Slow Down!

Could decelerating an overactive hippocampus halt Alzheimer’s disease in its tracks? Neuroscientist Michela Gallagher and her colleagues across the university aim to find out.

Illustrations by Stuart Bradford

By age 85, one of every three people will have Alzheimer’s disease. It’s now the sixth leading cause of death in the United States. But unlike cancer or heart disease, there is no way to prevent, slow, or stop its progression. It’s the most expensive affliction to treat, costing Medicare and Medicaid some $150 billion annually—a figure that could top $1 trillion by 2050. Just five drugs have ever been approved to treat the disease. Four are still available and each targets symptoms, such as memory loss, not the illness itself. None of them is particularly effective.

What perhaps is needed is an unconventional approach to the problem. A new target, if you will.

Enter Michela Gallagher, a professor of psychological and brain sciences in the Zanvyl Krieger School of Arts and Sciences. She and her team have adapted an unlikely medication, originally used to treat epileptic seizures, that appears to improve memory impairment during the pre-Alzheimer’s state, known as amnestic mild cognitive impairment (aMCI). After successfully testing the drug, levetiracetam, in animals and then in humans, Gallagher and her team are scheduled to begin a phase 3, worldwide clinical study of a patented version of the compound called AGB101 in early 2016. The medication won’t cure Alzheimer’s, but researchers see it as a possible tool in helping to prevent its advance in patients already suffering from the early stages of memory impairment—something that affects 5.6 million people in America and 25 million worldwide.

“For every year you can slow the progression of aMCI to a clinical diagnosis of dementia, you decrease the prevalence of the population with Alzheimer’s dementia by 10 percent,” says Gallagher. “If you can slow it by five years, that means you can decrease the population with dementia by half. That’s amazing! You don’t have to be a heroic genius who has connected all the dots in the pathology of Alzheimer’s disease if you can just slow it down. That’s what I’m trying to do.”

Going Against the Grain

photo of (l-r) Marilyn Albert, Michela Gallagher, Arnold Bakker
(l-r) Marilyn Albert, Michela Gallagher, Arnold Bakker

When Gallagher and her graduate student Arnold Bakker first presented their findings at the 2011 Alzheimer’s Association International Conference in Paris, the reaction was mixed.

For years, the pharmaceutical industry had been—and still is—focused on developing drugs targeting the buildup of beta-amyloids, bits of protein that cluster together to presumably form neuron-blocking plaques in the brain. The plaques gum up synapses, perhaps eventually killing neurons. Other drugs were being developed to halt “tangles,” twisted strands of another protein called tau found in dead and dying neurons.

More than 70 such drugs have been tested during the last two decades. All have failed, including one infamous compound that proved toxic in clinical studies.

But the work of Gallagher and Bakker involved an entirely different objective, as well as a novel way to address it. Gallagher had theorized that overactive neurons in the hippocampus, a region in the brain responsible for creating new memories, were damaging neural connections, causing accelerated memory loss in people with aMCI, and driving further decline on the path to dementia. At the time, the prevailing wisdom was that this hyperactivity was simply the brain’s way of compensating for an aging neural network. It was an adaptive response; the hippocampus was just doing extra duty. But Gallagher and Bakker’s work on human subjects—backed up by previous tests on animals—revealed that when people were given low doses of levetiracetam, overactivity in the hippocampus decreased and scores on memory tests improved.

“We were absolutely going against the grain, and we were aware of that, but Michela had really designed a very strong experiment to prove her case,” says Bakker, now an assistant professor of psychiatry and behavioral sciences in Hopkins’ School of Medicine, of their 2011 study. “The people who knew our research were excited, but I think people were also skeptical given the low dose, and this strange drug we used. It remains an open-ended question, but it’s our stand that it’s worth pursuing along with all the other avenues out there. Overactivation clearly contributes to the behavioral deficits and progressive cognitive decline, which is what we think about when we think about Alzheimer’s. It’s that worsening condition that puts people in nursing homes. It’s the memory loss that has such a devastating effect on families, so that is something we’ve always been focused on.”

Although neuronal hyperactivity was not a centrally recognized feature of the disease at the time Bakker and Gallagher presented their findings, it has grown to be. Gallagher’s theory has garnered support in the Alzheimer’s research community, as other researchers both at Johns Hopkins and around the world have conducted related experiments. The discussion has changed from the compensatory benefits of neuronal overactivity to it being part of the problem.

