Sunday April 20, 2014SUBSCRIBE
New Jersey Monthly Magazine
Top Doctors
| |     

The Cutting Edge of Alzheimer's

Researchers are piecing together the intricate puzzle behind a devastating disease that afflicts more than 5 million Americans. Theories abound, but treatment remains elusive.

Posted October 10, 2011 by Leslie Garisto Pfaff

Do you like this story?

Karl Herrup
In his Rutgers lab, professor Karl Herrup is seeking out the ultimate culprit in Alzheimer’s disease.
Photo by Nick Romanenko.

Robert Nagele
Professor Robert Nagele, left, has spent almost a decade analyzing the blood of Alzheimer’s victims in his lab at UMDNJ’s School of Osteopathic Medicine (SOM) with the help of student researchers, including, from left, Eric Nagele, an SOM medical student; Cassandra DeMarshall, a master’s student at UMDNJ’s Graduate School of Biomedical Sciences; and Dr. Min Han, a PhD. candidate at UMDNJ-Graduate School of Biomedical Sciences.
Photo by Nick Romanenko.

Jane Teixeira remembers the phone calls, sometimes 20 a day. It was her mother’s voice, frantic, claiming a man in the house was trying to kill her.

Teixeira, who in 2004 moved from Manhattan to Pennington to be closer to her parents in Toms River, knew the man was actually her father, but her mother—then 75 and in an early stage of Alzheimer’s disease—no longer recognized her husband of five decades. Over time, the phone calls stopped—not because her mother’s fears were allayed, but because the woman could no longer speak or use the phone.

Four years later, Teixeira and her family are calmer, but they’re braced for the next round of storms and lulls that often mark the progression of Alzheimer’s disease. “We get on these plateaus,” she says, “and we can bear it for a little while, and then my mother will have a progression downward, and we’ll have to adjust ourselves all over again.”

Until recently, adjustment has been pretty much the only option available to families grappling with Alzheimer’s, an incurable, degenerative disease, almost exclusively of the elderly, marked by progressive, debilitating memory loss and dementia. Today, it afflicts one person in eight in America over the age of 65, amounting to more than 5 million Americans—350,000 of them in New Jersey—and some 26 million people worldwide.

Dr. Bennett P. Leifer, a primary care physician in Midland Park who specializes in geriatric and internal medicine (and a 2011 Top Doctor), says Alzheimer’s may become “the defining disease of the baby boomers,” and with good reason. Experts predict that, by 2050, more than 100 million of us—or 1 out of every 85 people in the world—will be in the throes of Alzheimer’s disease. And because the illness—whose course can often run for a decade or more—takes such a toll on caregivers and family members, the number of afflicted people is actually much larger.

Those figures lend a particular urgency to the need for a cure or an effective way of treating, or better yet, preventing the disease. All of that has eluded the medical world since Alzheimer’s was first identified in 1906.  But recent advances in the field, including some significant research coming out of the Garden State, offer reason to hope that we may be on the cusp of a new era of Alzheimer’s diagnosis and treatment.  Even more tantalizing are indications that we may soon understand the mechanics of the disease, which have largely remained a mystery.

IS IT ALZHEIMER’S?
Draw a clock. Fill in all the numbers. Set the hands at 11:10. Got it down? If so, then you probably do not have Alzheimer’s. Like the Mini-Mental State Exam—a 30-point questionnaire assessing a patient’s ability to reason and remember—and “animal counting”—the measure of how many animals a patient can name in 60 seconds— the clock-drawing test is one of several basic tools doctors use to help reach a diagnosis of Alzheimer’s.

Of course, a seasoned practitioner can pick up subtle cues even before administering the tests. “When I’m taking a medical history, I pay attention to how the patient understands and answers my questions, and how fluent he is in giving the history,” says Dr. Pradip Shah, who practices geriatric medicine in West Caldwell (also a 2011 Top Doctor). He also poses a few simple math problems and throws out a couple of jokes to see if the patient gets them. Then Shah has to rule out other potential causes of dementia, some of which may be reversible (a drug reaction, for instance). “While Alzheimer’s accounts for some 60 to 70 percent of all dementias,” notes Leifer, “15 to 30 percent are caused by other progressive brain disorders.” 

