At the end of a meeting held 8 November 2010 at the European Medicines Agency in London, Bruno Flamion of the EMA capped the day’s discussions by saying: “What has changed today? We learned convincingly that autosomal-dominant patients have been excluded, and now realize they could be an extremely valuable population for trials.”

But what did the audience hear from those families themselves? No AD family representatives were there in person that day, but several people spoke and showed videos on their behalf. Nick Fox of University College, London, said, “The families are incredibly generous and motivated to take part in trials. We asked three of them what they would say if they were here.” Read these excerpts:

Woman 1, in her thirties: “My great-grandmother had the disease, my grandfather did, my mother did. I have the gene and my brother has it. I will get the disease. I have to live with that every day.”

Woman 2, in her fifties: “My father started having problems in his mid-fifties. He was making mistakes at work, needed prompting, and was diagnosed with AD. Soon after, one of his younger sisters, and a brother, also, started developing the same symptoms. I remember that my grandfather had had similar problems; my grandmother had looked after him. I put two and two together. I realized something must be going on here.”

Man, in his forties: “Dad developed symptoms at 60. We noticed that an aunt and uncle had it, too, and found out that his father had died in a mental hospital of similar symptoms. I made a family tree. I found lots of names and sent that to Martin Rossor and John Hardy. Within a couple of years, they came back to us and told us they discovered the fault on chromosome 21.”

Woman 1: “I chose to have the test done. I wanted to know whether I had it. I was hoping not to, but something inside me just knew I had it. The genetic counseling was fantastic. They made me think about how my whole family would think about it, not just I.”

Woman 2: “I chose not to have the test. If I want to do something, I do it now. I don’t defer it to later.”

Man: “Our support group is a fantastic forum. Most important to me, it helped me understand there are other families that have been through the very same thing. We felt very isolated. We asked: why us, why only us? Through the support group we now understand there are others who have been through a very similar journey.”

Woman 1: “I was planning to get married but kept putting it off. When I had the test results, we said let’s go and do it, which is exactly what we did!”

Man: “We live very much in the day. We don’t save for the rainy day so much.”

Woman 1: “I would not take back the test for anything.”

Woman 2: “I am the age when it starts. Whenever I lose something or forget something, I wonder, is that it? My husband looks at me and I know exactly what he is thinking. I tell him: ‘Don’t look at me like that!’”

Man: “Whenever I forget something, I wonder, is it now starting? In our family we joke about it but it is a real worry.”

Woman 1: “Being part of the research, you can only help. I want to pave the way for the future of my family.”

Man: “I don’t have to have taken the test to participate in the trial. I just want to participate to help in the cause; the benefit to me is secondary.”

Woman 2: “I hope there will be a lot more medications that at least will slow it down so people can enjoy the quality of life they have longer. And be treated like people, not just be stuck in a wheelchair for the rest of their lives.”

From the other side of the Atlantic, William Thies of the Alzheimer’s Association said that people with familial Alzheimer’s disease have a greater commitment to the next generation than do people with sporadic disease. “They are acutely aware of what they are passing on to their children. That makes them very willing to take part in research and accept risk.” About the current situation, the most frequent remarks he hears is, “Why can’t we get our parent into clinical trials? It is not fair.” Thies urged industry and regulators to do away with this exclusion. “We owe the families a better outcome. They are a unique population, and useful for trial design for prevention trials in sporadic AD.”

Huntington’s disease families had a representative at the EMA meeting in Astri Arnesen, who leads the Norwegian Huntington Patients Association. Arnesen spoke about her mother, who had Huntington’s for 30 years, and her four siblings. “My oldest brother and I are healthy. I chose to find out my status because one of my daughters really needed to know. I did not inherit the disease gene. My sister’s status is uncertain. I thought she was positive, but she also has Asperger’s syndrome and now I am thinking she may not have HD. My other sister has HD, and my younger brother Arne Dag was diagnosed at age 35.”

About this brother, Arnesen said: “When did he get sick? It is hard to say. He was an excellent student and studied engineering. But he never quite finished. He worked as a taxi driver and a guard. Ten years prior to his diagnosis, he was severely depressed.

“Like in familial AD, many HD patients are parents and have economic responsibilities when the disease hits them hard. Even a small delay in progression would make a huge difference for us. The HD community has had little hope, and like in AD, there is tremendous anxiety in these families. Huntington’s is very difficult to live with.”

Arnesen showed a video of Arne Dag, now 40, who said into the camera, in fluent English: “I would like to test a medicine as soon as possible. It would give me more hope. I hope science is on my side, that there is a possibility for me to test some medicine. Other people think the same way.”

So where do things stand? The ball is partly in industry’s court, but pharma representatives said little in the way of specifics at this particular meeting. Baltazar Gomez Mancilla of Novartis Biomedical Research Institute addressed the audience, saying that his company is interested but sees considerable uncertainty about practical and ethical issues, such as when to treat, how to randomize, and what effect sizes to expect. Gomez Mancilla noted that he was encouraged by the FDA and EMA’s joint support of biomarkers and a cognitive outcome as acceptable endpoints, and noted that longitudinal studies that further define the similarities and differences between ADAD and sporadic AD—such as DIAN and ADNI—would help his company move forward. DIAN is this fall collecting nomination packets from pharma companies for their respective compounds (see ARF related Honolulu story). In London, Bateman said some have already been submitted, and additional pharma companies have indicated they intend to submit.

When these trials finally happen, it will be not a day too soon for families. It is easy to forget that the families whose research participation enabled the discovery—to much fanfare—of APP and the presenilin genes in the 1990s continue losing loved ones now just as then. The disease is still eating its way through their younger generation. Before the London meeting, on 4 November 2010, Malcolm (Butch) Noonan passed away from Alzheimer’s disease in Falmouth, Massachusetts, at the age of 55. He appeared briefly in the 2004 PBS documentary “The Forgetting: A Portrait of Alzheimer’s,” which publicized familial AD in the U.S. Two of his older sisters had died earlier, both in their fifties; one, Fran, was shown receiving a visit by her siblings in the film when she was unable to speak any longer.

In a videocast 2004 lecture about ADAD, Butch spoke as the second of five siblings about how isolating it was for him, the sixth of 10 children, to grow up with the “unknown monster,” without a mother who was dying from Alzheimer’s, with an overwhelmed father, and a house full of children who were each struggling in their own way. He also spoke about his search for research opportunities as a young adult. At the time of this video lecture, he had been recently diagnosed. Butch continued to participate in research, and he donated his brain to science. As did his two affected sisters Maureen and Fran, Butch left behind adult children. They are now facing 50-50 odds of being next, while having young children of their own.—Gabrielle Strobel.


image image

Malcolm (Butch) Noonan, shown skiing in January 2007 (left) and in motion raising money for Alzheimer's research on the Alzheimer Association's Memory Ride, which the Noonan family started originally.

This concludes a four-part series. See also Part 1, Part 2, Part 3. View PDF of entire series.


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News Citations

  1. DIAN Dispatch from Hawaii: Glimpse at Data, Push for Trials
  2. London: Europe-U.S. Regulators Mull Prevention Trial in Familial AD
  3. London: What, No Argument? Speakers Agree on Trials for Familial AD
  4. London: What Regulators Say About Trials in Familial AD

Other Citations

  1. View PDF of entire series.

External Citations

  1. videocast 2004 lecture

Further Reading