There’s also increasing evidence that plaques and tangles and out-of-whack neural firings go hand in hand. “There’s more and more recognition that beta-amyloid causes neuronal hyperactivity and that overactivity causes the additional buildup of amyloid, a main ingredient in plaques,” says Gallagher. “The overactivity is pumping up the amyloid, and the amyloid also causes the overactivity. It’s sort of like a positive feedback loop.”

The hope is that Gallagher’s drug can effectively break that loop—or at least slow it down to a crawl.

Follow the Data

Ask Michela Gallagher’s colleagues to describe her, and they’ll respond that she sometimes has a penchant for going left when everyone else is going right. They refer to her as “a pioneer,” “incredibly focused,” “a force.”

“She’s indefatigable,” says Marilyn Albert, director of the Johns Hopkins Alzheimer’s Disease Research Center and a longtime collaborator. “She’s passionate and dedicated and really wants to make a difference.”

“She’s always someone who’s thinking outside the box,” says Patricia Janak, a Bloomberg Distinguished Professor and Gallagher’s colleague in the Department of Psychological and Brain Sciences. “She’s always asking: ‘What’s the next step? How can we push this further?’”

As a grad student at the University of Vermont, Gallagher was interested in studying the effects of aging on the brain because it seemed to be the biggest naturally occurring form of memory change. Everybody always says their memory changes as they get older. Gallagher wondered: “What do they really mean by that?”

As a professor at the University of North Carolina at Chapel Hill, where she spent 17 years, she found that most scientists were conducting studies on laboratory animals that had been inbred. Every animal was identical, and researchers would conduct studies around a known aspect of their biology. But Gallagher knew humans weren’t like that. Everybody is different. She wanted to explore the individual differences between animals and whether something about our unique biology is the basis for those changes over a life span.

So in another unconventional move at the time, she began her research using a biologically diverse population of rats in order to study how their individual memories changed as they aged to explore why some animals aged well, while others did not. In humans, aging well has become a field of inquiry now known as “successful aging.” She was also hoping to find some biological trigger—a biomarker—that preceded any measurable decline. She and her team developed tests for the rats involving spatial memory, memory retention, and memory of smells, and observed how effectively they performed these tasks over the course of their lives, typically 36 months. Eventually, via tiny sensors implanted within the rats’ brains, the researchers succeeded in discovering a population of neurons that appeared to fire more frequently in rats exhibiting memory decline. In 2003, she and her colleagues published a paper demonstrating that rats with the most activity in their hippocampi also had the most significant declines in memory.

Around the same time, other scientists were publishing papers about overactive hippocampi in humans and describing the phenomenon as compensatory, a good thing. Gallagher wondered how this could be.

She began searching for a drug that had the effect of quieting neuronal activity in the overactive region of the brain. “I started looking for existing compounds because I wanted to do the study right now,” she says. “I didn’t want to develop drugs. My motivation was very much as a scientist to see if this condition in people was similar to the condition in rats. I needed to find something I could use in both rats and people.”

One of the first drugs she tried was levetiracetam, which had been proved safe as an adjunctive medication in treating epileptic seizures even at high dosages of 1,000 to 3,000 milligrams.

The drug’s effect was powerful and immediate. Overactive neurons in the rats’ brains calmed, and their memories improved to normal levels for their ages.
The team received a grant from NIH for a phase 2 dosing study involving 54 people exhibiting signs of aMCI to test the effects on overactivity and memory performance. The initial results, presented at the Paris meeting in 2011, were positive. Full study results, published last spring, showed that AGB101 given at 125 or 250 milligrams daily reduced hippocampal activity to a normal range and significantly improved memory performance in aMCI patients.

“From my perspective, one of the most important things is that she tried many drugs that decreased activity, but only levetiracetam improved cognition in the rats,” says Albert. “There must be something different about this drug that we don’t understand. That’s not unusual in clinical medicine that you find treatments that work but you don’t know why.”

“One of the things I’ve learned from Michela is to follow the data,” says Bakker, who teamed up with Gallagher in 2009, adding his experience in advanced brain imaging to the team. “Even if the results don’t make sense, the data are the data. She stuck with that. If she hadn’t, the study would not have been successful.”

Hoping for Success

Even before the success of the phase 2 trial, Gallagher believed she was onto something special. In 2011, she formed a private company called AgeneBio in order to raise funds for a potential phase 3 study, with the hope of one day bringing AGB101 to market. (Patent rights that belong to Johns Hopkins are exclusively licensed to the company for commercial development.)

