Organ transplant drug may slow Alzheimer’s disease progression in individuals with seizures

PHILADELPHIA— Protein imbalances that increase brain cell excitability may explain why individuals with Alzheimer’s disease (AD) who also experience seizures demonstrate more rapid cognitive decline than those who do not experience seizures. These imbalances may be present in the brains of individuals before the onset of AD symptoms.The new findings, from a research team at the University of Pennsylvania’s Perelman School of Medicine, are published this week in Brain.

The team found that an existing drug called rapamycin, initially developed as an immunosuppressant for organ transplant patients that suppresses signaling between neurons, was able to regulate the over-excited neurons in mouse models of AD and seizures, and preserve cognitive function, like memory and the ability to learn new things. 

Previous research has shown similar brain activity in individuals with AD who experience epilepsy. Additionally, many individuals with AD have also experienced at least one seizure, and previous research has shown that these seizures cause a more rapid progression of the disease, and worsen cognitive impairment, like trouble with memory or learning. However, researchers have not been able to identify the underlying connections between AD and seizures. 

“Experts used to believe that seizures were an unfortunate byproduct of the neurodegeneration that causes Alzheimer’s disease, but now we see that seizures are actually advancing the disease itself,” said the study’s co-senior author, Frances E. Jensen, MD, chair of Penn’s Department of Neurology. “Now that we have identified the mechanisms that cause neurons to get over-excited and lead to seizures that accelerate AD, we can explore therapies, like rapamycin, that can reverse the imbalance, and slow AD progression.” 

In a healthy brain, two neurotransmitters work together to manage the messaging between neurons. Glutamate is responsible for excitatory signaling from one cell to the next, telling neurons when to send a message. GABA manages inhibitory signaling that makes the cell less likely to fire, telling the cell when to stop signaling. 

In this study, researchers evaluated post-mortem tissue from people with AD who also experienced at least one seizure and found that certain forms of these neurotransmitters were dysregulated. These neurons in these individuals exhibited increased excitability and suppressed inhibition, which result in the brain sending more signals between neurons than it needs to, a state that researchers refer to as a “hyperactive brain.” Medical histories of these patients also confirmed worse cognitive evaluation scores than peers with AD but no seizures. 

To determine at what stage of AD this dysregulation starts, researchers monitored the brain activity in mouse models of AD with seizures. They found increased excitability and decreased inhibition in neurons even in preliminary stages of the disease, before cognitive symptoms presented.

“By the time many individuals are diagnosed with Alzheimer’s disease and start receiving treatments, their disease is advanced, and they have lost significant cognitive function,” aid Aaron Barbour, PhD, a postdoctoral researcher in the department of Neurology, and co-senior author. “Our research is an exciting step towards being able to intervene with a treatment before symptoms develop to slow the devastating effects of the disease.”

This research was funded by the National Institutes of Health (R21NS105437, R01NS101156, R01AG077692, T32AG000255) and the Alzheimer’s Association (AARF-22-972333). 

For more information about Alzheimer’s disease treatment and research at Penn Medicine, visit: https://www.pennmedicine.org/for-patients-and-visitors/patient-information/conditions-treated-a-to-z/alzheimers-disease . 

For information on Alzheimer’s disease clinical trials at Penn Medicine, visit: https://pennmemorycenter.org/research/. 

###

Penn Medicine is one of the world’s leading academic medical centers, dedicated to the related missions of medical education, biomedical research, excellence in patient care, and community service. The organization consists of the University of Pennsylvania Health System and Penn’s Raymond and Ruth Perelman School of Medicine, founded in 1765 as the nation’s first medical school.

The Perelman School of Medicine is consistently among the nation's top recipients of funding from the National Institutes of Health, with $550 million awarded in the 2022 fiscal year. Home to a proud history of “firsts” in medicine, Penn Medicine teams have pioneered discoveries and innovations that have shaped modern medicine, including recent breakthroughs such as CAR T cell therapy for cancer and the mRNA technology used in COVID-19 vaccines.

The University of Pennsylvania Health System’s patient care facilities stretch from the Susquehanna River in Pennsylvania to the New Jersey shore. These include the Hospital of the University of Pennsylvania, Penn Presbyterian Medical Center, Chester County Hospital, Lancaster General Health, Penn Medicine Princeton Health, and Pennsylvania Hospital—the nation’s first hospital, founded in 1751. Additional facilities and enterprises include Good Shepherd Penn Partners, Penn Medicine at Home, Lancaster Behavioral Health Hospital, and Princeton House Behavioral Health, among others.

Penn Medicine is an $11.1 billion enterprise powered by more than 49,000 talented faculty and staff.