Part 5 of a five-part report.
Besides generating data, DIAN is charged by its funders to make its information available to scientists around the world. Now that resources have been built and data are pouring in, DIAN leaders are focusing on how to open its doors more widely. They are working to simplify and accelerate sharing, and voted in specific measures at the Alzheimer’s Association International Conference, held July 22 to 28 in Toronto. At the same time, knowledge about even earlier stages of Alzheimer’s disease is growing and becoming ever more widely known. This may gradually squeeze the space for many people’s wish not to know if Alzheimer’s is in their future.
To broaden access to its data, DIAN will retire a three-tiered access system. Until now, DIAN’s core leaders, who acquire and process the data, have enjoyed exclusive access to test hypotheses for a predetermined set of core publications before the networks’ larger group of site leaders could run and publish their own analyses. In turn, sites had one year of exclusivity before outside investigators could obtain access. At AAIC, DIAN leaders decided to no longer distinguish between cores and participating sites, though they stopped short of voting to lift the one-year access exclusivity vis-à-vis outside investigators just yet.
“As a core leader, I am not funded to do all the mutation-specific analyses that we need in order to understand the variance and find modifying genes. I want others to use this data so more science gets done, though I would offer expertise on how to conduct these analyses,” said Alison Goate of Icahn School of Medicine at Mt. Sinai University in New York City, who leads genetics within DIAN.
Outside scientists will still have to submit their projects for review, in part to ensure that data and samples remain blinded. In the past, DIAN has fielded criticism for its slow review of resource and data requests. The process has already sped up this year, with 10 requests granted since April, but opening the DIAN database by eliminating exclusivity for core leaders should make sharing faster still. “We want DIAN resources to be widely shared,” Bateman said.
With regard to tissue samples, the genetics core has banked 79 fibroblast lines representing 26 mutations in APP, PS1, and PS2 from DIAN participants who underwent a punch biopsy to create this resource for scientists around the world. Also available are eight iPSC lines, one each from a carrier and a non-carrier of three different PS-1s and one PS-2 mutation. Researchers can obtain these biospecimens with a brief description of the research rationale here. DIAN’s CSF biorepository currently contains 2,276 fluid samples collected from 15 sites, 268 longitudinal CSF, 393 longitudinal plasma, and 340 longitudinal serum samples, said Washington University’s Anne Fagan, who leads the DIAN biomarker core. Thus far, the core has filled 650 CSF and 120 plasma sample requests.
Another step to broaden access is an anonymized data set Virginia Buckles of Washington University, St. Louis, and colleagues are preparing. It took some years to assemble this, because each field must contain data from at least five people to render re-identification impossible. The data set is not quite ready yet, but once it is, it will be freely downloadable without application. Called the Anonymized DIAN Data Set, it will be so thoroughly scrubbed of identifying information that not even Buckles will be able to trace data back to the individuals from whom it came. It will contain dummy ID numbers, EYO, carrier status, and other variables, but not age, ethnicity, family relationship, etc. This data set can support exploratory analyses. To continue privacy protection of participants, about half of whom do not know their mutation status, deeper work with restricted DIAN data will still require a traditional data request, Buckles explained.
Preventing anyone from figuring out who is behind a given result in DIAN, either accidentally or intentionally, has been a central concern for DIAN from the outset. This commitment has animated everything DIAN scientists do, from its internal procedures to restricted outside access and even to limitations on how research results are graphed and published. Even so, as more data comes flooding into the project’s databases, it is becoming apparent that keeping a lid on unblinding will become trickier over time. After all, DIAN is a massive project to study particularly the preclinical decades of ADAD, and as it succeeds, the disease will eventually become well known in all its early features to scientists and participants themselves. In general, cohort studies of other autosomal-dominant diseases do not guarantee indefinite blinding.
A long-term forgetting test reveals differences in carriers and non-carriers of dominantly inherited AD mutations seven years before their expected year of clinical onset. [Courtesy of Philip Weston, UCL.]
