The mood among the more than 3,000 researchers who gathered in Lisbon, Portugal, at the end of March for the 14th International Conference on Alzheimer’s and Parkinson’s Diseases was downbeat. Just a few days earlier, Biogen, the Cambridge, Massachusetts-based biotech company, and Japanese pharmaceutical company Eisai Co had jointly announced the shuttering of two major trials of their Alzheimer’s drug aducanumab. The announcement marked yet another failure in the decades-long effort to find a drug to halt the devastating course of the terminal, memory-robbing disease.
“There was a sort of pall over the meeting,” says Ron Petersen, director of the Mayo Clinic Alzheimer’s Disease Research Center in Rochester, Minnesota. Many speakers prefaced their remarks with a reference to the news. But, Petersen adds, “It’s going to encourage the field to broaden the potential therapeutic targets we have for the disease.”
Scientists in academic and corporate labs are already pursuing a host of new approaches that they hope will offer pathways out of the Alzheimer’s doldrums. One idea gaining traction takes a page from the oncology playbook, where drugs that enlist the power of the immune system to attack tumors are transforming cancer treatment and drug discovery.
Alector, a Silicon Valley startup founded six years ago, already has two Alzheimer’s drugs in early human studies designed to strengthen the ability of the brain’s immune system to fight the disease. One of the drugs targets a gene called TREM2 and the other a gene known as SIGLEC3; certain mutations in these genes can contribute to conditions that allow Alzheimer’s to develop. In May, Alector treated its first person with Alzheimer’s with its drug targeting TREM2, and has begun human testing for the drug that targets SIGLEC3 as well.
“If the immune system in the brain is not operating normally, the nerve cells cannot function normally,” says Arnon Rosenthal, a neuroscientist and co-founder and CEO of Alector. “Eventually they degenerate and die. This is what leads to the disease.”
That view stands in contrast to the beta amyloid hypothesis that has dominated — and, some say, constrained — Alzheimer’s research for a quarter century. The hypothesis holds that the disease is caused by misfolded proteins that result in the accumulation of amyloid plaque in the brain that kills nerve cells and leads to dementia.
A new way to combat Alzheimer’s disease is even more daunting. One major hurdle is the track record of failure itself, which hobbles the ability of researchers to even design the right study. “We really haven’t figured out how to do a [successful] Alzheimer’s clinical trial,” says Philip L. De Jager, chief of neuroimmunology at Columbia University in New York. “Until we do, it’s hard to know how to conduct these trials effectively.”
There is no assurance that Alector’s approach will break the losing streak. “It’s exciting that this company has decided to invest in these clinical trials,” De Jager says, “but we really don’t know when and how the immune system is involved in the disease.”
The need could not be more urgent. The devastating effect of Alzheimer’s and other neurodegenerative diseases on the afflicted and their families is undeniable — and growing. The Alzheimer’s Association says 5.8 million Americans are currently living with the disease.
Pharmaceutical giants Eli Lilly, Roche, Pfizer, Johnson & Johnson, and Merck, in addition to Biogen, are among the companies that have invested billions in the hypothesis, testing drugs designed to clear out the plaque from the brain. Biogen’s aducanumab, like some other drugs before it, succeeded in reducing the plaque burden, but, like all others before it, still failed to halt the progression of the disease. “We need to challenge this approach,” says Alector’s Rosenthal.
Emerging research over the last several years suggests an alternative route, with some scientists arguing that Alzheimer’s is not caused directly by the buildup of plaque in the brain, but rather that the disease may be triggered by a viral infection. New research in mice from Stockholm University and Karolinska Institute in Sweden published May 27 in the journal Nature Communications suggests that pathogens such as the herpes simplex virus can trigger development of amyloid plaque in the brain.
The task of building consensus around an alternative cause for Alzheimer’s is one thing. Finding a new way to combat Alzheimer’s disease is even more daunting. In just six years, the number of people 65 and over with the disease is expected to jump 27% to 7.1 million. Without effective new treatments, the association says more than 13 million people will be living with the disease by 2050, with annual associated health care costs topping $1 trillion. Globally, the cost of treating the disease already exceeds $1 trillion, according to Alzheimer’s Disease International, with nearly 10 million new patients diagnosed each year.
“If we don’t fix this, we’re not going to fix Medicare,” says Mayo’s Petersen.
The prevailing amyloid hypothesis for Alzheimer’s is based in part on the discovery among patients with a familial form of Alzheimer’s that a person with certain rare mutations in any of three genes is almost certain to develop the disease. The genes are linked to the production or accumulation of beta amyloid. The finding emerged from studying a few hundred families afflicted with the disease worldwide, the Alzheimer’s Association says. But those genes may not be major drivers of the disease — estimates are that only about 1% of people diagnosed with Alzheimer’s have even one of the mutations.
