Treatments for Alzheimer’s Disease: Mishaps, Mysteries, and Moving Forward

By Lauren Vetere

Around this time last year, I was walking near Union Square when I overheard a family discussing a headline they had just seen in the New York Times. The phrase, “Did you hear about the new treatment for Alzheimer’s disease?” caught my attention. I remember feeling surprised, and skeptical –it had been 18 years since a new treatment for Alzheimer’s disease received FDA approval, despite numerous attempts. 

This newest approval, a drug from a pharmaceutical company called Biogen, sparked widespread controversy. Multiple members of the committee that advised the FDA resigned, doctors and hospitals refused to prescribe the drug, and the FDA opened an investigation into its own decision-making process. So, what is this controversial drug, why did it get approved, and what happens now?

Many recent attempts at developing Alzheimer’s treatments have targeted amyloid beta, a protein that builds up and forms abnormal clumps called plaques in the brains of Alzheimer’s patients. These plaques can damage nearby brain cells and impair their ability to communicate with each other. This damage is thought to be part of a process that eventually leads to neurodegeneration and memory problems.

Biogen’s drug, called Aduhelm, contains an antibody that binds to amyloid beta and signals a patient’s immune system to clear the protein out of the brain. When developing the drug, scientists thought that reducing levels of this protein might slow or stop progression of the disease. The good news is that this drug is successful at decreasing amyloid beta plaques in the brain. Researchers visualized plaques using brain scans (called PET scans) before and after treatment to verify this. Unfortunately, these reductions came with alarming side effects, such as brain swelling, and little (if any) positive impact on patients’ cognitive function.

So how did this drug get the green light despite these concerns? Biogen was able to secure FDA approval in part because there are so few treatment options available, and because the drug did have a measurable effect on proteins in the brain. Though two concurrent phase 3 clinical trials (the largest, final stage) were ended early because the drug seemed to be ineffective at slowing cognitive decline, Biogen’s later re-analysis found that there was a small benefit in one trial, but no effect in the other. The approval was also conditional – meaning that Biogen would need to do another trial to prove the drug worked in order to keep the approval. All of this uncertainty puts doctors and patients in a very difficult position. Is it better to try a risky treatment that might not work, or wait for something better?

Notably, this is different from FDA approval of, say, COVID-19 vaccines. We have lots of evidence showing that vaccines help the immune system respond to a virus and reduce our chances of getting sick. Conversely, we don’t have much evidence that reducing amyloid beta improves memory or stops disease progression in humans with Alzheimer’s. This has been a controversial topic in the Alzheimer’s field for many years and it remains unresolved. Meanwhile, the headlines reporting failed trials of similar Alzheimer’s drugs continue to pile up.

Overall, scientists tend to agree that amyloid plaques are a part of Alzheimer’s disease, and that drugs like Aduhelm can effectively clear these proteins from the brain. We just don’t know if clearing amyloid alone will be enough to stop or slow the disease.

Fortunately, this path toward Alzheimer’s treatments is not the only one that scientists are exploring. Alzheimer’s disease is much more complicated than a single protein, so perhaps the potential solutions should be too.

If proteins glomming up in the brain are harming brain cells and the connections they use to communicate, one potential approach is targeting the activity of those brain cells directly.

Multiple ongoing clinical trials are using technologies called transcranial magnetic stimulation (TMS) and transcranial electrical stimulation (tES) to influence brain activity. These noninvasive approaches use magnets placed near the head (TMS) or devices placed on the scalp (tES) to stimulate electric currents in the brain. This can alter or enhance the patterns of electrical activity the brain already produces. Some researchers have even found ways to modify brain waves by playing rhythmically pulsing lights or sounds. It’s thought that these methods can help synchronize distant brain regions so that they can communicate better or stimulate brain activity to help neurons form new connections.

Meanwhile, other scientists are investigating drugs with targets unrelated to amyloid.

In addition to plaques, Alzheimer’s disease is characterized by misfolding and accumulation of another protein called Tau, leading scientists to come up with drugs that could target this protein instead.

Inflammation in the brain also seems to play a role in the disease, spurring efforts to develop treatments that can reduce inflammation or stimulate healthy immune function. Fortunately, several drugs that act on inflammation are already approved for use in other diseases, which could fast-track the process to re-purpose them for Alzheimer’s disease.

Broader changes in Alzheimer’s research are being implemented to set these future efforts up for success, including improving the animal models we use to test potential treatments, and re-thinking clinical trial design to intervene earlier in disease progression.

All in all, though the headlines tend to highlight recent failures, there are many avenues under investigation behind the scenes and more than one reason for hope.

Lauren Vetere is a Neuroscience PhD candidate at the Icahn School of Medicine at Mount Sinai in NYC. Her research focuses on how brain regions that are involved in spatial memory communicate with each other, and how that communication can be disrupted in animal models of epilepsy and Alzheimer’s disease. Before starting grad school, she completed her BS in Neuroscience at University of Florida, where she studied how memory and decision making change during aging. When she is not doing science, Lauren enjoys baking, creative writing, growing way too many succulents, and petting dogs in central park. She also advocates for grad student and postdoc mental health as part of Sinai's Trainee Health and Wellness Committee.

Edited by Denise Croote, PhD