Nobody knew each other’s name. Even so, 60 people who either were at risk of having an autosomal-dominant Alzheimer’s mutation, or were accompanying someone who was, exchanged information about a shared problem. There were moments of validation—“Denial has divided my family, too!”—and apprehensive questions—“Do you want to know if you have it?” Family speakers on the program addressed the audience anonymously. Hotel staff knew only that they were hosting a medical symposium. The conference had no title. Such was the secrecy surrounding the first meeting of German-speaking families who are affected by dominantly inherited Alzheimer’s. It took place earlier this month near the historic city of Würzburg, a few miles northwest of Alois Alzheimer’s birth house in the small Frankonian town of Marktbreit.

Discretion notwithstanding, the conference marked a milestone. Starting in 2012, German researchers led by co-organizers Mathias Jucker at the Hertie Institute for Clinical Brain Research in Tübingen and his colleagues Adrian Danek and Johannes Levin at Ludwig-Maximilian-University in Munich, built a German branch of the increasingly worldwide DIAN observational study network. All three scientists have appointments at the German Center for Neurodegenerative Diseases (DZNE), which funds the German DIAN study. The two German DIAN sites have thus far recruited 50 participants from families plagued by pathogenic presenilin 1 and 2 mutations, APP mutations, or APP duplications. Scientists currently estimate that approximately 80 such families exist in Germany, though additional families in the country or its near neighbors may not yet know that a dominantly inherited gene causes their family condition, or about the DIAN initiative as a study opportunity. Public knowledge about autosomal-dominant AD remains limited in central European countries.

A 2012 story in Germany’s news magazine Der Spiegel anonymized sources to tell a family’s struggle with autosomal-dominant AD. See the text below for a link to the article. [Image courtesy of Spiegel Verlag.]

As is the case for the parent DIAN network, led by Randy Bateman at Washington University, St. Louis, the German arm of DIAN began as an observational cohort meant to prepare the ground and collect run-in biomarker and cognitive data for subsequent preclinical treatment studies with anti-amyloid and possibly other investigational drugs. When the DIAN trials unit (DIAN-TU) was planning its second treatment trial—it submitted its NIA grant application the week of the German family meeting—the time seemed right to convene German DIAN families to learn about a therapeutic research opportunity and get to know each other.

And come they did. Women who had cared for affected husbands came with their adult children. Siblings whose mother was mute and bed-bound by age 48 arrived together; an aunt who escaped the family mutation but cares for a sister accompanied her at-risk niece; a young woman came riven with pain for her cousin, who became demented in her 20s before the eyes of her four young children. The hotel conference room was packed with business managers, factory workers, lawyers, bankers, stay-at-home moms, all in their 20s and 30s.

Bateman welcomed the families into the DIAN-TU project by video link. Jucker told them that Germany had brought together half as many relatives as had the parent DIAN study for its own inaugural, highly successful family conference last summer at the AAIC conference in Washington, D.C. (see Aug 2015 conference news). Their second annual meeting will be on July 23 preceding AAIC in Toronto.    

The importance of the family gathering was not lost on the German medicines regulatory agency, the Bundesinstitut für Arzneimittel und Medizinprodukte, aka BfArM. Its president, Karl Broich, who trained in psychiatry and brain imaging, came to address the families. He told them that BfArM actively supports DIAN secondary prevention trials. Broich said he and his staff confer regularly with his counterparts at the U.S. Food and Drug Administration, the European Medicines Agency, and the Japanese Pharmaceutical and Medical Devices Agency. Their goal is to help ensure that the DIAN initiative to study preventive therapy in carriers of Alzheimer’s mutations can move forward in a way that is harmonized and efficient across its many different participating nations.

Jucker praised the German DIAN participants, saying that they were contributing a data set that is nearly complete across the many assessments the DIAN protocol demands. The main exception are PET scans, though the holdup lies neither with the families nor the researchers. Germany’s strict law limiting radiation exposure to healthy subjects holds back this part of the DIAN protocol, and the respective agency is notoriously slow. Solving the radiation issue is a top priority for Germany’s entry into the upcoming DIAN treatment trial platform, Levin told Alzforum.