What the test can’t do is identify the disease before it becomes symptomatic. “The National Institutes of Health just redid their criteria for Alzheimer’s disease, recognizing that it’s actually ongoing for up to 10 years before people even come in with the first symptoms,” says Robert Nagele, a researcher at the University of Medicine and Dentistry of New Jersey’s School of Osteopathic Medicine. That may not mean much now, but those 10 years could be crucial if (and many would say when) researchers come up with a drug that significantly slows the progression of the disease. “Early detection,” says Nagele, “will allow for early treatment”— which could translate into years, if not decades, of independent living.

Nagele and his research team at UMDNJ have spent nearly a decade analyzing the blood of Alzheimer’s victims and have come up with 10 autoantibodies that are markers for the illness. Based on that research, they have devised a simple blood test that requires a single drop of blood and can offer results in 24 hours. The test, which appears to be 95 percent accurate, still has to be validated by additional studies to get approval by the U.S. Federal Drug Administration. Assuming that it does, Nagele will then have to find an entity to mass-produce and market it. But if everything goes the way he hopes (as Nagele says, “in the best of all possible worlds”), we could theoretically have a blood test for Alzheimer’s disease within a year.

WHAT CAN WE DO ABOUT IT?
That’s a question Shah hears often, and it’s a particularly disheartening one for him. “I have a large patient population,” he says, “so I can see that, basically, you can’t change anything. That’s very frustrating to doctors and even more so to caregivers.” He says this in spite of the fact that there are two classes of Alzheimer’s drugs on the market now. For mild to moderate forms of the disease, doctors often prescribe one of the cholinesterase inhibitors like Aricept and Exelon, which block the breakdown of acetylcholine, a chemical messenger depleted in the brains of Alzheimer’s patients. For moderate to severe Alzheimer’s, the drug of choice is Namenda, which blocks the production of the brain chemical glutamate, an excess of which can lead to cell death. While both can help to control symptoms, they only work for a limited time, and they don’t work in every patient.

That could all change if even one of the scores of ongoing clinical trials—some of them taking place in New Jersey medical centers—ends up yielding a new class of drug designed to significantly delay the progression of Alzheimer’s. Most of these trials are for drugs that target amyloid plaques—abnormal protein deposits found on the outside of nerve cells (neurons) in the brain and a major hallmark of the disease—though at least one trial is focusing on another important hallmark, the tangles of nerve fibers that accumulate inside neurons. Several of the trials are already in phase three, the final step before potential FDA approval. “If they work, if they’re safe and efficacious, then they could be on the market in three to five years,” says Dr. Howard Fillit, a Tenafly neuroscientist and founding executive director of the nonprofit Alzheimer’s Drug Discovery Foundation.

Dr. Jeffrey Apter, a practicing psychiatrist in Princeton, has been in the Alzheimer’s trenches for two decades.  As president of Global Medical Institutes, a Princeton-based corporation that runs clinical trials for a variety of pharmaceutical companies, he’s seen hope flare up and flicker out for drugs that might have made a difference in the lives of Alzheimer’s patients but ultimately could not deliver on their promises. He’s also seen the earliest successes.

“We had patients on Aricept three years before it got approved,” says Apter. “We have patients on Bapi now three years before it may get approved.” Bapi is short for bapineuzumab, an investigational drug being tested at more than 200 sites around the country, which holds out the promise of slowing the progression of Alzheimer’s disease by helping the immune system clear plaques from the brain. If the trials show that Bapi works, and if the drug gets FDA approval, it has the potential to make a real difference in the lives of Alzheimer’s patients, particularly if their disease is caught—and the drug is started—in its earliest stages. Those, of course, are a lot of ifs—not surprising, given how much remains to be understood about the workings of a very complex disease.

WHAT IS ALZHEIMER’S DISEASE?
For two decades, researchers have focused on amyloid plaques not just as a possible target for the treatment of Alzheimer’s, but as a central factor in the workings of the disease. The so-called amyloid cascade hypothesis holds that the deposit of amyloid in the brain actually causes Alzheimer’s disease, and that the ongoing buildup of amyloid is responsible for its progression.

Karl Herrup is not convinced. The Rutgers professor, who chairs the university’s Department of Cell Biology and Neuroscience, has a healthy respect for those plaques—if there were a drug that could clear them from the brain, he says, he’d take it—but he suspects that the ultimate culprit in Alzheimer’s disease is age, not amyloid.

His hypothesis began with an unlined sheet of white paper, which is the way Herrup approaches any new disease model. On the paper, he noted all the pertinent facts he could think of about Alzheimer’s. Then he tried to reorder them in a way that made sense, without regard to previous theories. What he ended up with was a three-step model of the disease that pivots on the idea of age.

