (2017) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2017.09.018 · Cited by 27
Selenothymidine protects against biochemical and behavioral alterations induced by ICV-STZ model of dementia in mice
Thomé, G. R., Oliveira, V. A., Schetinger, M. R. C., Saraiva, R. D. A., de Souza, D., Rodrigues, O. E. D., da Rocha, J. B. T., Ineu, R. P., & Pereira, M. E. (2018) · Chemico-Biological Interactions · doi:10.1016/j.cbi.2018.08.004 · Cited by 26
Altered Brain Expression of Insulin and Insulin-Like Growth Factors in Frontotemporal Lobar Degeneration: Another Degenerative Disease Linked to Dysregulation of Insulin Metabolic Pathways
Liou, C. J., Tong, M., Vonsattel, J. P., & de la Monte, S. M. (2019) · ASN NEURO · doi:10.1177/1759091419839515 · Cited by 26
“On the other hand, consideration should be given to the rapidly growing literature supporting roles for insulin and insulin-like growth factor (IGF)-linked metabolic derangements, stress, and neuroinflammatory responses as mediators of AD and DLBD/Parkinson’s disease (PD; Mattson et al., 1999; Blass et al., 2002; Rive…”
BackgroundInfluential
Growth Hormone and Neuronal Hemoglobin in the Brain—Roles in Neuroprotection and Neurodegenerative Diseases
Walser, M., Svensson, J., Karlsson, L., Motalleb, R., Åberg, M., Kuhn, H. G., Isgaard, J., & Åberg, N. D. (2021) · Frontiers in Endocrinology · doi:10.3389/fendo.2020.606089 · Cited by 26
“Post-mortem studies have shown reduced IGF-I gene expression in AD brains (158, 159), and this was accompanied by resistance to signaling through the IGF-I receptor (158, 159).”
Background
Impact of Genetic Risk Factors for Alzheimer’s Disease on Brain Glucose Metabolism
Cho, S., Lee, H., & Seo, J. (2021) · Molecular Neurobiology · doi:10.1007/s12035-021-02297-x · Cited by 25
Sukkari dates seed improves type-2 diabetes mellitus-induced memory impairment by reducing blood glucose levels and enhancing brain cholinergic transmission: In vivo and molecular modeling studies
Mani, V., Arfeen, M., Mohammed, H. A., Elsisi, H. A., Sajid, S., Almogbel, Y. S., Aldubayan, M. A., Dhanasekaran, M., & Alhowail, A. H. (2022) · Saudi Pharmaceutical Journal · doi:10.1016/j.jsps.2022.03.016 · Cited by 28
Knowing Me, Knowing You: Can a Knowledge of Risk Factors for Alzheimer's Disease Prove Useful in Understanding the Pathogenesis of Parkinson's Disease?
Sutherland, G. T., Siebert, G. A., Kril, J. J., & Mellick, G. D. (2011) · Journal of Alzheimer s Disease · doi:10.3233/jad-2011-110026 · Cited by 26
“This may reflect defective insulin signaling [139], a factor that appears to result in the abnormal phosphorylation of tau [140].”
Background
Alzheimers Disease, Ceramide, Visfatin and NAD
Adams, J. D., Jr. (2008) · CNS & Neurological Disorders - Drug Targets · doi:10.2174/187152708787122969 · Cited by 26
“Recent evidence suggests that Alzheimer’s disease may be a brain specific form of diabetes [8].”
Background
Quantitative Expression Analysis of APP Pathway and Tau Phosphorylation-Related Genes in the ICV STZ-Induced Non-Human Primate Model of Sporadic Alzheimer’s Disease
Park, S.-J., Kim, Y.-H., Nam, G.-H., Choe, S.-H., Lee, S., Kim, S., Kim, J., Sim, B., Song, B., Jeong, K.-J., et al. (2015) · International Journal of Molecular Sciences · doi:10.3390/ijms16022386 · Cited by 26
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Glaucoma – Diabetes of the brain: A radical hypothesis about its nature and pathogenesis
Faiq, M. A., Dada, R., Saluja, D., & Dada, T. (2014) · Medical Hypotheses · doi:10.1016/j.mehy.2014.02.005 · Cited by 27
“[137,138,209,214] and improvement in cognitive function by use of insulin sensitizers and intranasal insulin has also been reported”
BackgroundInfluential
Alternations of central insulin‐like growth factor‐1 sensitivity in APP/PS1 transgenic mice and neuronal models
Zhang, B., Tang, X. C., & Zhang, H. (2013) · Journal of Neuroscience Research · doi:10.1002/jnr.23201 · Cited by 26
“It has been reported that mRNA levels of IGF-1 were significantly decreased in the brain of severe AD patients, whereas serum IGF-1 levels were increased in early stages of the disease (Rivera et al., 2005; Vardy et al., 2007).”
