Hope on the Treatment Front
Advances in deciphering the genetics of Alzheimer’s not only ferret out common DNA variants that more reliably predict risk, they also provide new clues to potential biological targets for drugs to prevent, stop or even reverse the disease. Until now, most promising treatments have fallen by the wayside. Drug companies have lost billions in Alzheimer’s therapies that looked good in early research but failed in larger clinical trials, leading one report to characterize the field as “a graveyard of hope.”
But those treatments were tested on people who already had symptoms of the disease. Recent studies in those with an inherited form of early Alzheimer’s detected the presence of rogue amyloid proteins up to two decades before symptoms emerged, suggesting that we’re intervening too late, when the damage is irreparable.
“That led to a search for individuals who are guaranteed by their genetics for developing Alzheimer’s and identifying them at an age before they have symptoms,” says Nixon. “Then we could treat the disease before it is like a locomotive that just can’t be stopped.”
In the past few years, two studies were launched to find out whether drugs that shrink plaques can halt the onset of the disease before symptoms appear in those genetically predisposed to develop Alzheimer’s. One study, known as DIAN (Dominantly Inherited Alzheimer’s Network), involves more than 260 people in the U.S., Britain, Germany and Australia. The other, the Alzheimer’s Prevention Initiative, encompasses 300 members of an extended family of about 5,000 who live in Medellín, Colombia, and the surrounding mountain villages.
The DIAN study is composed of families with an inherited form of early Alzheimer’s; many relatives have the disease or have died from it. People who harbor the mutant gene sometimes have symptoms in their 30s and 40s, usually around the same age that their parents started to show signs. On average, most develop symptoms before age 45 and are diagnosed with dementia by age 51. No one with this rogue DNA escapes this terrible fate.
DIAN participants were given one of two drugs, called gantenerumab and solanezumab. Both are antibodies that bind to amyloid proteins and help remove the toxic proteins from the brain before they have a chance to turn into plaques. In the study of the Colombian family members who develop early-onset Alzheimer’s, scientists are testing another drug, crenezumab, which acts similarly to the other drugs. If these therapies can somehow halt or slow the development of memory loss, confusion or plaque formation, it might be possible to slow the progress of the disease.
Because the subjects in these closely watched studies are at such a high risk, researchers should know within the next few years if the experimental drugs will halt or delay the onset of the disease. “The characterization of these families has been so thorough, based on all their siblings and parents, that we know when any one person will start to develop cognitive deficits,” says Ronald DeMattos, an Alzheimer’s researcher at Indianapolis-based Eli Lilly and Co., which makes solanezumab and is co-sponsoring the DIAN trial. “If they progress more slowly than usual within that time frame, that would suggest these treatments are having their desired effect.”
But what about people who don’t have a strong familial history of the disease? In the past year, two other long-term clinical trials began to test therapies that might either prevent or delay Alzheimer’s in healthy volunteers who are not genetically at risk of developing the early-onset form of Alzheimer’s. One study, called A4 (the anti-amyloid treatment in asymptomatic Alzheimer’s trial), will test solanezumab in 1,000 cognitively normal people age 65 to 85, who have abnormally high levels of amyloid proteins. Participants will be selected based on the results of a PET brain scan to detect the presence of the haywire proteins.
The other trial, called the TOMORROW study, will give an FDA-approved diabetes drug, pioglitazone, to healthy volunteers to see if it can delay the first symptoms of cognitive impairment. The clinical trial will eventually encompass 5,000 participants who harbor two specific genes linked to Alzheimer’s: APOE and TOMM40. An observational study conducted by German scientists in 2014 suggests that long-term use of this drug may protect against dementia. Using prescribing information from a German database, they looked at 145,000 adults 60 or older who did not have dementia. During follow-up six years later, they found that 10 percent of the cohort — about 14,000 people — developed dementia, but the risk was lower in those who were taking the diabetes medication. “People with diabetes may have an increased risk of Alzheimer’s,” says Keith Fargo, director of scientific programs and outreach at the Alzheimer’s Association. “The drug may reduce these odds by controlling glucose metabolism and because it has an anti-inflammatory effect. Many researchers now believe inflammation plays a big role in Alzheimer’s.”
And in another advance, a research team led by Tanzi has concocted what they call “Alzheimer’s in a dish.” The team used human embryonic stem cells — which can transform into any cell of the body — and cultured them in a mixture of chemicals to grow human brain cells. Then they implanted Alzheimer’s genes into the neurons, which obligingly began churning out the telltale clumps and tangles that characterize the disorder.
“Within six weeks, the nerve cells produced amyloids, and within eight weeks, we got tangles,” says Tanzi. “This is a much better model than what we have, and it’s faster and cheaper. We can now screen drugs within two months in a dish.”
This discovery will solve one of the key stumbling blocks in devising therapies: the lack of a human model that can shed light on how the disease progresses. Scientists characterize the advance as a game changer that could dramatically accelerate the testing of new drug candidates.
It’s likely that a combination of strategies will be needed to halt the disease’s progression, using a cocktail of medications aimed at different targets in much the same way AIDS and many cancers are now treated.
“We’ve been operating under the assumption that a single drug would do the trick in terms of reversing the deficits,” says Frank LaFerla, director of the Institute for Memory Impairments and Neurological Disorders at the University of California, Irvine. “But it’s like trying to put out a raging fire with a bucket of water. Once a fire reaches that point, you need to bring out the firetrucks and helicopters.”