Scientists Have Discovered a New Cause of Alzheimer’s Disease and a Drug That Halts its Progression

A promising experimental compound developed by researchers at ETH Zurich could offer a new way to slow the progression of Alzheimer’s disease. In studies on mice, the treatment reduced the loss of nerve cells, extended the animals’ lifespan, and specifically targeted a biological process that existing Alzheimer’s drugs do not affect. The active ingredient, referred to by the researchers as “Compound 10,” is the result of nearly two decades of work led by Ursula Quitterer, professor of molecular pharmacology at ETH Zurich.

A Long Search for New Clues About Alzheimer’s

The research began nearly 20 years ago when Quitterer received brain tissue samples from a colleague at Ain Shams University Hospital in Cairo. The samples were collected during tumor surgeries and came from both people with dementia and those without the disease. These samples were the starting point for the investigation of a protein called GRK2, which has been the focus of Quitterer’s research for many years.

GRK2 plays an important role throughout the body. As a regulatory protein, it helps cells respond to signals and adapt to stress. It is active in several organs, including the heart and the brain, where it supports the healthy function of nerve cells. Using human brain tissue and mouse models of Alzheimer’s disease, the ETH Zurich team found evidence that GRK2 could play a significant role in dementia. Their findings were recently published in the journal Cell Reports Medicine.

When a Protective Protein Becomes Harmful

GRK2 exists in cells in two forms. One form functions normally, while the other becomes inactive through cellular processes. The researchers found that the inactive form accumulates in large quantities in the brains of people with dementia. Similar patterns were also observed in mice that develop Alzheimer’s-like symptoms. Further experiments showed that inactive GRK2 molecules clump together in nerve cells. These clumps attach themselves to mitochondria—the structures often referred to as the “powerhouses” of cells—and impair their function.

“The GRK2 aggregates block the pores of the mitochondria, which reduces the amount of energy they can supply and leads to a stress situation inside the cells,” explained Quitterer. The team also discovered that inactive GRK2 appears to increase the production of amyloid-beta, a protein fragment widely associated with Alzheimer’s disease. This creates a harmful cycle. Amyloid-beta places additional stress on the nerve cells, leading to the formation of even more inactive GRK2. The more GRK2 accumulates and forms aggregates, the faster the disease process progresses.

Compound 10 Breaks the Cycle

To break this cycle, the researchers developed several experimental compounds and tested them in cell cultures and in mice. Among these, Compound 10 delivered the best results. The substance apparently prevents inactive GRK2 molecules from clumping together into harmful aggregates. These aggregates typically accumulate on the mitochondria—the cells’ powerhouses—and impair their function. By inhibiting aggregate formation, the mitochondria were better able to maintain their energy production, thereby reducing cellular stress. As a result, amyloid-beta deposits decreased, nerve cells remained healthy longer, and cell death was slowed. The researchers suspect that the reduction in cellular stress also helps lower amyloid-beta production, thereby breaking the disease-promoting cycle.

The positive effects were not limited to the brain. Since GRK2 also plays an important role in other organs, the team examined additional tissues and found that Compound 10 also appeared to improve heart function in mice. Furthermore, the scientists observed evidence of a slowing of age-related changes. For instance, treated animals developed fewer gray hairs in old age than untreated mice. The researchers view this less as a cosmetic effect and more as a possible indication that the substance influences fundamental processes related to aging, mitochondrial health, and oxidative stress. Although these results are promising, Compound 10 has so far been tested exclusively in cell cultures and animal models. Future studies must yet show whether the observed effects can be transferred to humans.

Why the Research Took Nearly Two Decades

The team has completed the basic research phase and filed a patent application for Compound 10. According to Ursula Quitterer, a key reason for the long development time is the unique nature of Alzheimer’s research. “It simply took so long because everything takes so long in Alzheimer’s research,” explains the scientist. Unlike many other diseases, Alzheimer’s develops over years or even decades. To replicate the human disease as realistically as possible, the researchers worked with older mice, which were typically between one and a half and two years old and had thus already reached an advanced age for mice. Since many changes typical of the disease only occur as the animals age, the animals first had to be observed over long periods of time before the actual experiments could begin.

In addition, the effects of new active compounds on complex processes such as memory loss, nerve cell damage, amyloid deposits, and mitochondrial dysfunction cannot be assessed within a few weeks. After each series of experiments, extensive examinations of brain tissue, molecular analyses, and the evaluation of large amounts of data were required. Only after the results had been carefully reviewed and confirmed could the next phase of research be initiated. Furthermore, over the years, the scientists developed and tested numerous experimental compounds before Compound 10 emerged as the most promising candidate.

“Everything moves much more slowly than in cancer research, for example,” says Quitterer. While tumor cells often change within a few days or weeks and corresponding experiments can yield results relatively quickly, Alzheimer’s researchers frequently have to wait months or even years for disease-relevant changes to develop. It is precisely these long observation periods that make research into neurodegenerative diseases particularly time-consuming and costly. The nearly twenty years of work by the ETH researchers therefore highlight not only the complexity of Alzheimer’s disease but also the patience and perseverance required to develop new therapeutic approaches from the initial observation in the lab to a potential drug candidate.

A New Target for Future Alzheimer’s Treatments

ETH Zurich and the research team are now looking for a company interested in advancing Compound 10 to the next phase of drug development. With the completion of basic research and the patent application filed, the long journey from a promising laboratory discovery to a potential drug now begins. Before the compound can be tested in humans for the first time, extensive preclinical studies are required. Among other things, safety, tolerability, metabolism, dosage, and the drug’s ability to cross the blood-brain barrier must be carefully evaluated.

“Alzheimer’s is a very complex disease,” says Ursula Quitterer. In fact, numerous therapeutic approaches that showed promising results in animal models have failed to deliver the hoped-for success in clinical trials in humans. The causes of the disease are still not fully understood and involve a complex interplay of protein deposits, inflammatory processes, mitochondrial dysfunction, genetic factors, and age-related changes in the brain. Current medications cannot cure the disease but can only slow its progression. Even the latest therapies generally achieve only a limited delay in the disease’s progression.

This is precisely why the researchers view their discovery as a significant breakthrough. “That is why it is so important that we have now identified a new target protein in GRK2, as well as a drug that acts via GRK2 and thus through a different mechanism than existing Alzheimer’s medications,” emphasizes Quitterer. While most currently available therapies target amyloid-beta directly and attempt to remove existing deposits, Compound 10 intervenes much earlier in the disease process. By preventing harmful GRK2 aggregation, the aim is to preserve mitochondrial function, reduce cellular stress, and mitigate the subsequent formation of amyloid-beta. The compound thus takes an approach that potentially addresses a deeper underlying cause of neurodegenerative processes.

The scientists therefore see great potential, particularly in a possible combination therapy. Future treatments could use existing drugs to reduce amyloid deposits, while a compound like Compound 10 simultaneously combats the underlying cellular damage and metabolic disorders. Such a multi-pronged approach could prove more effective than therapies that address only a single disease mechanism. Although many years of research are still needed before it becomes clear whether the results from mouse models can be translated to humans, the identification of GRK2 as a new target opens up a promising direction for the development of future Alzheimer’s therapies. Should the approach prove successful in clinical trials, it could, in the long term, help to slow the progression of the disease more effectively and maintain patients’ quality of life over a longer period of time