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Cited by 265Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

Contributions of Brain Insulin Resistance and Deficiency in Amyloid-Related Neurodegeneration in Alzheimerʼs Disease

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de la Monte, Suzanne M.·2012·Drugs
DOI 10.2165/11597760-000000000-00000PMC PMC4550303
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Abstract

Alzheimer's disease (AD) is the most common cause of dementia in North America. Growing evidence supports the concept that AD is fundamentally a metabolic disease that results in progressive impairment in the brain's capacity to utilize glucose and respond to insulin and insulin-like growth factor (IGF) stimulation. Moreover, the heterogeneous nature of AD is only partly explained by the brain's propensity to accumulate aberrantly processed, misfolded and aggregated oligomeric structural proteins, including amyloid-β peptides and hyperphosphorylated tau. Evidence suggests that other factors, including impaired energy metabolism, oxidative stress, neuroinflammation, insulin and IGF resistance, and insulin/IGF deficiency in the brain should be incorporated into an overarching hypothesis to develop more realistic diagnostic and therapeutic approaches to AD. In this review, the interrelationship between impaired insulin and IGF signalling and amyloid-β pathology is discussed along with potential therapeutic approaches. Impairments in brain insulin/IGF signalling lead to increased expression of amyloid-β precursor protein (AβPP) and accumulation of AβPP-Aβ. In addition, they promote oxidative stress and deficits in energy metabolism, leading to the activation of pro-AβPP-Aβ-mediated neurodegeneration cascades. Although brain insulin/IGF resistance and deficiency can be induced by primary or secondary disease processes, the soaring rates of peripheral insulin resistance associated with obesity, diabetes mellitus and metabolic syndrome quite likely play major roles in the current AD epidemic. Both clinical and experimental data have linked chronic hyperinsulinaemia to cognitive impairment and neurodegeneration with increased AβPP-Aβ accumulation/reduced clearance in the CNS. Correspondingly, both the restoration of insulin responsiveness and the use of insulin therapy can lead to improved cognitive performance, although with variable effects on brain AβPP-Aβ load. On the other hand, experimental evidence supports the concept that the toxic effects of AβPP-Aβ can promote insulin resistance. Together, these findings suggest that a positive feedback loop of progressive neurodegeneration can develop whereby insulin resistance drives AβPP-Aβ accumulation, and AβPP-Aβ fibril toxicity drives brain insulin resistance. This phenomenon could explain why measuring AβPP-Aβ levels in cerebrospinal fluid or imaging of the brain has proven to be inadequate as a stand-alone biomarker for diagnosing AD, and why the clinical trial results of anti-AβPP-Aβ monotherapy have been disappointing. Instead, the aggregate data suggest that brain insulin resistance and deficiency must also be therapeutically targeted to halt AD progression or reverse its natural course. The positive therapeutic effects of different treatments that address the role of brain insulin/IGF resistance and deficiency, including the use of intranasal insulin delivery, incretins and insulin sensitizer agents are discussed along with potential benefits of lifestyle changes to modify risk for developing mild cognitive impairment or AD. Altogether, the data strongly support the notion that we must shift toward the implementation of multimodal rather than unimodal diagnostic and therapeutic strategies for AD.

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  • Alzheimer's disease exhibits several possible causal mechanisms, including oxidative stress, chronic inflammation, impaired insulin metabolism and cholinergic deficiency.

    “AD is a disease that exhibits several possible causal mechanisms, including oxidative stress, chronic inflammation, impaired insulin metabolism and cholinergic deficiency [129].”

    From Beneficial Effects of Spirulina Consumption on Brain Health (2022) · cites this paper as [129]

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Authors
de la Monte, S. M.
Venue
Drugs
Publisher
Springer Science and Business Media LLC
Published
2012-01
Volume
72
Issue
1
Pages
49-66
ISSN
0012-6667 (ISSN-L)
DOI
10.2165/11597760-000000000-00000
PMC
PMC4550303
OpenAlex
W2080512251
Cited by
265
References
178
Citations by year
2026: 9 · 2025: 22 · 2024: 21 · 2023: 25 · 2022: 15 · 2021: 19 · 2020: 18 · 2019: 17 · 2018: 20 · 2017: 14 · 2016: 17 · 2015: 20 · 2014: 17 · 2013: 16 · 2012: 15
FWCI
1.64
Type
journal article
Language
en
Open access
Locations
  • Drugs (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health (5r01aa011431-26)
  • National Institute on Alcohol Abuse and Alcoholism (R01-AA011431, AA-12908, K24AA016126, AA16260, 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
Alzheimer's disease, brain insulin resistance, insulin-like growth factor, amyloid-beta, amyloid precursor protein, hyperinsulinemia, neurodegeneration, oxidative stress, energy metabolism, peripheral insulin resistance, anti-amyloid therapy, Alzheimer's disease biomarkers, insulin therapy, neuroinflammation, tau hyperphosphorylation, cerebrospinal fluid
MeSH terms
Alzheimer Disease, Brain, Humans, Insulin Resistance, Models, Biological, Amyloid beta-Protein Precursor

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