Alzheimer's disease doesn't begin the first time you misplace your keys or have trouble remembering a loved one's name. Recent research shows that the illness develops much earlier—possibly as much as two decades before any outward symptoms appear. That's why researchers believe that current treatments may not be effective. By the time the symptoms are apparent, the brain damage may be too far along.

One of the earliest signs of Alzheimer's is the accumulation of amyloid-beta, a sticky protein that occurs naturally in the brain. In a healthy nervous system, excess amyloid-beta is cleared away as fast as it's produced. But if the brain produces too much amyloid-beta, or can't clear it away fast enough, the protein clumps together and is deposited in the brain tissue as amyloid plaques. Many scientists believe that this dysregulation of amyloid-beta is a critical factor in causing the brain degeneration that occurs in Alzheimer's.

In the past decade, thanks to advances in brain imaging technology, doctors have been able to observe these toxic plaques in living brains. Using positron emission tomography (PET) scans, neurologists can now identify people who do not yet show any symptoms of Alzheimer's but are at a higher risk for becoming symptomatic because of an abundance of amyloid in their brains.

This understanding forms the basis for the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) trial, which is currently enrolling patients at 60 sites across the United States, Canada, and Australia.

The Promise of Much Earlier Treatment

"We're hoping to learn whether we can delay or prevent memory decline by starting treatment 10 years earlier than previous trials have done," says Reisa Sperling, MD, the lead investigator of the A4 trial, a professor of neurology at Harvard Medical School, director of the Center for Alzheimer Research and Treatment at Brigham and Women's Hospital, director of the Neuroimaging Core and the Outreach Core of the Massachusetts Alzheimer's Disease Research Center at Massachusetts General Hospital, and a member of the American Academy of Neurology.

She and her colleagues are testing solanezumab, an intravenous drug that they hope can sweep out excess amyloid in the brains of otherwise healthy adults with elevated levels of the protein. This could potentially put a stop to the disease before it ever has a chance to develop.

"The idea is to not let people get clinically symptomatic, or to delay symptom onset for as long as possible," says study investigator Rachelle S. Doody, MD, PhD, a professor of neurology and director of the Alzheimer's Disease and Memory Disorders Center at Baylor College of Medicine and a Fellow of the American Academy of Neurology (FAAN). "We really don't know how big the effect could be or how lasting it could be."

This preventive approach "is very similar to what we do in heart disease, where we try to lower cholesterol before you have a heart attack or stroke," adds Dr. Sperling. "In any disease where we have made progress, we almost always do it by treating people before they have a lot of symptoms."

The Trial Drug

In two previous clinical trials, solanezumab did not successfully slow the progression of dementia in a group of patients with moderate Alzheimer's disease. But when Dr. Sperling looked at the data, she found that people with the mildest form of Alzheimer's seemed to improve on the drug.

"Combined across the two studies, that subgroup [of people with the mildest form of Alzheimer's] had an estimated 34 percent slowing of cognitive decline," she says. "If we could make that happen 10 years earlier, as in the A4 trial, we could prevent dementia in a substantial number of people." Based on that effect, and the fact that the drug appeared to be safe and well tolerated in patients, the researchers felt confident that the compound merited additional testing.

"We don't know whether solanezumab—or any treatment—will be more effective in the early stages of the disease than after symptoms emerge," says John C. Morris, MD, FAAN, director of the Charles F. and Joanna Knight Alzheimer's Disease Research Center at Washington University in St. Louis, who is a member of the Neurology Now editorial advisory board. "But the evidence suggests that it may have a better chance if we administer it before the symptoms appear, while the brain cells are still intact."

Regardless of the outcome of the A4 study, Dr. Sperling is confident that she and her colleagues will learn plenty from the 3,000 PET scans they will be collecting during the trial. "We will learn about the genetic and lifestyle risk factors that help predict amyloid buildup. We'll also understand the factors that tell us whether someone is going to progress toward Alzheimer's dementia, or be resilient and progress more slowly."

For More Information

• The A4 trial website
• Alzheimer's Association resources on Alzheimer's disease
• Alzheimer's Disease: The Basics
• Brain & Life articles about amyloid and Alzheimer's disease

What You Need to Know to Enroll in the A4 Trial

1. You must be between the ages of 65 and 85.
2. You must take a set of thinking and memory tests in order to determine whether your cognitive faculties are intact. If you're already experiencing memory loss or other symptoms of dementia, you will not qualify.
3. You will undergo positron emission tomography (PET) and magnetic resonance imaging (MRI) scans to look for elevated levels of amyloid in the brain, as well as other biological markers of Alzheimer's disease. If your amyloid levels are markedly elevated, you can qualify for the trial; if not, you may be enrolled in another study, which explores what other factors might contribute to Alzheimer's in people without elevated amyloid (see "More to LEARN" below). Whether you qualify or not, you will be given your PET scan results. "In some studies, people are not told what their biomarkers [the biological signs of disease] show," says Rachelle S. Doody, MD, PhD, FAAN, a professor of neurology and director of the Alzheimer's Disease and Memory Center at Baylor College of Medicine. "We want to counsel people to make sure they do not get upset or depressed by the information."
4. If you qualify for the study, you will be randomly assigned to receive either an intravenous (IV) dose of 400 milligrams of solanezumab every four weeks, or an IV solution with no active drug (placebo). You will continue receiving the drug or placebo for three years. At the end of the study, you will have PET and MRI scans again to look for changes in amyloid levels, and take the same cognitive tests to see whether your thinking and memory have improved, worsened, or stayed the same.

Visit A4 Study Site Locations for more about how and where to enroll.

How Alzheimer's Disease Spreads Through the Brain

Plaques and tangles (shown in the blue-shaded areas) tend to spread through the brain in a predictable pattern as Alzheimer's disease progresses. But the rate of progression varies, depending on age at diagnosis and coexisting health conditions, among other factors.

Typically, though, the disease progresses in this way:

• Preclinical AD: Changes may begin 20 years or more before diagnosis.
• Mild to Moderate AD: Generally lasts from two to 10 years.
• Severe AD: May last one to five years.

More to LEARN

An accompanying trial studies amyloid-beta buildup among low-risk people.

Volunteers for the A4 trial who show no sign of amyloid buildup may be enrolled in the Longitudinal Evaluation of Amyloid Risk in Neurodegeneration (LEARN) study. These participants will receive the same brain scans and cognitive tests as those in the A4 trial.

"We'll see whether the amyloid levels of these people in the LEARN study change over time," says study investigator Rachelle S. Doody, MD, PhD, a professor of neurology and director of the Alzheimer's Disease and Memory Disorders Center at Baylor College of Medicine and a Fellow of the American Academy of Neurology (FAAN). "This will help us to understand the risk for Alzheimer's for people whose amyloid is not high."

The researchers all stress that the presence of amyloid in the brain does not guarantee that a person will develop Alzheimer's. Autopsy studies have shown that some people with elevated amyloid never develop the disease. "It may be that some people can tolerate that increased amount of amyloid in the brain and will never develop symptoms of Alzheimer's," says John C. Morris, MD, FAAN, director of the Charles F. and Joanna Knight Alzheimer's Disease Research Center at Washington University in St. Louis. In contrast, some people who show no evidence of amyloid plaques on imaging will still progress to dementia, possibly due to other, still largely unknown risk factors.

The LEARN study hopes to shed more light on why some people develop Alzheimer's and others do not.