The problem the authors were trying to connect
Alzheimer’s disease includes neuronal loss, amyloid-beta accumulation, abnormal tau, synaptic disconnection, impaired glucose use, mitochondrial dysfunction, oxidative stress, inflammation and DNA damage. Many of these changes appear before severe dementia is evident.
The authors asked whether impaired insulin and IGF signalling could provide a framework linking several of these abnormalities instead of treating them as unrelated events.
Insulin has work to do in the brain
Insulin is widely associated with blood sugar, but insulin and IGF receptors are also present in the nervous system. Their signalling participates in neuronal survival, synaptic plasticity, energy metabolism and the regulation of pathways involving Akt, GSK-3 beta and other cellular proteins.
When signalling is reduced or cells become less responsive, energy use and stress responses may change. The review proposes that these disturbances can contribute to vulnerability rather than acting as a single switch that creates Alzheimer’s disease.
Evidence from human brain tissue
The review describes post-mortem studies comparing Alzheimer’s-affected brain regions with normal ageing. Investigators reported reduced expression of insulin, IGF peptides and their receptors, together with impaired receptor binding and downstream signalling.
Some abnormalities became more pronounced with advancing Braak stage, which is used to describe the spread of tau pathology. These observations establish association with disease severity, but post-mortem tissue alone cannot prove which changes began the disease.
Energy, tau, amyloid and oxidative stress
Insulin and IGF pathways influence mitochondrial function, cell survival and GSK-3 beta activity. Disrupted signalling could therefore contribute to lower energy production, greater oxidative stress and changes in tau phosphorylation.
The authors also discuss how oxidative stress and inflammation may influence amyloid precursor protein expression and amyloid-beta accumulation. These processes can reinforce one another, creating cycles of cellular stress rather than a simple one-direction pathway.
What animal models contributed
Experimental models allowed researchers to disrupt insulin-related signalling in the brain and observe changes in memory, energy metabolism, tau, amyloid-related proteins and inflammation. These studies offered cause-and-effect evidence for particular mechanisms.
Animal and cell models remain simplified systems. A result produced experimentally does not establish that the same intervention will prevent or reverse human Alzheimer’s disease.
Diabetes, obesity and dementia risk
Population studies have associated type 2 diabetes and mid-life obesity with higher risks of cognitive impairment and dementia. Possible contributors include vascular disease, chronic hyperglycaemia, inflammation, advanced glycation products and impaired insulin sensitivity.
The overlap is incomplete. Many people with diabetes never develop Alzheimer’s disease, and many people with Alzheimer’s never had diabetes. The review’s own experimental work concluded that obesity and type 2 diabetes may act as cofactors but are not sufficient to reproduce the full disease.
What “type 3 diabetes” actually means
The authors used the phrase to describe combined insulin deficiency and insulin resistance that appears largely within the brain. It was intended as a mechanistic concept highlighting metabolic features of neurodegeneration.
It is not a standard diagnostic category, does not replace Alzheimer’s diagnostic criteria and should not be used to tell a patient that Alzheimer’s is simply diabetes of the brain.
Treatment questions remain open
The metabolic framework encouraged research into intranasal insulin, insulin-sensitizing approaches and incretin-based medicines. A plausible pathway is not enough: each intervention requires randomized clinical trials measuring meaningful cognition and function.
Recent GLP-1 trials illustrate this distinction. Biological markers may change without slowing established Alzheimer’s disease. Protecting vascular and metabolic health remains valuable, but no supplement, diet or diabetes medication should be presented as a proven Alzheimer’s treatment without direct evidence.