The rarest kind of Alzheimer's disease, the form that is inherited from parent to child with a cruel 50 percent likelihood, has long been marked by its untapped opportunities. Affected families have made possible both the discovery of the first three Alzheimer’s genes and the elaboration of the amyloid hypothesis. Beyond that, these families have much more to give to research, and gain from it, because the preclinical phase of AD can be studied and targeted for prevention in still-healthy carriers who are certain to develop AD in the future. This has been difficult to do because these families are rare and live all across the globe. Now, an international registry called Dominantly Inherited Alzheimer’s Network (DIAN) is preparing to fill the gap. Starting in January 2009, this 10-center, publicly funded consortium will open its doors for adult children of eFAD families. Carriers, non-carriers, and those who do not want to know their genetic status are welcome to join a comprehensive study that aims to pave the way for future prevention trials.
Series
DIAN: International Network to Chart AD Preclinical Decade
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.
References
News Citations
- DIAN Part 2: The Science, Inner Workings of the Network
- Spain Offers Study for Families With Monogenetic Dementia, eFAD
- DIAN Part 3: Genetic and Data Protection for Volunteers
Book page Citations
Other Citations
External Citations
Further Reading
DIAN Part 2: The Science, Inner Workings of the Network
Scientifically, the Dominantly Inherited Alzheimer Network (DIAN) will test three hypotheses. The first proposes that there is a long presymptomatic period in eFAD mutation carriers who will get AD, and that biochemistry and brain imaging can detect this outwardly quiescent phase. This hypothesis rests on ample prior data, and it can be cleanly tested by comparing how a range of potential biomarkers change, or do not change, in mutation carriers versus their non-carrying siblings.
The second hypothesis posits that the preclinical changes will show up in a given sequence in time. By that hypothesis, CSF Aβ42 would start edging down first, amyloid deposition would start appearing in the brain next, and then the person’s metabolic activity in brain would fall off and certain brain regions would atrophy. Somewhere in this sequence, subtle personality and cognitive changes would emerge. Here, too, prior evidence exists to support each of these markers; however, how many years before AD symptoms they begin and if indeed they appear in this order is unknown.
Third, DIAN proposes that symptomatic autosomal-dominant AD is largely the same as “sporadic” or late-onset AD. The test for this hypothesis will come from comparing DIAN’s results to those gathered in ADNI and also to data collected at the National Alzheimer’s Coordinating Center. ADNI follows 819 people diagnosed as cognitively normal, mildly impaired, or having early AD for three years with the same assessments to be used in DIAN. For its part, the NACC is an ongoing initiative to assemble clinical and cognitive assessments, at baseline and longitudinally, on tens of thousands of AD patients seen at the 29 federally funded U.S. Alzheimer’s Disease Research Centers in a unified way. To date, the centers have submitted uniform data on more than 12,500 patients to NACC, Morris wrote in DIAN’s grant application. In order to enable comparison of all these large datasets, the 10 DIAN centers will use the Uniform Data Set (UDS) of clinical and cognitive instruments that is also being used by the ADRCs, in ADNI, and by the ADCS.
Beyond the Unified Data Set, which uses paper and pencil, DIAN is considering eventually using Web-based cognitive tests, as well. This is necessary because many DIAN participants will be young and cognitively healthy, whereas the UDS was developed for elderly people and those whose cognition is already declining. Hence, the investigators expect that some study DIAN participants may ace the UDS tests, which may then miss the first signs of subtle change. At a planning meeting held last July in Chicago, neuropsychologists from the participating sites discussed what those additional tests should focus on. One early clue that might be exploited is that people who later develop dementia tend not to improve when they take the same test repeatedly. Cognitive domains such as problem solving, attention, visuospatial processing, and language hold promise as well, as do assessments of personality changes years prior to dementia. Ideally, these additional tests should be set up such that the participants can take them independently at study visits or even at home; they are not intended to supplant whatever protocols the participating sites already are using for their other studies, emphasized Martha Storandt of WashU. These computerized tests are still being developed, and will be incorporated into DIAN later, not when the study starts next January.
