A vaccine or drug that can prevent healthy, yet high-risk people from developing the memory loss, confusion and other devastating cognitive problems that characterize Alzheimer’s disease is the Holy Grail for researchers, drug companies and patient advocates.

Interest in developing such a treatment is growing as it becomes increasingly clear that physiological changes occur in the brain years, even a decade, before patients experience the cognitive decline that we think of Alzheimer’s disease (AD). What was once deemed “early Alzheimer’s” is now recognized as a much later stage of the disease. And the truth is that dozens of drugs have failed to show efficacy in treating AD and the few available offer only modest benefits for alleviating symptoms. Frustration, paired with new research illuminating the molecular underpinnings and progression of Alzheimer’s is fueling a keen interest in devising drugs that can treat the “clinically silent” phase of the disease; years before cognitive symptoms become apparent. An oft-quoted analogy is heart disease, where preventing atherosclerosis is far more successful than treating heart failure.

Interestingly, researchers now think that drugs designed to prevent or delay Alzheimer’s disease may be far less effective in treating its later stages. The reason: New preventive treatments focus on what researchers believe is the underlying cause of AD—namely, the over-production and build-up of a protein fragment called amyloid-beta in key areas of the brain. The goal is to either slow production of amyloid-beta or to remove it from the brain before it creates the tangles and clumps that damage neurons. In the laboratory, some of these drugs are proving quite effective at doing this. But the few clinical trials of amyloid-clearing therapies have proved disappointing, says Todd Golde, an Alzheimer’s researcher at the University of Florida College of Medicine. In a recent Q&A, he tells The Scientist that the problem is that these new drugs appear to have little effect on quelling symptoms or halting progression of AD because they are being tested on people with late-stage disease who have “longstanding pathology and massive signs of neural degeneration,” i.e. the damage has already been done. Golde asks, “Why would removing the trigger of the disease at that point really have a major benefit?”

So far, drug companies have shied away from funding Alzheimer’s prevention trials with their newer (and more promising) investigational drugs because they view such clinical trials as too expensive and risky. And as currently designed, they are. Prevention studies tend to take a minimum of 5-7 years, cost upwards of $500 million and by design, include thousands of research subjects. Almost all such trials enroll moderate-to-late stage Alzheimer’s patients, or at best, those who are mildly cognitively impaired. There is a good likelihood that amyloid-clearing drugs will prove ineffective in these patients and companies worry that the trials will run so long that their proprietary drug will lose patent protection. Taken together, “conventional treatment trial design could sink the prospects of what might have been a respectable pre-symptomatic therapy,” says Gabrielle Strobel, author of a wonderful series of articles on AD research and therapies on the Alzheimer’s Forum site (a non-profit, research-driven group that accepts no money from drug companies).

Of course, companies are aware that a drug that could prevent or slow progression of Alzheimer’s disease would have an enormous market as our population hits its “senior bubble” in a few years. According to one study, worldwide sales of Alzheimer’s disease treatments are expected to more than triple from  $4.3 billion in 2009 to $13.3 billion in 2019 as new agents with the potential to slow progression of the disease enter the market. Some 35 million people are afflicted by AD and other dementias; this number is estimated to nearly double every 20 years, to more than 65 million in 2030. If used judiciously in people clearly at risk, these new drugs could end up reducing suffering as well as saving money by cutting the huge medical costs associated with the years of care required for AD patients.

But there are a lot of hurdles to overcome. Ideally, research subjects should be at risk of AD but still healthy, with no sign yet of cognitive decline. That means any potential therapy must have an excellent safety profile—in other words, highly unlikely to cause significant side-effects or long-term health issues. The other problem is that in order to demonstrate prevention, drugs must bring about observable, physiological changes in the brain; i.e. proof that they block or slow the build-up of amyloid-beta plaques. The standard clinical tests—mostly memory and other cognitive drills—that are designed to track cognitive decline over time are useless for tracking progression of the disease in the brains of pre-symptomatic people.

As I wrote in this HealthBeat post, in the last few years, researchers have identified several promising biomarkers (proteins found in spinal fluid and structures seen on brain scans) that give insight into the changing pathology of the brain as disease progresses. Why not use biomarkers to measure effectiveness in prevention trials? It turns out that the FDA is still struggling with a fundamental question; if a drug has a measurable effect on biomarkers for amyloid-beta plaques in the brain, is that biomarker then also providing an accurate indication of how effective the drug will be in preventing disease progression? Currently, the agency has not approved any biomarker tests and puts the onus on trial sponsors to show that changes in biomarkers reasonably predict that a person will benefit clinically from a drug.

The National Institute on Aging helped fund basic research and early development of AD biomarkers. But the larger-scale clinical trials needed to provide hard evidence that a biomarker can either diagnose AD or provide an accurate measure of its progression are also very costly. Companies are reluctant to fund these studies too, and those that have find the approval process for biomarker tests gets complicated by the larger ethical issue of using of these tests as general screening tools to diagnose Alzheimer’s in healthy adults. These tests will undoubtedly be expensive, and accuracy is absolutely imperative. With doctors unable to offer prophylactic treatment, the testing could result in nothing but dread and suffering for those who are notified that they are positive for the disease.

