Insulin resistance in the brain may link Alzheimer’s and epilepsy

Researchers at the University of São Paulo (USP) in Brazil have succeeded in showing, in an animal model, that the process of insulin resistance in the brain affects both Alzheimer's disease and epilepsy and may be a linking factor between the two diseases.

The work, supported by FAPESP, confirms clinical evidence that people with epilepsy are at greater risk of developing Alzheimer's disease as they age. It is also not uncommon for people with Alzheimer's disease to have seizures.

"In addition to demonstrating that insulin signaling in the brain, when altered, affects both epilepsy and Alzheimer's disease, the study reinforces the idea that Alzheimer's disease is even more complex and therefore requires a broader therapeutic approach. Drugs that focus on just one feature of the disease tend to have a very limited effect. That's why we need more diverse studies on the subject," says Norberto Garcia-Cairasco, professor at the Ribeirão Preto Medical School (FMRP-USP), director of the Laboratory of Neurophysiology and Experimental Neuroethology and corresponding author of the article published in the Journal of Neural Transmission.

Alzheimer's disease is a complex, multifactorial neurodegenerative disease for which there is no cure and no known cause. Among the various hypotheses to explain its onset, the amyloid cascade stands out, according to which the deposition of beta-amyloid plaques in the brain is the initial and critical event that triggers a series of processes that culminate in neuronal death, synapse loss, and ultimately dementia. 

Formulated in 1992, this theory has guided Alzheimer's research for the past several decades.

Other important hypotheses include a decrease in acetylcholine, a neurotransmitter essential for memory, and neuroinflammation, which impairs communication between neurons and can be triggered by the accumulation of amyloid peptides in the brain. In addition, hyperphosphorylation of the tau protein, the second main biomarker of Alzheimer's disease, leads to the formation of "tangles" in brain cells, impairing their function and contributing to the progression of the disease.

"Currently, the drugs most commonly used to treat Alzheimer's [anticholinesterase and antiglutamatergic drugs] have low efficacy and are only symptomatic. And cases of people with beta-amyloid plaques in the brain [the result of the deposition of amyloid peptides] without symptoms of Alzheimer's have already been described," the researcher says.

Metabolic nature

Another hypothesis to explain the onset of Alzheimer's, highlighted by Garcia-Cairasco, is that the process of cerebral insulin resistance leads to neuronal damage and defective synaptic plasticity in a brain area called the hippocampus. Brain insulin resistance could even impair cholinergic function, increasing the likelihood of neuroinflammation and neurodegeneration, and triggering the production and accumulation of beta-amyloid and tau proteins in brain tissue. 

It is worth noting that although patients with diabetes have a higher risk of Alzheimer's, it is possible to have central insulin resistance without having type 1 or type 2 diabetes.

According to this hypothesis, which is not yet a consensus among experts, Alzheimer's would be due to a type of diabetes called type 3, which describes a state of insulin resistance in the brain.

Epilepsy, on the other hand, is a group of disorders characterized by recurrent and spontaneous seizures (convulsive or non-convulsive), with a higher prevalence in children and older adults. Among the various factors that trigger epileptic seizures is low blood sugar (hypoglycemia). The cause of the disease may also be genetic or related to brain trauma, autoimmune disorders, metabolic problems and infectious diseases. 

There are scientists who associate Alzheimer's exclusively with neuroinflammation, changes in neurotransmitters or type 3 diabetes. We believe that Alzheimer's can be classified as a much more complex disease and that a deeper understanding of its relationship with epilepsy and insulin resistance can help us understand one of these factors related to the causality of the disease."

Norberto Garcia-Cairasco, Professor at the Ribeirão Preto Medical School (FMRP-USP)

The study is one of the first to show a direct link between insulin resistance in the brain and increased susceptibility to seizures. In addition, the work is part of a larger project that has already won two outstanding scientific awards in 2024 – the Aristides Leão Award (Best Paper in the Basic Area), at the 40th Brazilian Congress of the Brazilian Epilepsy League, and the Best Poster Award in Geriatrics, at the 12th Brazilian Alzheimer's Congress.

It looks like an epileptic seizure

To arrive at these results, the FMRP-USP researchers discovered that rats microinjected intracerebrally with streptozotocin – a chemical substance used to experimentally induce Alzheimer's disease – also exhibited characteristics of epilepsy.

"To test the type 3 diabetes hypothesis in an animal model, we injected the rodents with streptozotocin, a compound known to induce insulin resistance and used to model diabetes and Alzheimer's disease. Surprisingly, some of the animals began to show seizure-like symptoms after receiving a high-intensity sound stimulus. Although the study was exclusively about Alzheimer's, it was being conducted in an epilepsy lab, which piqued the interest of other researchers. With this, we demonstrated that the process of insulin resistance has an effect not only on Alzheimer's but also on epilepsy," says Suélen Santos Alves, PhD student and first author of the study.

The opposite was also observed: rats of the Wistar Audiogenic Rat (WAR) strain, genetically engineered to study epilepsy, also began to show molecular changes of Alzheimer's disease, such as hyperphosphorylation of the tau protein and a decrease in insulin receptors in the hippocampus.

A single dose of the drug injected into rodents with epilepsy and Alzheimer's disease not only induced brain resistance to insulin but also worsened the rodents' memory and increased the frequency and severity of seizures.

"In addition to memory deficits, we found that this model exhibits increased susceptibility to audiogenic seizures, along with elevated neuronal activation in brain regions rich in insulin receptors. These findings strengthen the notion that brain insulin resistance plays a crucial role in epilepsy and may be one of the main mechanisms linking this disorder to Alzheimer's disease," says Alves.

"In addition, the results observed in the WAR strain highlight the importance of genetic background in shaping response to treatment, suggesting that intrinsic characteristics may influence perturbations in insulin signaling that affect disease progression," the researcher concludes.

It is worth noting that the strain of rats with epilepsy and Alzheimer's disease genetically developed at FMRP-USP was donated to the Rat, Resource and Research Center (RRRC) at the University of Missouri (United States), where it is currently available to researchers from around the world who wish to conduct experiments.

Before being donated, the strain was sanitized at the Multidisciplinary Center for Biological Research in the Area of Science in Laboratory Animals (CEMIB) of the State University of Campinas (UNICAMP) to overcome international health barriers.

The group continues to study the relationship between the two diseases. Through a study supported by FAPESP and conducted in collaboration with the Epilepsy Surgery Center (CIREP) of the general and school hospital (Hospital das Clínicas) of FMRP-USP, they will replicate the study carried out on rats using tissues from patients who have undergone surgery to treat epilepsy (and are therefore resistant to pharmacological treatment). 

The variation in gene and protein expression in the cells of these patients will also be analyzed using proteomic and transcriptomic techniques in another collaboration with researchers from Harvard University in the United States.