Alzheimer’s drug trials aim to halt disease in its tracks

Ted, who has early-onset Alzheimer’s disease, is taking part in the DIAN-TU drug trial at Sunnybrook. The trial is one of two that could offer the best hope yet for answers on how to stop the destructive disease in its tracks. 

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His mother, an aunt and three uncles: in the previous generation alone, Ted has lost five close family members to Alzheimer’s disease. Another uncle – one of the six out of nine siblings who were diagnosed with the disease – is now in long-term care.

So it felt especially cruel when Ted’s doctor told him eight years ago, at the age of 44, he had autosomal dominant Alzheimer’s disease (ADAD), also known as early onset familial Alzheimer’s disease. It was the same condition that had claimed the lives of his mother and her siblings when they were in their 60s.

“That’s the scariest part,” says Joanne, Ted’s wife. “They died so young — it’s really frightening when you think about it.”

Since the diagnosis in 2008, Joanne and Ted have lived in a state of anxious anticipation – watching and waiting for worsening symptoms of ADAD, a disease caused by rare, inherited gene mutations whose effects typically start to appear when patients are in their 30s and 40s.

But the Toronto-area couple is also hopeful. Earlier this year, Ted, a former entrepreneur (who asked to be identified only by his first name), became one of the first Canadians to participate in a global study looking at the potential of antibody drugs to prevent or slow down the development of early onset ADAD, a rare form of Alzheimer’s found in less than one per cent of patients with the disease.

A positive test for any one of three ADAD gene mutations virtually guarantees the onset of Alzheimer’s disease, and also means there’s a 50-50 chance of passing on the gene mutation to children.

“(ADAD) is quite aggressive, so it’s important to have these trials going on,” says Ted, now 52. “We want to help and be part of finding a cure.”

The Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU) study is one of two research projects at Sunnybrook investigating the use of drugs to prevent or slow memory loss caused by Alzheimer’s disease, which currently affects an estimated 750,000 Canadians.

Both studies are using therapeutic drugs to target betaamyloid, a toxic brain protein, which can deposit in amyloid plaques outside the nerve cells, damaging the brain leading to memory loss, word-finding difficulty and other cognitive problems.

The studies hold exciting promise for patients in the early or presymptomatic stages of Alzheimer’s: a chance to live life with their memories and intellectual abilities intact, for much longer than they would likely have been able, if the anti-amyloid antibody drugs work.

The studies are international in scope. DIAN-TU, led by the Washington University School of Medicine in St. Louis, Mo., has sites in the United States, Canada, the United Kingdom, Germany, Australia and Argentina.

The second study – called Anti-Amyloid Treatment in Asymptomatic Alzheimer’s, or A4 for short – has site locations in the U.S., Canada and Australia, all coordinated through the University of Southern California’s Therapeutic Research Institute.

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“It’s important to have these trials going on. We want to help and be part of finding a cure.”
– Ted, DIAN-TU trial participant[/mks_pullquote]

DIAN-TU’s focus is on early onset familial Alzheimer’s, while the A4 study is focusing on late-onset Alzheimer’s disease (AD), testing participants aged 65 to 85 who have family or other risk factors for AD, but do not yet have the disease.

“If we can start removing the beta-amyloid early enough, we hope to postpone this pathology from expressing itself. Maybe we can control this rogue protein before it spreads its toxic effects through the brain,” says Dr. Sandra Black, director of Sunnybrook’s Hurvitz Brain Sciences Program and lead investigator of the A4 trial at Sunnybrook, which is looking to study 10 elder volunteers who are at risk of AD, often because of a family history.

Scientists believe amyloid build-up outside nerve cells can cause inflammation and prevent cells from communicating with each other. It may also lead to deposits within nerve cells, called tangles, made up of the second major misfolded protein seen in Alzheimer’s, called tau.

Normally, tau stabilizes channels that transport nutrients and proteins from the nerve cell body to the nerve endings, where they make contact with other nerve cells.

“In diseases like Alzheimer’s, the tau starts to misfold and deposit inside cells. This abnormal form spreads from one nerve cell to other nerve cells that are functionally connected, degrading that functional network,” explains Dr. Black. “We’re not quite sure how amyloid and tau work together, but it seems that if you have beta-amyloid deposits, you are more likely to have tau deposits as well. Mobilizing and removing the amyloid may remove an inciting factor that promotes the tau tangles.”

The A4 study is testing the antibody drug solanezumab, while DIAN-TU is testing both solanezumab and a second drug, gantenerumab. Both drugs are designed to bind to amyloid – each drug targeting a different part of the protein – to help move it out of the brain.