Already, preclinical cognitive hints of Alzheimer’s disease are under intense scrutiny in many research groups. They could become highly useful to science but also lead people to realize early on whether they are on the road to AD. To cite but one example, Philip Weston of University College, London, showed at AAIC that among his center’s local cohort of 35 at-risk relatives of families with autosomal-dominant AD, mutation carriers could be picked out as early as seven years before EYO by way of a long-term memory loss that unmasks a failure of memory consolidation. Carriers and non-carriers were in their 30s and performed equally well on standard cognitive testing. The two groups also did equally well learning a word list and remembering it 30 minutes later. Alas, seven days later, the list tended to be wiped from the minds of the mutation carriers while their relatives still remembered it. Carriers were twice as likely to have forgotten, and their group’s 95 percent confidence interval did not overlap with that of the non-carrier group. The result recapitulated a recent mouse study (Jun 2016 news on Beglopoulos et al., 2016.)
“We can distinguish preclinical AD from normal aging by assessing long-term forgetting,” Weston told the audience. He cited three phases of memory: encoding (tested right after the word list), early retention (tested after 30 minutes), and long-term retention. On the long road from healthy cognition to AD dementia, long-term retention fails first, early retention fails at the CDR 0.5/aMCI stage, and encoding fails at the dementia stage. This long-term forgetting may be part of what troubles people when they voice subjective memory complaints, an early stage of dementia that is drawing increasing research attention across the field at large. At AAIC, several dozen presentations attempted to define the cognitive, imaging, and other features of this state, called, variously, subjective cognitive decline or subjective cognitive impairment.
Weston’s AAIC presentation was news to researchers because they do not generally assess word-list memory days after the study participant has left their clinic. But word-list recall—the 30-minute, short-term kind—is the memory skill that tends to crumble first in DIAN longitudinal observation, as well. In fact, Weston’s finding is an extension of studies reporting as early as 1998 that verbal memory such as remembering lists preceded other cognitive problems in ADAD mutation carriers years before they became symptomatic (Fox et al., 1998). If long-term forgetting was replicated as a specific alarm bell of future Alzheimer’s dementia in late-onset disease, it could become useful to help the large asymptomatic LOAD therapy trials that are ramping up internationally, and which are mightily challenged to recruit participants. Trial leaders at AAIC said that with a simple follow-up phone call after a trial participant’s screening visit, this feature could possibly pick out people who are likely to have AD pathology in their brain, and reduce the screen failure rate for these trials.
Even so, the flip side of Weston’s finding was not lost on researchers at AAIC. Could a DIAN participant guess their mutation status by way of this long-term forgetting? Nick Fox of University College, London, does not think so, because one would first need to know what the age-related normal range is. But more broadly, as scientists are learning more about the nature of the preclinical phase of AD, families have become more observant as well. “In my experience, these families continually monitor themselves for memory problems, and both carriers and non-carriers can be convinced they are going to get the disease because of memory lapses,” Fox wrote to Alzforum.
The field’s collective push toward ever-earlier trials in the Alzheimer’s prodome brings with it a general realization that even without direct genetic disclosure or a data-handling mistake, research results such as this and future ones will increasingly reveal features of preclinical AD that may tip off carriers to their mutation status earlier than was previously the case.—Gabrielle Strobel
- Beglopoulos V, Tulloch J, Roe AD, Daumas S, Ferrington L, Watson R, Fan Z, Hyman BT, Kelly PA, Bard F, Morris RG. Early detection of cryptic memory and glucose uptake deficits in pre-pathological APP mice. Nat Commun. 2016 Jun 1;7:11761. PubMed.
- Fox NC, Warrington EK, Seiffer AL, Agnew SK, Rossor MN. Presymptomatic cognitive deficits in individuals at risk of familial Alzheimer's disease. A longitudinal prospective study. Brain. 1998 Sep;121 ( Pt 9):1631-9. PubMed.
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