Alzheimer's dementia has more causes than previously thought – this could be a reason for hope

Few drugs experience such a rocky start. Initially, the European Medicines Agency refused to approve the new Alzheimer's drug lecanemab. The EMA committees had ruled a year ago that its effectiveness was too weak and the risk of dangerous side effects was too high. The manufacturer filed a lawsuit, and the agency relented. But then several EU member states vetoed the drug, finding it too expensive.

Since September 1st, the time has come, at least in Germany and Austria. The last EU member states have given up their resistance. Germany and Austria are the first two countries where patients can be treated with the antibody drug. In Switzerland, the wait is even longer. The review is still ongoing, explains the drug authority Swissmedic. It began two years ago.

"From a scientific perspective, lecanemab is a historic breakthrough," says Frank Jessen, Director of the Department of Psychiatry and Psychotherapy at the University Hospital of Cologne. "After 120 years of Alzheimer's research, we have succeeded for the first time in intervening in the disease process and slowing its progression."

However, the hesitant attitude of the regulatory authorities also makes it clear that lecanemab is a start, not a miracle cure. Only 10 to 30 percent of those affected are even eligible for treatment – ​​and even then only in the early stages of the disease. This is due to pre-existing conditions and other exclusion criteria that further increase the risk of side effects such as cerebral hemorrhages or swelling: genetic risk factors, blockages and calcification of the cerebral arteries, or the use of blood thinners, for example.

And even those among those lucky enough shouldn't get their hopes up too much. In patients who received the drug in clinical trials, the decline in cognitive performance was slowed by 30 percent after eighteen months. That sounds like a lot. In concrete terms, however, this corresponds to only 0.45 points on an 18-point scale used to assess functions such as memory and problem-solving. In the placebo group, cognitive performance deteriorated by 1.66 points, while in the study participants treated with lecanemab, it was only 1.21 points.

Depending on the course of the disease, this may still mean that patients retain their mental abilities for longer. However, lecanemab has only been tested for eighteen months. Therefore, no one can say whether the effect will continue after that. Or, conversely, whether it will increase with continued use.

One thing is already clear: the drug has dashed one hope: that researchers might have understood the trigger for Alzheimer's disease. Thirty years ago, scientists proposed the theory about the development of the disease that is still valid today: the so-called amyloid cascade hypothesis. It states that initially, a small piece of protein called beta-amyloid accumulates in the brain and clumps together, known as amyloid plaques.

As the plaques spread throughout the brain, a second process begins: A protein called tau becomes tangled within increasing numbers of nerve cells. These tangle-like structures ultimately lead to the death of the cells. Eventually, the typical symptoms of Alzheimer's dementia become noticeable. These include forgetfulness, speech impairment, and disorientation.

Amyloid – tau – neuronal death – mental decline: According to conventional wisdom, the disease develops along this cascade. However, it's not quite that simple, as Swiss researchers recently demonstrated. They investigated how well the amyloid hypothesis describes the course of the disease. The further a patient progresses along this cascade, the more clinical symptoms they should – according to the hypothesis – exhibit. At the beginning of the disease, when the amyloid plaques form, there are hardly any noticeable mental impairments. As tau spreads in the brain, dementia should then progress.

But that wasn't what the researchers observed in their 256 subjects. Some of the test subjects had abundant amyloid and tau in their brains but suffered hardly any symptoms. Conversely, in others, the brain structure was still relatively intact, yet they were at an advanced stage of dementia. "The biology and clinical symptoms are not so strongly linked," says lead author Augusto Mendes of the University of Geneva. "Only one-third of the patients exhibited clinical symptoms as one would expect from the corresponding pathological changes."

So far, we can only speculate about the reasons. Clearly, the disease process doesn't follow a flow chart. Genetic, clinical, and environmental factors can all slow or accelerate the path to Alzheimer's dementia.

For example, individuals who are cognitively remarkably fit despite amyloid and tau in their brains may have a higher brain reserve capacity. This means their neural network can withstand more damage before losing its functionality. They are able to recruit replacements when failures occur. It is now well documented that people with a high level of education or high cognitive activity show symptoms comparatively late when their brains are destroyed by Alzheimer's disease.

Conversely, in individuals whose cognitive performance is worse than would be expected based on their amyloid and tau distribution, additional disease-promoting processes are likely at play. Possible causes include microinfarctions caused by calcified blood vessels, or inflammatory processes and protein deposits, which are actually typical of other neurodegenerative disorders.

For example, Lewy bodies containing a protein called α-synuclein are often found in the nerve cells of Alzheimer's patients. These protein clumps likely cause cell death in Parkinson's disease. Some researchers believe they could play a similar role in the brains of Alzheimer's patients, where they further promote cognitive decline.

In fact, a recent study shows that, in addition to amyloid and tau, a whole range of other brain changes can contribute to Alzheimer's dementia. "Current anti-amyloid drugs may have limited effectiveness because they only target a small part of the biology underlying the disease," says Geneva-based neuropsychologist Mendes.

Frank Jessen is convinced that stronger effects would be possible with anti-amyloid antibodies like lecanemab if patients were treated earlier, before the tau spreads in the brain. However, he also suspects that there will be a limit. "Perhaps it will be possible to increase the 30 percent delay in progression to 40 percent with even more effective antibodies, but at some point, it will stop," he says. "Alzheimer's dementia is a complex disease. Simply removing the amyloid won't stop it, especially if symptoms are already present."

However, the other pathological changes are difficult to detect today. The tests used to detect Lewy bodies, for example, are not yet widely available. "However, the field is very dynamic; in the coming years, the diagnosis and treatment of Alzheimer's could become much more sophisticated," believes Frank Jessen.

In his view, we are at the beginning of a new era in which more and more neurodegenerative destructive mechanisms can be detected and treated early. However, this requires additional drugs that target tau or Lewy bodies, for example. "Today, we have anti-amyloid antibodies. At some point, there may also be anti-tau and anti-α-synuclein drugs," says Jessen. Thanks to such combination therapies, he believes, the treatment of Alzheimer's disease should continue to improve.

Our understanding of Alzheimer's is evolving. One thing is clear: the disease is much more than just amyloid. There is a complex network of other factors that can accelerate or slow cognitive decline. Discovering how these interact to delay the progression of symptoms as long as possible—that will be the major challenge of the coming years.

An article from the « NZZ am Sonntag »