The issue is coming to a head. To date, there are several promising imaging agents in Phase III clinical trials. On January 20th, an advisory committee at the Food and Drug Administration voted 13-3 to reject a New Drug Application (NDA) from Avid Radiopharmaceutical (owned by Eli Lilly since November) for Amyvid, the first imaging agent that could be used specifically to diagnose Alzheimer’s disease.

Avid was seeking approval to market its imaging agent to help diagnose the presence of so-called “β-amyloid aggregates” (the protein plaques) in the brain. The NDA stated only that a negative scan would be clinically useful for ruling out beta-amyloid plaques as the cause of dementia or other cognitive symptoms in patients. Daniel Skovronsky of Avid told Alzheimer’s Forum, “We see Amyvid as simply an added tool in the clinicians' armamentarium to help them find out what’s going on in a patient.”

The Alzheimer’s Forum notes that Avid’s NDA does not seek FDA approval for its imaging agent to be used to diagnose Alzheimer’s disease or as an AD screening test for cognitively healthy or mildly impaired people. “The question of what a positive scan means was not on the table at this meeting. That said, many practitioners are interested in amyloid imaging for these purposes, and worried patients are expected to demand it. Indeed, some advisory committee members asked pointed questions about what, in the real world, would stop Amyvid from being used broadly should it be approved.” Surely these concerns were implicit in the committee’s rejection.

For the Alzheimer community, the lack of preventive options can be excruciating. NIH-funded trials of possible candidates; estrogen replacement, anti-inflammatory drugs like naproxen (Aleve), Vitamin E and other off-patent and relatively safe therapies have been disappointing. As I reported in my last Alzheimer’s post, an NIH panel recently said; “Although numerous interventions have been suggested to delay Alzheimer’s disease, the evidence is inadequate to conclude that any are effective.”

How do we get around the seemingly insurmountable hurdles to conducting prevention trials? The answer is to pursue a novel and seldom-used concept in commercial drug development: cooperation. Historically hyper-competitive pharma companies will have to join forces; public funders and industry will have to balance the need for open access to certain data (on the accuracy of biomarkers, for example) with intellectual property concerns; and principle investigators will have to hew closely to ethical guidelines when conducting their trials—agreeing, for example, to only include people who are at high risk for AD.

There are signs that the various stakeholders are at least open to the idea of cooperation—if not fully convinced. According to Strobel, last January “high-level representatives of 19 different pharma, biotech, and medical companies from across the U.S. and Europe – businesses that compete fiercely for the same market – spent the entire day cooped up in one room. There they engaged in a searching, at times surprisingly candid, discussion with academic research leaders, funders, and regulatory and statistics experts. Their topic? How they could set aside their competition in order to advance a shared vision of testing candidate drugs in people who are at imminent risk for Alzheimer’s disease (AD) but have no symptoms.”

The organizers of the conference, Eric Reiman and Pierre Tariot from the Banner Alzheimer’s Institute and the Arizona Alzheimer’s Consortium in Phoenix, Arizona, suggested proceeding in a “precompetitive” fashion—with joint funding from public and private sources for prevention trials. Strobel, who attended the meeting, reports that things got “sticky” when conversation turned to choosing which drug or drugs to use in such a “public-private pre-symptomatic” trial. “[P]harma’s pre-competitive spirit comes to a cold stop when the discussion broaches their own or their competitors’ drugs,” she writes, and the entire day passed without a specific treatment name having been uttered by any of the attendees.

The meeting last year marked the official start of the Alzheimer’s Prevention Initiative (API), a program funded by the National Institute on Aging that includes a five-year research initiative to speed the development of vaccine and other novel approaches for preventing AD. How it proceeds is still to be determined. Drug companies want the FDA to extend patent protection for any new drugs they include in prevention trials. They also want the FDA to use an expedited approval process for these drugs to cut down on research costs and to accept biomarker results as evidence that a therapy is effective. Meanwhile, the government has offered to help pay for biomarker research in industry-funded prevention trials in exchange for the right to openly publish the biomarker results. The cooperation game is still in its early stages—for now, promising research will continue to take a backseat to the business of pharma profits.

As these negotiations continue, it may be that the first prevention clinical trial will involve a group of people in Colombia who carry a gene for a rare form of early-onset familial Alzheimer’s disease.  Reiman and Tariot have already visited the area where an NIH-funded trial on biomarkers is currently underway and the FDA has signaled that it might be willing to accept biomarker data as surrogate trial results in this group. Now the researchers need to find a company willing to take the plunge and test a promising preventive therapy.

In the end, the likelihood of finding one “cure” or effective therapy to delay progression of this most devastating of illnesses is probably slim, according to Howard Fillit, Executive Director of the Alzheimer’s Drug Discovery Foundation (ADDF). “Most chronic diseases, particularly those associated with old age, involve multiple pathways. We still haven’t cured heart disease…We still don’t have a disease-modifying drug for diabetes, although insulin has been available for over 100 years.” For Alzheimer’s progress will be incremental, he says, “The goal is to delay onset—we won’t eliminate it.” Clearly, it’s time to get started on that worthy goal.