Background
DPP4 Inhibitors Can Be a Drug of Choice for Type 3 Diabetes: A Mini Review
Chalichem, N. S. S., Gonugunta, C., Krishnamurthy, P. T., & Basavan, D. (2017) · American Journal of Alzheimer s Disease & Other Dementias® · doi:10.1177/1533317517722005 · Cited by 26
Therapeutic Advantages of Dual Targeting of PPAR-δ and PPAR-γ in an Experimental Model of Sporadic Alzheimer’s Disease
Reich, D., Gallucci, G. M., Tong, M., & de la Monte, S. M. (2018) · Journal of Parkinson’s Disease and Alzheimer’s Disease · doi:10.13188/2376-922x.1000025 · Cited by 26
“Previous studies using the same model showed that i.c. causes neurodegeneration with brain insulin resistance accompanied by impaired signaling downstream through PI3K-Akt pathways [28,68-70].”
BackgroundInfluential
Intranasal Administration of KYCCSRK Peptide Rescues Brain Insulin Signaling Activation and Reduces Alzheimer’s Disease-like Neuropathology in a Mouse Model for Down Syndrome
Tramutola, A., Lanzillotta, S., Aceto, G., Pagnotta, S. E., Ruffolo, G., Cifelli, P., Marini, F., Ripoli, C., Palma, E., Grassi, C., et al. (2023) · Antioxidants · doi:10.3390/antiox12010111 · Cited by 27
“These abnormalities were negatively correlated with global cognition and memory scores regardless of Aβ and Tau levels [16], suggesting that brain insulin resistance contributes to cognitive impairment independently from AD neuropathology [15].”
Polyoxidovanadates a new therapeutic alternative for neurodegenerative and aging diseases
González‐Cano, S. I., Flores, G., Guevara, J., Morales‐Medina, J. C., Treviño, S., & Díaz, A. (2023) · Neural Regeneration Research · doi:10.4103/1673-5374.380877 · Cited by 26
“As neurodegenerative diseases progress, the insulin gene and the expression of IRS decrease significantly, establishing brain IR (Rivera et al., 2005; Sędzikowska and Szablewski, 2021).”
Background
Concordant and Discordant Cerebrospinal Fluid and Plasma Cytokine and Chemokine Responses in Mild Cognitive Impairment and Early-Stage Alzheimer’s Disease
de la Monte, S. M., Tong, M., & Hapel, A. J. (2023) · Biomedicines · doi:10.3390/biomedicines11092394 · Cited by 28
Pharmacological Approaches Using Diabetic Drugs Repurposed for Alzheimer’s Disease
Adem, M. A., Decourt, B., & Sabbagh, M. N. (2024) · Biomedicines · doi:10.3390/biomedicines12010099 · Cited by 30
“Additionally, studies have indicated that brain insulin resistance and insulin-like growth factor 1 (IGF-1) resistance both play a large role in the development of AD [70,71], earning it the name type 3 diabetes.”
Background
The Hypothalamus and β-Cell Connection in the Gene-Targeting Era
Schwartz, M. W., Guyenet, S. J., & Cirulli, V. (2010) · Diabetes · doi:10.2337/db10-1149 · Cited by 25
“This finding adds to a literature that strongly supports this conclusion despite papers that appear from time to time implying the opposite (most recently in the Alzheimer disease literature) (26).”
Result
Mini Review: Opposing Pathologies in Cancer and Alzheimer's Disease: Does the PI3K/Akt Pathway Provide Clues?
Barker, R. M., Holly, J. M. P., Biernacka, K. M., Allen, S. J., & Perks, C. M. (2020) · Frontiers in Endocrinology · doi:10.3389/fendo.2020.00403 · Cited by 25
“Reduced levels of insulin, IGF-I, II and their receptors associate with severity of pathology (19, 72).”
Background
Reprint of: ‘Brain insulin signaling: A key component of cognitive processes and a potential basis for cognitive impairment in type 2 diabetes’
McNay, E. C., & Recknagel, A. K. (2011) · Neurobiology of Learning and Memory · doi:10.1016/j.nlm.2011.11.001 · Cited by 26
Human brain organoids containing microglia that have arisen innately adapt to a β-amyloid challenge better than those in which microglia are integrated by co-culture
Wenzel, T. J., Desjarlais, J. D., & Mousseau, D. D. (2024) · Stem Cell Research & Therapy · doi:10.1186/s13287-024-03876-0 · Cited by 27
Conquering Insulin Network Dysfunctions in Alzheimer’s Disease: Where Are We Today?
de la Monte, S. M. (2024) · Journal of Alzheimer s Disease · doi:10.3233/jad-240069 · Cited by 28
“In AD, progressive declines in frontal and temporal lobe expression of all three trophic factors and their corresponding receptors correlate with Braak Stage severity of neurodegeneration [15], indicating that impaired insulin signaling is not the only neuroendocrine target in need of remediation.”
Neuron‐derived extracellular vesicles as a liquid biopsy for brain insulin dysregulation in Alzheimer's disease and related disorders
Cleary, J. A., Kumar, A., Craft, S., & Deep, G. (2025) · Alzheimer s & Dementia · doi:10.1002/alz.14497 · Cited by 25
The Link Between Nutrition and Alzheimer’s Disease: From Prevention to Treatment
Martins, L. B., Silveira, A. L. M., & Teixeira, A. L. (2021) · Neurodegenerative Disease Management · doi:10.2217/nmt-2020-0023 · Cited by 26

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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