By Gabrielle Strobel

Editor's note: For definitions of early onset familial Alzheimer disease (eFAD), early onset AD (EOAD), and late-onset AD (LOAD), please visit What Is Early Onset Familial Alzheimer Disease.

Historically, people with early onset Alzheimer disease have handed science two breakthroughs. The German woman, Auguste D., whose case gave the disease its name, was 51 when she came to Alois Alzheimer's attention. He published her case 100 years ago. Some 80 years later, families with early onset AD in England, the U.S., and elsewhere donated blood, and dying relatives donated their brains so scientists could identify three genes that cause AD. Looking to the future, it is again these stricken families who might make their biggest contribution yet by paving the way to prevention.

To families and researchers alike, preventing Alzheimer disease represents the ultimate goal. The idea would be that doctors screen people for certain risk factors of AD and prescribe preventive measures before the disease process begins. Or doctors would screen for the earliest markers of the disease process and prescribe preventive treatments as soon as the underlying disease starts developing, years before symptoms of the clinically defined disease become apparent. This vision remains perhaps decades away from becoming reality, but recent scientific progress has put it within reach, at least conceptually. Families with early onset familial AD have the potential to validate preventive treatments before science embarks on the much larger and more expensive endeavor of proving their efficacy in the population at large. In this way, families with eFAD could give their third, and biggest, gift yet, not only to others in their situation, but possibly to all people with Alzheimer disease, including the vast majority who get it late in life.

A growing number of scientists are recognizing this opportunity. They realize the field may well be casting aside promising therapies because they are being tested exclusively in people whose brains have already withered beyond a point of no return. Increasingly, scientists view the symptomatic, diagnosed phase of AD as merely its final stage—an end-organ failure that caps a decade-long pathogenic struggle. One analogy scientists cite is with cancer. Even the most potent drug stands a greater chance at saving a life when it can get to work on a small, asymptomatic tumor diagnosed early than when it's rolled out late in the metastatic stage. The two main challenges in developing a preventive treatment are spotting people at the early, presymptomatic stage and knowing that the intervention indeed has prevented the disease.

In AD, anti-amyloid therapies are a case in point. An early, failed vaccine trial managed to remove amyloid pathology from the brains of patients, but it helped them only a bit with the clinical symptoms of their disease (see follow-up results). Researchers argue about what this means. One view holds that the vaccine came too late. "If you wait until all the neurofibrillary destruction and the synapse loss has occurred, you can take all the amyloid-β you want out of the brain and it may not do much good," said William Klunk, a physician-researcher at the University of Pittsburgh, Pennsylvania. ""It would be a tragedy to pass over a good preventative therapy simply because we tested it in the wrong population. I want to see anti-amyloid trials in FAD carriers who already have amyloid pathology but no symptoms yet. I am convinced it is this kind of secondary prevention that will show us the optimal effect of these therapies."

Other scientists take a dim view of anti-amyloid therapies altogether. They argue that available resources should be poured into alternative approaches because amyloid-β is not what causes AD. Both sides agree, however, that prevention studies could settle this critical question.

Typical prevention studies are so large, difficult, and expensive that relatively few of them can be done at any given time. Because scientists do not know who will get the disease of interest in the future, they enroll thousands of people in separate treatment and control groups so enough people will develop disease for the scientists to be able to detect a difference between the treated group and the untreated group. This trial design requires that huge cohorts of people be followed over many years. In stark contrast, in families with genetically diagnosed eFAD, researchers can know exactly which individuals will develop disease and which won't. A trial to intervene and prevent disease in them would therefore require far fewer people.

Klunk is one of the most ardent proponents of testing anti-amyloid therapies in eFAD families. With his colleagues Chester Mathis and others, Klunk has developed the most advanced version of an up-and-coming group of chemical tracers that render amyloid visible in the brains of people after they have spent an hour in a PET scanner. The Pittsburgh group, as well as some others, is observing how β amyloid pathology builds up over time in the brains of people with FAD mutations who have no symptoms whatsoever, but will get them within the next 5 to 15 years (Klunk et al., 2007). Other ongoing work with this tracer is suggesting that the amyloid load in some areas of a person's brain has built up nearly to its full extent even before symptoms are apparent. During the subsequent clinical course of AD, it increases primarily in additional brain areas as the pathology spreads more broadly. Still further ongoing work compares amyloid deposition and emerging, subtle symptoms in very mildly affected people. It suggests that, at this early stage, amyloid load still tracks with impairment (Forsberg et al., 2007), though in later years it no longer does.

