Billions of dollars have been spent on clinical trials of Alzheimer’s drugs that target amyloid plaques—the hallmark protein tangles that clog brain cells in people with the memory-robbing disease. So far, all have failed, leading some frustrated researchers to say it’s time to move on to other drug targets. Others say the drugs have not yet been fairly tested because they were administered too late, after brain damage is irreversible. Yesterday, the National Institutes of Health (NIH) announced that it is giving $33 million to a study that researchers hope will either revive the amyloid hypothesis, or put it to bed.
The new trial—estimated to cost at least $100 million overall, with most of the remaining funds provided by partners in the pharmaceutical industry—will be part of the Alzheimer's Prevention Initiative, a large consortium of researchers attempting to identify biomarkers and treatments that can slow or stop the disease. Lead researchers Eric Reiman and Pierre Tariot of the Banner Alzheimer’s Institute in Phoenix plan to give a yet-to-be identified anti-amyloid drug, or placebo, to 650 people who carry two copies of the APOE4 gene—a genetic double whammy that confers a 10-fold increased risk of developing Alzheimer’s late in life. All participants will be between the ages of 60 and 75 and healthy, including free of recognized Alzheimer’s symptoms. Roughly a third will likely not have much amyloid in their brains yet, allowing the researchers to track whether the drug affects its accumulation, Reiman says.
The Banner trial “is a very reasonable approach” to figuring out whether anti-amyloid drugs can effectively prevent Alzheimer’s disease, says Gary Landreth, a neurologist who studies the disease at Case Western Reserve University in Cleveland, Ohio. He notes, however, that it is quite unusual that the drug to be used has not yet been identified, given the size of the grant. Given that no anti-amyloid/Alzheimer's drugs have yet shown any clinical efficacy, “I think this really reflects the state of desperation felt in the scientific community as well as the public at large that we have no effective therapeutics in the face of an ongoing epidemic of AD,” he says. “They are taking a gamble.”
The APOE4 trial builds on another trial of an anti-amyloid drug in 300 members of a Colombian family who carry a gene mutation that places them at high risk of developing an early-onset form of Alzheimer’s disease. Rather than wait for the results of that study, Reiman says that he and his colleagues decided to conduct the two trials simultaneously to ensure that any positive results from the Colombian study can be quickly tested into a more representative population—drugs that work for people with early-onset Alzheimer’s might not necessarily help those with late-onset Alzheimer’s, he says.
Maria Carrillo, vice president of medical and scientific relations at the Alzheimer’s Association, an advocacy group, applauds NIH’s giving the trial a green light: Targeting the APOE4 population will “increase the possibility that participants in the trial will become symptomatic during the period of the study so that the scientists can assess whether the drug intervention is having an impact on delaying or preventing Alzheimer’s symptoms, without having to wait 10 or 15 years or more,” she says.
The U.S. government has placed a high priority on tackling Alzheimer’s disease, which is expected to strike 10 million Americans by 2050, according to the U.S. Department of Health and Human Services (HHS). The 2011 National Alzheimer’s Project Act, for example, has mandated that HHS establish a national plan to prevent or effectively treat Alzheimer’s disease by 2025. The new APOE study will use up the lion’s share of the $45 million that Francis Collins, director of NIH, has set aside for Alzheimer’s research in fiscal year 2013. (The $45 million total includes a $5 million contribution from the National Institute on Aging [NIA]). According to Neil Buckholtz, director of the NIA Division of Neuroscience, the investment reflects a shift toward trying to prevent the disease before it ravages the brain, rather than reverse its effects, and a commitment to testing the amyloid hypothesis properly. “We believe this hypothesis has not received an adequate test,” he says. He acknowledges, however, that putting so many research dollars into one basket is a “high-risk” strategy.
NIH also announced funding for five additional grants to Alzheimer’s research, with a sixth award pending:
A $1.5 million trial testing three new anti-amyloid beta drug treatments—gantenerumab, solanezumab, and a third, undetermined drug—in volunteers with an inherited form of early-onset Alzheimer’s. Led by Randall Bateman of Washington University in St. Louis, the international trial will have the potential to gain $6 million in funding over 4 years.
A $2.4 million, 12-week phase 1 trial testing the safety and tolerability of the steroid allopregnanolone for treatment of mild cognitive impairment and Alzheimer’s, led by Roberta Brinton and Lon Schneider of the University of Southern California in Los Angeles. Animal studies have shown that the drug can lower amyloid levels, restore cognitive function, and spur the generation of new neurons.
A $1.7 million drug discovery effort to identify molecular and genetic risk factors and new therapeutic targets for cognitive decline and Alzheimer’s disease, based on data from the Religious Order Study and the Rush Memory and Aging Project. Led by Philip De Jager of the Brigham and Women's Hospital, the Broad Institute, and Harvard University, and David Bennett, of Rush University Medical Center in Chicago, the study will focus on drugs that have completed phase 1 testing, and could be granted $7.9 million over 5 years.
A $1.6 million effort to study the complex mechanisms of the disease and identify existing drugs that might be able to be used for Alzheimer’s treatment or prevention, led by Eric Schadt of Icahn School of Medicine at Mount Sinai in New York City. The study has the potential to be granted $8.2 million over 5 years.
A $1.6 million study of the role of the immune system and brain inflammation in Alzheimer’s disease, led by Todd Golde of the University of Florida in Gainesville. The study has the potential to be granted $7.7 million over 5 years.