By Gabrielle Strobel
Editor's note: For definitions of early onset Alzheimer disease (EOAD) and early onset familial Alzheimer disease (eFAD), please see our essay,What Is Early Onset Familial Alzheimer Disease (eFAD)?
Families with eFAD who are willing to volunteer for research now have a number of options across the U.S. and Europe. However, families and physicians alike find it difficult to obtain information about such studies and which might be best for a given family. This section briefly describes ongoing studies geared specifically toward eFAD, as well as studies that are targeted more broadly but pay special attention to families with eFAD. The listing is currently focused on a few larger studies, but aims to become comprehensive over time. Alzforum will continually update it and invites researchers from across the world who conduct human studies with familial AD to write to managing editor Gabrielle Strobel (please select "Early Onset Alzheimer Disease" from our Contact Us Category List). We will post a brief description of each study along with a contact address for families who wish to learn more. Likewise, we will report studies suggested by families and list them where appropriate. This page does not solicit study participation; it merely informs interested families.
Even while Alzforum was assembling this listing, the National Institute on Aging issued a call for applications for a grant to fund the formation of an international network for the coordination of individual eFAD research studies (see details of grant announcement). Clearly, the Institute recognizes the importance of this special group of families. The funding would serve to expand and coordinate efforts across different centers so that together, the studies can have more meaning and statistical power. A fundamental problem with current studies is that each of them has few participants because autosomal-dominant eFAD is rare. The grant calls for a network where participating centers would share data, samples, and other resources, and gather data in such a way that it can be analyzed together. Participating volunteers would have access to procedures offered at any of the network centers. In the future, such a network could provide the framework for intervention studies.
First off, four general points about research participation. It is important that families are aware of what kind of information they can and cannot expect to receive through the study, and whether receiving this information is standard or optional. In general, eFAD research studies will not formally disclose research data from ongoing research studies to families. Many people understandably feel they have a right to know about their spinal fluid reading, or their brain scan, but they will not necessarily see those data as the study proceeds, if at all. (To learn why not, see sidebar.) On the other hand, research physicians tend to keep their study participants abreast of everything they hear about emerging treatments, and they educate study participants about the best care and prevention measures available.
Genetic information is treated with special care because of its substantial implications for the individual and for other family members. For many eFAD observation studies, some members of the research team must know a participant's genetic status, but the researchers may or may not be able to share genetic information. If the information is to be shared, it may not be until after the study is completed, and formal genetic counseling is sometimes required. For some people, the desire to obtain genetic information is part of their motivation for joining a study, particularly because research testing will generally be free and not included in the medical record. Many other at-risk relatives do not want to know their genetic status, or want to defer knowing until a later time in their life. They prefer having the testing done purely on a research basis without disclosure to them. That way they can contribute to scientific advances on their family's disease, yet avoid the psychological impact of knowing their genetic future.
Second, research participation itself is always free, as are all procedures and assessments performed during its course. Even so, families who need to travel to a distant site may incur travel expenses or other costs related to taking time off work or obtaining care for young children. People who have or are at risk for FAD are in the work force and raising children, and therefore tend to face tighter constraints on time off and travel than do retired people. For families who are struggling on many fronts already, logistical and financial support can be a deciding factor for whether they are able to enroll in a study, especially if it is far away from home. Investigators seeking their participation are required to be clear about how much logistical and financial support a study will provide.
In recent years, awareness about this issue has increased among institutional review boards. IRBs review and monitor human study protocols; no study can proceed without their approval. Financial support falls into the two categories of expense reimbursement on the one hand, and payment for the time and discomfort of specific procedures on the other. On the former, the availability of research funds, not IRB approval, frequently is the limiting factor. On the latter, academic scientists and IRBs have traditionally felt leery about offering financial incentives that might inadvertently lure poor people into participating in studies that they would not otherwise want to join. But IRBs are increasingly weighing in the grave circumstances of eFAD in their recommendations of what a study should pay for. "I was unsure about whether it was appropriate to pay people for their time spent in a scanner. It seemed insulting to those who do it for altruistic reasons, and an improper enticement for others who might need the money," said John Ringman of the University of California, Los Angeles. "But our IRB felt it was most ethical to compensate people at least minimally for their time, so we do." Each study has a different reimbursement budget; families may want to ask ahead. To spare the family the awkwardness of asking, researchers may volunteer this information up front; in addition, this information is spelled out clearly in the informed consent process.