In 2013, Rosenthal and his colleagues looked at the results of genome-wide association studies involving tens of thousands of people with non-inherited cases of Alzheimer’s, the kind that includes the vast majority of people who develop the disease. When they compared their genetics with those of people without Alzheimer’s, it turned out that mutations in 30 to 40 genes affected a person’s risk for the disease.
Surprisingly, Rosenthal says, even though Alzheimer’s is primarily a disease of nerve cell degeneration, most of the genes the analysis identified were expressed not in nerve cells but in the brain’s immune system cells known as microglia. That, combined with research advances showing that the brain’s immune system plays multiple roles in the health and maintenance of nerve cells and neuronal connections, pointed to the immune system as a target for treating dementia. Alector and its emerging pipeline of drug candidates was founded on that premise.
“What was clear from the human genetics is that insufficient activity of the immune system is allowing the disease to develop,” Rosenthal says. “It’s like a car — the accelerator is broken, not the brakes. The immune system is not going fast enough.”
The slowing down is a function of aging, as Alector describes it. Plaque buildup is one consequence. A sharp reduction in nerve cell connections, decreased blood flow to the brain resulting in reduced levels of oxygen and glucose, and a gradual degrading of the myelin sheath that protects nerve cells are among other factors that are part of the downward spiral to dementia. Other types of cells that normally produce nutrients for the brain begin releasing toxins instead.
These “insults on the nerve cells” would normally be contained, repaired, or mitigated if the brain’s immune system were healthy, Rosenthal says. The company likens the at-risk brain to a city under a crime wave. “You need the microglia cells to be the police force,” says Robert Paul, Alector’s chief medical officer. “If the microglia can no longer handle this kind of damage, that is when the neurons are dying.”
Last month Alector treated its first Alzheimer’s patient with its drug that targets TREM2, a receptor on microglia that is a “damage sensor,” says Sabah Oney, Alector’s chief business officer. The idea is that by activating this receptor, the drug will trigger an increase in the number of microglia and direct them to areas of damage for repair — essentially restoring normal function to the brain’s immune system. The company has also begun initial human testing of its drug that targets the SIGLEC3 receptor, which in a normal brain acts as a brake to keep the immune system under control. The drug is designed to release the brake and enable the immune system to act against Alzheimer’s-related injury.
The company expects initial data from these early studies by the end of this year, Oney says, and will be looking for evidence that the drugs can get into the brains of Alzheimer’s patients and hit their targets. The pharmaceutical company AbbVie, which was an early venture investor in Alector, has upped its investment and is co-developing the Alzheimer treatments with the company. Alector, which went public in February, is developing the drug for frontotemporal dementia on its own.
“Instead of trying to remove the pathological proteins, we are recruiting the immune system to treat the disease for us,” Rosenthal says. “Basically, we are resetting the aging immune cells back to a younger era when the cells are still fully functional and can counteract the disease.”
Alector is hardly alone in seeking new targets for Alzheimer’s. Cortexyme, a South San Francisco-based company, just launched a late-stage study for people with mild to moderate Alzheimer’s, testing a drug the company is developing that’s intended to block inflammation and neurodegeneration that it says is caused by a pathogen associated with gum disease.
More broadly, the Dementia Discovery Fund, which launched more than three years ago with the backing of the British government, has invested in 11 new companies pursuing novel approaches to neurodegenerative diseases. The fund, which is based in London and Boston, has raised $318 million from investors including seven pharmaceutical companies, the AARP, and Bill Gates. Its mandate is to identify promising new scientific ideas for dementia “but not to invest in amyloid,” says Tetsu Maruyama, chief scientific adviser to the fund. “We felt it was the other areas that need resources.”
Alector was the fund’s first investment in January 2016. The investors see the company’s strategy as “a clear, compelling simple idea,” Maruyama says, based on strong genetics and with parallels to the success of the immuno-oncology approach to treating cancer.
“The immune system is an important component of Alzheimer’s disease, as we’re beginning to appreciate”
“For dementia [efforts] to become more successful, we have to borrow from other areas where progress has been made,” Maruyama says.
Will it work? Rosenthal, a former Genentech scientist and co-founder of two other companies, has a strong track record in drug development: He’s an inventor of two drugs — one for migraines and one for cancer — that are on the market, as well as a non-opioid pain medicine that Pfizer and Eli Lilly have in late-stage development. (He’s also an inventor on an anti-amyloid drug that Pfizer acquired more than a decade ago but shelved in 2011.)
But previous results don’t guarantee future success, and it’s way too early to know whether the new strategy will be effective. “The immune system is an important component of Alzheimer’s disease, as we’re beginning to appreciate,” says Columbia’s De Jager. “We’re still very early in understanding it [in] this context.” He says there are many other important disease pathways that need to be pursued as well. Even anti-amyloid drugs might eventually work — just not in the way they’ve been tested so far.
“It will be similar to cancer,” De Jager says. “There’s not going to be any single drug that will cure the disease. It will be multiple different drugs at different times that will be required to take care of it.”