Can a new drug shield the brain's delicate, vital neurons—the cells that process and transmit information—from the ravages of Alzheimer's disease? A study now underway at 50 hospitals in the United States aims to find out.

Many Alzheimer's disease drugs under development focus on clearing away beta-amyloid, the toxic protein fragment that forms plaques between neurons. As more and more of these plaques accumulate, once-healthy neurons begin to deteriorate, lose their ability to function and communicate, and ultimately die.

But instead of targeting beta-amyloid directly, what if Alzheimer's disease could be slowed by a drug designed to protect neurons from damage? That's the goal of the NOBLE study, which is testing just such a compound, called T-817MA.

A Neuroprotective Drug

In animal studies, T-817MA appears to be neuroprotective, meaning it seems to shield neurons against amyloid toxicity, says Laurie Ryan, PhD, chief of the Dementias of Aging branch in the division of neuroscience at the National Institute on Aging (NIA). (The NIA supports the Alzheimer's Disease Cooperative Study, or ADCS, the consortium conducting the trial, but is not funding the trial directly; all financial support comes from Toyama Chemical Co., the drug's manufacturer.)

"The drug also seems to be neurotrophic, which means it makes new connections between cells," says Robert Stern, PhD, director of the Clinical Core at Boston University's Alzheimer's Disease Center and an investigator for the NOBLE study.

That combination of neuroprotective and neurotrophic qualities is rare, Dr. Stern says. In the current lineup of compounds being studied for Alzheimer's disease in human trials, he says he knows of no other drugs that offer that specific double benefit.

It's also promising that T-817MA is an entirely new drug, Dr. Ryan says. "Repurposing existing drugs or compounds that have been tested in other diseases happens often, and it's great. But this is a novel compound that was found to have these neuroprotective properties."

And that's good news for the Alzheimer's community, says James Hendrix, PhD, director of Global Science Initiatives for the Alzheimer's Association. The fact that the trial focuses on the mild to moderate stages of the disease is also important, he adds. "Prevention trials and studies targeting early-stage disease are exciting, but they won't help people whose disease has already progressed."

Looking for Volunteers with Alzheimer's

The NOBLE study is now in phase 2, which means it successfully finished preliminary phase 1 human studies to test its safety. In phase 2, the researchers will investigate both the safety and effectiveness of the drug. They are now recruiting a total of 450 people aged 55 to 85 to participate. Volunteers must have mild to moderate Alzheimer's disease and be stable on donepezil (Aricept) or rivastigmine (Exelon), two drugs currently approved for the symptomatic treatment of Alzheimer's. People on galantamine (Razadyne) are ineligible due to potential drug interactions. Those taking memantine (Namenda) are also ineligible because the trial drug is designed to be added on to an acetylcholinesterase inhibitor like donepezil or rivastigmine.

Unlike studies that look at ways to slow or prevent the onset of Alzheimer's disease early on, or even before symptoms appear, the NOBLE trial is designed for people who already have dementia caused by the disease. "Alzheimer's drugs, such as donepezil, memantine, and rivastigmine, help people for a limited amount of time. We are hoping that this drug will help people continue to function better for a longer period than current therapies," Dr. Ryan says.

The researchers hypothesize that the drug will prevent further damage to neurons by protecting them from the harmful effects of the amyloid protein, Dr. Stern says. "And for the neurons that are still living, we hope this drug will improve connections between them."

Searching for Clues

The study will use two tests to compare people who are taking the new drug with those who are receiving a placebo. The first is called the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog), a commonly used measure of overall brain function. It tests cognitive functions like the ability to name objects, perform a series of steps involved in a specific task (such as addressing and mailing a letter), and respond to an increasingly complex series of commands.

The other is the ADCS-Clinical Global Impression of Change, or ADCS-CGIC, which records doctors' observations of changes in the patient's cognitive, functional, and behavioral performance since the beginning of the trial. It also includes information reported by the patient's spouse or adult child about his or her ability to perform common activities of daily living, such as using the telephone or microwave, bathing, taking medication, and preparing meals.

"We're not looking for improvement, necessarily, but less decline in the group taking the drug," says Dr. Stern. "That's probably the best we can hope for right now and in the foreseeable future. It's unlikely we'll see significant improvement in people who have already started losing cognition."

Rules of Engagement

Robert Stern, PhD, director of the Clinical Core at Boston University's Alzheimer's Disease Center and an investigator for the NOBLE study, urges people with mild to moderate Alzheimer's disease and their families to consider participating in the trial. "Recruitment for Alzheimer's disease trials is not easy, and requires a tremendous amount of money and effort nationally and internationally."

To volunteer for the study, participants must:

• Be 55 to 85 years old and have a diagnosis of mild to moderate Alzheimer's disease
• Live in the community (either at home or in an independent living facility, but not in a nursing home)
• Be stable on either donepezil (Aricept) or rivastigmine (Exelon)
• Have a study partner (such as a spouse, adult child, or other companion or caregiver) who has at least 10 hours of contact with the participant weekly, and who can attend study visits
• Weigh no more than 220 pounds
• Commit to approximately 12 to 14 office visits that may last a couple of hours or most of the day
• Take medication daily and consistently, and save the packaging to bring back for the next visit in order to keep track of the medication
• Agree to regular imaging scans; people who cannot have a magnetic resonance imaging (MRI) scan would have computed tomography (CT) scans instead.

Vital Reminder: Enroll in a Trial

The Alzheimer's Association estimates that 5.1 million Americans currently have Alzheimer's disease. By midcentury, that number is expected to rise to 13.5 million people, with nearly half in the severe stage of the disease.

"Between one-third and half of people aged 85 and older have Alzheimer's dementia," says Dr. Stern. "But the disease doesn't just affect people in their 80s. Baby boomers are turning 60 at the rate of 330 an hour, and it's not uncommon for people in their 50s and 60s to have symptoms of Alzheimer's and, in many cases, dementia from the disease. In order to change this picture, we need adequate numbers of people to participate in clinical trials."