Third, researchers interviewed for this series emphasized that groups studying eFAD must collaborate with one another. "The one thing that is limited, besides funding, is the patient population. It's especially important to coordinate effort in order to make advances for this special population," says Randall Bateman of Washington University, St. Louis, Missouri. In practice, he added, this means that a given family should have the opportunity to participate in all types of studies, not just the ones that happen to be available at their nearest center or at the center they are already working with. In other words, scientists should look beyond advancing their own favorite technique and refer the families they work with to other collaborating sites for assessments they are not set up to do themselves. For their part, families should feel free to ask for additional opportunities. A related aspect is that researchers must work toward collecting samples and research data in such a way that they can be compared side-by-side between centers and studies, or analyzed jointly across centers. That will boost the power of research on small groups of participants. Here, too, families can make themselves knowledgeable and ask their centers about collaboration and sharing. Invariably, family members insisted that if they are going to lie down for a procedure such as a lumbar puncture, they want to be sure that researchers will make the most of the samples. Families are often grateful to researchers for studying their disease. But they also represent a precious resource for the betterment, potentially, of all people with AD. They are perfectly within their rights to expect of scientists that they compare notes and share the privilege to learn from a family whose members generously put themselves through multiple research procedures.
Fourth, eFAD families play a unique role in the understanding of AD. Although research can be a burden, this burden is offset by the contribution such families can make. Each member of each family must decide whether the burden is worth it. eFAD families have already contributed immeasurably to our understanding of AD, and can also blaze the way to the future. Beyond their well-established role in finding AD genes, families in the past few years have helped scientists to begin to define a crucial prodromal, or presymptomatic, period in the development of AD. As with other research questions, there is extensive research on presymptomatic AD in other populations, too, but eFAD families, especially presymptomatic carriers, are especially important to research. This period precedes by several important years the classical symptoms that begin with forgetfulness and later become official with a clinical diagnosis of probable Alzheimer disease. Research into the prodromal period is actively ongoing, but the current working model describes it as subtle changes at different levels of scientific observation, from biochemical alterations to nerve cell loss to slippage in neuropsychological performance. The concentration of tau protein in the spinal fluid creeps up, while that of the Aβ42 protein drops; certain small brain areas begin to shrink, they use less glucose when called upon; amyloid shows up in the brain in small isolated spots and then spreads. Not until a few years after that does performance in certain cognitive tests, especially those measuring short-term memory and what scientists call "executive function," or planning, organizing, and sequencing, edge downward. The person may seem less sharp, and may be depressed. To cite some examples, one study of families with eFAD showed that years before diagnosis, asymptomatic women who carried the mutation (but did not know it) were more likely to be depressed than same-age relatives who carried the normal gene (Ringman et al., 2004). Another found that 5 years before diagnosis, a brain area called the hippocampus already shrinks faster in carriers than in non-carriers (Ridha et al., 2006), and a third began to visualize amyloid buildup in the brains of asymptomatic carriers (see ARF related news story). It is important for science to be able to develop a set of objective measures for this prodromal period, because then they can move treatment back to an earlier stage where the brain has sustained less damage. Families with eFAD make understanding this period possible, and eventually everyone with AD may benefit.
Below we list ongoing eFAD studies in the U.S. and abroad. We welcome additions. All of these studies include both carriers and non-carriers (the latter serve as a comparison group to help see the effects of the mutation). Some of these studies are invasive or tiring, and the investigators note that volunteers have the right to stop at any time.
|Study Name and Site||Principal Investigators||Procedures||Length of Visits||Support for Participants|
|Familial Adult Children Study (FACS), Washington University, St. Louis, MO||Randall Bateman, M.D.||
||4-5-day stay||Travel and hotel for volunteer and accompanying family member; stipend|
|University of California Los Angeles, Los Angeles, CA||John Ringman, M.D.||
||4-5-day stay||Travel and lodging for volunteer and accompanying family member at UCLA guest house; stipend|
|University of Pittsburgh, Pittsburgh, PA||William Klunk, M.D., Ph.D.||
||2-day stay||Travel and hotel for volunteer and accompanying family member; stipend|
|Massachusetts General Hospital, Brigham and Women's Hospital, Harvard Medical School Boston, MA||Keith A. Johnson, M.D.; Reisa Sperling, M.D.||
||2-3-day stay||Stipend available to offset travel and lodging costs|
|Litwin-Zucker Research Center, Long Island, Great Neck, NY||Peter Davies, Ph.D.||
||Variable||Travel and lodging for volunteer and accompanying family member|
|University College London, UK||Martin Rossor, M.D.; Nick Fox, M.D.||
||Variable||Travel and lodging for volunteer and accompanying family member|
|Hospital Clinic/Villarroel, Barcelona, Spain||Raquel Sánchez-Valle||
||2-day stay||Travel for volunteers living outside Catalonia, follow-up|