By Gabrielle Strobel

"My mother raised us in hardship, with my father ill and violent with early onset AD. Now she has to watch the disease slowly take her children away. She cares for them yet again, and fears for her grandchildren."

—Unaffected sibling, 47.

"Our family feels so helpful instead of helpless when we are involved in research. Even our most advanced affected sibling talks about how (s)he wants to help others, even though (s)he probably can't be helped."

—Unaffected sibling, 46.

One hundred years after Alois Alzheimer described a mysterious dementing illness that left the brain shrunken and peppered by dense protein deposits, Alzheimer disease has become a household word. Today's baby boomers are all too familiar with the agony and havoc wrought by AD. They care for ailing parents while wondering if the disease will derail their own expectations of a strong and lucid old age. Most are vaguely aware of the public health crisis that looms in the coming decades, with 12 million U.S. cases and 81 million worldwide by 2040 if preventive therapies are not found. But lost amid these vast numbers is a rarer form of the disease that remains largely unknown to society. It is early onset familial Alzheimer disease (eFAD), a particularly aggressive version that strikes in the prime of life, often just as its victims are raising their own families. Some begin to deteriorate in their early thirties. Worst, this form of AD is inherited, afflicting one generation after the other. These familial early onset cases are relatively rare—an estimated 1 to 5 percent of all cases. But that small fraction still works out to some tens to hundreds of thousands of people in the U.S. alone, making early onset AD as common as cystic fibrosis, Lou Gehrig's disease (ALS), or Huntington disease. "Early onset AD is not something people think about, or talk about," said neurogeneticist Thomas Bird of the University of Washington, Seattle. "For example, Huntington's disease is a defined entity and many in the general public know what you mean when you say the word. The idea that there are families with a gene that causes AD in people in their forties is just not on anybody's radar screen."

But these families exist, often in isolated obscurity, and they wrestle with a special set of problems. A diagnosis of hereditary mid-life AD is a catastrophe for the whole family. Personal questions can be wrenching. Whom to tell? When and how to tell the children? Will the marriage hold? What about genetic testing? Families face financial peril. How long can the affected parent hold on to his or her job? How can the spouse keep supporting the family? What about social security disability, long-term care insurance, college tuition for the kids? What to do if the patient makes irresponsible financial decisions? How best to persuade a 45-year-old that it is time to stop driving? What does one tell young children who wake up to find their parent wandering about the house in the throes of dementia? Finding care can be maddeningly difficult because nursing homes, even AD care institutions, tend to be poorly equipped to handle demented patients who are so young and healthy. Imagine managing a 180-pound man who has the judgment of a 3-year-old. "Care placement at the moderate stage is a major problem in England, just like in the States," said dementia researcher Nick Fox of London. "Some patients end up for years bed-bound and mute because their hearts and lungs work well."

A sense of isolation compounds the burden. Alzheimer support groups have become an important source of advice and companionship for caregivers and, increasingly, early stage patients themselves. But most of these groups serve people who are a generation older. Support groups have to "click" to be productive for all members, and early onset caregivers say they do not fit in because of differences in their activity level, life problems, topics of conversation, and even simple things like music preferences at gatherings.

Lack of recognition poses problems throughout the community, from fellow shoppers who gawk as a childishly playful patient embarrasses her frazzled daughter in the supermarket, to the social security clerk sneering doubtfully, "Alzheimer's? Yeah right!" as a sibling applies for disability for the recently fired brother. Indeed, simply finding out what is wrong can involve a frustrating odyssey of wrong diagnoses and treatments, as primary care providers and even some community-based neurologists and psychiatrists do not recognize early onset FAD.

The full force of this disease hits families in mid-life, while they are already busy juggling jobs and family responsibilities. Teenagers are thrust into caring for a parent who can no longer guide them through their formative years. These teens reach adulthood wondering if they will ever marry, have children, and risk propagating the disease further. Each sibling and child of an eFAD patient faces the wrenching choice of whether to be genetically tested for a disease that is incurable. Among those who undergo the test, some bravely try to assert control over their futures by using pre-implantation genetic diagnosis to bear mutation-free children. Others terminate a fervently desired, naturally conceived pregnancy if it turns out to carry the disease gene. Yet others, in one of the unpredictable, deeply personal twists of life and hope prevailing against one's seemingly better judgment, decide to just have a baby the old-fashioned way even as they know they are carrying the disease silently themselves and could pass it on to their children.

