An Unexpected Dementia Defense

For people with Down syndrome, an anti-seizure medication may block early changes linked to Alzheimer’s

At Quinlan Terrace, a residential home on Chicago’s North Side for aging adults with disabilities, about half of the 60 residents are people with Down syndrome who have developed Alzheimer’s disease.

Director Susy Rivera says care needs vary from person to person. “Many residents can experience rapid decline over a relatively short period of time, including increased mobility needs, memory loss, and changes in perception or behaviors,” she says.

According to Michael Rafii, MD, PhD, medical director of the Alzheimer’s Therapeutic Research Institute and a clinical neurology professor at the University of Southern California, nearly all people with Down syndrome develop features of Alzheimer’s disease by age 40. Alzheimer’s disease is the leading cause of death for adults over age 35 with Down syndrome.

In an unexpected twist for this population, researchers at Northwestern University have found that an anti-seizure medication, available by prescription for decades, can prevent the build-up of toxic the protein fragments that leads to Alzheimer’s.

“It started about 10 years ago when we were studying the preclinical stage of Alzheimer’s,” says Jeffrey Savas, PhD, an associate professor in Northwestern University Feinberg School of Medicine’s neurology department.

Alzheimer’s disease ultimately decreases the brain’s synapses, the specialized cell junctions that transmit communication among neurons. Yet Savas and researchers in his lab found that parts of the synapses actually swell in early stages of disease.

The researchers analyzed human brain tissue from people with Down syndrome who had died in their 20s or 30s from car accidents or other causes. They also built on research that showed a link between early stages of Alzheimer’s and seizure activity.

They started treating mice with levetiracetam, also known as Keppra — a common anti-seizure drug that reduces abnormal electric activity in the brain. After testing it on mice and human neurons, they found that it prevented neurons from forming a toxic protein fragment, called amyloid-beta 42, that leads to Alzheimer’s disease.

Essentially, the drug quiets abnormal bursts of brain activity. “It could suppress the ability of amyloid-beta 42 to be produced, thereby preventing the onset or delaying the onset of Alzheimer’s,” Savas says.

These findings are particularly significant for people with Down syndrome, who have a much higher risk of developing plaque in their brains.

Their increased risk comes from the extra chromosome that defines Down syndrome: chromosome 21. People with Down syndrome are born with an extra copy of that chromosome, which typically contains a gene called the amyloid precursor protein (APP) gene. An extra copy of that gene means more amyloid proteins. Enzymes then process those proteins into amino acid fragments called beta amyloid peptides.

“Beta amyloid is a protein that, in high amounts, is toxic to the brain and develops into plaques,” says Rafii, who was not affiliated with the study. This causes tangles in the brain. “When tangles develop, then you have brain cells that are injured. They’re not doing what they’re supposed to do, and they die off. That leads to shrinkage of the brain and symptoms of dementia.”

Everyone has the APP gene. Some individuals have an extra copy of it but don’t have Down syndrome, and not all people who have Down syndrome have an extra APP gene. However, most do.

Rafii thinks of Alzheimer’s disease as a faucet and a drain in a kitchen sink. The faucet is wide open in genetic forms of Alzheimer’s, producing too much amyloid, which eventually clogs a normal-functioning clearance system — the drain, Rafii says. “And so the sink fills up, and that’s how the plaques develop.”

In the more common form of Alzheimer’s disease, the faucet lets out a trickle of amyloid, but the brain’s clearance system becomes impaired, and the drain clogs. “Both, overproduction and underclearance, result in too much amyloid in the brain and subsequently Alzheimer’s disease dementia,” Rafii says.

Medication used to treat Alzheimer’s typically attempts to clear the drain. The use of levetiracetam approaches the disease differently.

The results suggest that with this drug, “you could turn down the faucet, so that you don’t overwhelm the drain and protect people from developing the plaques in the first place,” Rafii says.

While the findings mostly apply to people with Down syndrome, Rafii says they could eventually lead to a better understanding of how to treat Alzheimer’s in the general population, too.

Next, Savas and other researchers hope to develop a version of levetiracetam that lasts longer in the body, making it more effective at preventing Alzheimer’s.

“The drug breaks down in the body very quickly,” Savas says. “You have to take it very frequently. The effects are pretty quick-acting, but also short-lasting.”

For the residents at Quinlan, which is part of the Misericordia network of residential homes, Alzheimer’s and dementia often progress quickly and manifest in changes in memory, mobility, communication, and behaviors.

Rivera says an effective preventative medication would mean a lot for people with Down syndrome, a group she says can go unnoticed.

“When we look at commercials on TV, when they talk about Alzheimer’s or dementia, you don’t see a resident that looks like my residents,” Rivera says. “They’re just like everyone else. They love to make someone laugh, and they love to be around and needed.”

With age, Rivera adds, “We learn how important it is to feel needed or still feel independent.”
For people with Down syndrome, an anti-seizure drug may offer an unexpected path to making that possible, by preventing Alzheimer’s before it begins.