Epilepsy is a common neurological disorder, affecting 50 million people worldwide, and is characterized by the tendency to have recurrent unprovoked seizures due to abnormal neuronal activity in the brain. Epilepsy affects people of all ages, yet interestingly, it is also associated with the precocious development of Alzheimer’s Disease (AD)-type neuropathological changes, such as the accumulation of amyloid-β (Aβ) as senile plaques and increased microglial activation compared to healthy individuals. AD itself mostly affects older people, with onset typically occurring from the age of 65 years.
It is known that there is a genetic predisposition to AD, so that individuals carrying two copies of the Apolipoprotein E (ApoE) variant epsilon 4 have a much higher risk of developing the disease than those with other variants of this gene. But why is this?
In a research article recently published in BMC Medicine, Sue Griffin and colleagues elucidate the mechanism behind this using a remarkably simple yet clever model. Using temporal lobe tissue removed from the brains of temporal lobe epilepsy (TLE) patients as part of their treatment, the research team were able to investigate the physiological effects of various ApoE genetic variants on the brain tissue, while at the same time avoiding the confounding factors that would come with investigating these effects in AD patients’ brains. For instance, looking at tissue from younger brains meant that there were likely to be very few age-related changes.
The research team looked at different markers of neuronal injury and resilience in brain tissue derived from patients that had two copies of the episilon 4 variant and compared them to those that that two copies of the episilon 3 variant. They found that the episilon 4 variant is not only associated with an increased burden of Aβ plaques, but is also associated with a compromised ability to combat the neuronal toxicity of these plaques. In contrast, the episilon 3 variant was associated with neuroprotection, meaning that carriers of this variant are less likely to be adversely affected by AD changes.