Over the last few decades, the link between Alzheimer’s disease (AD) and type 2 diabetes (T2D) has been strengthened by numerous studies demonstrating that these two pathologies share underlying mechanisms. This association has led to the emergence of the term type 3 diabetes (T3D), often described as a form of insulin resistance in the brain. T3D has been suggested as a central factor in the pathogenesis of Alzheimer’s disease, opening up new avenues for understanding and treating this devastating disease.
Insulin resistance in the brain
Historically, insulin was seen primarily as a hormone that regulates blood sugar levels in peripheral tissues, with little impact on the brain. However, recent research has highlighted the essential role played by insulin in maintaining cognitive functions, in particular synaptic plasticity, memory and neuronal survival.
In the case of insulin resistance in the brain, a phenomenon characteristic of type 3 diabetes (T3D), these cognitive functions are impaired, producing effects comparable to those of Alzheimer’s disease. This dysfunction prevents neurons from responding adequately to insulin, disrupting the regulation of amyloid proteins and promoting hyperphosphorylation of the Tau protein – two key elements in the pathophysiology of Alzheimer’s disease.
Underlying molecular mechanisms: Insulin resistance disrupts signalling in the PI3K/Akt pathway, leading to increased activation of glycogen synthase kinase 3β (GSK-3β), an enzyme responsible for the abnormal phosphorylation of Tau protein. This alteration contributes to the formation of neurofibrillary tangles, a major pathological feature observed in Alzheimer’s disease.
This direct link between cerebral insulin resistance and the molecular mechanisms associated with Alzheimer’s reinforces the hypothesis that metabolic disorders, such as those observed in T3D, may play a determining role in the development and progression of this neurodegenerative disease.
Hyperglycaemia, AGEs and RAGE receptors
One of the key mechanisms linking type 2 diabetes (T2D) to Alzheimer’s disease (AD) is the accumulation of advanced glycation products (AGEs). These compounds are formed when proteins or lipids are exposed to high concentrations of glucose over a long period, a phenomenon often observed in chronic hyperglycaemia. AGEs accumulate in brain tissue and bind to specific receptors called receptors for advanced glycation products (RAGE), triggering a series of inflammatory and oxidative responses.
When RAGEs are activated in neuronal and microglial cells, they induce the release of pro-inflammatory cytokines and neurotoxic molecules, exacerbating oxidative stress and neuroinflammation. These two processes are essential for the progression of Alzheimer’s disease. In addition, the interaction between AGEs and RAGE receptors promotes the production of amyloid-beta (Aβ), thereby accelerating the formation of amyloid plaques, a major pathological feature of AD.
This complex link between hyperglycaemia, AGEs, RAGE and neuroinflammation explains why type 2 diabetes is increasingly considered to be a major risk factor in the development of Alzheimer’s disease.
What is the link between diabetes and Alzheimer’s disease?
Mitochondria, the energy centres of cells, play a vital role in the pathophysiology of both diseases. In T3D, insulin resistance interferes with the ability of neurons to use glucose efficiently, leading to mitochondrial dysfunction. The latter leads to excessive production of free radicals and oxidative stress, factors that contribute directly to the neuronal degeneration observed in AD.
Reactive oxygen species (ROS) produced in excess in damaged mitochondria cause damage to mitochondrial DNA and impair the cells’ ability to produce energy. This vicious circle encourages the accumulation of amyloid proteins and the abnormal phosphorylation of the Tau protein, thereby accelerating degenerative processes.
The impact of antidiabetics on Alzheimer’s patients
Given the pathophysiological links between diabetes and Alzheimer’s, anti-diabetic therapies are currently being explored as potential interventions against AD. Among the most promising drugs are GLP-1 receptor agonists, such as liraglutide and exenatide, which have shown neuroprotective effects in animal models.
These treatments target insulin and glucose signalling pathways in the brain, improving insulin sensitivity and reducing the production of amyloid plaques and hyperphosphorylation of the Tau protein. Preclinical and clinical studies have shown that administration of these drugs can improve cognitive performance and slow the progression of Alzheimer’s disease.
The concept of type 3 diabetes provides a new perspective on Alzheimer’s disease, suggesting that the same pathological mechanisms at work in type 2 diabetes, such as insulin resistance and oxidative stress, also contribute to neurodegeneration.
This understanding opens the way to new therapeutic strategies aimed at improving insulin signalling in the brain, reducing mitochondrial oxidative stress and curbing the accumulation of pathological proteins.
Future studies should further explore these links and the use of anti-diabetic drugs in the treatment of Alzheimer’s, in the hope that this may not only slow the progression of the disease but also offer new solutions for the millions of people affected by this devastating pathology.
Sources
- True or false? Alzheimer’s disease is type 3 diabetes: Evidences from bench to bedside August 2024