As the DIAN-TU gears up toward its so-called NexGen trial, the conference served to inform families about clinical trials in general and the DIAN trial in particular. “This meeting is for you, so you can decide if joining this trial is the right approach for you,” Jucker told the audience. Eric McDade, like Bateman at Washington University, explained the rationale and logistics of the coming DIAN-TU NexGen trial. It is set to start in spring 2017 for a treatment period of four years. The drug of choice has not been announced yet. What is already clear is that the trial will feature design innovations such as adjusting doses during the treatment period to achieve a maximal effect, comparing ongoing results with a computational disease model developed in part with data from the ongoing observational study, and home-based cognitive testing to make the trial less disruptive for the participants’ lives.

The German families’ questions echoed those voiced by participants in the first DIAN-TU treatment trial that is now fully enrolled, with 210 participants in the United States, United Kingdom, Australia, France, Italy, and Spain:

  • “Can I join the study without having to find out my mutation status?” The answer is yes.
  • “Can I be sure to be on drug, not placebo”? The answer is no. During the blinded treatment period, one in four participants will be on placebo; afterward all can go on study drug for an open-label extension.
  • “If the drug works, will I continue to get it between the end of the trial and the drug’s regulatory approval?” The answer is yes. Broich told the audience that in these instances, BfArM requires pharma companies to supply medicine to trial participants at no cost on a compassionate-use basis to avoid a gap in supply, or a sudden financial charge, between the end of Phase 3 and the time when doctors are allowed to prescribe it.
  • “What do I have to do as part of the trial?” Participation is a big commitment. The current DIAN-TU trial of the therapeutic antibodies solanezumab and gantenerumab involves a monthly infusion and vital-sign checking, either at a nearby clinic or at home from a visiting nurse, plus quarterly MRIs and an annual multi-day visit for a slew of measurements. How often, and by which route, the study medicine is taken may change for the new trial depending on which drug is chosen, but the biomarker assessments will remain intensive.
  • “What are the side effects?” All side effects are described in the informed consent; though thus far no serious ones have appeared in the first DIAN-TU trial.

By the end of the day, all eligible attendees indicated in an anonymous survey that they would want to enroll.

Barbara Schäuble works at Roche, one of two companies, besides Eli Lilly, with an investigational drug being tested in the first, ongoing DIAN-TU trial. Schäuble told the families that biomarkers such as the ones being measured through their DIAN participation had put AD therapy development on a new footing after the spate of negative trials in the past decade. “The clinical and biomarker signals we have seen recently with beta amyloid targeting drugs suggest that we are now on the right path,” Schäuble said. 

Besides Roche, the DIAN-TU pharma consortium (see Dec 2011 news) currently includes nine other companies. This group has jointly funded the preparation work for the first DIAN-TU trial. Each company nominates drugs they would like to see evaluated in the next trial, but a separate panel of academic Alzheimer’s researchers then chooses which among these nominated drugs stands the best chance of success for the trial at hand. Importantly, McDade explained, DIAN-TU is being built as an ongoing platform, where the researchers intend to continuously test one medicine after another until one clearly works. Nomination, drug selection, designing and starting trials are ongoing, interconnected processes. This, the researchers hope, will lead to success faster than the old way of doing trials separately and sequentially, where teams would disband after a trial was over and reassemble and start from scratch for a new one. For information on drugs in clinical trials, see the Alzforum Therapeutics database.

As at the family meeting in D.C., too, young people in Germany told of parents losing their minds in the prime of life, and of placing 50-year-old mothers into nursing care next to patients in their 80s. The wife of an affected man spoke of finding joy in their life together despite repeated intracerebral bleeding brought on by his CAA, sometimes made worse by contraindicated treatment in hospital stroke units that were unaware of his rare condition. A young engineer moved the audience to tears when he shared how learning he had the family mutation plunged him into hopelessness until meeting his wife revived his strength to embrace life and fight the disease.

