Expanding the Horizon in Alzheimer's Disease

The search for an effective Alzheimer’s therapy has been a marathon rather than a sprint. At the end of 2022, it was reported that the anti-amyloid antibody lecanemab, which immunologically removes the amyloid beta peptide from the brain, moderately slows the progression of cognitive decline in patients at a very early disease state. Another antibody, donanemab, showed a similar, moderate slowing of cognitive loss, as was published in mid-2023. The US Food and Drug Administration (FDA) has already approved lecanemab for Alzheimer's therapy in the United States. Development of yet another antibody, aducanumab, the first of these immunotherapy antibodies, which was approved already in 2021, has now been stopped, and so has the associated confirmatory trial as recently announced.¹

Clinical Meaningfulness of Immunotherapy Effects

It has become clear that the currently available anti-amyloid antibodies unfortunately do not offer a cure. They cannot stop the progression of cognitive decline; they—as all experts agree—can at best delay it to some extent (that has been shown to be mathematically significant). The results of further, currently ongoing studies will display whether this measured effect can be enhanced, will remain the same, or will diminish with an extension of antibody use beyond the current treatment duration of 18 months.

While the immunotherapy as such has been evaluated positively, the possible occurrence of a series of (sometimes severe) side effects, such as brain swelling and microbleeds, in a portion of treated patients is undisputed. Upon closer analysis of the published data, further limitations of this immunotherapy become apparent: For example, the effects of lecanemab are not statistically significant in women or in carriers of a double copy of the APO E4 gene, an Alzheimer's risk gene. This severely limits the group (and number) of patients who could benefit from lecanemab therapy. Additionally, it is also recommended to exclude patients with various pre-existing conditions and patients on anticoagulants from this therapy. The question of whether affected individuals can truly and individually experience the mathematically calculated positive effects (i.e., the question of clinical meaningfulness) is highly debated in the field.

A Breakthrough or Not?

Many in the Alzheimer's research community regard the reported effects of anti-amyloid antibody therapy as a major advancement. The results are partly celebrated as a "breakthrough" because—unlike previous treatment approaches defined as symptomatic therapy (e.g., acetylcholinesterase inhibitors)—for the first time, a therapy concept based on a biological disease hypothesis seems to be effective. The aforementioned hypothesis on the development of Alzheimer's disease is the "amyloid cascade hypothesis," formulated in 1992 and awaiting clinical proof since then. The hypothesis postulates that the formation and deposition of the amyloid beta peptide in the brain are the initial triggers of the disease process. Thus, this peptide was defined as the pharmacological main target of a disease-modifying therapy more than 30 years ago.

Since then, numerous anti-amyloid approaches have been developed, but all have clinically failed (e.g., amyloid aggregation inhibitors or enzyme/secretase inhibitors); lecanemab and donanemab, the newly developed antibodies targeting amyloid beta, have now yielded a first statistically significant therapeutic effect. However, Alzheimer's disease is a very complex and multifactorial, multicausal, and polygenic disease, which develops over decades. Especially due to the many amyloid beta peptide-based but failed therapy approaches of the last approximately 20 years, a considerable amount of literature has accumulated, suggesting that amyloid is very likely not the initial trigger of the disease process. It is suspected, among other things, that the peptide aggregates and deposits are rather a stress reaction of the brain and only have late secondary negative effects, such as triggering inflammation in the brain. Incidentally, amyloid deposits are also found in the brains of many older people without cognitive impairments.²

Alzheimer’s Disease: Time to Rethink Its Definition

In recent decades, a variety of alternative biological hypotheses about Alzheimer's pathogenesis have been developed, but they have largely been overshadowed by the dominance of the research focus on amyloid beta. Many of these sometimes forgotten alternative explanatory approaches have been experiencing a revival in recent years and should—in my opinion—at least receive the same attention as further investigations into the role of amyloid beta. Alzheimer's disease has long been defined solely by amyloid plaques and tau tangles (the tau protein is said to play a role in later stages of the amyloid cascade). This has greatly narrowed Alzheimer's research from the beginning. Amyloid plaques and tau tangles were initially described by Alois Alzheimer more than 100 years ago. Today, we know that the majority of people diagnosed with "Alzheimer's" have a very mixed brain pathology with a variety of protein deposits and vascular changes. Furthermore, more recent research has identified dozens of relevant risk genes that determine the onset and course of the disease.³

In recent years, however, parts of the Alzheimer's field have started to question the focus on amyloid beta. For many clinicians, Alzheimer's disease remains a comparatively poorly defined multifactorial dementia syndrome, characterized by age-associated progressive cognitive impairments. In the future, the method spectrum of personalized medicine could possibly shed light on the basis of the individuality of Alzheimer's disease—individual risk genes, individual onset, individual course—an approach similar to personalized cancer therapy, which has already recorded success.

Alternative Pathways Could Explain Alzheimer’s

It remains to be seen whether we will be able to see more distinct and more encouraging findings in the currently ongoing clinical trials with therapeutic anti-amyloid antibodies and whether the side effect profile can be mitigated. Additionally—and regardless of this—I advocate for abandoning the focus on the amyloid peptide and expanding Alzheimer's research by both amyloid-excluding and amyloid-including alternative research approaches. To enable this, however, Alzheimer's disease must also be defined more broadly in biological terms, not solely by the deposition of amyloid beta or tau proteins.

The research field has to open up and re-approach this brain disease, this dementia syndrome, which was defined as Alzheimer's disease more than 100 years ago. Today’s knowledge of risk genes and modifiable risk factors (e.g., lifestyle, nutrition, cardiovascular health) also offers the chance to develop new avenues for effective prevention measures.² I am convinced that a different and expanded view of this still incurable disease—a change in perspective—will be highly beneficial on the way to effective therapy and prevention.

Dementia Essential Reads

Research Offers New Ideas for Treating Alzheimer’s

Does Herpes Put You at Higher Risk for Alzheimer's Disease?

"When you change the way you look at things, the things you look at change." —Max Planck