In the war against aging, Alzheimer’s disease is one of our biggest foes. But while we seem to be losing the battle, we may finally have found some chinks in its armor. The most common form of dementia already affects an estimated 5.2 million Americans and 45 million others worldwide, and these numbers are projected to triple by the year 2050 as the baby boomer generation reaches retirement.
Faced with the grim prospect of an Alzheimer’s epidemic, researchers have raced to understand the biology of the disease, and pharmaceutical companies, tempted by the huge profits that an effective treatment would bring, have poured huge amounts of money into researching and developing new drug treatments.
They have developed hundreds of drugs, the vast majority of which have failed when tested in humans. Earlier this year, Genentech, a San Francisco-based biotechnology company, made a big announcement about their latest clinical trial data, at an Alzheimer’s conference.
But the results turned out to be disappointing—overall, these trials failed, too. Their results suggest, however, that early treatments may be effective, and they also emphasize the importance of finding new ways to effectively diagnose the disease as early as possible.
A Long Road
Alois Alzheimer described the first case of the disease that now bears his name in 1906. He noted its pathological hallmarks—the tangles that build up within the neurons of the cerebral cortex and the sticky plaques that accumulate in the spaces around the cells.
By the 1990s, researchers thought they had it all figured out. They had identified the proteins that make up the tangles and plaques—called Tau and amyloid beta, respectively—along with the genes that encode them. They also determined various genetic mutations associated with the disease and found that most of them alter the way in which neurons process these proteins, causing the proteins to fold up incorrectly and clump together, forming “seeds” of the tangles and plaques that can spread between cells.
Animal studies suggested that it was the plaques and not the tangles that kill brain cells in Alzheimer’s. The amyloid protein quickly became a target for new drugs, and researchers began developing drugs that either prevent plaque from forming or break down existing ones. Many of these drugs alleviated memory deficits in genetically-engineered mice carrying known human Alzheimer’s mutations. But when tested in Alzheimer’s patients, however, they failed to slow the rapid decline in memory function characteristic of the disease.
Proponents of the leading hypothesis—that amyloid plaques cause the disease—claimed that the drugs failed because they weren’t administered early enough, pointing out that the pathological hallmarks appear long before disease symptoms.
But some began to question the amyloid hypothesis, too, and turned to Tau proteins and their tangles as the main culprit. Meanwhile, the discovery of numerous other cellular malfunctions—in the energy-producing mitochondria, for example, and in microglia, the immune cells that normally clean up cellular debris—highlighted a big gap in our understanding of the basic biology of the disease, prompting researchers to explore new avenues.
Trial after trial failed, and pharmaceutical companies cut back on their spending, scrapping or halting development of over 100 Alzheimer’s drugs during the 13-year period leading up to 2011. But minor successes in the latest trials offer a glimmer of hope.
Slowing the Decline
Genentech presented the results of two phase II clinical trials for crenezumab at the Alzheimer’s Association International Conference (AAIC) in Copenhagen, Denmark, in July. The drug is a genetically-engineered monoclonal antibody that binds to human amyloid beta protein. Originally developed by the Swiss company AC Immune, crenezumab has been licensed to Genentech since 2006. The trials involved a total of 686 patients with mild to moderate Alzheimer’s disease. They were given either small subcutaneous doses of crenezumab, larger intravenous doses of the antibody, or a placebo.
Overall, the treatment had no significant effect on the participants’ cognitive function or daily functioning, but a subtle effect was observed in a subset of them—it slowed cognitive decline in those with mild Alzheimer’s who were given a large dose.
“It was very informative in identifying the patients who are most responsive to it,” says Carole Ho, a senior group medical director at Genentech. “It’s also important because it shows we can increase the dose safely.”
“We are now taking all the steps to move the trial into phase III, although the decision to proceed has not yet been made,” she adds.
Dean Hartley, director of science initiatives at the Alzheimer’s Association in Chicago, agrees that the results are promising. “They do suggest that there’s an improvement with these medications if you go earlier enough,” he says, adding that the partial success may encourage drug companies to re-invest in their Alzheimer’s drugs pipeline. “The positive results are important for them to stay engaged.”