In the minds of some scientists, this could perhaps mean that amyloid is an epiphenomenon to AD. But other investigators believe it instead indicates that the brain tries successfully for some years to counter whatever damage the amyloid pathology wreaks. By that logic, symptoms would show up as the brain exhausts its capacity to compensate. In other diseases, such as Parkinson's, heart failure, or kidney disease, doctors know that there, too, a person can remain largely without symptoms for years despite significant reductions in organ function.

Klunk wants drugs to start removing amyloid during these presymptomatic years. He argues that there are no better candidates to test the value of this treatment approach than eFAD mutation carriers who are a few years shy of the age when symptoms typically strike in their family and whose amyloid has been spreading from one brain area to the next for some years. "In those families you essentially have a crystal ball. You can enroll them 10 years ahead of the time when disease will start with certainty," said Klunk.

Eventually, Klunk suggests, all people who have amyloid but no symptoms, not just mutation carriers, may be seen as having presymptomatic AD, and will be offered preventive treatment at this point, if one is available. The percentage of people who have PIB binding in their brain but no clinical AD symptoms increases with age. Klunk said that data from several groups is suggesting that PIB binding roughly tracks tens of years behind the age-dependent prevalence of AD in the general population. For example, some 20 to 25 percent of clinically normal 70-year-old people are amyloid-positive, and 20 to 25 percent of 80-year-old people have AD. This makes sense based on clinical data suggesting that amyloid deposition starts about a decade before diagnosis, Klunk argues.

Klunk is not alone. Other scientists, as well, dream of offering presymptomatic carriers a trial. They envision a two-pronged trial along these lines: First, it would record people's disease indicators, including imaging of brain volume, activity, pathology, as well as imaging of white matter change. Simultaneously, the trial would monitor certain molecular markers in spinal fluid and blood. At the point when in a given person those indicators begin to change in the direction that foretells disease—brain regions shrink, activity dims, amyloid appears, levels of tau and perhaps inflammation markers in spinal fluid creep up—the person would start a treatment. Over the course of weeks and months, the scientists would monitor if the treatment changes any of those markers back to normal. Will the amyloid signal diminish? Does the tau level in spinal fluid drop? Does inflammation cool down? Over the course of years, the scientists would monitor for clinical symptoms to learn if the treated people indeed escape their genetic destiny of Alzheimer disease.

The scientists who study these families are personally invested in them. They watch relatives fade, they see children grow up in fear. They speak about what beautiful people the carriers are. But the scientists have broader plans, as well. They believe that heading off AD in people with eFAD will pave the way to doing the same in the millions who get AD later and without a known genetic cause. They envision prevention to come into being step by step: First prevent AD in carriers of known APP and presenilin mutations, secondly repeat the feat in people whose risk is high because a parent has AD and they themselves carry the ApoE4 gene variant, and thirdly try to extend the knowledge gained to catch AD presymptomatically in the general population. "I really do believe that what helps one group will help the other. We could save decades by testing familial early onset AD first," said Daniel Pollen, a physician-researcher at the University of Massachusetts Medical School in Worcester.

The notion that success in eFAD families might transfer to other forms of AD makes sense to scientists who believe that the rare and common forms of AD differ in their origin but not in the way they eventually damage the brain. Research data available to date suggest that imbalances in the production and degradation of the amyloid-β peptide lead to a situation where amyloid eventually accumulates and disturbs the proper working of brain cells. Put simply, many scientists believe that people with eFAD mutations generate more of those proteins than the general population and thus get AD earlier in life. This is a major question that observational studies of eFAD families (see Essay 7) are aiming to answer. By contrast, people with LOAD are thought to clear away normally produced amyloid less efficiently over time, a slowdown that is aided and abetted by numerous age-related changes in oxidative stress, gene expression, protein transport in their nerve cells, etc. The end result, however, is roughly the same: amyloid-β piles up and sets off destructive changes in the brain. "Based on the data we have available to us," said Randall Bateman of Washington University, St. Louis, Missouri, "there is a good chance that if you affect the final common pathway of amyloid-β, you have a real potential to make a difference for both forms of AD."

Preventive medicine offers an instructive lesson. Consider statin drugs. They lower LDL, or "bad" cholesterol, and in turn reduce by a third a person's risk of future heart attacks or strokes. Their impact on the nation's cardiovascular health, not to mention billions of dollars in annual sales, have made them a runaway success story. Few people realize, however, that scientists chose rare genetic forms of familial hypercholesterolemia for their very first human tests exploring the potential of the earliest statin. Those tiny trials lured in large pharma companies, who took over development. The trials also stimulated NIH funding for subsequent primary prevention trials. Researchers interviewed for this series pointed out that the history of statins (see sidebar) could inform strategies for developing preventive treatment in AD, as well.

NEXT: Devil in the Details—The Challenges of Prevention Trials