Insulin resistance and Alzheimer's disease
Open accessAbstract
Emerging data demonstrate pivotal roles for brain insulin resistance and insulin deficiency as mediators of cognitive impairment and neurodegeneration, particularly Alzheimer's disease (AD). Insulin and insulin-like growth factors (IGFs) regulate neuronal survival, energy metabolism, and plasticity, which are required for learning and memory. Hence, endogenous brain-specific impairments in insulin and IGF signaling account for the majority of AD-associated abnormalities. However, a second major mechanism of cognitive impairment has been linked to obesity and Type 2 diabetes (T2DM). Human and experimental animal studies revealed that neurodegeneration associated with peripheral insulin resistance is likely effectuated via a liver-brain axis whereby toxic lipids, including ceramides, cross the blood brain barrier and cause brain insulin resistance, oxidative stress, neuro-inflammation, and cell death. In essence, there are dual mechanisms of brain insulin resistance leading to AD-type neurodegeneration: one mediated by endogenous, CNS factors; and the other, peripheral insulin resistance with excess cytotoxic ceramide production.
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Alterations in the insulin signaling pathway have been suggested as potential contributors to cognitive dysfunction.
“Alterations in the insulin signaling pathway have also been suggested as potential contributors to cognitive dysfunction because of the pivotal role of this hormone in modulating brain structure and function.[12][13][14]”
The obesity-induced toxic internal environment does not spare the brain.
“It is becoming clear that the obesity-induced toxic internal environment does not spare the brain ([24](#B24), [46](#B46), [48](#B48), [52](#B52), [59](#B59), [95](#B95), [121](#B121), [127](#B127), [177](#B177), [182](#B182), [198](#B198)).”
From Food reward, hyperphagia, and obesity (2011) · cites this paper as [46]
Insulin resistance, a hallmark of diabetes, develops in Alzheimer's brains.
“Recent evidence suggests that insulin resistance, a hallmark of diabetes, develops in Alzheimer’s brains (, 2000; Craft et al., 1999; de la Monte, 2009; Moroz et al., 2008; Pedersen and Flynn, 2004; Razay and Wilcock, 1994; Watson and Craft, 2003).”
From The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer’s disease (2011) · cites this paper as de la Monte, 2009
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- [52]Tong M Lawton M Neusner A Longato L Wands JR de la Monte SM Nitrosamine-mediated type 2 diabetes mellitus, hepatic steatosis, and alzheimer-type neurodegeneration: potential role of environmental exposures in our insulin resistance diseases pandemic J. Alzheimers. Dis 2009 (In Press)
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- Authors
- De La Monte, S. M.
- Venue
- BMB Reports
- Published
- 2009-08-31
- Volume
- 42
- Issue
- 8
- Pages
- 475-481
- ISSN
- 1976-6696 (ISSN-L)
- PMC
- PMC4600067
- OpenAlex
- W1963640549
- Cited by
- 392
- References
- 57
- Citations by year
- 2026: 7 · 2025: 11 · 2024: 17 · 2023: 23 · 2022: 29 · 2021: 22 · 2020: 22 · 2019: 21 · 2018: 20 · 2017: 24 · 2016: 25 · 2015: 36 · 2014: 24 · 2013: 23 · 2012: 39
- FWCI
- 3.22
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by-nc
- Locations
- BMB Reports (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (5r01aa011431-26)
- National Institute on Alcohol Abuse and Alcoholism (R01-AA011431, AA-12908, K24AA016126, AA-16126, AA11431, R56AA011431, R01AA012908, R37AA011431)
- Topics
- Health Sciences › Medicine › Physiology › 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
- brain insulin resistance, Alzheimer's disease, insulin-like growth factor, cognitive impairment, neurodegeneration, type 2 diabetes, obesity, liver-brain axis, ceramide, blood-brain barrier, oxidative stress, neuroinflammation, neuronal cell death, insulin signaling
- MeSH terms
- Alzheimer Disease, Animals, Brain, Humans, Insulin Resistance, Models, Biological, Somatomedins, Amyloid beta-Protein Precursor
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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