at the beginning of the 20thand century, Alois Alzheimer first described a disorder of progressive memory loss and confusion in a 50-year-old woman.
After his death, he analyzes his brain and finds it contains protein deposits, or plaques. More than a century later, we know that these plaques are made of a protein called beta-amyloid and are a hallmark of the disease named after the German scientist. Although other features have since been discovered, the theory that beta-amyloid is the main cause of this incurable disorder still prevails.
There are many variations of the “beta-amyloid hypothesis,” but the general consensus is that this protein accumulates in the brain and then clumps together. During this process, nerve cells in the brain are damaged, leading to memory loss and other symptoms of Alzheimer’s disease. The therapeutic approach should therefore be quite simple: stop crowding to slow the disease.
Unfortunately, after decades of research, millions of dollars of investment, and countless unsuccessful clinical trials, it appears that this approach is not working. The most recent antiplaque treatment with disappointing results is aducanumab, a therapy in which antibodies supposedly bind to and destroy beta-amyloid.
Read more: The new authorized treatment for Alzheimer’s: medical breakthrough or commercial mirage?
Withdrawal from clinical trials
Initial data showed that the treatment actually cleared beta-amyloid from the brain. But this week Biogen and Eisai, the pharmaceutical companies that designed aducanumab, prematurely ended clinical trials with thousands of patients and said the trials “probably would not achieve their primary objective.” »
Many people then wondered whether we should abandon the hypothesis of amyloid as a cause of Alzheimer’s disease. In fact, few neuroscientists still believe that beta-amyloid plaques cause the symptoms.
Studies in mice have shown that memory loss occurs before plaques form in the brain. According to other studies, it is the smaller fragments (oligomers) of beta-amyloid that are actually toxic to nerve cells. It has even been argued that plaque formation is a way for the brain to bundle dangerous oligomers in one place to protect itself.
It is very difficult to say without complete information about the aducanumab trials, but the disease may have progressed too far in the participants for the treatment to be effective. Perhaps the small beta-amyloid oligomers had already done the damage, triggering the disease even before participants were recruited into the study.
Alzheimer’s Disease and Alzheimer’s Dementia?
At a recent Alzheimer’s Research UK conference, everyone agreed that it was time to separate the concept of Alzheimer’s disease from the risk of dementia.
Alzheimer’s disease is defined as the accumulation of beta-amyloid plaques and tangles of another protein, tau, associated with memory impairment. Dementia is a symptom of this disease. Thanks to advances in brain imaging, doctors can now detect indicators of Alzheimer’s disease much earlier (up to 25 years before the onset of dementia symptoms). A little-talked about fact is that progression to dementia is not inevitable. Not everyone who shows the clinical signs of Alzheimer’s will eventually develop dementia.
We are just beginning to study why some people with the disease escape dementia. Age is the most important risk factor for this progression: the younger you are when beta-amyloid starts to accumulate in the brain, the greater your risk of suffering from dementia. Diet, education and head trauma may also play a role in this process, but to what extent is unknown.
Genetics is another important factor that we are just beginning to understand. Small variations in our genes appear to influence not only the accumulation of beta-amyloid in the brain, but also whether it leads to symptoms of dementia.
The work of discovering the so-called “at risk” genes is slow. The advances come mainly from “big data” studies that track small changes in the two billion DNA bases of the human genome in tens of thousands of individuals and try to find links between these transformations and the prevalence of Alzheimer’s disease.
About thirty areas of the human genome have been linked to the risk of developing Alzheimer’s dementia, but there are certainly more to be discovered.
Aducanumab: the right treatment, but not at the right time?
As with many other human diseases, treatments like aducanumab can only be effective if given early enough, before the disease causes irreversible changes. Thanks to a better understanding of the environmental and genetic factors at the origin of Alzheimer’s disease and the evolution of brain imaging techniques, doctors will be able to identify the warning signs earlier and earlier, even before mild memory loss begins.
While screening and diagnosing a disease that is still incurable before symptoms appear raises several ethical dilemmas, it may represent a new opportunity to test beta-amyloid drugs such as aducanumab.
In conclusion, we need to direct research to understand the early stages of the disease to prevent Alzheimer’s disease before dementia sets in.