DIAN: Registry for eFAD to Chart Alzheimer’s Preclinical Decade
The rarest kind of Alzheimer disease (AD)—the autosomal-dominant form that runs in families—has long been marked by its untapped opportunities. Although understanding the alterations in Aβ metabolism in these genetic forms of AD has been central to the development of the amyloid hypothesis, further knowledge of the mechanisms of AD that might be uncovered by studies of these families has been thwarted by the fact that they are geographically dispersed. Hence, any one center engaged in research into these genetic forms of AD is stymied by the small samples available and the lack of scientific power. The situation is now changing. An international consortium of academic medical centers is gearing up to offer families with autosomal-dominant Alzheimer disease a research program designed specifically for their particular, heritable form of this devastating illness. Led by John C. Morris at Washington University, St. Louis, the $16 million initiative, funded by the National Institute on Aging, unites 10 separate research centers in the U.S., the U.K., and Australia. Their goal is to establish a patient registry for those rare families whose children face a whopping 50 percent risk of developing this disease if one parent has it. All adult children of patients whose Alzheimer’s was caused by a mutation in the APP or presenilin genes can join DIAN. The network is preparing to start enrolling in January 2009, and can accommodate 300 participants.
Called the Dominantly Inherited Alzheimer’s Network (DIAN), the study’s acronym playfully rearranges the letters of ADNI, the Alzheimer’s Disease Neuroimaging Initiative (see ARF related news series). This is more than a word game. The DIAN builds on ADNI’s infrastructure, protocol, and standardization, because it intends to collect data in a uniform manner that scientists can then compare directly with those of the 819 ADNI patients in many ways. In this sense, DIAN expands an ongoing movement to unify in the AD research field, which can sometimes come across as more fragmented and truculent than it actually is. Following the Alzheimer’s Disease Cooperative Study (ADCS), the Uniform Data Set of the National Alzheimer’s Coordinating Center (NACC), ADCC, and ADNI, DIAN represents the latest push to unify the way different groups carry out clinical research. These efforts do not negate valuable research differences between participating centers. Rather, they create a bedrock of uniform instruments and standard ways of collecting data. This later makes it possible to compare results in multicenter studies meant to achieve the field’s overarching goals.
In the case of DIAN, one overarching goal is to understand how AD develops during a presymptomatic decade before people notice symptoms. Another is to create a structure that gives scientific power to small, formerly single-center studies of a tiny population of people who are dispersed across the globe. In that sense, DIAN is an exercise in logistic and even cultural harmonization as much as in science. Families with autosomal-dominant Alzheimer disease account for less than 1 percent of AD cases. They are considered a special and vulnerable population, because a finding of such a gene mutation has grave implications for the entire family (for extensive background, see ARF eFAD series). At the same time these families harbor a unique potential to science, and researchers are clearly recognizing this potential. In essence, adult children who have inherited the afflicted parent’s gene are destined to develop the disease in the future. If they allow researchers to study them at regular intervals while they are still healthy, science has the chance to define objective biological signs that foretell the disease in a given person years before AD symptoms start breaking through the brain’s defenses. These signs, or biomarkers, then offer a handle toward testing preventive medications, much as high serum cholesterol today triggers statin treatment to ward off cardiovascular disease (see ARF statin prevention story).
While drug studies are not part of DIAN’s study plan at present, the hope to test drugs in the next phase is clearly in the back of the DIAN researchers’ mind. “Our long-range goal is to use the DIAN network to conduct trials in carriers of autosomal-dominant AD prior to onset of symptoms. This is part of the reason we are eager and excited to participate in DIAN,” said Paul Aisen. Aisen directs the ADCS, a federally funded consortium of some 80 clinical sites in North America that conducts drug studies and has done much to improve the methodology of clinical trials. Aisen is on DIAN’s steering committee, and the ADCS will actively support DIAN’s operations (see Part 2 of this series).
A growing awareness in the past two years of autosomal-dominant Alzheimer’s, which most often but not always becomes apparent in a person’s forties, fifties, and sixties, has given impetus for this budding international network to identify and follow families with this form of AD. (See a knowledge base on eFAD.) The National Institute on Aging responded to growing interest in the field by requesting an application to build such a network, and this September the agency officially informed Morris that it will fund the six-year study.
AD researchers worldwide know several hundred families who carry APP and presenilin mutations that almost guarantee its carrier will develop AD (see ARF Mutations Directory). Many of them already participate in research at academic centers in the country where they live. In some DIAN centers, for example, at the Institute of Neurology in London, researchers have studied and supported those families for so many years that they are now treating the second generation of patients, who as children came along to the clinic and played when their parents were being seen. For a partial listing of such studies, see eFAD Human Studies essay. But those studies are invariably very small, from a handful to at most a few dozen people at a time. Moreover, each center measures different parameters and even collects data differently. DIAN is news in part because it is the first time 10 such research groups are banding together in a systematic effort to enroll patients into a registry and study them all in exactly the same standardized, uniform way. DIAN will establish a central repository for clinical, cognitive, imaging, and biofluid data, which are gathered and processed in such a way that they can be compared with other large datasets currently being built for the sporadic, more common forms of AD.
Washington University, St. Louis, will host this database and, beyond that, form the network’s administrative core. Researchers at its Alzheimer disease research center have since the 1980s conducted a still-ongoing natural history study. It compares normal cognitive aging to the development of AD and has generated the hypothesis that AD has a preclinical decade. In the past eight years, these researchers, led by Morris and David Holtzman, have focused on characterizing this “silent” decade by searching for predictive biological markers with simultaneous imaging, biochemical, and psychometric research in an ongoing study of adult children of parents with AD.
Besides WashU, DIAN comprises these centers and respective leaders: University of California, Los Angeles (John Ringman); Indiana University in Bloomington (Bernadino Ghetti); Columbia University, New York (Richard Mayeux); Brigham and Women’s Hospital/Massachusetts General Hospital, Boston (Reisa Sperling); Butler Hospital/Brown University, Providence, Rhode Island (Stephen Salloway); Institute of Neurology, London (Martin Rossor), and an Australian consortium including Prince of Wales Medical Research Institute in Sydney (Peter Schofield), the University of Melbourne (Colin Masters), and Edith Cowan University in Perth (Ralph Martins).
Beyond these groups, a number of additional investigators in the U.S. and in other countries have expressed interest in joining, Morris said. The selection of the first 10 was based largely on funding limits, and on the need to keep this complex undertaking manageable. For this reason, Morris started the network with centers demonstrably committed to eFAD that have access to a set minimum number of study participants, that have much of the requisite infrastructure and the assessments from ADNI already in place, and whose language is either English or Spanish, the two languages in which DIAN’s standardized clinical and neuropsychological tests are currently available. That said, however, Morris emphasized that once DIAN is up and running, he will seek to broaden it to involve other research centers. Incidentally, one such center in Spain recently announced that it is beginning a similar study (see eFAD news). Cognitive assessments used in ADNI have recently been translated into Japanese for that country’s own ADNI initiative (see ARF story on worldwide ADNIs); hence, some of the preconditions for DIAN’s future expansion are developing independently in other places.—Gabrielle Strobel.
This is Part 1 of a three-part series. See Parts 2 and 3.
- As ADNI Turns Four, $64 Million Data Start Rolling In
- DIAN Part 2: The Science, Inner Workings of the Network
- Spain Offers Study for Families With Monogenetic Dementia, eFAD
- Worldwide ADNIs: Other Nations Follow Suit
- DIAN Part 3: Genetic and Data Protection for Volunteers
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