The DOI matches its Crossref record; 71 of the 71 references it cites were found in a registry or an index.
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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Steen, E., Terry, B. M., J. Rivera, E., Cannon, J. L., Neely, T. R., Tavares, R., Xu, X. J., Wands, J. R., & de la Monte, S. M. (2005) · Journal of Alzheimer's Disease · doi:10.3233/jad-2005-7107 · Cited by 1,703
Structure of the insulin receptor substrate IRS-1 defines a unique signal transduction protein
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“Significant P-values are indicated over the bar graphs. and ionized calcium-binding adaptor molecule 1 (IBA-1) to specifically detect neurons (Hu) [31–33], astrocytes (GFAP), or microglial cells (AIF1 and IBAI) [34, 35] (Table 2).”
Insulin-degrading Enzyme Regulates Extracellular Levels of Amyloid β-Protein by Degradation
Qiu, W. Q., Walsh, D. M., Ye, Z., Vekrellis, K., Zhang, J., Podlisny, M. B., Rosner, M. R., Safavi, A., Hersh, L. B., & Selkoe, D. J. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.49.32730 · Cited by 812
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Items 701–721 of 721
İNSÜLİN DİRENCİ VE ALZHEİMER HASTALIĞI ARASINDAKİ PATOJENİK BAĞLANTI: FARMAKOLOJİK MÜDAHALELER
Amin, A. M. (2025) · Ankara Universitesi Eczacilik Fakultesi Dergisi · doi:10.33483/jfpau.1487011
Khan, M. A., Aggarwal, J., Ahmad, M., & Verma, N. (2025) · Journal of Diabetology · doi:10.4103/jod.jod_229_24
Impact of oxidative stress on confluent diabetes and Alzheimer's disease
Ardhra, P. B., Thankachan, C., Devikrishna, P. R., Joshi, Y., & George, N. (2025) · Elsevier eBooks · doi:10.1016/b978-0-443-40559-4.00003-9
Epidemiology related to confluence of diabetes and Alzheimer
Yadav, P., & Singh, P. (2025) · Elsevier eBooks · doi:10.1016/b978-0-443-40559-4.00004-0
The Relationship between the IGF System, Nutrition, and Behavior
LEWITT, M. S. (2011) · Springer eBooks · doi:10.1007/978-0-387-92271-3_18
Wenzel, T. J., Desjarlais, J. D., & Mousseau, D. D. (2024) · Figshare · doi:10.6084/m9.figshare.26759543
Wu, H., He, L., & Li, D. (2026) · Mini-Reviews in Medicinal Chemistry · doi:10.2174/0113895575414424251128113543
ApoE, Obesity, and Metabolic Syndrome
Carvalho-Rassbach, M., & ALVAREZ-LEITE, J. I. (2025) · Springer eBooks · doi:10.1007/978-3-031-52641-1_27-1
Chen, Y.-J., Xie, M.-R., Zhu, Q.-Q., Zhou, S.-Q., Li, B., & Yuan, H. (2026) · Frontiers in Neurology · doi:10.3389/fneur.2026.1709559
Han, H., Hou, L., Lu, J., Sun, H., Ning, W., Liang, Y., Gu, Y., Yin, H., & Gao, Q. (2026) · Frontiers in Endocrinology · doi:10.3389/fendo.2026.1809245
Intranasal Drug Delivery in Treating Alzheimer’s Disease
Kumar, N., Nivatya, H. K., Singh, A. K., Sonam, Sharma, L., & Singh, V. (2026) · BENTHAM SCIENCE PUBLISHERS eBooks · doi:10.2174/9798898814953126010015
Mei, J., Xia, M., Peng, L., & Li, X. (2026) · The American Journal of Drug and Alcohol Abuse · doi:10.1080/00952990.2026.2645215
“Taken together, these studies suggest that depletion of neurotrophic factors may be a likely mechanism in the transition from alcohol exposure to neurodegeneration associated with AD and that restoring neurotrophic signaling may offer a therapeutic option (109, 110).”
ApoE, Obesity, and Metabolic Syndrome
Carvalho-Rassbach, M., & ALVAREZ-LEITE, J. I. (2026) · Springer eBooks · doi:10.1007/978-3-031-96089-5_27
Chen, J., Chen, X., Chen, T., & Hu, J. (2026) · Metabolites · doi:10.3390/metabo16060377
“Extensive studies have demonstrated that insulin resistance plays an important role in the onset and progression of AD [27–29].”
Venkei, Z. G., & Savelieff, M. G. (2026) · Exploration of neuroscience · doi:10.37349/en.2026.1006139
Gao, P., Su, J., Ma, X., Ma, X., Chen, Y., Shen, J., Wu, Y., Shi, C., & Li, J. (2026) · CNS Neuroscience & Therapeutics · doi:10.1002/cns.71044
“Another hypothesized mechanism involves the insulin-degrading enzyme (IDE) [27], which degrades A β and prevents the formation of senile plaques.”
Yue, S., Young, C., Garg, A., Sarovich, T., Chen, L., Dickerson, K., & Wang, Z.-J. (2026) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2026.1858227
“In the central nervous system (CNS), decreased IGF1 and IGF1R expressions have been reported in several brain regions of individuals with AD, including cortex, hippocampus and hypothalamus (Rivera et al., 2005; Steen et al., 2005).”
Jucha, J., Zając, D., Darasz, D., Łukawski, A., Slobozheniuk, L., Bieniak-Pentchev, M., Kaczorek, M., Machnik, K., Dziewięcka, O., & Ziębka, W. (2026) · International Journal of Innovative Technologies in Social Science · doi:10.31435/ijitss.3(51).2026.6010
Endocrine and diagnostic aspects of cognitive impairment
Johansson, P. (2013) · Gothenburg University Publications Electronic Archive (Gothenburg University)
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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