“Age is far and away the single greatest risk factor that we know of for Alzheimer’s disease,” he says. While we don’t know exactly how aging works in the body—“Aging is like art,” says Herrup; “you know it when you see it, but when you try to describe it, it’s actually quite ephemeral”—we do know that as the brain gets older, it weakens and becomes more susceptible to injury. And injury—in the form of head trauma like concussion or the kind of vascular damage seen in stroke—can breach the brain’s major line of defense, the blood-brain barrier, essentially a group of protective cells lining the brain’s capillaries. Normally, the barrier protects the brain from potential toxins circulating in the blood; when it breaks down, those toxins can flood the brain, and that, says Herrup, may begin the process that ends up as Alzheimer’s disease. “The problem that arises from a loss of blood-brain barrier integrity is that it increases the risk of a chronic inflammation starting in the brain.”

There is evidence that the connection to brain injury is more than hypothetical. For five years beginning in 2006, a Chinese research team studied more than 600 men and women aged 55 and older and found that those with vascular risk factors like high blood pressure and high cholesterol—which could lead to stroke and other injuries to the brain—were twice as likely to develop Alzheimer’s disease over the span of the study.  

In at least some people, Herrup suspects, brain injury leads to chronic inflammation, and inflammation, as it does elsewhere in the body, prompts some cells to divide. There’s just one problem with this process when it takes place in the brain: Neurons can’t divide. They can, however, begin the process of division by replicating their DNA and creating enough for two cells. After that, Herrup says, “they seem to stall; all of a sudden the nucleus has twice as much DNA as it’s supposed to have. It can’t go forward and totally divide, so it’s stuck in this limbo, but it’s forever changed.” And it’s the eventual death of those strange new cells, Herrup posits, that leads to the devastating brain changes of Alzheimer’s disease.

Like Herrup, Nagele at UMDNJ thinks that a breakdown in the blood-brain barrier is crucial to an understanding of Alzheimer’s and may even be the trigger. In Nagele’s model of the disease, the role of toxins in the brain is played by rogue antibodies, proteins the body creates to fight off disease. He believes that the development of Alzheimer’s involves “a two-hit process”: “You have to have one or more antibodies in your blood that can bind to something in the brain,” he says, “and you have to have a blood-brain barrier breakdown, which allows the antibodies to get into the brain.”  Without both, he hypothesizes, you can’t get the disease.
    
WHAT DOES THE FUTURE HOLD?
Right now, this is all hypothetical, but Herrup believes that the new model could eventually lead to a novel way of fighting Alzheimer’s. In the lab, he and his team have been hard at work trying to discover how healthy neurons keep in check the lethal process of almost-dividing. They have already identified two proteins that may be involved, one or both of which could, Herrup says, “offer some new targets for intervention.” 

Whatever tomorrow’s Alzheimer’s drugs end up targeting, prevention, suggests neurosurgeon Howard Fillit, is likely to look a lot like our current approach to preventing heart disease, which amounts to a combination of medication (such as Lipitor, to control blood cholesterol) and commonplace practices like exercise and a heart-healthy diet. “Ultimately,” he says, “the goal will be to prevent the dementia from Alzheimer’s disease by combining lifestyle measures”—controlling hypertension with diet and exercise, for example—“with new drugs that will, hopefully, come to market.”

That future can’t arrive too quickly for those who live with a family history of Alzheimer’s—a large and expanding group that includes both Nagele (on his mother’s side) and Teixeira, whose grandmother also suffered from dementia.

For now, Teixeira is not thinking too much about the future, busy as she is with the day-to-day business of balancing work, caregiving and a new marriage. “I didn’t get married until I was 47,” she says, “and my mother would always tease me. She’d say, ‘I want to be able to go to your wedding before I’m in a wheelchair.’  And last year she was at my wedding, but she was in a wheelchair. It was bittersweet.”

If Fillit’s vision—and the work of researchers like Herrup and Nagele—come to fruition, there should be considerably less of the bitter, and a great deal more of the sweet, for many of us.

Leslie Garisto Pfaff is a frequent contributor on health, education and other topics.

Click here to view the Top Doctors database.


Related Articles:

Jersey Choice: Top Doctors
The Annual Unveiling: Summer Beauty Tips
Only Mom Need Know: Snacks That Emphasize Nutrition
January's Hot Trends
Whatever the Weather: Modernizing Emergency Relief Efforts
Shedding Light on Autism in Ghana
Her Big Idea Is A Winner: A Morristown Teen's Invention Offers Hope


If you like this article please share it.