Alzheimer’s Researchers Push for Answers

by Aaron James

“We have a tsunami coming at us, and we’re sitting in a rowboat,” says neurologist Richard Mayeux of Columbia University.

By 2050, 13.5 million people are expected to have Alzheimer’s disease, at an annual cost of more than $1 trillion, according to the Alzheimer’s Association. Delaying onset of Alzheimer’s by just five years could reduce the number of patients by half, researchers say, if life expectancy doesn’t increase.

The impending epidemic is giving scientists, government agencies and the pharmaceutical industry a reason to collaborate. The urgent need for a solution, combined with emerging technologies, is driving a transformation in the fight against the disease: Instead of waiting until symptoms appear to begin treatment, the idea is to detect and respond to the disease in the earliest stages, before it can irretrievably ravage the brain.

“People take Lipitor because it lowers the risk of heart disease. We want to find the same thing for Alzheimer’s,” Mayeux says.

What makes the new approach possible are recently developed methods to detect and measure biomarkers — biological indicators of disease. New brain scanning techniques, genetic tests for “suspect” genes and measures of spinal fluid (which reveal what’s going on in the brain) probably won’t benefit patients for years, but they’re giving researchers a more sophisticated picture of the disease’s pathology.

The Banner Alzheimer’s Institute in Phoenix, Ariz. has already begun implementing this new philosophy. Alzheimer’s researchers Eric Reiman and Pierre Tariot have created the Alzheimer’s Prevention Initiative, a collaborative effort by scientists, academics and the pharmaceutical industry. “We want to help launch the era of Alzheimer’s prevention research,” Reiman says. “It’s a true collaboration between stake holders, the people afflicted, the families and people at risk.”

The institute is currently developing two studies, to begin in 2012, that will treat apparently healthy people who show the highest genetic risk for developing the disease. “They will be more or less free of symptoms when we begin,” Tariot says.

The researchers will then use biomarkers to track the impact of experimental drugs. “The hypothesis is that if we give pre-symptomatic people these treatments, we should be able to see some evidence of the effects,” Tariot says.

One study, to take place in the region around Medellin, Colombia, will focus on 2,000 living members of 25 extended families who share a common ancestry and a gene that, for some, leads to Alzheimer’s while they’re still in their 40s. Though early onset Alzheimer’s is rare, the underlying mechanisms are thought quite similar to when it appears later in life, usually in the 70s and 80s.

The initiative’s second study, to be conducted in the United States, will test 50,000 people aged 60 to 80 to see if they carry two copies of a gene, ApoE4, that evidence suggests is linked to Alzheimer’s. Of those people, Reiman expects 400 to be enrolled in the study, with the remainder entering a database for future study.

Participants will receive an experimental drug and be monitored for two years. If the treatment produces no improvement, the investigators will try another drug, looking for one to help prevent onset.

Giving experimental therapies to otherwise healthy people raises ethical questions. But researchers, doctors and pharmaceutical executives say the urgency of the problem justifies a certain amount of risk, which they’ll disclose to everyone participating in the studies.

“We need to be able to say: Here is what we know and here is what we don’t know about this drug,” Tariot says.

Instrumental in these and other preventive studies are new brain imaging technologies that can track the progress of the disease.

A Philadelphia company, Avid Radiopharmaceuticals, has developed a new PET scan dye, AV45; it binds with the amyloid protein that creates plaques in the brain that are the disease’s hallmarks. The dyed plaques then become visible on a PET scan.

“This is a compound that sees amyloid in the brain,” says Dr. Michael Weiner of the Alzheimer’s Disease Neuroimaging Initiative, who was not involved with the dye’s development, but intends to use it in future studies. “Another way of saying it, is that it sees Alzheimer’s in the brain,” which is confirmed by a subsequent autopsy.

Before the advent of amyloid imaging technologies, autopsy was the only way to see amyloid plaques and therefore obtain a definitive Alzheimer’s diagnosis.

Although AV45 is not the first amyloid dye, it represents an important advance because researchers can use it for about two hours before it degrades. Use of an earlier amyloid dye was limited because its fleeting radioactivity — it’s only effective for 20 minutes — meant it had to be made on site and used immediately.

“This tracer can be used much more broadly,” researcher Susan Landau, of the University of California, Berkeley, says of the newer AV45.

Landau is leading a study that seeks to determine which biomarkers can best predict Alzheimer’s. Her work has shown that a particular PET scan, which measures overall brain function, used in conjunction with memory tests, can distinguish which patients with mild cognitive impairment (an early Alzheimer’s symptom) will go on to develop Alzheimer’s and which won’t.

“Overall, in the field, there’s the hope that we will be able to predict it before symptoms appear,” Landau says.

To date, remedies for Alzheimer’s remain frustratingly limited. Currently, the FDA has approved two types of drugs for Alzheimer’s: acetylcholinesterase inhibitors, such as Aricept, Razadyn and Exelon, and the so-called NMDA receptor antagonist, Namenda. The drugs don’t provide a cure; they only treat the cognitive symptoms and are effective for a few years, if at all. Some patients report success with the treatments; others see no improvement.

More than 150 Alzheimer’s drugs are already in developmental stages, most targeting amyloid plaques, although more novel ideas are also being tested.
Enthusiastic as researchers are, they face a long road. Even if they determine which biomarkers are best at predicting the disease, and discover drugs that slow the progress of those biomarkers, there’s no guarantee that the drugs will arrest the cognitive decline.

Recent experimental drugs have been effective in removing amyloid from patients’ brains, for example, but produced no change in their symptoms. That has fueled debate about whether the telltale plaques may be only a sign of the underlying disease, not its cause.

“Amyloid plaques may be like gravestones that signify the end stage of the disease,” Tariot says. “The toxicity may have occurred long before the plaques appear.”

“Creating knowledge is a long way from making drugs,” acknowledges Howard Fillit of the Alzheimer’s Drug Discovery Foundation, which engages in “biomedical venture philanthropy” by bridging the gap between public funds for research and what industry will spend for drug development. The foundation invests in start-up biotech firms, existing companies and academic research in an attempt to accelerate the process. Because the financial risk is so high, only 20 of the 1,600 worldwide biotech companies have an Alzheimer’s program. It can cost $1.2 billion to bring a new drug to market, Fillit says.

“We give this money for a very specific purpose and we want specific milestones,” Fillet says. “The only way out of this conundrum is to find new drugs.”

In a report released last year, the Alzheimer’s Study Group, co-chaired by former Speaker of the House Newt Gingrich and former Sen. Bob Kerrey, warned that the Alzheimer’s epidemic will progress like the disease itself, slowly. But if we ignore it, the group says, it could have the same disastrous consequences as ignoring the levees in New Orleans or looking the other way as sub-prime loans subverted the financial system.

But the convergence of an enormous population at risk and research innovation has made Alzheimer’s a national priority.

“We’re excited about this change of momentum,” Tariot says. “We’ve captured people’s imagination and attention.”