“The goal must be to prevent the onset of dementia symptoms”

Amyloid – a protein that accumulates in the brain in Alzheimer’s disease – has long been considered a potential target for treatment of this most common form of dementia. However, it was not until recently that corresponding drugs showed the hoped-for effect in human studies. “Lecanemab”, an anti-amyloid drug, is now on the market in the USA, and the approval process for Europe is underway. For “Donanemab” – a similar drug from another manufacturer – marketing authorization is currently being reviewed by the U.S. Food and Drug Administration. In clinical trials, both compounds have shown to reduce the amount of amyloid in the brain in the early stages of Alzheimer’s disease and to slow down cognitive decline. However as yet, there is no long-term experience with these novel drugs and the achieved clinical benefit has been modest. The question then arises: How can anti-amyloid therapy be improved? Prof. Mathias Jucker comments on the needs for research.

Mr. Jucker, how do you see the current development of anti-amyloid therapy?

After years of setbacks, the field has gained quite a bit of momentum. The new anti-amyloid drugs offer, for the first time, the chance to address the causes of Alzheimer’s disease. It should be remembered that traditional therapies are only symptomatic. They alleviate symptoms, but do not prevent the disease from progressing in the brain. The situation is changing with the new drugs. Admittedly, they are expensive, their application is complex, and they cannot stop the disease. But they do slow disease progression and the deterioration of cognitive abilities. This is real progress. On the other hand, we will have to wait and see how this new therapy performs in practice. After all, the experience gained so far has all come from clinical studies.

Could you please explain?

In the course of Alzheimer’s disease, individual amyloid molecules stick together to form increasingly large aggregates. Depending on their size, these aggregates are soluble or are deposited as so-called plaques in the brain. Thus, there is a wide spectrum of amyloid species, which changes over the course of the disease and also differs to a certain extent among patients. For all we know, some of these amyloid species are more harmful than others. Such amyloid aggregates are complex molecular entities. In principle, there are many sites to which an antibody can dock.

What does this mean for the existing drugs?

The different antibodies that have been tested so far bind to different sites and to amyloid aggregates of different sizes. We don’t yet know what type of aggregate would be optimal to eliminate. This could also depend on the stage of pathology, because – as previously stated – the spectrum of amyloid species changes during the course of the disease. To make progress in this respect, studies comparing different antibodies under equal conditions would be helpful. Also, we need studies of the molecular structure of the different amyloid species. In general, however, it is important to start treatment as early as possible!

Because otherwise it would be late?

So to speak. Evidence suggests that Alzheimer’s disease starts at least 20 years before symptom onset and the disease progresses in two phases. Initially, amyloid is driving the disease, i.e. increasing aggregation of amyloid molecules is the domino that triggers everything else. In the second phase, other phenomena come into play. Inflammatory processes occur and another protein aggregates, the so-called tau protein. This transition is believed to happen around ten years before symptoms of dementia manifest. In this second phase, amyloid is apparently no longer the only driver of disease; now, the situation is much more complex. That’s why, sole anti-amyloid therapy has limited effect at this stage. In fact, that’s what’s been observed in the recent studies. When they began all volunteers already had mild symptoms of dementia. In terms of symptoms, they were still in the early stages, but in terms of what was happening in the brain, the disease was already several steps further along. Presumably, this is why the antibodies could slow down the course of the disease, but could not stop it. In this situation, a combination therapy that targets different disease processes would probably be more effective.

How early should treatment start?

The goal must be to progress from treatment to prevention. In other words, to prevent the onset of dementia symptoms or at least delay the onset as far as possible. If symptoms of dementia are already manifest, effective treatment becomes increasingly difficult. Although the existing amyloid antibodies can then still slow down the course of the disease, we certainly want to achieve more in the future. We therefore need to find the optimal timing for treatment, we need better early diagnosis, and we also have to determine how often and for how long treatment should occur. One key to this are biomarkers, which are indicators of what exactly is happening in the brain. Suitable data for this purpose can be obtained from blood, cerebrospinal fluid or PET brain scans. These options are already being harnessed. But in some cases, the biomarkers that have been used so far are not conclusive enough or we do not yet understand exactly what they mean. Research on biomarkers is therefore a focus at DZNE, in particular also in my research group.

The existing amyloid antibodies are not free of side effects either.

That’s correct and another issue to be addressed. One side effect observed in the clinical studies is swelling around brain blood vessels and small hemorrhages. These abnormalities have been identified from brain scans. However, most of the affected individuals did not notice any of this, or they only had mild symptoms. Dizziness, for example. In the studies, these anomalies usually disappeared when the dosing of the antibodies was adjusted. Three study participants unfortunately died and the death was linked to the use of blood thinners and certain genetic predispositions. We need to better understand these factors and minimize the risks of treatment. What also has become clear is that amyloid deposits in the blood vessels are the major risk factor for all these side effects.

What is this all about?

Amyloid deposits in brain tissue between neurons are hallmarks of Alzheimer’s disease. However, many people with Alzheimer’s also have such deposits in their brain vessels. Laboratory experiments suggest that these deposits increase the risk of brain hemorrhage when amyloid antibodies are administered. That’s another argument for starting treatment as early as possible. Because amyloid burden on blood vessels is not so high in the early stages of Alzheimer’s disease. Basically, as with any therapy, the benefits and risks must be weighed up. However, I am confident that it will be possible to reduce the risks of treatment with amyloid antibodies and also increase efficacy. I believe we are still in the early stages of development.

^{September 2023, Interview: Marcus Neitzert}