Insulin Resistance and Neurodegeneration: Progress towards the Development of New Therapeutics for Alzheimer's Disease
Open accessAbstract
Alzheimer's disease (AD) should be regarded as a degenerative metabolic disease caused by brain insulin resistance and deficiency, and overlapping with the molecular, biochemical, pathophysiological, and metabolic dysfunctions in diabetes mellitus, non-alcoholic fatty liver disease, and metabolic syndrome. Although most of the diagnostic and therapeutic approaches over the past several decades have focused on amyloid-beta (Aβ42) and aberrantly phosphorylated tau, which could be caused by consequences of brain insulin resistance, the broader array of pathologies including white matter atrophy with loss of myelinated fibrils and leukoaraiosis, non-Aβ42 microvascular disease, dysregulated lipid metabolism, mitochondrial dysfunction, astrocytic gliosis, neuro-inflammation, and loss of synapses vis-à-vis growth of dystrophic neurites, is not readily accounted for by Aβ42 accumulations, but could be explained by dysregulated insulin/IGF-1 signaling with attendant impairments in signal transduction and gene expression. This review covers the diverse range of brain abnormalities in AD and discusses how insulins, incretins, and insulin sensitizers could be utilized to treat at different stages of neurodegeneration.
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Impairment of brain glucose/energy metabolism induced by metabolic disorders such as obesity, diabetes, and hyperinsulinemia is widely accepted to be implicated in Alzheimer's disease progression.
“Among those attracting particular attention, the impairment of brain glucose/energy metabolism induced by metabolic disorders such as obesity, diabetes and hyperinsulinemia, has been widely accepted to be implicated in the AD progression (de la Monte, 2017; Ettcheto et al., 2020).”
From Exploring the Therapeutic Potential of Phytochemicals in Alzheimer’s Disease: Focus on Polyphenols and Monoterpenes (2022) · cites this paper as de la Monte, 2017
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References 267 · Cited by 331
Research works printed but not linked: 1
- [229]Garcia-Casares N Garcia-Arnes JA Gomez-Huelgas R Valdivielso-Felices P Garcia-Arias C Gonzalez-Santos P Glucagon-like peptide-1 (GLP-1) mimetics: a new treatment for Alzheimer’s disease? Rev Neurol 2014 12 1 59 11 517 24 25418147
- Authors
- de la Monte, S. M.
- Venue
- Drugs
- Published
- 2016-12-17
- Volume
- 77
- Issue
- 1
- Pages
- 47-65
- ISSN
- 0012-6667 (ISSN-L)
- 1179-1950
- PMC
- PMC5575843
- OpenAlex
- W2563087870
- Cited by
- 331
- References
- 267
- Citations by year
- 2026: 24 · 2025: 40 · 2024: 42 · 2023: 33 · 2022: 37 · 2021: 44 · 2020: 39 · 2019: 31 · 2018: 25 · 2017: 14 · 2015: 1
- FWCI
- 2.74
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Drugs (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute on Alcohol Abuse and Alcoholism (AA-11431)
- 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
- Alzheimer's disease, brain insulin resistance, insulin/IGF-1 signaling, neurodegeneration, incretins, insulin sensitizers, amyloid-beta, tau phosphorylation, white matter atrophy, white matter hyperintensities, microangiopathy, lipid metabolism, mitochondrial dysfunction, astrocytic gliosis, neuroinflammation, dystrophic neurites, metabolic syndrome, diabetes mellitus, non-alcoholic fatty liver disease, therapeutic target
- MeSH terms
- Alzheimer Disease, Humans, Insulin Resistance, Neuroprotective Agents
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