People at genetic risk for Alzheimer’s disease to test prevention drugs
August 23, 2016
The two biggest risk factors for late-onset Alzheimer’s disease—age and carrying a risk gene—can’t be changed. But what if people could do something to counteract those risks and possibly tip the balance in their favor? A groundbreaking clinical trial aims to find out if two experimental drugs can prevent or delay dementia in people at high genetic risk for developing the disorder.
The Alzheimer’s Prevention Initiative’s (API) Generation Study is studying cognitively normal older adults with two copies of the APOE ɛ4 gene. People with two copies of this risk-factor gene are more likely than not to develop late-onset Alzheimer’s, the most common form of the brain disorder, which so far has no cure.
A growing number of trials are testing promising therapies that may prevent or delay memory loss and other symptoms of Alzheimer’s in the most vulnerable people. The drugs being tested in A4, DIAN, API’sAutosomal Dominant Alzheimer’s Disease trial and now Generation are designed to attack beta-amyloid, a protein that plays a key role in the brain changes that lead to Alzheimer’s dementia.
Supported by a public-private partnership, with $33.2 million from the National Institute on Aging (NIA), part of the National Institutes of Health, the Generation Study will be conducted at about 90 sites in North America, Europe, and Australia, about half of them in the United States. The research team plans to enroll 1,340 cognitively normal adults, age 60 to 75, who will be randomly assigned to take either a test drug or a placebo for at least 5 years.
The NIA-supported Banner Alzheimer’s Institute (BAI), based in Phoenix, Ariz., is running the trial with Novartis Pharmaceuticals, which is providing the drugs to be tested, CAD106 and CNP520, and Amgen, which helped develop CNP520.
Attacking an early Alzheimer’s culprit
The failure of past anti-amyloid drugs to stop Alzheimer’s in people with mild to moderate dementia has led researchers to test some of the same drugs, and new ones, earlier in the disease process, when therapies might be most effective at altering the course of the disease.
In a handful of prevention trials, experimental therapies are being tested in symptom-free people who, because of their age, genes, or amyloid levels in the brain, are most likely to develop Alzheimer’s disease—sooner rather than later.
“The results of this and our other prevention trials will help us learn whether and how anti-amyloid therapies can slow or perhaps prevent cognitive decline in individuals who are most likely to develop Alzheimer’s disease,” said Laurie Ryan, Ph.D., chief of the Dementias of Aging branch at NIA’s Division of Neuroscience. “We’ll also gain valuable biomarker data that will be shared with the wider scientific community.”
She added, “The ultimate goal is to find a way to block Alzheimer’s damage in the brain at the earliest possible point, long before symptoms appear, and to prevent a disease that burdens more than 5 million Americans and many more around the world.”
Zeroing in on uncommon genetic risk factors
The Generation Study seeks people who have inherited two copies of a specific form of theapolipoprotein E (APOE) gene, called APOE ɛ4. APOE, which helps transport cholesterol and other fats in the bloodstream, has three forms. About 25 percent of people carry one copy of the APOE ɛ4 gene, which increases the likelihood of developing late-onset Alzheimer’s and is associated with an earlier age of onset.
About 2 to 3 percent of the world’s population has two copies of APOE ɛ4. Studies show that up to 60 percent of them will develop Alzheimer’s dementia by age 85, compared with 10 to 15 percent of the general population. However, some people with an APOE ε4 allele never get the disease, and others who develop Alzheimer's do not have any APOE ε4 alleles.
API’s prevention trial in Colombia involves a different genetic risk. It is studying 300 cognitively normal adults who are at high risk of developing a rare, inherited type of early-onset Alzheimer’s that can begin in people in their 30s.
Drs. Pierre Tariot, Jessica Langbaum, and Eric Reiman
The Generation and Colombia trials share an ambitious goal: to determine whether data collected from brain scans and cerebrospinal fluid measurements can predict clinical benefit. The hope is that these measurements could be used to quickly test prevention therapies in a much larger segment of the population.
“We have to find that sweet spot between starting early enough before Alzheimer’s pathology develops and yet late enough so that there’s enough decline over the next few years to see if the treatments actually work,” said Eric Reiman, M.D., executive director of BAI and one of API’s leaders.
“Our goal is to help individuals at the highest imminent risk in a way that helps everyone at risk for Alzheimer’s, and to do so as soon as possible,” he added.
Thousands of volunteers needed
Banner scientists expect to screen about 80,000 people to find enough participants for the Generation Study. “People with a family history of Alzheimer’s are good potential volunteers for this study because they may carry the APOE ε4 gene,” said Jessica Langbaum, Ph.D., a BAI scientist and associate director of API. “We need more people to join to fight this devastating disease.”
To speed the process for this and other studies, Banner started GeneMatch, a registry that will collect genetic information from adults age 55 to 75 living in the United States. GeneMatch’s genetic testing will allow researchers to match potential volunteers with and without the APOE ε4 gene for this and other studies. (See below for more information about GeneMatch.)
Testing two new drugs
The two drugs being tested in Generation, CAD106 and CNP520, attack beta-amyloid in different ways. If the brain produces too much beta-amyloid or does not clear it fast enough, it clumps together into the plaques found in Alzheimer’s. Over time, these plaques damage and destroy nerve cells throughout the brain, leading to problems with memory, reasoning, and other cognitive functions.
CAD106 is an active immunotherapy designed to trigger the body’s immune system to produce antibodies that attack different forms of amyloid. This second-generation drug does not have the brain-inflammation side effect found with some first-generation immunotherapies, said Dr. Pierre Tariot, M.D., one of API’s leaders and director of BAI.
CNP520 inhibits beta-secretase, an enzyme that helps turn a normal protein into harmful beta-amyloid. “The idea is to block production of pathological amyloid,” Dr. Tariot said.
Researchers will determine if either of the drugs leads to changes in overall cognition and how long it takes participants to be diagnosed with mild cognitive impairment (a condition that often precedes Alzheimer’s) or dementia. The drugs’ safety and side effects will also be assessed.
In addition, investigators will gather biomarker data to compare to results of cognitive tests. Participants will undergo brain scans to measure the accumulation of amyloid plaques and tau tangles, as well as declines in brain size and energy utilization that are associated with Alzheimer’s. They will also have lumbar punctures to measure Alzheimer’s-related proteins in cerebrospinal fluid.
“The hope is that we will be able to relate biomarkers to treatment benefit,” Dr. Reiman said. “To what extent does a biomarker move in response to treatment? Can we show a biomarker effect at 2 years that will predict [a change in cognition] at 5 years?”
Other Alzheimer’s prevention trials
API’s Generation and Colombia trials are among the first Alzheimer’s prevention trials. Others supported by NIA include:
Dominantly Inherited Alzheimer Network Trial (DIAN)—testing the drugs gantenerumab and solanezumab in people age 18 to 80 with a genetic mutation for early-onset Alzheimer’s or who have a parent or sibling with such a mutation
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