A planning and training meeting held in Chicago last July made evident that DIAN is being set up to cooperate closely with other large initiatives in AD research in terms of its structure, assessments, and data handling. In terms of structure, DIAN’s coordinating center at WashU will take advice from a steering committee that is the main decision-making body, plus from an external advisory group. The steering committee includes the leaders of the ADCS (Aisen) and ADNI (Michael Weiner of UCSF), besides WashU’s DIAN administrative and core leaders and the leaders at the participating sites. Representatives from the FDA and NIA, one family member each of an English-speaking and a Spanish-speaking family with eFAD, and Kimberly Quaid of Indiana University, a bioethicist and expert on genetic testing in neurodegenerative diseases (see article on genetic testing), serve on this committee. Like ADNI, DIAN has a resource allocation review committee. This group oversees requests by outside scientists to obtain fluid or tissue samples for their own analyses. It comprises research leaders who are active on this issue within the ADCS (Douglas Galasko, UCSD), ADNI (John Trojanowski, UPenn), and the Alzheimer’s Disease Genetics Consortium (Gerard Schellenberg, UPenn). Also like ADNI, DIAN has cores dedicated to the requisite sub-areas: clinical, biostatistics, neuropathology, biomarkers, genetics, imaging, and informatics, each headed by a scientist at WashU. The genetics core, headed by WashU’s Alison Goate, will collaborate with the National Cell Repository for AD in Indianapolis for the establishment of cell lines, as done in ADNI. For a detailed look at DIAN’s structure and people, see slides: DIAN structure, steering committee, other committees.
In terms of assessments, DIAN’s imaging, clinical, and biomarker cores will collaborate especially closely with ADNI and ADCS, Morris said at the July meeting. Led by WashU’s Mark Mintun, the imaging core contracted with Clifford Jack at the Mayo Clinic, Rochester, Minnesota, to perform quality control and preprocessing for MRI scans taken at the 10 sites, and with Robert Koeppe of the University of Michigan, Ann Arbor, to do the same for PET scans. DIAN has retained Chet Mathis at University of Pittsburgh, who heads ADNI’s amyloid imaging sub-study, to certify that the participating DIAN sites synthesize 11C-PIB correctly. The participating sites will upload their scans to WashU’s DIAN central archive, from where the quality control groups will pull it, check it, resolve with the local sites any problems that might crop up, and provide some pre-processing. They will then release the clean imaging data to DIAN investigators for further processing and analysis. In a departure from ADNI, DIAN’s raw scans will be placed under quarantine until quality control is finished, whereas ADNI scans are available instantly to the world’s scientific community (see ADNI Snafus). DIAN will use the ADNI imaging protocols so that data will be comparable, but details about the precise MRI sequences will be updated slightly to reflect progress in neuroimaging since 2004 when ADNI was designed. All DIAN participants will receive MRI and PET scans so scientists can measure brain atrophy, search for small hemorrhages, and image the buildup of amyloid deposition, the brain’s glucose metabolism, and some network function.
DIAN’s clinical core will work closely with the ADCS. This consortium was founded in 1991 by the National Institute on Aging; Neil Buckholtz of the NIA is that agency’s representative of the ADCS, ADNI, and now also DIAN. The late Leon Thal of UCSD pioneered the ADCS, and he supported a registry for observational science preceding prevention trials until his untimely death (see Thal quotes in eFAD prevention story and eFAD clinical trials essay). While the ADCS is best known for running clinical trials, it focuses intensely on markers as well. “The ADCS is involved in imaging and biomarker work. That is critical for finding disease-modifying therapies, because they are most likely to succeed at the earliest, even preclinical stages. DIAN is a clear extension of that interest,” Aisen said at the planning meeting in Chicago. The ADCS has much to offer DIAN because its research staff has spent the past decade establishing clinical infrastructure and standard operating procedures. This may not be flashy, career-building science, but it is essential for large, multicenter clinical studies to succeed.
