At the annual Alzheimer’s Association International Conference this week, attendees eagerly anticipated the result of a 15-month trial of a new drug to combat the disorder. If successful, it could potentially have been one of the first effective treatments for the brain-destroying disease, which afflicts more than 40 million people worldwide.
But on Wednesday, researchers at the Toronto conference announced that the drug, leuco-methylthioninium-bis (LMTM) had failed to demonstrate a benefit for most trial participants, supportng what experts have long believed: that winning the battle against Alzheimer’s will involve a cocktail of drugs and changes in lifestyle habits such as diet, sleep habits and physical exercise, rather than a magic bullet.
An estimated 5.2 million Americans 65 and over have Alzheimer’s, and the number is predicted to nearly triple by 2050 if no new treatments are found. Currently five FDA-approved drugs can alleviate the disease’s symptoms, but in the past twelve years no new drugs have been approved for Alzheimer’s, so scientists, doctors, and families are hungry for any studies that hold promise.
Alzheimer’s disease is the only leading cause of death in the U.S. that has no therapies to prevent, cure or slow its progression. At $236 billion a year, it is also the most expensive disease in the U.S. But government funding for Alzheimer’s research is nowhere near the amount given to heart disease, cancer, or HIV/AIDS.
Recently, however, it has begun to ramp up. Last year, research for Alzheimer’s and related dementias got a $350 million infusion, bringing the annual amount of NIH funding to $991 million, just under half of the $2 billion advocates say is needed to maximize the chances of curing or preventing the disease by 2025. And last month the Senate Labor-HHS Appropriations Subcommittee proposed another $400 million increase.
Research increasingly shows that Alzheimer’s can not be easily put into a box: it manifests itself in different ways among women and men, younger and older patients, and people of different ethnic and racial backgrounds. Vascular health and diet also contribute to the equation, as does complexity of work and richness of social connections.
Recent research has focused on two conditions associated with the disease – the accumulation of beta-amyloid, a protein that forms sticky plaques in the brain, and the buildup of tau, which ordinarily helps maintain the structure of a neuron but can collapse and twist into tangles, destroying the neuron.
Other areas of interest include inflammation caused by the beta-amyloid plaques and tau tangles (although recent research suggests that inflammation may in fact protect against the disease); and insulin resistance, which has been shown to affect brain cell function.
Despite the paucity of new drugs, researchers say this is an exiting time in the field. “It’s a breathholding time for the field; I think the field is in so much of a need of some kind of positive indication that we are on the right track,” said Ronald Petersen, director of the Mayo Clinic Alzheimer’s Disease Research Center and the Mayo Clinic Study of Aging. “I think we can have a little more optimism about drug trials that are coming down the road.”
One such study, expected to conclude later this year, is for the drug solanezumab, an antibody designed to lower the level of beta-amyloid in the brain. The results are of particular interest because the study uses better diagnostic tools now available to detect amyloid levels in living patients, Petersen said.
“One of the causes of the failures in recent years has been misdiagnosis” as autopsies of people with dementia often end up showing no evidence of amyloid after all. “The new studies underway now require a positive PET scan or a positive spinal tap for amyloid...so you should have biological evidence that some of the amyloid was removed by the drug and that would be the evidence that we’re on the right track.”
Researchers are also studying a vaccine that stimulates the immune system to attack an abnormal form of tau protein that destabilizes the structure of neurons. And a prevention trial underway is tracking brain changes in pre-symptomatic people who have rare gene mutations associated with Alzheimer’s.
The drug in the trial presented on Wednesday was thought to reduce the accumulation of the protein tau into potentially toxic tangles in the brain among 891 patients with mild to moderate Alzheimer’s.
Most did not show a significant benefit. But a small subset – 15 percent – who received LMTM as a monotherapy, meaning they had not taken other Alzheimer’s drugs, did see improvement.
That group was too small to extrapolate from, but just the fact that this was the first phase 3 trial for tau was a large step in furthering understanding, said Heather Snyder, the Alzheimer’s Association’s senior director of medical and scientific operations.
“Over the next few weeks we’re going to see the scientific community interpret this and analyze this and digest this,” she said. A second Phase 3 trial with the same drug, targeting people with mild Alzheimer’s, is expected to announce results later this year.
The results among the small group offered hope, Petersen said, that it could be tested in the future on people with mild cognitive impairment, who would not yet have taken drugs for Alzheimer’s.