Insulin Resistance and Alzheimers Disease: Molecular Links & Clinical Implications
Abstract
Hyperinsulinemia as well as type II diabetes mellitus are among the risk factors for Alzheimer's disease (AD). However, the molecular and cellular basis that link insulin resistance disorders and diabetes with AD are far from clear. Here, we discuss the potential molecular mechanisms that may explain the participation of these metabolic disorders in the pathogenesis of AD. The human brain uses glucose as a primary fuel; insulin secreted by the pancreas cross the blood-brain barrier (BBB), reaching neurons and glial cells, and exerts a region-specific effect on glucose metabolism. Glucose homeostasis is critical for energy generation, neuronal maintenance, neurogenesis, neurotransmitter regulation, cell survival and synaptic plasticity. It also plays a key role in cognitive function. In an insulin resistance condition, there is a reduced sensitivity to insulin resulting in hyperinsulinemia; this condition persists for several years before becoming full-blown diabetes. Toxic levels of insulin negatively influence neuronal function and survival, and elevation of peripheral insulin concentration acutely increases its cerebrospinal fluid (CSF) concentration. Peripheral hyperinsulinemia correlates with an abnormal removal of the amyloid beta peptide (Abeta) and an increase of tau hyperphosphorylation as a result of augmented cdk5 and GSK3beta activities. This leads to cellular cascades that trigger a neurodegenerative phenotype and decline in cognitive function. Chronic peripheral hyperinsulinemia results in a reduction of insulin transport across the BBB and a reduced insulin signaling in brain, altering all of insulin's actions, including its anti-apoptotic effect. However, the increase in brain insulin levels resulting from its peripheral administration at optimal doses has shown a cognition-enhancing effect in patient with AD. Some drugs utilized in type II diabetes mellitus reduce cognitive impairment associated with AD. The link between insulin resistance and neurodegeneration and AD, and the possible therapeutic targets in preventing the insulin-resistance disorders are analyzed.
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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]”
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- Authors
- Neumann, K., Rojo, L., Navarrete, L., Farias, G., Reyes, P., & Maccioni, R.
- Affiliations
- University of Chile (CL)
- Venue
- Current Alzheimer Research
- Publisher
- Bentham Science Publishers Ltd.
- Published
- 2008-10-01
- Volume
- 5
- Issue
- 5
- Pages
- 438-447
- ISSN
- 1567-2050 (ISSN-L)
- OpenAlex
- W2154208298
- Cited by
- 236
- References
- 105
- Citations by year
- 2026: 1 · 2025: 5 · 2024: 10 · 2023: 11 · 2022: 9 · 2021: 14 · 2020: 9 · 2019: 11 · 2018: 14 · 2017: 13 · 2016: 16 · 2015: 21 · 2014: 24 · 2013: 27 · 2012: 12
- FWCI
- 8.82
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Current Alzheimer Research (publishedVersion)
- PubMed (publishedVersion)
- Universidad de Chile (submittedVersion)
- 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
- insulin resistance, Alzheimer's disease, hyperinsulinemia, type 2 diabetes, blood-brain barrier, brain glucose metabolism, amyloid-beta clearance, tau hyperphosphorylation, cyclin-dependent kinase 5, GSK3β, insulin signaling, neurodegeneration, cognitive impairment, insulin therapy, antidiabetic drugs, therapeutic target
- MeSH terms
- Alzheimer Disease, Cognition Disorders, Diabetes Mellitus, Type 2, Glucose, Humans, Hyperinsulinism, Insulin, Insulin Resistance
About these checks
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.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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