The ADCS provides clinical and cognitive assessment monitoring for ADNI, and will do the same for DIAN. In practice, this means that ADCS will create a DIAN site. Its staff will support DIAN’s clinical, biomarker, and genetics cores. For example, the 10 distributed sites will enter their raw clinical and psychometric data to a DIAN site at ADCS, where ADCS staff will perform quality control, among other functions. Once those data are “clean,” ADCS staff will upload it to the DIAN central archive at WashU—an informatics resource that will host a unified database of all DIAN data. This arrangement makes available to DIAN ADCS’s innovations around real-time, online data entry from distributed sites. For example, data entry for ADCS studies resembles online ordering, where quality assurance is built into the system so that it prompts the person entering clinical data to fix problems with given fields before allowing the data into the system. The online, real-time case report form then serves as the source document, not the original paper record. “The key about that is that only clean data will be allowed into the system,” Jennifer Emond of the ADCS said at the Chicago DIAN meeting. ADCS also will deploy its clinical operations group to help coordinate DIAN. They develop and distribute procedures manuals, train site personnel in these procedures, and make sure sites adhere to them. The ADCS has nine permanent clinical monitors, who evaluate sites for their capacity to carry out DIAN and review HIPAA, regulatory, and other records to ensure sites follow the protocol procedures. Both Devon Gessert and Mario Schittini from the ADCS noted that their team will keep DIAN moving apace by insisting that sites submit their data within three days of a participant’s visit, but they softened their muscle-flexing with offers to provide extensive training in study procedures. “All this serves to reduce site variance,” Schittini said.
The DIAN center at ADCS will also support DIAN’s fluid biomarker work. Like in ADNI, DIAN study participants will be asked to donate blood and CSF at each visit, though there are some small differences in how they will be analyzed. (For example, DIAN will not analyze homocysteine, isoprostane, and sulfatide levels, as the investigators believe that these factors are less important in autosomal-dominant AD than in sporadic AD. It will also not collect urine samples.) The 10 sites will send most samples to the DIAN biomarker core at WashU (led by Anne Fagan) for analysis. Here, too, the ADCS will coordinate sample collections at the sites and information management, before transferring clean data to the DIAN central archive.—Gabrielle Strobel.
This is Part 2 of a three-part series. See also Parts 1 and 3.
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References
News Citations
- Bumps Along the Way—ADNI’s Snafus
- DIAN: Registry for eFAD to Chart Alzheimer’s Preclinical Decade
- DIAN Part 3: Genetic and Data Protection for Volunteers
Other Citations
External Citations
Further Reading
DIAN Part 3: Genetic and Data Protection for Volunteers
DIAN asks a lot of its study volunteers. Much like in ADNI, repeated clinical, neurological, and neuropsychometric testing are only part of their to-do list at every visit. In addition, they will have blood drawn for genetics analyses, enter a brain scanner at least three times (for PIB-PET amyloid imaging, FDG-PET metabolic imaging, and MRI structural and functional imaging), and will be asked to undergo a lumbar puncture to donate a CSF sample. All this adds up to a three-day stay. DIAN pays for travel and accommodation, and study staff handles the necessary arrangements.
Participants will have the option to see a genetic counselor and, if they wish, obtain formal genetic testing to find out if they inherited their affected parent’s mutation or not. This is strictly optional; family members can also participate in the entire six-year study without ever knowing their genetic status if they prefer. DIAN pays for genetic counseling and/or testing, if desired. Because families with eFAD are so few and far between, and themselves often scattered across cities and states, most DIAN participants may have to travel to the nearest DIAN site for study visits. In practice, this means DIAN participants, many of whom will be middle-aged working adults and/or parents of young children, must arrange for days off and childcare.
Concern that all this would place too great a burden on family members and overstretch the coordination capacity on the part of study staff has held back the formation of such a large network in the past. However, in previous research with smaller groups of potential DIAN volunteers at individual sites, scientists were struck by how motivated these volunteers proved to be. For example, Randy Bateman’s ongoing eFAD study at WashU, which requires a four- to five-day visit complete with a 36-hour hospital stay during which CSF samples are collected hourly from an indwelling catheter, has seen a determined response from participants. Bateman will lead the clinical core of DIAN. In another eFAD study at WashU, 27 of 28 eligible family members participated in all assessments ranging from imaging to lumbar puncture, Morris wrote.