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There have been some reports about the unsuccessful results of the drug Solanuzemab from a study that tested the therapy in mild Alzheimer’s Dementia, which means these individuals are no longer independent and require help with day-to-day functioning.

While the drug appeared to be well-tolerated and safe, the treatment did not significantly slow cognitive decline.

In the A4 study being conducted at Sunnybrook and other sites, our researchers are targeting individuals who are still cognitively normal, and still may be many years before symptoms begin, when the burden of disease is at a much earlier stage. In the DIAN-TU study, genetic forms of the AD in their early stages are being targeted, and these forms may be different from the more common late onset forms in response to this medication.

Our researchers have reason to hope that Solanuzemab immunotherapy at this very early stage may still be helpful in slowing disease progression.

» Learn more about these studies
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While previous studies have looked at ways to treat Alzheimer’s disease at various stages when it is already causing problems, DIAN-TU and A4 are groundbreaking, because they focus on individuals who are at risk of developing Alzheimer’s, but show no symptoms of the disease at the start of the trial.

DIAN-TU is also the first to focus on prevention or delayed development of early onset familial Alzheimer’s. In addition to cognitive testing, biomarkers such as amyloid levels in the cerebrospinal fluid and in the brain are being used as outcome measures.

“Traditionally, studies of Alzheimer’s disease will just use memory tests to measure outcomes,” says Dr. Mario Masellis, lead investigator for the DIAN-TU site at Sunnybrook. “The problem with this is that people with early stages of the disease often don’t have a measurable deficit.

With DIAN-TU we looked at developing something that can act as a surrogate measure of the benefits of the drugs being tested – something more sensitive and indicative such as amyloid uptake in the brain.”

DIAN-TU will follow an “adaptive clinical trial” approach, testing two drugs simultaneously to allow researchers to advance quickly if one drug shows more promise than the other, or, conversely, to stop testing a drug that produces adverse side effects without halting the entire study. With this adaptive model, new drugs may be added as they become available, says Dr. Masellis.

The use of advanced imaging technology also sets DIAN-TU and A4 apart from other studies on Alzheimer’s prevention. For example, in both studies, participants undergo an amyloid PET scan, which uses a radioactive tracer designed to bind to amyloid in the brain to quantify the extent of amyloid deposits in the brain. In A4, if the amyloid scan is positive, the participants are then randomly assigned to get solanezumab or placebo infusions monthly for three years.

“It used to be that you could only detect deposits of brain amyloid in the brain in an autopsy, but now you can see this in people while still alive,” says Dr. Black. “Also, in the two to three years since the study started in the U.S., a radio-tracer has been developed that can detect tau in the brain, so that’s now also offered to participants of both studies.”

Getting people to sign up for the studies is not an easy task. With both A4 and DIAN-TU, being accepted into the treatment trial essentially confirms what most people don’t want to hear: that they’re likely to develop Alzheimer’s.

“The majority of people don’t want to find out,” says Dr. Masellis. “It can affect their insurance, career or job, or their outlook on life, but if a new therapy is developed then maybe more people would want to be tested.”

One participant in the A4 trial at Sunnybrook, a retired nurse whose parents both had serious memory-loss problems – although they were never officially diagnosed with Alzheimer’s – said she signed up for a number of reasons.

“For me it’s to get information on what’s going on with Alzheimer’s, and to get myself prepared for the future,” says the woman, a Toronto resident who asked not to be identified. She said she is selling her house and getting her affairs in order in the event she becomes debilitated by loss of cognitive function down the road.

She hasn’t told anyone in her family she’s part of the A4 study, although she did mention to a sibling that she was getting tested for amyloid build-up.

“And my sister told me she wouldn’t want to know,” says the woman.

With the A4 and DIAN-TU studies, by luck of the draw, one group gets monthly infusions of antibody, while the other group gets infusions containing no active drug. For Ted and Joanne, this means taking a chance – and embracing an opportunity.

So far Ted remains functional in his day-to-day life, but his short-term memory has deteriorated over the last eight years and he tends to repeat himself. As a result, he tends to be anxious in social gatherings, notes Joanne.

“I am extremely hopeful that Ted is receiving the drug and that it will slow down his symptoms,” says Joanne. “And then there’s the next generation – if this trial goes well and there’s a cure 10 years down the road, there’s hope for our two children and Ted’s many cousins who are younger than him, as well as for other people who may unfortunately inherit the gene for this disease.”

All photography by Tim Fraser