Posted 3 October 2007
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Where to Turn for Research: Human Studies of eFAD
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)?
View list of ongoing eFAD studies
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
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.