Unlike in D.C., however, these first accounts remained undocumented by the media, not posted on YouTube or retold to television crews. In Germany, cultural norms at present favor a reserved stoicism and prize privacy, keeping a shroud of secrecy around early onset dementia. This stands in contrast to the recent movement toward public outreach in the United States, where families with dominantly inherited AD are increasingly telling their stories to the media and are advocating for public awareness and research funding before Congress (for example, Oct 2012 news; Chuck Jackson on National Public Radio in 2007; Tal and Giedre Cohen on NPR in 2015; and the Heinrich family on NBC News in 2011). Together, this openness has pushed Alzheimer’s closer to the fore of the country’s research agenda.

Near Würzburg, the families spoke of rude, uninformed stares by passersby when they take their loved ones out, and of branches of the family becoming estranged when one relative’s decision to confront the disease is pitted against another’s denial. German media frequently cover dementia and Alzheimer’s, but few stories thus far have humanized early onset or genetic forms of the disease, or articulated the promise these forms hold in the search for disease-modifying treatments (for an exception, see the Spiegel story). The pharma industry’s negative public image among the media and the general public breeds little interest in reporting on the complex science of secondary prevention research. Even so, coverage of DIAN may pick up as trials get going, Joachim Mueller-Jung, who leads the science desk at The Frankfurter Allgemeine Zeitung, the country’s most highly regarded daily newspaper, told the assembled families.  

For his part, Broich encouraged the families to keep hope. He assured them that the country’s regulators had changed their previous, reactive stance, which consisted mostly of reviewing new drug applications and managing post-marketing crises. BfArM have adopted a more active role, where agency scientists offer regulatory advice and guide therapy development projects such as DIAN from their early days in hopes of boosting their chance of success. As an example, he noted the EMA’s new priority medicines, aka PRIME, a pathway launched in March 2016 whereby a regulatory scientist accompanies an investigational medicine for pressing medical needs such as Alzheimer’s in a formal dialogue that starts at the beginning of a drug’s development and ends in accelerated assessment when the time comes to apply for marketing approval. This past May, the EMA accepted the first Alzheimer’s medication, the Biogen antibody aducanumab, into the PRIME program (see Jun 2016 news release). 

The family conference offered information on other aspects of living with dominantly inherited Alzheimer’s. Andreas Gal is a geneticist who chairs the Northern Germany ethics commission overseeing applications for preimplantation genetic diagnosis. This method enables couples facing a dominantly inherited disease to conceive a child born free of the family’s disease mutation, in some cases without the affected parent having to know if he or she carries the mutation (see July 2014 Alzforum news series).  Gal reviewed German ethics law on this procedure, which involves discarding some embryos within the first week after in vitro fertilization, and offered one-on-one advice to couples who might want to learn more. Sabine Jansen of Germany’s Alzheimer Society in Berlin reminded the families that her organization’s “Alzheimer Phone” hotline offers advice and referral to resources.

Full disclosure: This reporter spoke at the conference about the experience of U.S. families with the DIAN observational and therapeutic studies since the initiative’s start in 2008.—Gabrielle Strobel


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News Citations

  1. 100 DIAN Family Members Gather for Their First International Meeting
  2. DIAN Forms Pharma Consortium, Submits Treatment Trial Grant
  3. Families Fight Back As Disease Claws at Next Generation
  4. Preimplantation Genetic Diagnosis Can Stop Inherited Disease in a Family

Therapeutics Citations

  1. Solanezumab
  2. Gantenerumab
  3. Aduhelm

Other Citations

  1. Therapeutics

External Citations

  1. German branch
  2. BfArM
  3. YouTube
  4. National Public Radio
  5. NPR
  6. NBC News
  7. Spiegel story
  8. PRIME
  9. Jun 2016 news release

Further Reading

No Available Further Reading