IIn June 2021, the US Food and Drug Administration (FDA) approved the first Alzheimer’s disease drug in 18 years: aducanumab (also known by its trade name Aduhelm). At the time of writing, the drug is also under review in the EU, Japan, and several other countries.
For the roughly 30 million people worldwide living with Alzheimer’s, this is unprecedented news and must sound like cause for optimism. Unlike existing drugs, which only weakly suppress cognitive symptoms, aducanumab attempts to target the underlying cause of the disease to stop and cure Alzheimer’s.
Having seen the disease up close and personal, I long for a cure too much. However, I am not exactly very happy with the aducanumab news. To borrow the words of Harvard medical professor Aaron Kesselheim, aducanumab was “probably the worst Drug approval decision in recent US history ”. Kesselheim served on an FDA advisory committee that voted almost unanimously in favor of not approve treatment.
To understand the controversy, we must start with the brain of an Alzheimer’s patient. In general, it harbors two types of pathology: first, plaques or deposits, which are scattered among the nerve cells; second, fibers that form tangles within cells. The plaques consist of a protein fragment known as beta-amyloid. The tangles consist of a protein known as tau.
Scientists have long suspected that these two substances are the underlying cause of Alzheimer’s. Of the two, beta-amyloid has garnered much more interest, for some good reason. In 1991, John Hardy’s team from St Mary’s Hospital School of Medicine in London discovered that genetic mutations that affect beta-amyloid causes early-onset Alzheimer’s, a rare inherited form of Alzheimer’s that has the same brain changes as the more common late-onset version of the disease. The discovery led Hardy to propose the amyloid hypothesis, which suggests that excessive beta-amyloid accumulation is the cause of Alzheimer’s.
Since its inception, the amyloid hypothesis has been periodically updated to explain new findings, and has cemented its position as the dominant paradigm in the Alzheimer’s study. The latest update doesn’t blame beta-amyloid plaques in the final state, but rather intermediate deposits known as beta-amyloid oligomers.
The amyloid hypothesis is able to explain a variety of Alzheimer’s-related phenomena, but it also has difficulty answering important questions. Chief among these is why decades of clinical trials with anti-amyloid drugs have failed. From inhibitors that prevent beta-amyloid from forming in the first place to vaccines that remove existing beta-amyloid, we have hit a brick wall in our efforts to stop cognitive decline. Even aducanumab, well, more or less.
Developed by Massachusetts-based Biogen, aducanumab is a vaccine that comprises antibodies against beta-amyloid. He burst onto the scene in March 2015 when an early stage clinical trial showed that it drastically reduced the levels in the brain. More impressive still, the cognitive and functional abilities of those who took the drug did not decline as much as those of those who received a placebo.
That trial was hailed as a game changer, a confirmation that if it lowers beta-amyloid enough, Will see a clinical benefit. However, there is a small problem. This so-called groundbreaking study only evaluated 165 people, and they were divided into smaller groups of about 30 each. With these small sample sizes, cognitive findings have little value beyond their usefulness as advertising advertising. Not only that, but the trial didn’t even measure oligomers, the most likely current culprit. You just measured the plates and assumed that the oligomers also decreased.
Undeterred, Biogen went ahead with two large trials in fall 2015 that were supposed to confirm the cognitive effect. But the plan went wrong. In March 2019, an interim analysis showed that the trials were unlikely to be successful and stopped in their tracks.
Then a plot twist: Seven months later, Biogen stated that the interim analysis was, well, wrong, and that at its highest dose, aducanumab slowed cognitive decline in one of the trials (not enough in the other). participants received that increased dose). Biogen went ahead to get FDA approval.
Usually a positive study is not enough to get a green light. But the FDA put Biogen on the Fast Track Approval track, designed to speed up the process of potentially valuable therapies for serious diseases. As a result, less weight was put on having definitive evidence of cognitive benefit – reducing beta-amyloid plaque was considered sufficient.
This is a problem, according to critics of the amyloid hypothesis. The connection between the two, plaque reduction and cognitive enhancement, that is, is far from secure. In fact, some believe that beta-amyloid may not be the underlying cause of the disease at all.
Remember that other marker for Alzheimer’s disease, tau tangles. Tau proteins help support axons, the long, thin part of a nerve cell that sends electrical signals to other nerve cells. If tau malfunctions, axons collapse and brain signals stagnate. That, some say, is the true cause of Alzheimer’s. Still others suggest that Alzheimer’s disease is a metabolic disease, in which the brain suffers from reduced glucose use and energy production. In this view, you can almost think of Alzheimer’s disease as “type 3 diabetes” caused by impaired insulin signaling and reduced metabolism, starving neurons.
For proponents of these theories, the continued dominance of the amyloid hypothesis represents a failure to think outside the box and a frustrating block to meaningful progress. There is some truth to this, but equally, if there was an obvious alternative, it probably would have paid off by now.
Yes, anti-amyloid drugs don’t have a good track record, but neither do tau or metabolic treatments. And every theory has its fair share of unanswered questions, of things that don’t add up.
In any event, the approval of aducanumab has ensured that for the foreseeable future the amyloid hypothesis goes nowhere. After all, it has shown researchers and companies that the search for anti-amyloid drugs can be profitable in the region of $ 56,000 (£ 40,000) per year per patient. Of course, if post-marketing studies show that aducanumab does not actually work, the approval can be revoked. But these studies are difficult to conduct: patients will not want to enroll in a trial and potentially receive a placebo when they can get a drug “approved” by their doctors.
More interesting than the aducanumab controversy are the several ongoing trials designed to test antiamyloid drugs in cognitively healthy people (for example, study A4). The researchers behind these are motivated by the idea that once cognitive symptoms appear, any beta-amyloid reduction may be too little, too late. In other words, prevention, not treatment, may be the key to defeating Alzheimer’s disease, and people at risk may in the future be encouraged to take what might be considered “statins for the mind.” . If the results of these studies, which are anticipated in one to four years, also turn out to be appalling, it may be because of the amyloid hypothesis. But until then, there is still a spark of hope. And as we strive to solve the enigma of this debilitating disease, close to an answer but with firm evidence of success still tantalizingly out of reach, hope is a precious commodity.
George is Digismak’s reported cum editor with 13 years of experience in Journalism