The future of Alzheimer's treatment can't bank on just one drug

Roughly seven months ago, Biogen gave up on aducanumab.

In late 2018, the Cambridge, Boston-based pharmaceutical company was in the midst of two late-stage clinical trials for its great hope: an anti-Alzheimer's treatment. But in March this year, results from an interim analysis showed the drug wasn't working. Biogen halted the trials.

This week, though, aducanumab got a second chance at life.

After reanalyzing results from those two trials with more patient data included, Biogen announced on Tuesday, Oct. 22 that it would submit aducanumab for approval by the US Food and Drug Administration (FDA)-and with its odds looking good, its share prices soared. There hasn't been a new drug approved to treat Alzheimer's since 2003.

The absence of progress in the field has been looming over the heads of neuroscientists studying dementia, especially as a growing percentage of the global population lives past 65. Already, care for dementia-the majority of which is caused by Alzheimer's disease-costs the globe $1 trillion. With no foreseeable treatment in sight, costs associated with dementia are projected to reach $2 trillion by 2030.

The thought of a new drug to treat Alzheimer's is a rare ray of hope for scientists, doctors, patients, and caregivers. But Biogen's success (if it is indeed a success) would be a single victory in a century-old war. Realistically, if scientists and clinicians want to mitigate the looming threat of dementia, they're going to have to continue to tackle the disease from all sides.

For the vast majority of Alzheimer's patients-those who don't have a dominantly inherited genetic mutation-scientists still don't know why brains succumb to buildups of protein. It's likely the disease doesn't have a cause, but rather many. "We don't think it's going to be one single pill," says Rebecca Edelmeyer, the director of scientific engagement for the Alzheimer's Association, a non-profit advocacy organization.

Aducanumab is based on the popular theory that Alzheimer's symptoms are primarily caused by the buildup of misshapen forms of amyloid protein in the brain. The drug is an antibody, like the kind our immune system uses to mark pathogens as meals for waste-clearing cells. Instead of bonding with a virus or bacteria, though, this antibody binds with amyloid.

Together, the amyloid with the latched-on antibody can be cleared out by other cells in the brain. "The antigen-antibody complex is more readily detected by scavenger cells in the brain," says Dennis Selkoe, a neurologist at Brigham and Women's Hospital in Boston who enrolled some of his patients in the aducanumab clinical trials. Sure enough, patients who received the highest dose of aducanumab over 18 months had less amyloid in their brains than those who got a placebo, and had fewer signs of cognitive decline.

That's no guarantee: The results are still preliminary, and one of the trials did fail, as so many amyloid drugs have throughout the years. In that time, though, research has pointed to a number of other potential causes for the disease, each of which represents a potential intervention.

Some of the most promising research has been in preventing the disease through lifestyle changes. At the Alzheimer's Association International Conference in July of this year, some of the biggest buzz was around research showing that adults who adhered to four out of five healthy habits-like abstaining from smoking and drinking, getting exercise, keeping a healthy diet, and regularly solving brain-challenging puzzles-had lower rates of dementia than those who did not. It's not clear why these lifestyle changes are somewhat protective against dementia, but there's evidence that there's a connection between heart health and brain health.

Social and environmental factors may play a role in brain health, too. Research has found that for women, time spent in the workforce may be protective against cognitive decline. Conversely, the stress of discrimination based on sexual orientation or gender identity may increase dementia risk. Air pollution has also been implicated in cognitive decline and dementia. It's not clear how these factors may tip the scales of whether or not a person develops dementia, but they all represent potential research targets.

There are other potential biologic targets for therapies, too. A growing body of research has postulated that Alzheimer's may be the result of some type of infection. Common pathogens, like the herpes virus or the bacteria that causes gum disease, have been tied to dementia as well. If research implicates these infections, antiviral or antibacterial treatments may work for some patients, too.

There's even some work that suggests dementia is a result of misfiring brainwaves. At the Society of Neuroscience conference taking place in Chicago this year, MIT neuroscientist Li-Huei Tsai gave a special lecture about her work studying how the brain's waves are involved in Alzheimer's disease. Her team's work in mice has found that when groups of neurons fire at similar frequencies-40 times per second, to be exact-they're better at recruiting other brain cells that can clear out waste, like amyloid. It seems that in diseased brains, fewer neurons fire at these frequencies than in healthy brains.

One way to generate these specific oscillations, called gamma rhythms, is to flash a light, or play a clicking noise at the frequency. For some unknown reason, Tsai says, neurons like to sync up their firing with external sources. Her work is currently in early clinical trials run by the company she co-founded, Cognito.

Just like there is no one cause of chronic conditions like heart disease, there's no one treatment that will work for everyone who goes on to develop Alzheimer's. "I think we have to have combination therapies," says Selkoe.

This diversity of approaches is particularly important because of evidence that shows Alzheimer's manifests differently in people of diverse racial backgrounds. At the same time, minorities have been historically excluded from clinical Alzheimer's research, and the majority of new cases of Alzheimer's will occur in people of color. (Biogen has not yet reported which populations were included in its clinical trials.)

Tackling amyloid may cut off one of the disease's pathways, but there are likely others that need treatment, too. Maintaining a robust body of research into potential Alzheimer's treatments ensures that everyone who may develop the disease has options to slow it down.