Families with early onset FAD have contributed profoundly to science's understanding of the disease. The first mutations were discovered in the early 1990s in the three genes known to cause the autosomal-dominant form of AD. Since then, new mutations in these genes have cropped up regularly. By the spring of 2007, a worldwide database maintained in Belgium had captured reports of about 200 separate disease-causing mutations in about 450 families, all of whom volunteered to participate in research. The discovery of these eFAD genes and the ensuing molecular and cellular biology have established the scientific knowledge base that supports virtually the entire program of rational, mechanism-based drugs currently in development for all of Alzheimer disease.

Ironically, however, members of these very same families are excluded from participating in treatment trials because of their young age. Most Alzheimer clinical trials do not enroll people younger than 55 or 50. By that age, many people with early onset FAD are well into the middle stages of dementia and brain degeneration, by which point drugs are much less likely to help than when given at earlier stages. Indeed, many trials exclude patients at these advanced stages. People who carry an eFAD mutation are forced to passively await symptoms; there are no prevention trials available to try to stop or blunt the impact of their genetic destiny. Presymptomatic carriers are outwardly healthy, raising the required safety bar for experimental drug administration to a practically insurmountable level. Yet a growing scientific consensus that clinically diagnosed AD represents the end-stage of a decade-long silent disease process raises the question of whether presymptomatic AD carriers really are free of disease. A few pioneers have decided to bravely face genetic testing and participate in observational biomarker research. This is a burden for them, and every visit to the research hospital brings all the fears and worries painfully to the surface. And yet they are finding comfort in this engagement with science: at least they are fighting the disease on behalf of their children. But even these studies are few and not widely known among prospective participants. Families talk about a sense of isolation and exclusion.

A growing number of scientists acknowledge that early onset FAD patients are not only underserved but could also have yet more to contribute if only the field could come together. To date, obstacles at every level of the research and drug development process have prevented scientists from approaching clinical research on eFAD as a shared goal. Clinical geneticists and genetic counselors abide by an ethics code of not influencing at-risk relatives toward obtaining genetic testing. At-risk relatives hesitate to embark on genetic testing while there is not a drug trial in which they can enroll. Spread all around the country, family members are in the care of neurologists who are not communicating with colleagues about what could be done better. AD neurologists tend to be fiercely protective of "their" families for legitimate privacy reasons but also perhaps with an occasional dash of professional rivalry thrown in. In this fragmented situation, no investigator can find enough patients to give sufficient power to their own fledgling efforts to test biomarkers and drugs, promising as they may be. Pharmaceutical companies point to current Food and Drug Administration (FDA) positions and are loath to shoulder added risk in drug development. They prefer a strategy whereby they push drugs to market "as fast as possible" by testing them in late-onset patients, as they have always done, hoping that eFAD patients will then benefit when the drugs come to market. Scientists counter that this strategy may overlook some drugs that could be useful for early stage or even preventive treatment. Patient advocacy groups for other rare diseases complain that the FDA does too little to promote compassionate use of study medications. For early onset FAD, discussion of compassionate use or expanded access has not even entered the public arena. Yet the dire situation clearly begs the question of when a potential drug is safe enough that such discussions should be held.

Amid all of these perceived barriers, research on potential biomarkers and candidate drugs for AD is making strides to the point where new opportunities are opening up. There are tantalizing leads and ideas, even if nothing is formally validated across the field and sanctioned by the FDA. "I believe the answer to successful treatment of AD lies with eFAD families," said Bill Klunk, a neurologist at the University of Pittsburgh who is best known for having co-developed a PET imaging method to visualize amyloid in the brains of living people. "The familial cases have already taught us so much about AD pathophysiology. They can also teach us about early recognition, better therapy, and even prevention, too." Klunk's view is shared by Daniel Pollen, the author of Hannah's Heirs: The Quest for the Genetic Origins of Alzheimer's Disease (Oxford University Press, 1996). Pollen is a neurologist at University of Massachusetts Medical School in Worcester and has followed early onset families for decades. "I believe that the single best study group for any new therapeutic agent is presymptomatic eFAD carriers," Pollen asserts.

The challenge is as much social as it is scientific. If families with eFAD and their doctors organized themselves into a network to share valuable information for clinical studies of biomarkers, they could possibly help themselves, and in so doing help the millions of Alzheimer disease patients at large.—Gabrielle Strobel.

NEXT: What Is Early Onset Familial Alzheimer Disease (eFAD)?