Researchers are increasingly recognizing the role inflammation plays in Alzheimer’s. Inflammation is a normal immune response, and when microglia, the brain’s immune cells, become activated, they are thought to be helpful at first because they normally clear away plaques, dead cells, and other potentially hazardous materials. But then they may become harmful.
Some scientists now believe that not only do over-active microglia begin to damage healthy cells, but that these immune mechanisms also might be the real cause of the disease. Indeed, in some trials, naproxen, a common non-steroidal anti-inflammatory often prescribed for rheumatoid arthritis, slowed cognitive decline in some Alzheimer’s patients. In others, however, the drug hastened the decline.
Sid O’Bryant, an assistant professor at of the University of North Texas Health Science Center in Fort Worth, and his colleagues have identified key inflammatory biomarkers and are profiling the pro-inflammatory molecules in Alzheimer’s patients using protein array technology. O’Bryant also presented data at the AAIC meeting, showing that biomarker profiling may be one way of diagnosing the disease early. Perhaps more promising, it can distinguish between patients who respond well to the anti-inflammatory drugs and those who respond badly.
“We took blood samples from a previously conducted trial of naproxen and celebrex and assayed the pro-inflammatory markers,” O’Bryant says, “and we’ve shown that, in a sub-group of patients, many of these markers are way too high.” These findings support the idea that there are different types of Alzheimer’s disease which could respond differently to varying treatments. They also suggest that identifying these patient sub-groups, or what O’Bryant calls “endophenotypes,” will be an important step in developing personalized treatments for Alzheimer’s and other neurodegenerative diseases.
“We have to get away from the notion that all Alzheimer’s patients are the same,” he says. “Inflammation is very important for about 15% of patients but not for the others, and I think we can break the disease up into about ten different types, but we still don’t target drugs to the individual.”
O’Bryant’s is one of several research groups trying to develop a blood test for Alzheimer’s based on pro-inflammatory and other biomarkers associated with the disease. The work is in the earliest stages, but O’Bryant and various of his collaborators have compiled a set of guidelines for others doing the same thing, to be published later this year. “The field is trying to unify and create standards so we can get consistency across studies,” he says. “I don’t know about a timeframe [for a blood test], but once that starts to move forward systematically, we’ll be closer to getting something into the clinic.”
Clifford Jack of the Mayo Clinic in Minnesota and his colleagues are using a similar approach, combining brain imaging with measurements of blood plasma levels of key Alzheimer’s biomarkers, to determine how the biomarkers are related to pathological and behavioral changes. They have developed a theoretical model of biomarker dynamics in Alzheimer’s, and they argue that this could be used to track the progression of the disease.
Several years ago, a string of surprising discoveries revealed more potential drug targets. As the brain develops, it forms its connections by trial and error then prunes back the incorrect ones. In the mature brain, old connections are constantly removed, and new ones formed, in response to experience, a process thought to be critical for learning and memory.
Various groups of researchers then published evidence that microglia eliminate unwanted synapses in the embryonic brain and, possibly, throughout the mature brain, too. This has led some to speculate that incorrect activation of this process may cause the loss of synaptic connections seen in Alzheimer’s. They are beginning to identify the signaling molecules that target synapses for destruction and initiate the process, and are designing drugs that block, which they aim eventually to test as potential treatments.
Power of the Antibody
Meanwhile, Genentech is involved in another large trial designed to test the preventative power of antibodies. Most of the participants in the five-year, $100 million study will belong to a large extended Colombian family containing more than 5,000 members, many of whom carry a genetic mutation that causes them to begin showing cognitive impairments in their mid-40s and full blown dementia by their early 50s.
Some family members carrying the mutation will be given crenezumab every two weeks while others will be given a placebo. Although hereditary forms of Alzheimer’s account for only a small proportion of cases, the trial includes family members who are still decades away from developing the disease. It’s an opportunity that could provide researchers with valuable information about the earliest stages of the disease.
Hartley welcomes these new approaches and emphasizes the vital importance of obtaining more funding for Alzheimer’s research. “We have to expand our horizons,” he says, “and to find an end to this terrible disease we’ll need more research, more clinical trials, and new ideas, so we have to make sure researchers get all the funds they need.”