Lumbar puncture is a concern, because fears about it are pervasive. But in ADNI, too, researchers initially expected that a fifth of participants would consent to a lumbar puncture, and then were surprised to discover that more than half did, prompting an add-on study to the original protocol to accommodate people’s willingness to participate fully. “Never underestimate the patient,” Clifford Jack noted about this experience. Jack, of the Mayo Clinic in Rochester, Minnesota, heads not only the ADNI MRI core but will also oversee MRI quality control for DIAN’s MRI scans. Growing up, prospective participants in DIAN have watched autosomal-dominant AD decimate their families, and therefore many of them have an abiding interest in helping advance research. Reisa Sperling, who leads DIAN’s Boston site, noted that many relatives of affected families know exactly what may lie ahead of them, and that some are waiting for a comprehensive study that directly addresses their situation. (See also interview with eFAD carrier.)
At present, the 10 DIAN centers together follow roughly 400 candidate research participants for the network. In addition, some families do not know if they are candidates for DIAN because their family has not conducted testing for a causative mutation. In some of these situations, DIAN will support what’s called “discovery genetic testing,” i.e., a scan for a pathogenic mutation in APP and PS1 (PS2 mutations are exceedingly rare) in an affected parent with AD. However, this can only be done in rare pedigrees where the pattern of inheritance is truly autosomal-dominant, not every time AD clusters in a family. Other risk factors, most prominently ApoE4, can drive up a family’s risk, but DIAN is only for those mostly stringently genetic cases where an asymptomatic mutation carrier faces near certainty to develop AD.
DIAN is currently funded to enroll 300 participants and follow them for six years. Cognitively healthy and very mildly symptomatic people can enter DIAN. Relatives with more advanced disease cannot enter the study because DIAN’s primary goal is to characterize the asymptomatic period; however, they are encouraged to consider consenting to an autopsy and donating samples of brain tissue to DIAN’s neuropathology core, headed by Nigel Cairns at WashU. This would not only confirm the genetic and clinical diagnosis of AD in the family, but also ensure a uniform neuropathological examination of DIAN families.
The DIAN investigators expect to enroll about as many carriers as non-carriers. Importantly, participants need not know their genetic status, and study staff as well will stay blinded to a person’s mutation status wherever possible. How often study participants will visit their DIAN site depends on how many years away in age they are from their family’s average age at onset. Those who are more than 10 years younger will only come once every five years. Those between 10 and three years younger will come every two years. They will also talk on the phone once a year with study staff, and if that call triggers concern, or if their spouse/partner/sibling believes that their cognition appears to have declined, they will be invited for annual visits. Those between three years younger and three years older than average family age at onset will come once a year, and those who are more than three years older will have annual phone calls with study staff.
One point of pride for ADNI lies in the broad access to its data and the ease of data sharing. Open access was a decision from the get-go, and ADNI’s informatics leader Art Toga at UCLA and his group have built informatics systems that make it possible for all qualified scientists around the world to download its research data for their own analyses. DIAN’s data will also become widely accessible but not in the same instant open-access fashion, Morris wrote. This is partly because families with eFAD are considered a special population who require heightened sensitivity for privacy; hence de-identification of the data will have to be done with extra care. Partly, DIAN investigators want quality control before data are shared. And partly, DIAN investigators will be encouraged to use the data first; once they do, the data will become more publicly available. The details of access to DIAN data are still being worked out, Morris wrote. Dan Marcus, who leads DIAN’s informatics core, is a neuroinformatics researcher at WashU with a commitment to data sharing. Marcus directs development of an open source data management platform called the Extensible Neuroimaging Archive Toolkit (XNAT), as well as the public data sharing project OASIS (see ARF related news story). While DIAN preparations continue, this group has set up www.dian-info.org, which will post public information about DIAN, much as www.adni-info.org does for that initiative. At this initial stage, the group is focusing on developing the tools necessary for data management within the research network and for building DIAN’s integrated database. —Gabrielle Strobel.
This concludes a three-part series. See also Parts 1 and 2.
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References
News Citations
- Changes In Cortical Thickness Mirror Loss of Network Connectivity in AD
- DIAN: Registry for eFAD to Chart Alzheimer’s Preclinical Decade
- DIAN Part 2: The Science, Inner Workings of the Network
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