Recently, NIH awarded the university a $7.5 million grant to pursue the phase 3 study, in a public-private partnership led by AgeneBio with Johns Hopkins participation. The phase 3 study will test the efficacy of the drug and possible side effects in hundreds of participants at many sites around the world. This is one of five public-private grants the agency has awarded nationally for Alzheimer’s prevention trials but the only one to test a drug targeting neural overactivity and aMCI. That money will be combined with another $60 million AgeneBio will raise through private investment for the trial, which is planned to roll out worldwide early in 2016.

The 18-month study, dubbed HOPE4MCI (Hippocampal Overactivity Prevention in the Elderly), will involve hundreds of patients who exhibit early signs of aMCI. Patients will receive 220 milligrams of AGB101 once daily, while undergoing memory tests and brain imaging scans before, during, and after the study. Another group in the study will receive a placebo.

The NIH grant involves not only the Krieger School, but also faculty in the Hopkins schools of medicine, public health, and engineering. The Whiting School of Engineering’s Center for Imaging Science will process the hundreds of brain scans, logging changes in the brain, particularly in the entorhinal cortex, the “gateway” to the hippocampus and the site where neurodegeneration takes place in the earliest stages of Alzheimer’s disease.

At the School of Medicine, Albert, who is also the study’s co-principal investigator, will help plan the trial and oversee all the patient data collected at the hospital. Gallagher, due to her conflict of interest as an inventor of the technology licensed to AgeneBio, will not participate in any clinical activities or have contact with patients in the trial.

Overseeing the study on the analytical end is Scott Zeger, a professor of biostatistics at the Bloomberg School of Public Health and a former consultant for Merck and the FDA. He says he’s amazed at what Gallagher has been able to accomplish thus far. “Michela is a traditional arts and sciences scholar who has focused on studying mechanisms of neurodegeneration and along the way discovered a very interesting lead on something that we might utilize to intervene to slow the rate at which Alzheimer’s progresses. It’s a very important health problem and a very exciting example of fundamental science giving rise to a potential treatment. Hopefully, her work will have an impact on what’s really one of the most severe epidemics of our time.”

The results of the study likely won’t be released until 2018 at the earliest. If successful, Gallagher’s company would likely partner with a large pharmaceutical company to market and sell the drug.

Researchers involved in the trials are hopeful and understandably anxious to see if their theories play out successfully once again.

“Look, we don’t know if this is going to work, but it’s more than worthwhile to find out,” says Bakker, who will play a leading role in the study at the medical school. “Michela’s goal has been to do the absolute best science to answer the question properly.”

Gallagher, who last year was awarded the Society of Neuroscience’s Mika Salpeter Lifetime Achievement Award for her work in mentoring young scientists, is the first to admit she’s still a little overwhelmed at times by the transition in her research from the bench doing basic science to clinical research and now the treatment of patients.

“My perspective remains as a scientist in this clinical work,” she says. “But what has gotten added to that is something I have never had enter into my career before—the potential impact of all this. The work has amazing implications for public health. This is something I just have to do. I’ve got to see it through.”

Is Your Hippocampus Overactive?

So how do you know if you or a loved one has aMCI, a condition in which a person’s memory is worse than would be expected for his or her age?

Gallagher says people should be aware of changes in their abilities to keep track of experiences, what researchers call episodic memories. “People use the term ‘senior moment’ to apply to any kind of mind burp,” says Gallagher, “but forgetting someone’s name or struggling for a word ‘on the tip of the tongue’ is not the kind of memory problem emblematic of aMCI. Episodic memory refers to your ability to remember events and the experiences in your life. Losing your keys more frequently could be symptomatic, particularly if you don’t recall where you put them after finding them. Repeating the same story at dinner—and not remembering that you told it already—is another example. In amnestic MCI, it’s the kind of memory responsible for recalling experiences or episodes in rich detail that’s affected first.”

Today, there is no therapy that is effective for treating the symptoms of aMCI or slowing its progression. Detecting aMCI before it blooms into Alzheimer’s dementia is vital, which is why Gallagher thinks there will be greater awareness for early detection. This is particularly true if the promise of AGB101 holds. “People aren’t walking around saying, ‘I have aMCI,’” she says. “But if they notice their memory is not as strong as it used to be or if their relatives notice it, they need to talk about it with their physicians. It’s the same situation if you have risk for stroke or heart disease; you take preventive medication. You don’t wait until all the damage is done to try to cure it. One day, that will be the case in Alzheimer’s prevention.”