Great hopes in Alzheimer’s research are currently pinned on the drug aducanumab. The US Food and Drug Administration (FDA) could decide on approval on June 7, and the European Medicines Agency (EMA) by the end of the year.
The drug has shown the ability to effectively remove harmful amyloid beta plaques (known as A-beta for short) from the brain. But debate continues in the scientific community: Is this also enough to stop memory decline?
A dilemma: Patients would have to take the drug long before they show the first symptoms of dementia.
A look at the healthy, not the sick
The inventors of the drug come from the University of Zurich. Roger Nitsch and Christoph Hock did not primarily look at Alzheimer’s patients, but at healthy and fit people of advanced age. They looked specifically for immune cells able to form antibodies against A-beta. And they found what they were looking for.
In painstaking work, they decoded the antibodies and reconstructed them in the lab. Together with the US company Biogen, they then brought the active substance into clinical trials.
Like a waterfall
Alzheimer’s researchers now largely agree that Alzheimer’s disease takes the form of a very long-lasting cascade in which various deterioration processes of brain cells follow one another. Central to this is the formation of amyloid beta plaques. The protein occurs in all humans as a monomer (simple molecule). However, when it combines to form oligomers (a precursor of plaques), it becomes harmful. Next comes the activation of cellular immune defenses and the subsequent formation of more deposits, the tau plaques.
Researchers also see the biggest problem in this cascade: Only if it is possible to combat it at an early stage can memory loss possibly be stopped in the long term.
Christian Haas, professor of molecular neurodegeneration at the German Center for Neurodegenerative Diseases (DZNE) in Munich, compares the progression of the disease to waterfalls, in an interview with DW: “If we want to turn off the water at the top, we have to do it directly with the amyloid. If we go in too late and too much of the amyloid has accumulated, the tau protein alone can keep the waterfall going.”
So the success of a treatment depends on how early doctors detect the disease and whether they manage to intervene with the right agent. The problem is that Alzheimer’s usually goes unnoticed for a long time, and by the time memory loss becomes apparent, it is already too late. This problem was also reflected in the clinical trials of aducanumab.
Up and down in the clinical trials
Three clinical trials, named Prime, Emerge, and Engage, had been conducted by Biogen before the company submitted the compound to the FDA for approval in 2019 and to the EMA in 2020. The researchers’ assessment of the study results kept changing; it was like a roller coaster ride.
In the Prime trial, aducanumab had successfully targeted A beta plaques in 166 Alzheimer’s patients in 2016. However, in the subsequent Emerge and Engage studies with a total of 3,200 participants, there were conflicting assessments of the results. In March 2019, both studies were halted because interim results showed no cognitive improvements in the patients. “And in the end, that’s all that really matters,” Christian Haas said.
But in October 2019, the researchers changed their assessment. There had been a demonstrable positive effect on memory performance in patients in the Emerge study. Biogen then applied to the FDA for approval.
Shortly thereafter, however, an independent panel of experts commissioned by the FDA again confirmed that the drug was of little benefit. This contradicted an initial assessment by the public health agency. As a result, it extended the review process for the drug until June 2021.
A lot helps a lot ― or does it also do harm?
The different assessments of the efficacy of aducanumab was also related to the dosage of the drug that participants received in the various studies. The physicians were able to determine the strongest effect in the test subjects who had received a particularly high dosage. In them, the decline in cognitive performance seemed to slow down.
But there is a problem with high doses. Aducanumab can lead to brain swelling especially for people with a certain genetic predisposition called APOE4. Patients who showed such changes were immediately removed from the study. “These changes also seem to regress,” Haas reports. The prerequisite for this regression is that the swelling is detected correctly.
Interestingly, patients who have the APOE4 predisposition respond particularly well to aducanumab. “There seems to be a connection there. But it’s unclear why,” Haas said.
The side effects aren’t a reason to discard the drug, the Munich Alzheimer’s researcher added. “Aducanumab is, after all, one of the drugs that manages to virtually completely clear the underlying pathology in patients’ brains.” That, he said, can be demonstrated very well with imaging techniques. “It’s a pretty fantastic story: the more you give of this antibody, the more of this pathology can be cleared.” Now, he said, it’s important to explore these relationships further.
The earlier, the better
In Alzheimer’s, the goal is to interrupt the neurodegenerative cascade as early as possible. “In all clinical trials, people have gone in way too late,” Haas said. The pathology of Alzheimer’s often begins 10 to 20 years before physicians notice anything. “And if the tau proteins are already there, amyloid-based therapy can’t work.”
But even small advances are a huge success in Alzheimer’s treatment, he said. “After all, it would be wonderful if we could stabilize a patient at the mental status they walk into our clinic with.”
At the beginning of treatment, Haas explained, many sufferers are still out and about on their own. “They often still come in by car or public transportation,” Haas said. “They’re still perfectly capable of living a normal life and doing it on their own.”
In the future, it will be important to start drug treatment when patients are completely normal in terms of memory. That’s why physicians are searching for biomarkers to improve early detection. But so far it is not clear whether this will ultimately be enough to allow timely intervention with A-beta antibodies such as aducanumab.
Microglial cells ― activating the brain’s waste disposal system
When it comes to combating and eliminating plaques in the brain, cellular waste removal also plays an important role. This starts quite early in Alzheimer’s patients, probably in response to the formation of the first A-beta plaques. On the one hand, this immune defense is considered to be part of the problem, but researchers also want to make use of it in the fight against Alzheimer’s disease.
The microglial cells responsible for this are unique: They serve as phagocytes (cells that protect the body by ingesting harmful foreign particles, bacteria and dead cells) and as a precursor for nerve cells at the same time.
If they are overactivated, they can trigger dangerous inflammatory, or autoimmune, reactions, which can be detected in patients with advanced Alzheimer’s.
On the other hand, it’s also a problem if the microglia remain inactive when they would be urgently needed to combat plaque formation. Haas is currently working with US company Denali to develop an appropriate antibody for initial clinical trials in humans. The idea is to prepare the microglial cells at an early stage to recognize and combat plaques.
They could then be used together with aducanumab. “Aducanumab sits on top of the plaques. The plaques are better recognized by the microglia cells boosted by our antibody, and they begin to eat away at the plaques early on,” Haas explained. “But we have to try all that now.”