- By Rita Rubin
When geriatrician and neuroscientist Dr. Howard Fillit went to medical school in the early 1970s, he’d never heard of Alzheimer’s disease.
Since 1998, though, Fillit has directed the Alzheimer’s Drug Discovery Foundation, which supports the search for effective treatments for the disease.
“I’ve seen in my lifetime amazing progress,” Fillit said in Sept. 2015 at in a press briefing to discuss some of the more promising research his organization is funding. “We have caught up… to understanding as much about the biological mechanisms of Alzheimer’s disease as we know about cancer and heart disease.”
But although scientists have cured mice of Alzheimer’s hundreds of times, all the basic knowledge that they have accumulated has yet to translate into new treatments for patients, Fillit said.
He predicts that is about to change. “In three to five years, we’re going to have potentially more than one drug approved that has some disease-modifying effect,” Fillit said, noting that nearly 100 human trials of potential Alzheimer’s treatments are now underway.
No Cure As of Now
Alzheimer’s disease affects an estimated 5.1 million Americans 65 and older, according to the Alzheimer’s Association, which notes on its website that the disease “is the only cause of death in the top 10 in America that cannot be prevented, slowed or cured.”
And since aging is the leading risk factor for Alzheimer’s, the numbers of affected Americans will only explode as boomers get older, unless effective treatments can at least stave off the disease. In 10 years, the number of Americans 65 and older with Alzheimer’s is expected to hit 7.1 million — an increase of 40 percent over 2015, according to the Alzheimer’s Association.
Much of the research focus has been on drugs to rid the brain of amyloid plaque, deposits of a protein whose role in Alzheimer’s has been widely debated. According to a 20-year-old hypothesis, the build-up of amyloid in the brain causes memory loss in Alzheimer’s. However, anti-amyloid drugs have failed in large clinical trials, raising questions about the role of amyloid plaque in Alzheimer’s.
“There are over 150 different kinds of amyloid, and many of those are secondary to things like inflammation and other problems,” Fillit said. “We’re going to need many other classes of drugs for Alzheimer’s disease.”
The Forces at Play
Together, aging, genetics, inflammation and amyloid trigger the degeneration of neurons in Alzheimer’s disease, said Dr. Frank Longo, chair of neurology and neurosciences at Stanford University, who won the inaugural Melvin R. Goodes Prize for Excellence in Alzheimer’s Drug Discovery from Fillit’s foundation.
“This is a highly robust disease,” Longo said, so you “can’t just chip away at the edges.”
He received the award for the development of drugs that can mimic normal brain proteins called neurotrophins. Neurotrophins promote the growth and survival of neurons, or nerve cells.
One of the drugs developed by Longo and his colleagues is expected to begin Phase II safety and efficacy testing in patients with mild to moderate Alzheimer’s in the second quarter of 2016, Longo said. Phase I safety tests in healthy people found no significant side effects, he said.
“We’re affecting multiple (Alzheimer’s-related) mechanisms. We’ve treated mice at extremely late stages (of Alzheimer’s) and found true reversal,” Longo said.
Together, aging, genetics, inflammation and amyloid trigger the degeneration of neurons in Alzheimer’s disease.
— Dr. Frank Longo, chair of neurology, Stanford
To make sure that what they were seeing wasn’t related to the fact that the mice were genetically engineered to develop severe Alzheimer’s, he said, they also tested the drug in normal mice who had reached the ripe old age of 2 years, ancient for a mouse. With normal aging in both humans and other mammals, the numbers of certain types of nerve cells in the brain shrink, but the drug was able to reverse the decline in the aged mice that did not have Alzheimer’s, Longo said.
Treatments in the Pipeline
Other promising research that Fillit’s foundation is funding includes:
- “Repurposing” a low-dose form of an epilepsy drug called levetiracetam to treat amnestic mild cognitive impairment (aMCI). MCI causes a slight but noticeable decline in memory and thinking skills, and aMCI predominantly affects memory. People with MCI are at a higher risk of developing Alzheimer’s disease. In a phase II trial, the drug significantly improved memory in elderly aMCI patients.
- Using a fat-soluble form of vitamin B1, or thiamine, to increase glucose (sugar) metabolism and slow cognitive decline associated with aMCI or mild Alzheimer’s disease. The brain uses more energy in the form of glucose and oxygen than any other organ, and if it doesn’t get enough, cells will degenerate, Fillit said. “Thiamine itself doesn’t get into the brain very well,” he said. “This is basically sort of a better vitamin.”
- Testing a drug in patients with mild-to-moderate Alzheimer’s that stimulates the clearing of amyloid from the brain, reduces inflammation and improves cognition. None of the other anti-inflammatory drugs that have been tested in Alzheimer’s have worked, Fillit said.