Reduced brain insulin signaling: A seminal process in Alzheimer's disease pathogenesis
Open accessAbstract
The synaptic dysfunction and death of neurons that mediate memory and cognition account together for the behavioral symptoms of Alzheimer's disease (AD). Reduced insulin signaling in the brain is a hallmark of AD patients, even in the absence of systemic type 1 or type 2 diabetes, prompting some researchers to refer to AD as brain-specific, or type 3 diabetes. A key question that arises about this signature feature of AD is "how, if at all, does the brain's impaired ability to utilize insulin contribute to the behavioral deficits associated with AD?" The fact that type 2 diabetes is a risk factor for AD suggests a causative role for impaired insulin responsiveness in AD pathogenesis, but how that might occur at a detailed molecular level had been elusive. Here we review recent findings that mechanistically link soluble forms of amyloid-β (Aβ) and tau, the respective building blocks of the amyloid plaques and neurofibrillary tangles that accumulate in the brains of AD patients, with neuronal decline that is associated with poor insulin responsiveness and may begin long before AD symptoms become evident. We discuss how Aβ and tau work coordinately to deprive neurons of functionally accessible insulin receptors and dysregulate normal signaling by the protein kinase, mTOR. Finally, we suggest how newly gained knowledge about pathogenic signaling caused by reduced brain insulin signaling might be exploited for improved early detection and therapeutic intervention for AD. This article is part of the Special Issue entitled 'Metabolic Impairment as Risk Factors for Neurodegenerative Disorders.'
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Despite alterations in insulin signaling proposed to contribute to AD, leading some to describe the disorder as type 3 diabetes, the evidence remains mixed.
“Moreover, despite the alterations in insulin signaling within the brain that have been proposed to contribute to AD, leading some to describe the disorder as “type 3 diabetes”, the evidence remains mixed [76].”
From Toward a Unified Framework in Molecular Neurobiology of Alzheimer’s Disease: Revisiting the Pathophysiological Hypotheses (2026) · cites this paper as [76]
The Introduction and Section 4 describe impaired brain insulin signaling and explain why some researchers call AD “type 3 diabetes.” The Introduction acknowledges uncertainty about whether insulin resistance is upstream or downstream of other disease processes. But the paper does not characterize the evidence overall as mixed; Section 5 instead calls insulin resistance a prime factor in early AD pathogenesis. (LLM, conf=0.83)
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Differences in the pattern of hippocampal neuronal loss in normal ageing and Alzheimer's disease
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- Authors
- Bloom, G. S., Lazo, J. S., & Norambuena, A.
- Affiliations
- University of Virginia (US)
- Corresponding author
- Bloom, George S.
- Venue
- Neuropharmacology
- Publisher
- Elsevier BV
- Published
- 2018-07
- Volume
- 136
- Issue
- Pt B
- Pages
- 192-195
- ISSN
- 0028-3908 (ISSN-L)
- PMC
- PMC5876069
- OpenAlex
- W2760581692
- Cited by
- 44
- References
- 6
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 3 · 2023: 6 · 2022: 1 · 2021: 7 · 2020: 9 · 2019: 4 · 2018: 9 · 2017: 1
- FWCI
- 0.77
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Neuropharmacology (acceptedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Owens Family Foundation
- NIH (RF1 AG051085)
- Cure Alzheimer's Fund
- Alzheimer's Association (4079, ZEN-16-363266)
- The Virginia Chapter of the Lady's Auxiliary of the Fraternal Order of Eagles
- University of Virginia President's Fund for Excellence
- Alzheimer's and Related Diseases Research Award Fund (17-5)
- 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 signaling, type 3 diabetes, amyloid-beta, tau protein, insulin resistance, mTOR signaling, insulin receptor, synaptic dysfunction, neurofibrillary tangles, amyloid plaques, early detection of Alzheimer's disease, neurodegeneration
- MeSH terms
- Alzheimer Disease, Animals, Brain, Humans, Insulin
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